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On the face of it, the phrase chimeric antigen receptors (CARs for short) might not sound particularly exciting. But as Clive Gray, Professor of Immunology in the Division of Molecular Biology and Human Genetics at Stellenbosch University tells Spotlight, there is a lot more to this new class of immunotherapies than immediately meets the eye.

For one thing, the name is derived from a fantastical hybrid monster in Greek mythology called the Chimaera often depicted as having two heads, one of a goat and one of a lion. In The Iliad Homer describes the being as A mingled monster of no mortal kind, Behind, a dragons fiery tail was spread, A goats rough body bore a lions head, Her pitchy nostrils flaky flames expire, Her gaping throat emits infernal fire.

As Gray explains, the word chimaeric or chimeric comes from the word Chimaera.

The connection lies in the fact that, as with the mythical beast, CARs are assembled from parts one wouldnt normally expect to see together. Rather than a goats body with a lions head, however, CARs are made up of at least two distantly related genetic arms that code for recognising parts of the bodys immune system that would never be found together naturally. These CARs are then used therapeutically to treat disease.

As Gray points out, a chimeric antigen receptor is completely artificial and is made in very specialised laboratories.

He explains that so far there are at least 80 to 90 different CARs that recognise targets in the body and that are being used to treat people with different cancers. They are proven to be really, really useful immunotherapeutic tools, he says.

While new CARs are being developed all the time to try to treat different diseases, the field where it has shown the most success is in cancer, according to Gray. As a cancer treatment, he describes CARs as a razor-sharp treatment, because they specifically target cancer cells and eliminate them. Chemotherapeutic drugs, on the other hand, although effective, are a much blunter treatment because many other cells in the body are killed besides the cancer cells.

The A in CARs stands for antigen. Antigens can be thought of as any substance that the immune system mounts a response against. In more technical language, Gray explains that an antigen is a very small part of a protein derived from a pathogen or a tumour and is presented by a unique set of inherited molecules that are inherited equally from both parents and are able to be directors of the immune systems T-cells. As we will see, the T-cell bit is important.

Dr Katherine Antel, a clinical haematologist from South Africa currently conducting research at the Dana-Farber Cancer Institute at Harvard University in the United States, tells Spotlight that CAR therapy involves taking an antigen receptor specific to a diseased cell, like a cancer cell, and putting that receptor into an immune system cell.

These modified cells are then used to train the persons immune system, according to Antel, to go and find the antigen and kill the cell that is expressing that specific antigen, in this case, a cancer cell expressing an antigen unique to the cancer.

The chimeric antigen receptor would fit perfectly onto the antigen thats on the cancer itself and would go and bind to that [cell]. And then there would be a number of downstream signals that would enable the cell thats now bound to that antigen to kill that cell, she says.

She adds that while T-cells are the most common cells used for CAR therapy, known as CAR T-cells, other immune system cells known as NK cells can also be used.

While it is unclear whether CARs will ever be a safe and effective treatment for HIV, some in the HIV world think there is potential. During a session at this years Conference on Retroviruses and Opportunistic Infection (CROI) Dr James Hoxie, a Professor of Medicine in the Haematology-Oncology Division at the University of Pennsylvania, classified CARs as an exciting scientific advance with a potentially high impact for HIV and other fields.

I can think of few areas that are as breath-taking as this one, specifically because it has led to cures of acute leukaemia, chronic lymphocytic leukaemia, and non-Hodgkins lymphoma, Hoxie says.

Achieving the same kind of success in treating HIV with CARs will however not be easy. That is because HIV presents an additional complexity.

What were doing with the CAR T-cells is allowing the therapy or the CAR intervention to cause proliferation of HIV specific T-cells which allows these HIV specific T-cells to recognise the HIV infected targets, Gray explains. The downside of this approach is that youre also going to cause a proliferation of CD4 cells, which are targets for HIV. So, you then have to render the CD4 cell resistant to HIV, so it becomes really complicated.

Jim Riley, a professor of microbiology at the University of Pennsylvania, presented preliminary data at CROI about an ongoing clinical trial using CAR T-cells to target HIV cells. An excellent write-up on HIV i-Base summarised the study as using CAR T-cells designed to target HIV infected cells in combination with CD4 T cells that have been genetically modified to block expression of the CCR5 receptor. Blocking the CCR5 receptor on a CD4 T cell prevents HIV from entering the cell.

Riley shared data from eight participants, where half started ATI (analytical treatment interruption) the day after the infusions and the other half received ATI eight weeks after the infusion. Everyone in the first group experienced viral rebound and had to restart ART before the end of the 16 week-ATI. While people in the second group were able to complete the 16-week ATI, as viral loads did increase but then decreased again.

According to HIV i-Base, Rileys research group has another CAR T-cell design theyre planning to trial, an enhanced CAR T-cell that includes the co-stimulatory molecules 4-1BB and CD28 and, in animal models, showed increased proliferative potential and activity.

The research being done by Riley and others is still very much at an early experimental stage. The ClinicalTrials.gov database currently lists only six clinical trials containing the search terms HIV and CARs, although one of these studies are looking at HIV-Associated Aggressive B-Cell Non-Hodgkin Lymphoma.

For now, antiretroviral therapy remains the only proven way to suppress HIV and to help people living with HIV to stay healthy.

While CARs have already shown very impressive results in the treatment of cancer, there is a lot more research to be done and still a lot more potential.

Antel says that at the moment the indications for where CAR T-cell therapy can be used are for certain types of blood cancer.

According to the National Cancer Institutes website, the FDA has approved six CAR T-cell therapies to date, for use in treating acute lymphoblastic leukaemia (ALL), B-cell non-Hodgkin lymphoma, B-cell lymphoma, follicular lymphoma (FL), Mantle cell lymphoma and multiple myeloma.

Theres a lot of research at the moment using them for solid tumours, but there are a number of limitations. One of the main problems is that its quite difficult to get these cells back into a solid tumour space. Butwith the cancer cells circulating in the blood or in the bone marrow its much easier for the T-cells to get [to it], Antel explains.

Antel explains that CAR T-cells to treat cancer are currently manufactured using the patients own T-cells in order to prevent graph versus host disease. She uses the example of the CD19 CAR T-cells, used to treat leukaemia and lymphoma (one example is diffuse large B cell lymphoma).

She says that the patients T-cells are extracted using a plasmapheresis, similar to the process of donating platelets. The T-cells are then genetically engineered in a lab using a lentiviral backbone, which allows the cells to be engineered to express a receptor that, in this case, binds to the CD-19 antigen. This same receptor signals to the bodys T-cells to kill the abnormal cells.

The genetically modified T-cell then has the CAR on its surface, according to Antel.

These cells are then multiplied and are infused back into the patient after theyve had chemotherapy to deplete the remaining T-cells in their body. This is normally done as an inpatient procedure, with the patient in hospital for two to four weeks. The whole process can take around six weeks.

But this process can cause a cytokine storm in the patients body, where the T-cells release interleukins and other pro-inflammatory proteins, which can cause a number of side effects, says Antel, including neurotoxicity. But this problem can be combated by monitoring the patient and giving them drugs to suppress the inflammation.

She adds that the amount of time the CAR T-cells stay active in a patients body after infusion is variable and depends on the antigen.

Unfortunately, in myeloma, we tend to see that these T-cells disappear around a year or up to two years [after infusion], which is a problem because thats frequently then when patients relapse, she says.

[For] the CD19 CARs that are used for leukaemia and lymphoma the T-cells last longer and thats probably because theyre exposed to the antigen more frequently, she explains.

Antel is hoping to come back to South Africa and carry on with her research on using NK cells to produce antibodies to fight myeloma; and work with clinicians and researchers to find ways to make CAR-T therapy accessible to patients in South Africa.

I hope that despite the high costs we can find a way to creatively do this [in South Africa], to offer this to patients. We have excellent clinicians who are ready to treat patients with CAR-T cells but need to find ways to manufacture them and bring down costs radically to make it accessible, she says. DM/MC

This article was published by Spotlight health journalism in the public interest

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SPOTLIGHT: Cutting-edge cancer treatment may also have potential for treating HIV - Daily Maverick

Mr. and Mrs. Smith, we finally have an answer for you. The couple, whose real names we are protecting for privacy, looked at me anxiously. I had been evaluating their young daughter, Sally, in my role as a medical geneticist at the Childrens Hospital at Montefiore in the Bronx, a borough of New York City. For years, the Smiths had been searching to learn why Sally was suffering from epilepsy, why she didnt seem to understand them and why she wasnt speaking at 6 years of age. In 2021, they ended up in my clinic.

I decided to send a sample of Sallys blood for whole-exome sequencing, a test that could identify a change in one of her genes that might be responsible for her symptoms. A few weeks later I had the answer.

Sally has an extremely rare disorder that youve probably never heard of, I told them. Its so rare that it doesnt even have a real name yet. Its called NAA10-related disorder. The family looked at me with blank stares. I took a deep breath and continued.

