Category Archives: Transhuman News

The p53 protein earned the nickname guardian of the genome because it plays a key role in DNA damage response by preventing cells with faulty DNA from dividing. Mutations or malfunctions in p53 have been implicated in many types of human cancers.

In some tumors, normal p53 function is blocked by high levels of another protein called MDM2. Now, scientists from the Karolinska Institutet in Sweden and U.S. biotech Aileron Therapeutics have early evidence that reactivating p53 by inhibiting MDM2 with a drug developed by the company could boost the immune response against tumors. They reported their findings in the journal Cancer Discovery.

Based on positive results in mice and patient tissue samples, the researchers suggested that the MDM2 inhibitor could be used alongside checkpoint inhibitors to help more cancer patients benefit from immuno-oncology agents.

The p53 protein protects against genomic changes in part by blocking repetitive DNA elements that could alter the human genome. These include sequences known as endogenous retroviruses, which were incorporated into the human genome from ancestral infections.

The Karolinska-led team was surprised to discover that p53 could induce the expression of endogenous retrovirus sequences in different cancer cell lines from breast cancer, osteosarcoma, colon cancer and melanoma.

RELATED:Unleashing the cancer-fighting gene TP53 in leukemia with a novel combination treatment

The researchers went on to explore reactivating p53 with MDM2 inhibitors in lab dishes. When we blocked the suppressor MDM2, p53 activated endogenous retroviruses which induced antiviral response and boosted the production of immune-activating interferons, Galina Selivanova, the studys senior author, explainedin a statement.

Interferons are inflammatory molecules needed for effective immune responses. They're also major regulators of tumor-infiltrating immune cells, the researchers noted. In addition to affectinginterferons and related genes, p53 activation enhanced antigen presentation and processing, which could prime cancer cells for targeting by the immune system, the team showed.

Based on thosefindings, the scientists figured the method might work well with PD-1 inhibition, which lifts the brakes that tumors impose on the immune system.

In another mouse model of colon cancer, treatment with Ailerons ALRN-6924, an advanced analog of thedrug, promoted the recruitment of tumor-infiltrating immune cells, especially CD8+ killer T cells, as well as an increase of tumor-suppressing M1 macrophages, the team reported. Combining the drug with a PD-1 inhibitor also produced a complementary anti-tumor effect.

RELATED:New approaches to treating cancer with off-the-shelf immune-stimulating bispecific antibodies

ALRN-6924 is in a phase 1b trial to prevent adverse bone marrow effects in patients undergoingchemotherapy. The Karolinska-led team analyzed biopsy samples from two melanoma patients in the trial before and after treatment. They found p53 was activated in tumors and that the interferon pathway and activity of other genes related to the anti-tumor immune response were enhanced.

This shows that there are synergies that should be exploited between substances that block MDM2 and modern immunotherapies, Selivanova said in a statement. A combination of these can be particularly important for patients who dont respond to immunotherapy.

Aileron recentlylaunched another phase 1b trial in patients with p53-mutated non-small cell lung cancer. The trial is testing ALRN-6924 as a protective agent for patients undergoing chemotherapy with or without immune checkpoint inhibitors.

Many other companies have MDM2 inhibitors in their arsenals. These include Roches idasanutlin, which failed a phase 3 acute myeloid leukemia (AML) trial last year. Through a licensing deal last year, Rain Therapeutics gained rights to Daiichi Sankyos milademetan (DS-3032). And Novartis is developing siremadlin (HDM201), while Amgen has AMG 232.

Selivanova is a co-founder of Boston biotech Aprea Therapeutics. The company is developing a p53 reactivator dubbed eprenetapopt (APR-246). The drug, used in tandem with AbbVie and Roches Venclexta and Celgenes Vidaza, just reporteda win from a phase 1/2 trial in TP53-mutant AML.

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Improving the response to cancer immunotherapy by reactivating the 'guardian of the genome' - FierceBiotech

Lee Schwartzberg, MD, FACP, of West Cancer Center & Research Institute, discusses the role of genomic testing in hormone receptor-positive breast cancer and compares information provided by various assays approved for use.

Kristie Kahl: So Dr. Schwartzberg, what are the genomic assays and what is their role in early breast cancer?

Lee Schwartzberg, MD, FACP: The third aspect of looking at factors that will help us determine prognosis and predict a value in adjuvant therapy for breast cancer are the newer genomic assays. Newer in the sense that theyve now been around for about 15 years and are used quite broadly. These assays look at an expression panel of genes in the tumor. This is not germane, of course. This is looking at the tumor and the expression panel. They were originally done with arrays of mRNA, or messenger RNA, which shows the expression of each of those genes. And either using a panel type of technology or using PCR [polymerase chain reaction] technology for the specific genes that would determine we can get a score of whether a particular tumor is low-, intermediate-, or high-risk for recurrence. Now, we have several different types of genomic assays or commercial assays that are available. Interestingly, they all use a different gene set to come to these decisions. All of them are validated. They are very good at prognosis in terms of telling whether a patients tumor and typically combined with the clinical features that I mentioned already, will be low-risk, intermediate-risk, or high-risk for recurrence of disease. Initially, these assays were established for node-negative patients.

Recently, we have had prospective studies looking in the node-negative or in the node-positive setting how well these assays predict for a recurrence of disease or not. These assays are also important to help us make a decision about chemotherapy up front. The 21-gene assay and the 70-gene assay have been looked at prospectively and give us information about the benefit of chemotherapy in those people that have low-, intermediate-, or high-risk scores. What we find is those with high scores benefit from chemotherapy in that setting whether they are node-negative or node-positive. So, that has become the standard for helping make the decision about chemotherapy in many patients with early-stage breast cancer. As I mentioned before, we do not use genomic expression profiles to make a decision about adjuvant endocrine therapy because we essentially offer that to any patient who is hormone receptor-positive.

Transcript edited for clarity.

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Role of Genomic Testing in HR Positive Breast Cancer - Cancer Network

Delta Plus, a sub lineage of Delta, a variant of Covid-19, has spread across many nations. It has also affected people in Indian states.

On the one side, the national vaccination programme is in full swing. The jab appears to be reassuring. In fact, the Centre has invited bids for drone-led vaccine delivery in remote areas and challenging locations. A standard protocol for vaccine delivery through Unmanned Aerial Vehicles (UAV) has been developed by the Indian Council of Medical Research (ICMR) in collaboration with the Indian Institute of Technology (IIT), Kanpur.

That doesnt mean to say that everyone is safe. No, far from that, theres a murky dimension to it. Delta itself has boosted the second wave of the infection in India. The World Health Organisation (WHO) has described Delta as a Variant of Concern (VoC). The second wave is not yet over, though the case trajectory is coming down. Being highly infectious, Delta has now mutated into Delta Plus, also known as AY.1.

What makes Delta Plus more dangerous than Delta is that it contains an additional mutation called K417N first found in the Beta variant of South Africa. This is in addition to the Delta variant (B.1.617.2), which drove India's deadly second wave of the pandemic. Delta Plus is very resistant to medication, treatment and vaccination, quite apart from being highly transmittable. Alarmingly, it affects the lung cells and is less responsive to the monoclonal antibodies therapy. That means those who have been vaccinated are likely to be affected by Delta Plus and it can even lead to clinical illness.

All these characteristics have been identified by INSACOG (Indian SARS-CoV-2 Genomic Consortia), a consortium of 28 laboratories of Ministry of Health and Family Welfare, Department of Biotechnology, Indian Council of Medical Research (ICMR) and Council of Scientific and Industrial Research (CSIR) for whole genome sequencing in the context of Covid-19. INSACOG also offers timely inputs on appropriate public health response measures to be adopted by states and union territories.

Many nations are weighed down by Delta Plus, but Indias burgeoning population makes the situation much more serious than many parts of the world. Its understandable that ICU beds are being filled up as mortality rates are increasing. This has already hit the headlines as many people have succumbed to it. Wherever the transmission of Delta Plus has happened, the Centre has said that the states should take up immediate containment measures. The emphasis is on enhanced testing, tracking and vaccination in districts and clusters where Delta Plus has spread.