The NAA10 gene codes for an enzyme that modifies critical proteins, enabling them to function properly. A single change in Sallys NAA10 gene would cause the enzyme to be made incorrectly, resulting in intellectual disability and seizures. The NAA10 gene is located on the X chromosome, which is one of two sex chromosomes in humans.

Males typically carry an X and a Y chromosome, while females usually have two X chromosomes; as a result, boys are usually more severely affected and girls have a less predictable course. I explained to the family that only about 50 other people with NAA10-related disorder have been reported across the globe. They then asked me about treatment. I replied sadly, none. I could see them struggling to wrap their heads around this.

They asked further questions about what might happen to Sally: Will she learn to speak? Will she be able to learn? Will she grow old? I told them that there is not enough experience to accurately predict what Sallys future will look like. Feeling useless, I said, Here is a patient support group that might be helpful. And with nothing more to offer, I added: Ill see you in a year.

Moments like this a long-awaited answer that is met with more bewilderment than relief are not uncommon in the practice of medical genetics. Most people expect that after a long, frustrating search, finding the underlying diagnosis will provide answers and a path forward. But sometimes, in cases like Sallys, the answer simply begets more questions.

Weve faced these difficult questions as two researchers with decades of experience in rare genetic diseases. One of us is a medical geneticist whose clinical work focuses on the diagnosis and management of individuals with rare genetic disorders; the other is a neuroscientist working to determine how rare genetic diseases impact brain function and possible ways to correct them.

Most so-called rare diseases are poorly understood and have no treatment. The National Institutes of Health has estimated that there are about 7,000 rare diseases, defined as ones affecting fewer than 200,000 Americans. Many rare diseases, however, are like NAA10-related disorders and affect only a handful of individuals.

Major advances in the precision and speed of gene sequencing technology followed by dramatic reductions in the costs of testing have radically changed how medical genetics clinics function. Next-generation genetic sequencing, which was so expensive just a decade ago that it was used only after all other testing options had been exhausted, is now the go-to test in most clinics.

But while sequencing can provide confirmation of a suspected, well-understood condition, it frequently results in a situation like that faced by the Smiths, where the testing result shows an incredibly rare disorder with little known about it.

The speed and ease with which modern gene sequencing can generate a diagnosis stand in sharp contrast to the prolonged effort required to understand how the genetic variant causes disease. Humans all have the same 20,000-plus genes, which govern the traits that make us characteristically human, such as a large brain, 10 fingers and round pupils. Changes, or variants, in these genes determine our uniqueness. So while we all have genes that tell our bodies to make hair, variants in these genes can make hair that is straight or curly, brown or red. Some genetic variants, however, change the gene product so significantly that they result in disease.

Unraveling the natural history of a rare condition requires years of focused attention by clinicians and scientists. Researchers like us also work to piece together the complex puzzle of how a rare genetic difference can alter metabolic pathways in the brain, as well as other organs that might be affected.

Over time, a fuller picture of the rare disorder begins to emerge. The role of the gene in normal cells or commoner diseases unfolds, as well as possible therapies. For instance, potential treatments might involve replacing or modifying a gene that isnt properly functioning, infusing a vital enzyme that an individuals body isnt making or prescribing a specialized diet or medications. But before one can determine how to treat a genetic disease, researchers first need to determine what is altered and not working normally. Only after this is understood can we begin to envision treatment.

To provide our patients and their families with more answers, we here at the Albert Einstein College of Medicine have begun a program in which we build what we call Gene Teams. These consist of parents or caregivers, their childs physician and interested scientists and their trainees. These researchers are typically working on deciphering the genes function, its encoded protein or the role the gene or protein plays inside of cells.

We bring all the team members together, and the childs physician outlines what is known about the clinical condition, followed by the parents sharing their childs story. The scientists and their trainees then provide an accessible tutorial to the families about what the gene and its associated protein do in cells. Whenever possible our team also discusses ways by which the condition could be treated.

These tutorials are the first encounters in ongoing relationships. Remarkably, three different families who were empowered by their Gene Team experience have gone on to establish foundations focused on their childs disease, and they have built networks to other families affected by the same rare condition worldwide. These are the STAR Foundation for SLC17A5, the KARES Foundation for KDM5C and the CACNA1A Foundation. The scientists, too, after the team meetings, have often gone on to build major research projects, some focused on the exact variant observed in the affected child.

[Over 150,000 readers rely on The Conversations newsletters to understand the world. Sign up today.]

We as scientists and our trainees have also been transformed by our involvement with the Gene Teams. Working directly with the families brings real-life experience to our laboratory work and inspires us and other researchers to remember that our work matters not only for expanding scientific knowledge but also for helping families in need.

We have learned that the blank stare experienced in the doctors office following diagnosis of a rare disease can be transformed by empowering families not only with greater knowledge of the involved gene, but also with an understanding that they are not alone and that there can be a more hopeful path forward.

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When it comes to the rarest of diseases, the diagnosis isn't the answer it's just the starting point - The Conversation

Olivia Rissland, DPhil, compares RNA to photocopies of pages of books at a library.

RNA is to DNA what photocopies are to precious books in library stacks: An abridged reproduction with a temporary existence, explains Rissland, a scientist with the University of Colorados RNA Bioscience Initiative.

You can read just a few photocopies, and only for a limited time. Understanding those copies depends on where and when you read them. Even then, you get a just a few clues about whats in the book; you dont get the whole story. Those pages wont easily yield the librarys secrets.

What is really cool about RNA is what happens to those photocopies once they leave the library is different for each photocopy, Rissland says.

Figuring out which photocopy to read and how to interpret what its saying before it disappears is a challenging task at best. It becomes a staggering enterprise when considering the numbers.

There are some 20,000 genes in the human genome. In humans, genes vary from a few hundred DNA base pairs to more than 2 million bases. Messenger RNA the temporary photocopy provides a picture of a piece of the DNA, a snippet of the story.

But ask Rissland about the challenge of studying those photocopies and you discover that its more than a practical question for framing a particular study. Its a philosophy.

I think about what research is, Rissland says. Research exists at the boundary of known and unknown. And so, what were always looking for are mysteries and things that dont make sense. We are trying to understand what it is that were missing, that explains what we see.

Rissland, an assistant professor of biochemistry and molecular genetics, joined the CU School of Medicine in 2017 when the school boosted investment into RNA research, thanks to a gift from The Anschutz Foundation and other supporters. Those funds allowed Dean John Reilly, Jr., MD, to target strategic growth opportunities, which is how the RNA Bioscience Initiative, or RBI, was born.

The goal with these investments is to bring together teams of scientists to work on some of the most challenging questions in human health.

I think were very lucky in the RBI, Rissland says. Its easy for us to foster collaborations. There were five of us who were hired in the same search. Were all close enough in our work that we can have a conversation with points of common interest. But were not so close that therell be competition. For me, that is probably the starting point for all the collaborations. We are bouncing ideas with others in the offices right here and then building out from there.

Risslands lab studies what happens to messenger RNA, or mRNA, after its made. Specifically, she and her lab team are trying to understand how the mechanics of protein production and of mRNA destruction connect with one another. Why do some mRNAs get destroyed quickly and others slowly?

The processes are connected, but how remains a multifaceted mystery and a source of endless fascination for Rissland and the team of scientists in her laboratory. Understanding what happens during that interaction could yield insights into genetic factors causing of human disease.

Although all cells have the same collection of genes, cells differ in which genes are turned on and which are turned off. When that process goes awry, adverse health conditions can result, such as cancer, neurodegeneration, or developmental defects.

One area of inquiry for Risslands lab is the impact of translation elongation speeds on how fast mRNAs are destroyed. Translation occurs when the ribosome in the cell reads the sequence on the mRNA and turns that into a sequence of amino acids, thus building proteins.

You have these machines theyre called ribosomes that are the actual interpreters that go between the different languages and make the protein, Rissland says. The speed at which the ribosome moves matters. A way to think about this is like on a freeway.

You accelerate as you get on the freeway, but your speed can vary once youre on the road. That time span between destinations is elongation. Your speed depends on weather, it depends on traffic, and sometimes you slow down or speed up depending on the conditions. In a cell, a traffic jam is a signal that theres a problem, that theres something a little bit wrong about the RNA, then the cell takes action to deal with that, Rissland says.

There are ample opportunities for traffic jams in a cell because the average cell produces 2 million protein molecules every minute. For a researcher, that means there are ample opportunities to explore.

Thats when you sit down and try to come up with what question to ask, she says. You read the literature and you say, Well, what things are here that dont make sense? What things surprise me? Or what is an implication of something that we know if this is true, then that would imply this is true?

Questions shape the experiments, and the experiments provide answers.

The majority of the time it doesnt work the way you think its going to, Rissland says. You think it could be answer A or it could be answer B. And its always answer C.

Surprise endings are nothing new in literature or life.

Rissland had planned to go to medical school after completing her undergraduate degree in Biology, Mathematics, and Classics (Latin) at Brown University in 2004. She was awarded a Rhodes Scholarship and went to University of Oxford where she earned a DPhil in molecular biology.

The plan actually was to come back to the States and go do my MD, Rissland says. Then Id be an MD, PhD, and drive off into the sunset.

Well, plans change, and the sun also rises. In Risslands case, the light on the horizon was the opportunity to become an independent investigator running a research laboratory.

When I came of age as a scientist was right when we started having all of these methods that allow us to ask questions about RNA and answer them. Five or 10 years earlier, this just wasnt possible, Rissland says. For me it was not only that there were all these questions that I wanted to answer, but we also had these tools to answer them. It was just this huge technological revolution. I mean, its like being a kid in a candy store. How could you say no to that?

The advent of high-throughput sequencing technology has allowed scientists to look widely and deeply into the full spectrum of genetic variations and other factors affecting biological change that were impossibly laborious to study for previous generations of investigators.

Classically, we were able to look at gene A or gene B and we looked at them one by one, she says. What high-throughput sequencing allowed us to do is to not look at things one-by-one, but to look at every single gene at the same time and that gives you just so much more power.

Its the power to think about the themes and larger plot of the story rather than paying attention to one or two characters in a book.

I am most interested in general principles, Rissland says. Specific examples dont provide general insight. They are fine, but theyre not what really get me out of bed in the morning. And to know if something is general you need to be able to look at many things. High throughput sequencing, then, is a really good match for the types of questions I like to ask.

After completing her doctorate, Rissland did postdoctoral work at the Whitehead Institute, an independent biomedical research institute in Cambridge, Mass., and then launched her laboratory at The Hospital for Sick Children, which is affiliated with the University of Toronto, in 2014.

Since starting her career as an independent investigator, her laboratory has trained more than 20 young scientists, nurturing their research, preparing them for their own careers, and encouraging them to ask questions.

I think success looks like someone who has taken real intellectual ownership of their project, who pushes back against my ideas, who tells me that Im wrong. I think when they do that, thats the best part. It means that they have the skills so that they can put those ideas into practice.

Its like reading a book that never ends.

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Reading a Book That Never Ends - University of Colorado Anschutz Medical Campus

Introduction

Cancer has been one of the leading causes of human death. According to estimates, more than 220 thousand new cases of lung cancer will occur in the United States in 2020.1 In general, lung cancer is subdivided into two categories, of which small cell lung cancer (SCLC) represents about 1315%. At diagnosis, about 80% of patients with SCLC are in an advanced stage and cannot undergo surgery.2

SCLC is a highly heterogeneous malignant neuroendocrine tumor.3 Small cell transformation has been demonstrated to be one of the ways in which non-small cell lung cancer (NSCLC) develops resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), leading to a poor prognosis.4 Although TP53 and RB1 are tumor suppressor genes with high incidence, few genetic driver events have been reported.5 Recent evidence reveals that immune checkpoint inhibitors (ICIs) and specifically programmed death ligand 1 inhibitors combined with standard platinum/etoposide can enhance progression-free survival with minimal adverse effects in patients with extensive SCLC.6,7 Furthermore, recent evidence shows that co-stimulatory B7-H3 may act as an independent prognostic indicator for SCLC cases, which might provide a theoretical basis for subsequent research targeting B7-H3.8,9

FOXM1 is crucial for SCLC tumorigenesis and is associated with a poor prognosis. After standard chemotherapy, patients with high FOXM1 expression had shorter progression-free survival compared to those with low FOXM1 expression (3.90 vs 8.69 months).10 In vitro experiments and experiments on xenograft (PDX) models derived from SCLC patient-derived xenograft reveal that pharmacological inhibition of DHODH can suppress the cell viability.11 Therefore, in SCLC treatment, DHODH has been a promising target.

SCLC is prone to develop chemoresistance due to its intratumoral heterogeneity.12 Despite recent advances, SCLC remains the most lethal lung cancer with limited therapeutic options. Studies report that patients with SCLC have a poor prognosis, except for a minimal number of early-stage cases.13

Accumulated studies demonstrate that SCLC is a highly heterogeneous tumor, although fewer genetic colonies have been reported comparison with NSCLC. Transcriptomic analyses reveal four different molecular subtypes, including SCLC-A driven by the transcription factor ASCL1, SCLC-N driven by NEUROD1, SCLC-Y by YAP1 and SCLC-P by POU2F3,14 allowing for more targeted therapeutic approaches. Subsequent studies confirmed that a unique YAP1 subtype did not exist, and an inflamed subtype of SCLC (SCLC-I) was recently proposed to replace YAP1 subtype.15 Although SCLC-I subtype experienced the greatest benefit from immune checkpoint inhibitor therapy, the clinical significance of this molecular subtyping in guiding treatment and estimating prognosis remains limited to other standard SCLC treatments.

The development of next-generation sequencing technology (NGS) has led to the identification of many genetic alterations in SCLC, including TP53 and RB1 inactivation and frequent chromosomal abnormalities (deletion 3p).16 In addition to the inactivated Notch pathway, MYC family amplification has a high incidence.17 Few druggable targeted molecules can be used in clinical practice.18 Currently, NGS is widely employed in routine clinical practice of non-small cell lung cancer to assist in therapeutic options and prognosis evaluation. Therefore, it is essential to investigate the genetic characteristics of SCLC and their clinical implications.

In this study, 18 cases of pathologically proven SCLC cases were sequenced using a panel of 520 cancer-related genes. The average median sequencing depth of the samples was 1260x. The average median q30 ratio of the samples was 91%, and all samples are qualified. Analyzing the sequencing results and pathological data revealed some genetic variants with distinctive characteristics.

SCLC presents a distinctive mutation spectrum compared to adenocarcinoma. In our cohorts, results reveal 72% cooccurring TP53/RB1 mutations. Furthermore, in the samples of small cell lung cancer, the core 8 gene was not detected. In SCLC, the frequency of gene mutations is significantly lower than in adenocarcinoma. The mutation frequency of Rb1, MSH6, KDR, IL7R, ATRX, EPHB1, PDGFRA and KIT in SCLC is markedly higher than those in lung squamous cell carcinoma. Due to the small sample size, it might be affected by some random factors.

Patients diagnosed with SCLC at Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, were enrolled in this study after obtaining informed consent. Biopsy specimens of advanced stage SCLC were obtained from the Department of Pathology Affiliated Cancer Hospital of Zhengzhou University. The study protocols were approved by the institutional ethics review board (Ethics Review Committee, Zhengzhou University). While collecting specimens for analysis, we complied with the declaration of Helsinki (2013 Edition) and relevant regulations. Additionally, the clinical characteristics were recovered in this research.

DNA extraction and targeted sequencing were performed in Burning Rock Biotech as described in the previous protocol.19,20 In brief, formalin-fixed, paraffin-embedded (FFPE) specimens were used for DNA extraction through QIAamp DNA kit (Qiagen, Germany). Subsequently, DNA purification, hybridization and amplification were performed. Target capture was conducted through a commercial 520 genes panel (OncoScreen Plus). The quality of fragments was determined using a Bioanalyzer 2100 (Agilent Technologies, USA). Finally, the samples were sequenced via the platform of nextseq 500 (Illumina, Inc., USA).

The reference genome Hg19 was used through Burrows-Wheeler Aligner version 0.7.10.21 Subsequently, sequence alignment and variant calling were performed through programs including varscan version 2.4.3 and the genome analysis tool kit version 3.2.22 The genes variants were annotated with ANNOVAR.23 The structural variations (SVs) were analyzed using Factera version 1.4.3.24

It should count as mutations that non-synonymous single nucleotide variants (SNVs) and indels in the coding sequences and two adjacent base pairs around these regions, while hot mutation, copy number variations (CNVs), structural variations (SVs), and SNPs were excluded.

The size of coding sequences required to estimate TMB is 1.003 MB in the 520 gene panel. The MB per patient was calculated using the following formula.

Table 1 lists the clinical and pathological information of SCLC patients. Prospective follow-up was conducted through routine hospital visits or telephone calls. Once every three months, trained medical staff made telephone calls to patients or their family members until death or the last follow-up. The follow-up data of this cohort is included in the Supplementary Materials. Overall survival (OS) was estimated from the day of SCLC diagnosis to the day of death from any cause and was analyzed using KaplanMeier estimates and Log rank test. The correlations between categorical variables were calculated using Chi-squared and Fishers exact tests. Statistical analyses were performed using SPSS23.0, and P 0.05 was considered statistically significant.

Table 1 Clinicopathological Characteristics of the 18 SCLC Patients

Capture-based targeted sequencing was performed by Burning Rock Biotech, Guangzhou, China. The average median sequencing depth of the samples was 1260x, consistent with expectations. The average median q30 ratio of the samples was 91%, and all samples were qualified (Supplementary Figure 1). The deletion of the tumor suppressor genes TP53 and RB1 has long been recognized as a common mutation in SCLC. Out of 18, 13 patients showed a co-mutation of TP53 and RB1, reaching a mutation rate of 72%, and the remaining five patients were found with wild-type RB1 as displayed in Figure 1A. Other frequent mutant genes are LRP1B, FAT3, KMT2D, KDR, PTEN, SPTA1, MSH6, Bcl6, EPHB1, etc. Figure 1B illustrates the distribution of identified mutations in SCLC.