Given its pace of spread, the Centre has initiated genome sequencing labs at the Lok Nayak Jai Prakash Narayan Hospital and the Institute of Liver and Biliary Sciences (ILBS) Hospital. These Delhi-based labs are gearing up for what could be a third wave of the pandemic by studying the mutating coronavirus. R&D professionals will work towards building scientific data on the strain. After detecting Delta Plus variants, Haryana and Rajasthan have become home to genome sequencing facilities. Scientists can monitor the changing variants of Covid-19.

Even as Delta Plus is making news, biopharmaceutical company AstraZeneca has partnered with healthcare startup Docon Technologies to digitise 1,000 clinics across the country. The clinics will be provided with electronic medical record (EMR) systems to manage patient history and administer treatment accordingly.

All this is happening as the country is inching closer towardsa third wave of Covid. ICMR has informed the media that its too early to say if the Delta variant would contribute to the third wave. It definitely remains a matter of concern, as Delta Plus continues to spread rapidly.

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View from India: Genome labs initiated to study virus mutations - E&T Magazine

Amid the devastating Covid-19 pandemic, two researchers are proposing a drastic way to stop future pandemics: using a technology called a gene drive to rewrite the DNA of bats to prevent them from becoming infected with coronaviruses.

The scientists aim to block spillover events, in which viruses jump from infected bats to humans one suspected source of the coronavirus that causes Covid. Spillover events are thought to have sparked other coronavirus outbreaks as well, including SARS-1 in the early 2000s and Middle East respiratory syndrome (MERS).

This appears to be the first time that scientists have proposed using the still-nascent gene drive technology to stop outbreaks by rendering bats immune to coronaviruses, though other teams are investigating its use to stop mosquitoes and mice from spreading malaria and Lyme disease.

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The scientists behind the proposal realize they face enormous technical, societal, and political obstacles, but want to spark a fresh conversation about additional ways to control diseases that are emerging with growing frequency.

With a very high probability, we are going to see this over and over again, argues entrepreneur and computational geneticist Yaniv Erlich of the Interdisciplinary Center Herzliya in Israel, who is one of two authors of the proposal, titled Preventing COVID-59.

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Maybe our kids will not benefit, maybe our grandchildren will benefit, but if this approach works, we could deploy the same strategy against many types of viruses, Erlich told STAT.

As the Covid-19 pandemic has killed more than 3.9 million people and triggered $16 trillion in economic losses, scientists, public health officials, ecologists, and many others have called for deeper investments in longstanding pandemic prevention measures.

Such measures include boosting global health funding, reducing poverty and health inequity, strengthening disease surveillance networks and community education, preventing deforestation, controlling the wildlife trade, and beefing up investments in infectious disease diagnostics, treatments, and vaccines.

Erlich and his co-author, immunologist Daniel Douek at the U.S. National Institute of Allergy and Infectious Diseases, now propose an additional measure: creating a gene drive to render wild horseshoe bats immune to the types of coronavirus infections that are thought to have triggered the SARS, MERS, and Covid-19 pandemics. They shared the proposal Wednesday on the Github publishing and code-sharing platform.

Though there is heated debate about whether the Covid-19 virus originated in a lab, most scientists say the virus is most likely to have originated in wild animals. There is strong evidence, for instance, that horseshoe bats carry the coronavirus that caused the SARS outbreak.

A gene drive is a technique for turbocharging evolution and spreading new traits throughout a species faster than they would spread through natural selection. It involves using a gene editing technology such as CRISPR to modify an organisms genome so that it passes a new trait to its offspring and throughout the species.

The idea of making a gene drive in bats faces such enormous scientific, technical, social, and economic obstacles that scientists interviewed by STAT called it folly, far-fetched, and concerning. Among other objections, they worried about unintended consequences with so radically tampering with nature.

We have other ways of preventing future Covid-19 outbreaks, argued Natalie Kofler, a trained molecular biologist and bioethicist and founder of Editing Nature, a group focused on inclusive decision-making about genetic technologies.