Figure 1 Mutation landscape of SCLC. (A) Genomic alteration profiling. X axis is specific specimens and Y axis is the detected mutations for a different gene. The percentage of mutation of a specific gene in total patients. (B) Distribution of mutations in SCLC.

The genetic alteration observed in our cohort was in accordance with the SCLC database of Burning Rock Biotech (RS_SCLC) (Figure 2A). Figure 2A includes genes detected in at least three samples. The gene mutation frequency in this cohort did not differ significantly from that in RS_SCLC database.

Figure 2 (A) Genetic alteration in our cohort consistent with Burning Rock Biotech SCLC database (RS_SCLC). (B) Genetic differences between SCLC and non-small cell lung cancer (NSCLC) (C). Single nucleotide variation analysis. *in (B and C) represents statistically significant differences (p < 0.05). **in (B and C) represents statistically significant differences (0.01

The genetic differences between SCLC and non-small cell lung cancer were further analyzed (Figure 2B) to explore the molecular genetic characteristics of SCLC. In comparison with NSCLC (adenocarcinoma and squamous cell carcinoma), the mutation spectrum of SCLC differed significantly from the adenocarcinoma database of Burning Rock Biotech (RS_LUAD). Neither the core eight gene nor the frequent mutations in SCLC were detected in adenocarcinomas. Compared to Burning Rock Biotechs database of squamous cell carcinoma (RS_LUSC), the mutation frequency of genes RB1, MSH6, KDR, IL7R, ATRX, EPHB1, PDGFRA, and KIT was significantly higher. Considering the small sample size, other factors might affect it.

Furthermore, a single nucleotide variation analysis revealed that C > A mutations were more frequent in SCLC, whereas C > T mutations were significantly lower, as illustrated in Figure 2C. Moreover, we analyzed the gene copy number variation (CNV) and tumor mutation burden (TMB) in our cohorts (Figure 3). There was no significant difference in gene copy number variation (CNV) between the cohorts of SCLC group and RS_LUSC group (P = 0.54). In contrast, there was a significant difference between SCLC and RS_LUAD groups (P = 0.014). In terms of tumor mutation burden (TMB), there was no significant difference between cohorts of SCLC and RS_LUSC groups (P = 0.80), whereas there was a considerable difference between SCLC and RS_LUAD groups (P = 0.003). In general, SCLC showed higher copy number amplification and TMB compared to lung adenocarcinomas.

Figure 3 Gene copy number variation (CNV) (A) and tumor mutation burden (TMB) (B) in our SCLC cohort differ from lung adenocarcinoma.

In the final analysis, we examined the association between gene mutation and clinicopathological data, including gender, smoking, specimen origins, metastasis site, progression-free survival and overall survival (Figure 4). The criteria for gene inclusion were as follows: a. genes detected in at least three samples, b. clinical factors with at least three statistics, c. baseline sample data were included for analysis. The results revealed a significant correlation between several mutant genes and clinical factors. The KaplanMeier curve showed that patients with LRP1B (Figure 5A) or MAP3K13 (Figure 5B) mutation exhibited significantly shortened PFS.

Figure 4 The correlation between mutant gene and clinicopathological data including gender, smoking, specimen origins, metastasis site, and progression free survival and overall survival. Red indicates statistically significant differences (p < 0.05).

Figure 5 KaplanMeier curve indicated that SCLC patients with LRP1B (A) or MAP3K13 (B) mutation had significantly shorter PFS. SCLC patients with MSH6 mutation had significantly longer OS (C) while OS was significantly shorter in patients with SPEN mutation (D).

Moreover, SCLC patients with MSH6 mutation had significantly longer OS (Figure 5C), while the OS decreased significantly in patients with SPEN mutation (Figure 5D). In conclusion, MSH6 mutations are associated with a better prognosis than SPEN mutations. The results of this study may help to diagnose and treat Chinese SCLC patients.

The proportion of mutant-PIK3CA was higher in patients with bone metastases (P = 0.012), and the proportion of mutant-FAT1 was higher in patients with liver metastases (P = 0.044), as displayed in Figure 6. Of 18, five patients eventually developed bone metastases; three were detected with PIK3CA mutation, while five of the patients with liver metastases were detected with FAT1 mutation. Based on these results, it can be concluded that related signaling pathways could play a role in regulating organ-specific metastasis.

Figure 6 The proportion of mutant-PIK3CA is higher in patients with bone metastases (A), the proportion of mutant-FAT1 is higher in patients with liver metastases (B).

The signaling pathways based on KEGG involved in mutant genes were analyzed (Figure 7). A pathway is deemed mutant when at least one sample has a mutation in it. Signaling pathways with statistical correlations are listed in Table 2, which requires further investigation. The results indicated that HIF1 signaling pathway, estrogen signaling pathway, chemokine signaling pathway and T cell receptor signaling pathway contributed to bone and lymph node metastasis. Additionally, signaling pathways linked to PFS and OS were identified, and these findings may provide genetic explanations for clinicopathological features.

Table 2 The Clinical Factors are Associated with Signaling Pathway Based on KEGG Pathway to Some Extent

Figure 7 The correlation between signaling pathways involved in mutant genes (based on KEGG pathway) and clinicopathological data including gender, smoking, specimen origins, metastasis site, and progression free survival and overall survival. Red indicates statistically significant differences (p < 0.05).

SCLC in the early stages is sensitive to radiotherapy and chemotherapy. In most patients, satisfactory treatment results cannot be achieved due to the diseases early progression, recurrence, and chemotherapy resistance. Despite recent advances in SCLC, even on standard platinum-containing two-drug chemotherapy combined with immunization, survival did not exceed two years.25 Nitin Roper et al disclosed that different transcriptional SCLC subtypes could experience clinical benefit to ICIs, as was Notch signaling activation, which might provide the means for more effective application of ICIs in SCLC.26 Chemo-immunotherapy has become the preferred initial treatment for advanced SCLC, but only a small subset of SCLC patients benefits from ICIs, and there is an urgent need for biomarkers with efficient prediction.27

SCLC has long been considered to have higher genomic instability than other types of cancer.28 The inactivation of TP53 and RB1 occurs early in the course of SCLC.29 Inactivation of RB1 allows cells to enter the cell cycle, while TP53 loss can prevent cell cycle arrest and apoptosis. Amplification of Myc family members may enhance cell proliferation, while ASCL1 promotes neuroendocrine fate.30

Furthermore, studies have found that histone modification is highly prevalent in SCLC. Overall, these genetic alterations result in replication stress in SCLC, providing a potential direction for gene intervention therapy. Therefore, the study examined various gene mutations associated with SCLC and the effects of those mutations on the pathogenesis of clinical events and their prognosis. In the cbioportal site, we observed whole-genome sequencing of 120 small cell lung cancer (SCLC) tumour samples and matched normal materials.31 The tumour samples in this study were enriched for earlier stages, while tumour samples were all advanced stages in our study. Surgical treatment is considered for less than 5% of early patients limited to the lung parenchyma for SCLC patients. Then, therapeutic options are completely different. The differences in treatment outcomes were not comparable, but there were no significant differences in the frequency of key gene mutation (P53,RB), diagnosis age and sex ratio, indicating that our cohort is representative to some extent.

It is worth mentioning that KaplanMeier curve suggested that SCLC patients with LRP1B or MAP3K13 mutation had shorter PFS in our study. LRP1B (low-density lipoprotein receptor-related protein 1b) is a putative tumor suppressor. Recent evidence suggests that LRP1B might be a genetic marker for immune checkpoint inhibitors (ICI) in multiple types of cancers.32,33 However, nuclear LRP1B, which was released by the intracellular LRP1B domain and transported to the nucleus, increased the invasion activity of breast cancer cells by upregulation of NEAT1.34 Further studies are required to understand the molecular significance of LRP1B in SCLC progression. MAP3K13 (encoding LZK) is an amplified driver gene in head and neck cancer cells and plays a crucial role in maintaining mutant p53 expression.35 Qiang Zhang36 revealed a regulatory pathway that supervised Myc protein stability via MAP3K13-TRIM25-FBXW7 signaling axis, suggesting a potential therapeutic target for cancers that over-express Myc. Considering that MAP3K13 is a targetable oncogenic kinase, its clinical application deserves further investigation in SCLC.

Researchers found that MSH6 mutations have a better prognosis compared to SPEN mutations. DNA mismatch repair genes (MMR) function in maintaining genomic stability. The dysfunction of MMR genes could lead to accumulation during the repair process of DNA and lead to gene instability and overexpression of cancer-related genes, causing tumor initiation and progression.37 Nine MMR genes related to human mismatch repair have been isolated from human bacteria. MMR is a bacterial MUTS homologue and mainly forms a mismatch complex with MSH2 (MSH2-MSH6) to play a role in mismatch repair.38,39

SPEN family transcriptional repressor (SPEN), also known as SMART/HDAC1-related repressor protein, can regulate transcription and is essential for X chromosome inactivation.40,41 Multiple studies have demonstrated that SPEN can perform different functions in tumorigenesis. SPEN mutation alters a protein complex that represses the transcription of chronic lymphocytic leukemia NOTCH1 target genes.42 SPEN induces miR-4652-3p expression by activating PI3K/AKT/c-JUN signaling to target HIPK2.43 High levels of SPEN RNA are associated with early metastasis in two independent cohorts of 77 (HR 2.25, P = 0.03) and 170 (HR = 2.23, P = 0.004) patients with ER-negative breast cancer.44 In contrast, SPEN is a tumor-suppressor gene that may be clinically useful as a predictive biomarker of tamoxifen response in ER-positive breast cancers.45 In colon cancer, it acts as an oncogene for its pathogenesis, since it positively regulates Wnt signaling.46 However, the molecular mechanism of SPEN in SCLC remains unknown. In our cohort, the OS of SCLC patients with SPEN mutation decreased significantly, indicating that SPEN could be used as a prognostic biomarker.

PI3K/Akt-mediated pathways have been implicated in many tumors. PIK3CA is a P110 catalytic subunit of phosphatidylinositol-3 kinases (PI3Ks), which encodes the PIK3CA protein, namely PI3KP110A.47 PIK3CA plays a role in multiple signaling pathways and controls cellular functions.48 Among them, PIK3CA encoding PI3KP110A is the only oncogenic gene with somatic mutation among the members of the PI3K family found at present. About 4/5 mutations of PIK3CA occur in two hot spots, the helix region (Exon 9) and the kinase region (Exon 20).49 PIK3CA has been identified as an oncogene based on its function and genetics. In tumor cells, the pathogenic mutation of PIK3CA causes abnormal encoding of the p110 subunit that leads to continuous activation of PI3K enzyme. Furthermore, it can activate the downstream Akt, causing independent cell proliferation and enhancing the ability of cells to metastasize.50,51 A series of PIKK3CA mutations have been reported in various cancer lines, including SCLC (3.44.3%), colorectal cancer (3040%), ovarian cancer, thyroid,52,53 cancer,54 gastric cancer, and breast cancer (740%).55 This gene has also been targeted in previous studies of SCLC. Triciribine, a small-molecule Akt inhibitor, was found to act as a pathway inhibitor and was more sensitive to SCLC types with PIK3CA mutations.56 In this study, three samples had PIK3CA mutations, and all of them had bone metastases, resulting in a poor prognosis for the patients. Further studies are needed to understand how this gene could improve the treatment of patients with SCLC.

FAT1 is a member of the cadherin superfamily, which encodes procadherin and is frequently mutated in human cancers, especially squamous cell carcinoma.57,58 Similarly, our results also showed that nonsense mutations of FAT1 are common and can cause loss of gene function. Previous studies have linked FAT1 mutations to poor outcomes in cancer patients. Recurrent somatic mutation of FAT1 in multiple human cancers could result in aberrant Wnt signaling activation, thus promoting the tumor progression.59,60 Studies have demonstrated that FAT1 can encode a protein that binds to -catenin and antagonizes -catenin to enter cells to target and activate Wnt that can inhibit cell proliferation and tumor growth.61 The experiments on constructed mouse models of skin squamous cell carcinoma and lung cancer found that loss of FAT1 can inhibit adhesion and promote epithelial to mesenchymal cell transformation (EMT) and thus promote tumor genesis, development and metastasis.62 From an independent International Cancer Genome Consortium dataset, FAT1 mutation in oral cancer co-occurred with the top mutated genes TP53 and CASP8. Poor overall survival or progression-free survival was observed in patients with FAT1 mutation or altered HER3_pY1289, IRS1, or CAVEOLIN. Pathway analysis revealed dominant ERBB/neuregulin pathways mediated by FAT1 mutations in HNSCC.63 FAT1 plays various roles in different types of cancer and can be used as an oncogene or a tumor suppressor gene. Studies have confirmed that the expression of FAT1 in liver cancer is higher and acts as a tumor protector than in nontumor liver tissue.64,65 Our results show that patients with FAT1 mutation were more prone to liver metastasis, an alternative therapeutic target for SCLC patients. Farago et al reported that combining olaparib and temozolomide in relapsed SCLC could significantly improve the prognosis of SCLC patients.66 After that, they identified a molecular signature predictive of the response to this regimen. Olaparib is PARP inhibitor and has been proved to be effective for BRCA-mutated metastatic breast cancer and ovarian cancer.67,68 We found BRCA2 mutant in our SCLC cohort, which might suggest better sensitivity to olaparib.

Next-generation sequencing demonstrates that the genetic landscape of SCLC is different from that of adenocarcinoma and squamous cell carcinoma. Part mutant genes are linked to clinical factors to some extent. Mutation status of LRP1B, MAP3K13, MSH6 and SPEN has prognostic significance, which might be potential therapeutic targets. We found possible genes and related signaling pathways that affect metastasis. Oncologists might acquire important information to assist in therapeutic options and prognosis evaluation, and SCLC patients might benefit from NGS in clinical practice, and the underlying mechanism deserves further investigation.

We are grateful to all peer reviewers and editors for their opinions and suggestions.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

This work was supported by grants from Henan Cancer Hospital Doctors Initiation Foundation (Grant No. 310103010210962) and Medical Science and Technology Research Program of Henan Province (Grant No. LHGJ20190636). Natural Science Foundation of Henan Province (Grant No.222300420353).

The authors declare that they have no conflicts of interest in this work.

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DetailsCategory: AntibodiesPublished on Tuesday, 19 April 2022 09:24Hits: 507

Primary Efficacy Analysis Demonstrates no Clinically Meaningful Differences Compared to STELARA

THOUSAND OAKS, CA, USA I April 18, 2022 I Amgen (NASDAQ:AMGN) today announced preliminary results from a Phase 3 study evaluating the efficacy and safety of ABP 654 compared to STELARA (ustekinumab) in adult patients with moderate to severe plaque psoriasis. The study met the primary efficacy endpoint, demonstrating no clinically meaningful differences between ABP 654 and STELARA.

The primary analysis evaluated the percentage improvement from baseline to week 12 of psoriasis area severity index (PASI), which showed a mean difference of percentage improvement between ABP 654 and STELARA of 0.14, which was within the prespecified margins. The safety profile of ABP 654 was comparable to STELARA.

"Amgen remains committed to providing patients who live with inflammatory diseases access to high-quality biosimilar medicines," said David M. Reese, M.D., executive vice president of Research and Developmentat Amgen. "We look forward to continuing to expand our inflammation portfolio to offer patients a variety of treatment options."

ABP 654 is being developed as a biosimilar candidate to STELARA, an approved human interleukin-12 and interleukin-23 antagonist indicated for the treatment of moderate to severe plaque psoriasis in adults and pediatric patients (6 years or older) who are candidates for phototherapy or systemic therapy, active psoriatic arthritis in adults, as well as for adult patients with moderately to severely active Crohn's disease and moderately to severely active ulcerative colitis.

Amgen has a total of 11 biosimilars in its portfolio, including five that have been approved by the U.S. Food and Drug Administration (FDA) and three that are approved in the EU.

About PsoriasisPsoriasis is a serious, chronic inflammatory disease that causes raised, red, scaly patches to appear on the skin, typically affecting the outside of the elbows, knees, or scalp, though it can appear on any location.1 Approximately 125 million people worldwide have psoriasis, including around 14 million people in Europe and more than 7.5 million people in the United States.2,3 About 80% of those patients have plaque psoriasis.4

About the ABP 654 Comparative Clinical Study (20190232)The Phase 3 study was a multicenter, randomized, double-blinded, comparative clinical study (study number 04607980) that evaluated the efficacy and safety of ABP 654 compared to STELARA (ustekinumab) in adult patients with moderate to severe plaque psoriasis. There were 563 patients randomized, with 281 patients in the ABP 654 group and 282 patients in the ustekinumab group.

About ABP 654ABP 654 is being developed as a biosimilar candidate to STELARA (ustekinumab), an approved human interleukin-12 and interleukin-23 antagonist indicated for the treatment of moderate to severe plaque psoriasis in adults and pediatric patients (6 years or older) who are candidates for phototherapy or systemic therapy, active psoriatic arthritis in adults, as well as for adult patients with moderately to severely active Crohn's disease and moderately to severely active ulcerative colitis. ABP 654 has the same pharmaceutical form, dosage strength, route of administration and dosing regimen as United States-licensed and European Union (EU)-approved ustekinumab.

AboutAmgenBiosimilarsAmgenis committed to building uponAmgen's experience in the development and manufacturing of innovative human therapeutics to expandAmgen's reach to patients with serious illnesses. Biosimilars help to maintainAmgen's commitment to connect patients with vital medicines, andAmgenis well positioned to leverage its over four decades of experience in biotechnology to create high-quality biosimilars and reliably supply them to patients worldwide.