We need to be thinking about changing the unhealthy relationship of humans and nature, not to gene drive a wild animal so that we can continue our irresponsible and unsustainable behavior that is going to come back to bite us in the ass in the future.

Coming from anyone else, the idea might be laughed off.

But Erlich has a reputation as a visionary. In 2014, for instance, he and another scientist predicted that genetic genealogy databases might one day be used to reveal peoples identities. Four years later, that happened, when law enforcement officials used the method to identify a former California police officer as the notorious Golden State Killer. Erlich has since become chief scientific officer of the genetic genealogy company MyHeritage and he is also founder of a biotech startup, Eleven Therapeutics.

Now, Erlich says, its worth thinking about how a gene drive could work in bats.

Erlich proposes to modify bat genomes so that they would block coronavirus infections. He would create a genetic element, called a shRNA, that targets and destroys coronaviruses. He would then use CRISPR to insert this element into the bat genome. The insertion would also contain a component that pushes bats to preferentially pass the shRNA to their offspring, so that entire bat populations would soon resist coronavirus infection.

Its almost like creating a self-propagating vaccine in these bats, Erlich said.

The idea is intriguing, said geneticist and molecular engineer George Church of the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Most of the proposals Ive heard involving gene drives have seemed quite attractive, and this is probably the most attractive, he said.

Creating a gene drive in bats would be enormously difficult, and perhaps impossible, other scientists say. Researchers have created gene drives in mosquitoes and mice in the lab, but none has been released in the wild. The most advanced gene drive projects intended for field use involve modifying mosquitoes to prevent the spread of malaria and attempting to engineer mice to stop them from causing ecological damage.

But its been difficult to engineer effective gene drives in mammals. Developmental geneticist Kim Cooper and her team at the University of California, San Diego, engineered a gene drive that spread a genetic variant through 72% of mouse offspring in her lab. That isnt efficient enough to quickly spread the desired trait in the wild.

Whats more, creating a gene drive in bats would be much harder than it is in mice, because bat researchers lack the genetic tools available in mice, said Paul Thomas, a developmental geneticist at the University of Adelaide in Australia, who is trying to engineer mouse gene drives.

And unlike mice, which can breed at 6 to 8 weeks of age, bats take two years to reach sexual maturity, so it would take much longer for a trait to spread throughout wild bat populations than in lab mouse populations.

They say the proposal is not an easy feat from a technical standpoint, and I think that underplays how hard it might be, Cooper said.

Biologists also say that Erlichs proposal is unlikely to work in the wild even if researchers get bat gene drives to work in a lab because bats are incredibly diverse.

There are 1,432 bat species, including multiple horseshoe bat species that carry coronaviruses and pass them among each other.

Wild viruses similar to the human Covid-19 virus have been found in bats across Asia, and in pangolins. And in June, Weifeng Shi of the Shandong First Medical University & Shandong Academy of Medical Sciences in Taian, China, found 24 coronavirus genomes in bat samples taken from in and around a botanical garden in Yunnan province, in southern China.

Engineering one gene drive in just one bat species would not solve the problem, biologists say.

Youd have to develop systems for entire bat communities, said evolutionary biologist Liliana Dvalos of Stony Brook University. Its the job of visionaries to come up with creative ideas, but this is a giant blind spot in their thinking.

Biologists are also concerned about focusing on bats themselves, because they may not be the most important source of human epidemics. No one has found the exact bat analog to the human Covid-19 virus, or definitively proven that spillover from bats did start the pandemic. Coronaviruses have also been found in other species, including palm civets, pangolins, and camels.

Further, nobody knows how eliminating coronaviruses might affect bats.

We dont know the implications of wiping out coronaviruses in bat populations, because we dont know how bats have evolved to coexist with these viruses, said virologist Arinjay Banerjee of the Vaccine and Infectious Disease Organization at the University of Saskatchewan in Saskatoon, Canada.

Some scientists, though, welcomed Erlichs proposal, hoping that it will focus attention on what it would take to create successful mammalian gene drive systems.