For more information, visitwww.amgenbiosimilars.com.

About AmgenAmgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to beone ofthe world'sleadingindependent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

Amgen is one of the 30 companies that comprise the Dow Jones Industrial Average and is also part of the Nasdaq-100 index. In 2021, Amgen was named one of the 25 World's Best Workplaces by Fortune and Great Place to Work and one of the 100 most sustainable companies in the world by Barron's.

For more information, visitwww.amgen.comand follow us onwww.twitter.com/amgen.

SOURCE: Amgen

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Amgen announces positive top-line results from phase 3 study of ABP 654, biosimilar candidate to Stelara (ustekinumab) | Antibodies | News Channels -...

The disease took Noemi Flemings elderly mother slowly, the first hints in repeated anecdotes or phrases. Then misplaced keys and bills. Then, Fleming caught her mother walking outside in the middle of the night, looking for the newspaper.

Mama, its 1 oclock in the morning, Fleming would tell her. The newspaper doesnt get here until 8.

On HoustonChronicle.com: Alzheimers diagnoses are increasing in Harris County. This tour aims to educate caregivers and public.

Flemings mother died at 91 in their hometown of Rio Grande City after a two-decade battle with Alzheimers, a brain disorder that slowly destroys memory and thinking skills. The familys story is a familiar one in Starr County, a mostly rural, heavily Hispanic county of about 65,000 on the Texas-Mexico border, where about 26 percent of Medicare beneficiaries have been diagnosed with Alzheimers and related dementias. That rate is the second highest among all U.S. counties, according to Medicare data.

The Starr County figures underline a recent push in the Rio Grande Valley to better understand how and why the disease disproportionately affects Hispanics, who along with Black people are traditionally underrepresented in Alzheimers research. The countys first private clinical research site, El Faro Health & Therapeutics Center, recently opened in Rio Grande City, and federal funds were awarded last month to the University of Texas Rio Grande Valley to investigate a wide spectrum of underlying causes.

The efforts are still in the early stages, but eventually, the researchers hope to identify ways to diagnose and treat the disease more effectively.

One of the problems, because theres no real cure, is that a lot of the focus has just been trying to prepare families for what lies ahead, and making sure families have things in order, said Dr. James Falcon, the primary investigator at El Faro.

Fleming, 69, jumped at the opportunity to join the first Alzheimers study at El Faro.

The research would help develop inexpensive tests to detect amyloid plaques, or sticky clumps of protein that build up around brain cells and disrupt brain activity.

In addition to watching her mothers decline, Fleming had worked as a nurse for more than 30 years at Starr County Memorial Hospital. She understood the value of learning her diagnosis early and potentially helping others do the same. And she could easily drive to the three required appointments.

Im glad they did it in Starr County, Fleming said. Because (usually) when it comes to clinical trials, youd probably have to go to a larger city.

On HoustonChronicle.com:New ruling clouds future of Alzheimers drug Houston doctor had seen promise with

Studies from the National Institutes of Health have linked underrepresentation to the lack of research efforts within minority communities. Other barriers include a mistrust of the predominantly white research establishment and inadequate education about the purpose of the research. Studies also cite medical staffing that does not represent participants culture, and eligibility criteria that disproportionately excludes minorities.

The El Faro clinic was created as an antidote to those issues, said John Dwyer, president of the Global Alzheimers Platform Foundation, an advocacy group that opened the clinic in partnership with James Falcon and his father, Dr. Antonio Falcon. The elder Falcon, a longtime family practitioner, grew up in Rio Grande City.

There is an appropriate and profound effort toward making sure that all clinical trials represent the population more broadly afflicted with disease, said Dwyer, pointing to one common estimate: Black people are twice as likely to be diagnosed with Alzheimers compared with white people, and Hispanics are 1.5 times as likely.

Dwyer said the study is still in the recruiting phase. The group is aiming for at least 20 percent of participants to be either Black or Hispanic.

When Fleming enrolled in the El Faro study, she was not surprised to learn her community was disproportionately affected by Alzheimers. She frequently saw patients with the disease in the hospital. But she always wondered why it affected some people and not others.

At El Faro, a series of tests revealed that she faced a low risk of Alzheimers. Her mothers siblings did not have Alzheimers, yet Fleming remembers at least one of her mothers relatives hospitalized with dementia a general term for a loss of thinking abilities severe enough to affect daily life.

New research may lead to possible answers.

A large-scale study published April 4 by the UK Dementia Research Institute found 42 genes that can serve as pathways for Alzheimers development, providing compelling evidence that inflammation and the immune system play a role in the disease.

Lifestyle factors such as smoking, exercise and diet influence our development of Alzheimers, and acting to address these now is a positive way of reducing risk ourselves, according to a statement from study co-author Julie Williams, center director at the UK Dementia Research Institute at Cardiff University. However, 60 to 80 percent of disease risk is based on our genetics and therefore we must continue to seek out the biological causes and develop much-needed treatments for the millions of people affected worldwide.

On HoustonChronicle.com: The disturbing link between veterans and Alzheimer's, and what Houston experts are doing to fix it

Dr. Gladys Maestre, director of the Rio Grande Valley Alzheimers Disease Resource Center for Minority Aging Research, has several theories for the high prevalence of Alzheimers in Starr County and the surrounding area.

Social isolation or chronic stress related to a heavy presence of border patrol might contribute, she said. It also could be related to the high number of uninsured residents about 35 percent in Starr County alone coupled with the low number of nonprofit health centers, she said.

Maestre, who also serves as a professor of neuroscience and human genetics at the University of Texas Rio Grande Valley, is working toward gathering 2,500 seniors with Alzheimers to participate in a study funded by a $2.9 million National Institute on Aging grant.

She will investigate a wide range of risk factors through in-person interviews and special technology, such as facial recognition software and memory tests using virtual reality. She is starting her work in Brownsville.

Hopefully we can learn from that, and we can get to Zapata and to Starr counties, she said.

For Antonio Falcon, clearer answers cannot come soon enough.

After more than four decades caring for patients in the city where he grew up, he became used to telling Alzheimers patients and their families the difficult truth: He did not have any medications that treated the disease itself, only those that can prolong comfort and independence. Deterioration was inevitable.

So when the Food and Drug Administration last year granted accelerated approval of Aduhelm, a monoclonal antibody drug designed to slow the onset of the disease by targeting amyloid plaques, he was ecstatic. It was the first drug approved to treat Alzheimers in 18 years, and the only one designed to treat the underlying cause.

It was a huge door that opened for us, he said. All of a sudden we were at the forefront of possibly getting medications for our patients.

Doubt quickly surrounded the drug. Questions lingered about its benefits, and some patients reported serious brain swelling or bleeding. Public health officials strongly advised to limit its use.

On HoustonChronicle.com: UTHealth administers first dose of controversial Alzheimer's drug in Texas

The FDA is investigating its own approval of the drug. And last week, the Centers for Medicare and Medicaid Services dramatically limited coverage of Aduhelm, all but ensuring Alzheimers patients in Starr County would not access the medication, which is estimated to cost around $28,000 for a year of treatment.

The decision was applauded by Alzheimers experts who continue to urge caution around its use. Both Antonio and James Falcon remain disappointed the agency did not open up access to more vulnerable groups.

But they are hopeful for three new monoclonal antibodies therapies currently in clinical trials. In the immediate future, they are focused on drawing more interest to the El Faro study.

People are developing (Alzheimers-related dementia) as we speak, and its not going to stop, Antonio Falcon said. Thats a one way street for them at this point.

julian.gill@chron.com

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Texas county has the 2nd highest Alzheimer's rate in the US. Why? - Houston Chronicle

In a November 1983 report of a World Bank appraisal mission to Kenya to look into the Kiambere hydroelectric dam on the Tana River, then under construction, there is a small footnote about other Kenyan rivers with hydroelectric potential. One of those identified is the Arror River, a major tributary of the Kerio River in the North Rift. Arror is a Marakwet word that means the river that flows and makes a loud sound and, in the last few years, the river has more than lived up to its billing. It is the site of one of two phantom dam projects (the other is on the Kerio River near Kimwarer village) that have been used to siphon billions of shillings from public coffers. Even for a government with a well-earned reputation for thievery, the Arror-Kimwarer scam is a breath-taking and unparalleled display of corruption.

The idea of building a dam on the Arror River dates back to 1986. According to the Nation, at the time, Arror Dam was projected to cost KSh414 million, it never materialised but due to lack of funds. Answering a question in Parliament in February 2009, then Assistant Minister for Water and Irrigation, Mwangi Kiunjuri said that the Kerio Valley Development Authority (KVDA) commissioned an Italian firm to carry out a feasibility study for dams for irrigation and hydropower generation in Arror River Basin that indicated the suitability of the project to generate hydropower and develop a potential area of about 6,460 acres of irrigation. According to Kiunjuri, the project would add 70 megawatts to the national grid. However, according to figures cited by Kiunjuri, in the 23 years since the project was first proposed, the cost of the project had increased 42-fold, ballooning to Kshs16.8 billion which, he said, exceeded the entire allocation to his ministry.

Kiunjuri was answering a question from then Member of Parliament for Marakwet West, Boaz Kipchumba Kaino, about plans to construct two dams for irrigation and hydropower generation in Arror and Chesuman Locations in Marakwet District ... which were factored in the 1995-1996 development plan. According to Kaino, many studies have been carried out on the same project. Each study has come up with the same 70 megawatts potential.

In September 2009, Kaino again put Kiunjuri on the spot regarding the two dams. While reiterating his answer from seven months before, the latter added that there had been a request in 1994 to build 11 small dams in the Kerio Valley, and that the only attempt that has ever been made in that area to have a dam for irrigation and production of hydropower was in 1986, an apparent reference to the Arror dam.

Interestingly, in these exchanges, there was no mention of a dam at Kimwarer, only at Chesuman, nearly 90 kilometres to the north. The plan for a multipurpose dam in Kimwarer appears to have been mooted sometime after the Arror dam. It is listed in the National Water Masterplan 1992 as one of 28 multipurpose dams for hydropower, irrigation, domestic water supply and flood protection and was said to be at the pre-feasibility level in a 2003 report for the World Bank, alongside Sererwa Dam located on the Arror river.

A decade later, when the National Water Masterplan 1992 was updated to the National Water Master Plan 2030, Kimwarer was listed together with Arror as one of six multipurpose dam projects in the Rift Valley Catchment Area designed for hydropower and irrigation. According to information from the KVDA, the hydropower component of the Kimwarer Dam would have an installed capacity of 20 MW. By 2012, a pre-feasibility study had apparently been completed. The KVDA published the Request for Proposal for the new Arror project (which included Kimwarer in this latest version) in December 2014.

In 2015, there was a new commitment to the dam project from the Italian government. Then prime minister Matteo Renzi visited Kenya in July. It was his second trip to the continent in two years. Several European countries, including Italy, were indeed keen on strengthening their relationships in Africa at that time. The main International challenges were fighting global terrorism and curbing migration. Renzi was among the initiators of the Khartoum and Rabat Processes. Launched in Rome the previous year, the Khartoum Process was a platform for political cooperation amongst the countries along the migration route between the Horn of Africa and Europe. The European Union launched the EU Trust Fund for Africa in November 2015 in Malta, a tool to deliver an integrated and coordinated response to the diverse causes of instability, irregular migration and forced displacement. Renzi travelled to Ethiopia and Kenya in this context. (Renzis meeting with president Uhuru Kenyatta made the headlines less for its content than for a picture shared by The Star in which Renzi seemed to be wearing a bulletproof vest under his blazer.)

During the visit of Italian Prime Minister Matteo Renzi to Kenya, SACE, Intesa Sanpaolo and BNP Paribas announced the finalization of a 306 million loan to finance the Itare Dam project, built by CMC-Ravenna on behalf of the Kenyan National Treasury, the SACE press office reported the day after the visit of the Italian Export Credit Agency. Intesa Sanpaolo is among the biggest Italian banks while CMC, the Italian construction company awarded the project, would feature prominently in the Kenyan dams saga. CMC signed the contract in May 2015. Itare was the very first dam awarded to the Italians in 2014 but, like the others, the project has never been concluded. It is listed in the Kenya Vision 2030 project, an ambitious development plan that has been ongoing since 2008.

After Itare, public invitations to tender were issued for Arror and Kimwarer, dam projects that by July 2015 appeared to present a unique opportunity for Italian companies to invest in. Italy has had an historical presence in Kenya since 1966 when the San Marco space launch platform was built near Malindi, a town now dubbed Little Italy. San Marco is still used by the Italian Space Agency to launch satellites into space. Italians soon followed, making investments along the Malindi coastline, exploiting Kenyas natural resources and gaining privileged access to the country in the process. These long-lasting ties did not prevent the failure of the dam projects, however, which turned out to be a political game rather than a development opportunity.

Itare was the very first dam awarded to the Italians in 2014 but, like the others, the project has never been concluded.

Yet when cancelling the Kimwarer dam project in 2019, the government, through a statement from State House, claimed that the dam, which by then was to cost KSh22.2 billion, was neither technically nor financially viable. The statement further said that a technical committee formed following the discovery of irregularities and improprieties surrounding the Kimwarer and Arror Dams, had established that no current reliable feasibility study had been conducted on the former. The only feasibility study carried out on a similar project twenty-eight (28) years ago had revealed a geological fault across the 800 acre project area, which would have negative structural effects on the proposed dam. If a feasibility study had shown this in 1991, why then was the dam included in the National Water Master Plan formulated a year later and again when the plan was updated over a decade later? And what accounts for the over 68-fold increase in the cost of the Arror project to KSh28.3 billion in 2009 from an initial KSh414 million in 1986? In fact, according to former Prime Minister Raila Odinga, Kimwarer and Arror dams were planned for during Mwai Kibakis government and the contract awarded to an Iranian company, which estimated the entire cost at Sh5 billion, now the figure has escalated to KSh63 billion.

To get to grips with the saga surrounding the construction of the controversial dams, in late 2020 Dauti Kahura travelled to Elgeyo Marakwet County in the greater Rift Valley region, where the twin dams were to be built. It is one of the 20 smallest of Kenyas 47 counties, with an area of 3,050 square kilometres and a population of slightly less than half a million people, according to the 2019 population census.

Agriculture is the countys economic mainstay. Potatoes are grown in the highlands while in the flat middle belt, maize plantations dot the landscape. Fruits such as avocadoes, mangoes, pawpaw and grains such as green grams, sorghum and millet do very well in the Kerio Valley. The topography, climate and availability of water make the area ideal for the production of these crops.

The countys biggest town is the world-famous Iten, renowned for producing elite athletes and world-class marathoners. But other than a huge banner announcing You Are Now Entering Iten Home of World Class Athletes, there is little else about the bustling little rural town that tells you anything about its great sons and daughters.

Leaving Eldoret in neighbouring Uasin Gishu headed north-east to Iten, ones attention is drawn to the rolling plateau of hectares upon hectares of maize plantations that disappear into the horizon. It is harvest time, the morning sun is out and the ready-to-be-harvested maize stalks are arranged like igloos. Massey Fergusson and John Deer tractors and combine harvesters dot the landscape, an indication that maize farming is serious business here.

Speeding across the undulating flatland one comes across scores of lithe, mostly male, runners tackling the 38 kilometres between Iten and Eldoret, a morning ritual for runners who hope to one day break world marathon records. They are joined by a band of European athletes who are persuaded that by running alongside the amateur athletes, they will perhaps crack the secret to the Kenyans success in long-distance races.

The countys biggest town is the world-famous Iten, renowned for producing elite athletes and world-class marathoners.

From Iten to Kapsowar is a distance of 46 kilometres, and the higher you climb the cooler it gets. Many of the matatus here are Probox saloon vehicles and although people are not packed inside them like sardines, the cars are driven at terrific speeds by chatty, confident drivers. Nine kilometres from Cheptongei, the road starts winding upwards as you approach Kapsowar trading centre.

At Kapsowar, the boda boda (motorcycle taxi) rider Kahura hires to take him to the bottom of the valley, where the Arror dam was meant to be built, says that few outsiders have shown interest in going down into the area. The dam was to be built in Marakwet West constituency between Hossen and Kipsaiya, two facing ridges that share a border on the valley floor. The rider says that KVDA officials had come here to persuade the people to agree to the proposal to build the dam. According to a report in the Business Daily newspaper, the officials had promised that locals would be compensated with up to five times as much land as they would give up for the two dams. KSh6 billion was promised as compensation to the more than 900 families that would be affected, although to date that too is yet to materialize.

No dam was built, says Salome Chebet, a local resident. It was a huge con from our leaders. The only thing they put up was a container office, which served as a liaison office. It has since been carted away. With hindsight, its a good thing the dam was never built, she says. We no longer desire it because it was all a political con game from people who we elected and who claim to represent our interests. Chebet says KVDA officials and elected representatives, including Marakwet West Member of Parliament William Kisang, Senator Kipchumba Murkomen and Governor Alex Tunoi Tolgos, had frequented Kapsowar to sell the imaginary dam to the people. In parliament in 2016, the then Senate Majority Leader, Murkomen had declared that, under the Arror and Kimwarer Projects, it is expected that over 10,000 acres of land in Kerio valley will be irrigated. Through the project, there will be generation of 80 megawatts of hydropower as an enabler to manufacturing, provision of clean water for 80,000 households and livestock; and support to the Arror and Kimwarer rivers catchments conservation initiatives.

The boda boda rider agrees with Chebet. It is true. For a while, there was a flurry of activities at Kapsowar. The KVDA officials accompanied by these politicians would descend here hoping to convince the people of the viability of the said dam. But these were thugs, ready to fill their pockets.