Royden Saah, for instance, coordinates the Genetic Biocontrol of Invasive Rodents (GBIRd) program, which is trying to engineer gene drives in mice to prevent island bird extinctions. He wants to see more funding to help scientists solve the technical obstacles to such projects, and involve more communities in discussions about these ideas.

I would be concerned if this proposal detracted from the need to fund public health infrastructure, said Saah. But with that caveat, he added, I think this proposal could make people think, OK, if we were to use this technology in this animal in this system, what would we need to do? There would need to be a foundation of ethical development, of clear understanding, of social systems and trust, and technology built in a stepwise manner.

Virologist Jason Kindrachuk of the University of Manitoba said that there are numerous technical and political challenges to a bat gene drive project, and that preventing future outbreaks should mainly involve tackling the challenges that drive spillover events, such as underfunded public health systems, poverty, food insecurity and climate-change-driven ecological disruption. But, he said, given the enormous economic and human toll of Covid-19 and other recent outbreaks, scientists and public health officials might also need to consider new approaches.

In the past, maybe we were blinded a little bit by our belief that we would just be able to increase surveillance and identify these pathogens prior to them spilling over, Kindrachuk said. We now realize that this is going to take a lot of different efforts, so theres an aspect from a research standpoint where we continue to look at things like this, and say, what are the top 5 to 10 things we should invest in.

Erlich acknowledges the obstacles to his proposal, but thinks they arent insurmountable. He thinks the project would require an international investment involving a multidisciplinary consortium.

While we totally agree about the technical complexities, technology advances at exponential rates, Erlich said. Things that are nearly impossible now can be totally reachable within a decade or so.

He also thinks a gene drive could be a better alternative than culling bats, which has been tried (unsuccessfully) in communities around the world, and that scientists could monitor for negative impacts on bat populations.

Lets discuss the idea and think about what we can do to identify a very rigorous and cautious way to test this approach, Erlich said. We dont like to mess with nature, but the current situation is not sustainable.

Excerpt from:
Could editing the genomes of bats prevent future pandemics? - STAT - STAT

Brihanmumbai Municipal Corporation (File photo)  |  Photo Credit: IANS

Mumbai: As per the experts, the 03rd wave of Coronavirus is likely to hit Mumbai and Maharashtra by July mid-week. But as far as the preparations for it are concerned, BMC has a list of delayed projects.

Setting up of a genome sequencing lab is one such project. BMC announced this Rs 12 cr project two months ago. It will be set up in Kasturba hospital. This decision happened after various experts, including the members of the state Covid task force pointing out the need of one such lab since last year. It was said that the lab will be functional by June end.

But this promise is far from being fulfilled. As per BMC, the lab machine (Next seq) is stuck in Singapore and this cargo issue is causing the delay. As per BMC, the machine is being brought from the US and because of Covid related situation, the machine is stuck in cargo in Singapore. BMC is expecting that they will receive the machine by the end of the week.

But that won't be all. Even after receiving the machine, BMC has to conduct trial runs, BMC will then have to write to the Central govt to approve the lab. The Central govt will send a deputation for testing of the lab to give it approval. And only after all this clearance, the lab will be functional.

BMC is claiming that all this will happen in the next 7-10 days. But the opposition parties in the corporation are claiming that the speed at which things are happening, the lab won't be functional for another 03 weeks.

The significance of this lab has increased by many folds since the cases of Delta plus variant are found in the state. Now all the samples have to be sent to NIV, Pune and it takes 02-03 months to get the report. The Delta plus cases were also of April month. With this lab, the reports will be available in 02-03 days and it will help the authorities in rapid screening and contact tracing. But the city will have to wait for some more weeks for this lab.

Additional Municipal Commissioner Suresh Kakani told Mirror Now that, "The machine is in Singapore cargo as of now. We are expecting to get it this week and the lab should be functional in a week after that."

Ravi Raja, Congress, Opposition leader BMC, told Mirror Now that, "This is happening because of the lack of seriousness in BMC officials. Many such projects are delayed because of this approach of BMC."

3) Reporter toss

4) Shots of Kasturba hospital

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[Exclusive] Delay in another Covid-related project of BMC, genome sequencing lab to take more time to start - Times Now