Indeed, the KVDA held several barazas where they extolled the virtues of the dam; how it would generate electricity, how the local people living up the valleythat has rich soils for growing fruits such as avocadoes, mangoes and pawpawwould benefit. Strangely, some of the people Kahura spoke to had not heard about the compensation arrangements. There is one thing they never addressed, even when pressed to do so: the compensation issue. How would they compensate the people? How much money were we talking about here? Where was the land where they would relocate the people as the dam was ostensibly being built? How suitable and viable was it in comparison to our land? says the rider.

You can imagine our consternation when we learnt that some of the money meant for the dam went into buying beddings and towels for a hotel, says an angry Chebet. She is referring to a February 2019 claim by the Director of Criminal Investigations, George Kinoti, that a company had been awarded a tender to supply towels worth Sh20 million, while another delivered tiles and carpets. According to his investigators, over a hundred companies were awarded tenders to supply items that had little to do with the actual dam construction, including food and wine worth KSh17 million, bedsheets and airline tickets worth Ksh1.5 million. The scale of the pay-outs to individuals and companies for the supply of goods and services for the fictitious construction is astounding, amounting to KSh21 billion according to reporting by Citizen TV.

All these were white lies, observes Arap Cherop who has lived in Kaptoiyoi since 1983. Residents of Kaptoiyoi village, which is situated on the floor of the valley between Hossen and Kipsaiya, would have been the most affected because they would all have had to be relocated. But where were we being relocated to? he asks.

The KVDA officials, sometimes led by their boss David Kimaiyo, on several occasions came here to apparently give us the benefits of the coming dam, which according to them, included irrigation and water for domestic use, but we also asked them questions and they couldnt answer many of them, he says.

According to residents, no compensation was ever paid, despite the disruptions to planting seasons between 2018 and 2020. Those Kahura spoke to said that after news of the scandal broke, the barazas that the KVDA used to hold all dwindled away.

Over a hundred companies were awarded tenders to supply items that had little to do with the actual dam construction.

Asked about the prospects for justice, the rider replies, Youve seen and heard for yourself. Money was eaten by our leaders, helped by the dubious Italians. But thats the nature of our politicsvery ethicized. It is our leaders who have short-changed their own people, but you know what? We cant be counted on to expose them. It would be akin to exposing our dirty linen in public, so well suffer in silence and when the elections come in 2022, well be swept in a wave of euphoria, be reminded that were all Kalenjin and that one of our sons will be gunning for the ultimate seat. Can we surely afford to embarrass him at that critical juncture, everything else notwithstanding?

The following day Kahura visited the site of the proposed Kimwarer dam, another phantom project, now cancelled, without anything to show for it on the ground. According to the Kenyan prosecutors, the dam was never approved by the Treasury. In 2019, CMC signed a bankruptcy agreement with the Court of Ravenna, the city on the Romagna coastline where CMC is headquartered. The bankruptcy agreement is a repayment plan that aims to avoid the closure of the company and save the jobs of its 5,454 employees. The COVID-19 pandemic has slowed down CMCs activities and consequently, the companys income for the past two years has been lower than expected. According to its 2020 balance sheet, CMC went into arbitration at the International Chamber of Commerce claiming damages of US$124 million from the KVDA, which was later replaced by the Kenyan State. The arbitration is in the initial phase and the presumed verdict will be in either the last trimester of 2022 or the first trimester of 2023, the balance sheet reads. According to a note shared with journalists from the CMC press office back in 2019, between 28th December 2017 and 9th November 2018 the KVDA made two advance payments for Arror and Kimwarer totalling over US$66 million.

Kimwarer is located in Keiyo South constituency, 60 kilometres from Eldoret town on the Eldama Ravine Road. Unlike the Eldoret-Iten Road, the Eldama Ravine Road is in dire need of repair. The gaping potholes and washed away sections of the road meant the trip took twice as long as the journey from Eldoret to Kapsowar, which is 84 kilometres. The road takes you to HZ centre, a trading centre named after the late Total Man and powerful politician Nicholas Biwotts construction company, HZ Construction and Engineering Company Limited. If the dam had been built, it would have swallowed up the unassuming little centre.

KVDA made two advance payments for Arror and Kimwarer totalling over US$66 million.

As opposed to Kapsaiya area, Kimwarer is less settled, so fewer people would have been displaced. Still, it is a semi-forested area, full of vegetation and lush greenery. It holds the community grazing area, where the local people leave their cattle to graze freely for weeks on end.

The initial descent into the valley is not as steep as when heading to the site of the Arror dam and it is possible to drive part of the way through the wet tropical-like vegetation, leaving the car to cut through the dense vegetation accentuated by tall indigenous trees. The two guides accompanying Kahura from HZ centre tell him they grew up grazing cattle in the area and know the geography of Kimwarer like the backs of their hands.

Once on the valley floor, gazing up towards HZ centre and towards the Eldama Ravine Road, the guides say that had the dam been built, the entire area would have been shorn off vegetation and anybody living there would have had to leave. But as it is, the only evidence that anything had happened here is drilling, says one of them. Only the gaping holes remain. Other large pits had been dug for soil testing though nothing was ever heard of the results. Many are now covered by vegetation or filled by the local people to avoid their cows falling into them.

Silas Kiplagat from Tulwobei village, the homesteads nearest to the site of the proposed dam, says the people are no longer interested in it, because as youve seen for yourself, this was one huge scam. Our politicians all took us for a ride. It was all so absurd. The former MP, Jackson Kiptanui, Senator Murkomen and Governor Tolgos all came here to persuade us to support the project.

KVDA officials, who we were told would be in charge of the project, had visited. They held a meeting at the HZ centre social hall and enumerated the advantages of the dam when finished, says Kiplagat. Other government officials whom Kiplagat says showed up were National Land Commission officials who also met the locals at the social hall and told them they were seeking their participation, insofar as the dams project was concerned.

Then all visits stopped suddenly, says Vincent Kiprop, also from Tulwobei village, and the ensuing scandal startled the people. How is it that your own leaders can conspire to rip you off? Kiprop asks. The residents are very angry with their leaders. But hey, what are our options? he shrugs.

The former MP, Jackson Kiptanui, Senator Murkomen and Governor Tolgos all came here to persuade us to support the project.

Kahura returns to Iten town where he meets with Kiptarus Kipkoros, a local journalist who is well acquainted with the dams saga. The dams project was meant to finance the 2022 election campaigns in the north Rift Valley region and especially in Elgeyo Marakwet, says Kipkoros. He blames the media for the misinformation and confusion surrounding the two dams. KVDA MD David Kimosop would hire a special helicopter to ferry journalists from Nairobi to the supposed dam sites. But you and I know their intention was not to establish whether the sites existed, report on the scandal or even investigate the story not as long as the brown envelopes were aplenty.

Kipkoros alleges that Kimosop would take the journalists on an aerial tour of Elgeyo Marakwet County, circle the areas around the two dams then return to Eldoret for a sumptuous meal before sending them back to Wilson Airport each with a brown envelope in hand. Therefore, the politicians [read the MP, Senator and Governor] and the journalists helped conceal the true extent of the mega-dams scandal. Journalists became part of the people who helped siphon the states money, says Kipkoros.

Before the scandal broke, weekends in Elgeyo Marakwet County were awash with choppers flying into the area. Here in Iten they would drop at St Patrick Iten School grounds, at the market field, or anywhere where there is a landing field, says Kipkoros. Afterwards, the whizzing of the choppers in the air over the weekends suddenly ceased. It is very painful to watch elected leaders robbing their own people, says the journalist. The politicians used the money for self-aggrandisement, he says, adding that

The journalist claims that the politicians and top KVDA officials used the cash to fund extravagant lifestyles, which astonished the people of the small, poor county of Elgeyo Marakwet. The politicians inundated the county with choppers loaded with money every weekend, dishing it out to their supporters and at hurriedly set-up fundraisers.

Before the scandal broke, weekends in Elgeyo Marakwet County were awash with choppers flying into the area.

Longrock Engineering Limited was named as one of the companies that allegedly received part of the money for the dams. The company was allegedly paid KSh6.2 million to supply furniture and provide transport services. Now, Longrock is a corruption of the name Kaplongorok, a family name that hails from Kipsait in Kapsowar, said Kipkoros. According to an investigation published by Africa Uncensored, there are five companies with Longrock in their names that were suppliers for the construction of the dams, all of whose directors or shareholders are directly linked to the KVDA and more specifically to board member Dinah Chelanga. You can see for yourself the extent to which the money was distributed to friends, loyal supporters and relatives, says Kipkoros.

The journalist says the politicians and the KVDA officials bought their girlfriends and wives brand new Toyota sedans and SUVS. Some even acquired new wives on account of that money.

However, even the journalist sees little prospect for real justice and accountability in the ongoing prosecutions over the scams. The war on corruption will not be won by engaging in politics of deceit and subterfuge, he says. What Uhuru is doing is not fighting corruption, but fighting [Deputy President William] Ruto and thats why the people will just be angry for a while but quickly revert to type that is ethnic politics.

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