Category Archives: Transhuman News

Illustration. Credit: Yuval Robichek, Weizmann Institute of Science

Proteins communicating through the DNA molecule constitute a newly discovered genetic switch.

Proteins can communicate through DNA, conducting a long-distance dialogue that serves as a kind of genetic switch, according to Weizmann Institute of Science researchers. They found that the binding of proteins to one site of a DNA molecule can physically affect another binding site at a distant location, and that this peer effect activates certain genes. This effect had previously been observed in artificial systems, but the Weizmann study is the first to show it takes place in the DNA of living organisms.

A team headed by Dr. Hagen Hofmann of the Chemical and Structural Biology Department made this discovery while studying a peculiar phenomenon in the soil bacteria Bacillus subtilis. A small minority of these bacteria demonstrate a unique skill: an ability to enrich their genomes by taking up bacterial gene segments scattered in the soil around them. This ability depends on a protein called ComK, a transcription factor, which binds to the DNA to activate the genes that make the scavenging possible. However, it was unknown how exactly this activation works.

(l-r) Dr. Nadav Elad, Dr. Haim Rozenberg, Dr. Gabriel Rosenblum, Jakub Jungwirth and Dr. Hagen Hofmann. Twisting a rope from one end. Credit: Weizmann Institute of Science

Staff Scientist Dr. Gabriel Rosenblum led this study, in which the researchers explored the bacterial DNA using advanced biophysical tools single-molecule FRET and cryogenic electron microscopy. In particular, they focused on the two sites on the DNA molecule to which ComK proteins bind.

They found that when two ComK molecules bind to one of the sites, it sets off a signal that facilitates the binding of two additional ComK molecules at the second site. The signal can travel between the sites because physical changes triggered by the original proteins binding create tension that is transmitted along the DNA, something like twisting a rope from one end. Once all four molecules are bound to the DNA, a threshold is passed, switching on the bacteriums gene scavenging ability.

We were surprised to discover that DNA, in addition to containing the genetic code, acts like a communication cable, transmitting information over a relatively long distance from one protein binding site to another, Rosenblum says.

A 3D reconstruction from single particles of bacterial DNA (gray) and ComK proteins (red), imaged by cryogenic electron microscopy, viewed from the front (left) and at a 90 degrees rotation. ComK molecules bound to two sites communicate through the DNA segment between them. Credit: Weizmann Institute of Science

By manipulating the bacterial DNA and monitoring the effects of these manipulations, the scientists clarified the details of the long-distance communication within the DNA. They found that for communication or cooperation between two sites to occur, these sites must be located at a particular distance from one another, and they must face the same direction on the DNA helix. Any deviation from these two conditions for example, increasing the distance weakened the communication. The sequence of genetic letters running between the two sites was found to have little effect on this communication, whereas a break in the DNA interrupted it completely, providing further evidence that this communication occurs through a physical connection.

Knowing these details may help design molecular switches of desired strengths for a variety of applications. The latter may include genetically engineering bacteria to clean up environmental pollution or synthesizing enzymes to be used as drugs.

Long-distance communication within a DNA molecule is a new type of regulatory mechanism one that opens up previously unavailable methods for designing the genetic circuits of the future, Hofmann says.

Reference: Allostery through DNA drives phenotype switching by Gabriel Rosenblum, Nadav Elad, Haim Rozenberg, Felix Wiggers, Jakub Jungwirth and Hagen Hofmann, 20 May 2021, Nature Communications.DOI: 10.1038/s41467-021-23148-2

The research team included Dr. Nadav Elad of Weizmanns Chemical Research Support Department; Dr. Haim Rozenberg and Dr. Felix Wiggers of the Chemical and Structural Biology Department; and Jakub Jungwirth of the Chemical and Biological Physics Department.

Dr. Hagen Hofmann is the incumbent of the Corinne S. Koshland Career Development Chair in Perpetuity.

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Calling Through the DNA Wire: A Newly Discovered Genetic Switch - SciTechDaily

DUBLIN, Sept. 1, 2021 /PRNewswire/ -- The "DNA Vaccines: Technologies and Global Markets 2021-2026" report has been added to ResearchAndMarkets.com's offering.

Research and Markets Logo

The global market for DNA vaccines should grow from $3.1 billion in 2021 to $11.5 billion by 2026 with a compound annual growth rate (CAGR) of 30.1% for the period of 2021-2026.

DNA vaccines market for research tools should grow from $2.2 billion in 2021 to $8.7 billion by 2026 with a compound annual growth rate (CAGR) of 32.3% for the period of 2021-2026.

DNA vaccines market for clinical vaccines should grow from $924 million in 2021 to $2.8 billion by 2026 with a compound annual growth rate (CAGR) of 24.5% for the period of 2021-2026.

Report Scope

The study's scope includes DNA vaccine products that already are commercialized or likely to be in the next five years. Both human and animal health markets are studied. DNA vaccine delivery technologies are also included. DNA vaccine candidates in clinical trials are examined by indication, and future market growth from 2021 through 2026 is forecast.

The role that DNA vaccines play in the overall vaccine industry is examined, as well as how the vaccine industry structure and dynamics are changing.

We examine DNA synthesis, biotechnology and pharmaceuticals firms, strategic industry alliances, and the role of gene delivery and synthesis technologies. The major markets for DNA vaccines, including infectious diseases, cancers, animal health, allergies and biodefense, are analyzed, and the main companies in these fields are highlighted.

The Report Includes

14 data tables and 55 additional tables

An overview of the global market for DNA vaccines and related technologies

Analyses of global market trends, with data from 2019, 2020, estimates for 2021, and projections of compound annual growth rates (CAGRs) through 2026

Coverage of delivery and synthesis technologies, the forces driving market growth, product formats, and market applications for these products

Identification of new opportunities, challenges, and technological changes within the industry and highlights of the market potential for DNA vaccines by delivery technology, format, function and region

Coverage of life cycle status and commercial status of DNA vaccine technologies and brief description of the Human Immune System

Details about vaccines, their evolution, and types including DNA vaccines and cancer DNA vaccines, their function, scope and clinical trials, and information on changing vaccine paradigm, antigen discovery, plasmid design and manufacture and delivery technologies

Detailed analysis of the current market trends, market forecast, and discussion of technological, and regulatory elements that are affecting the future marketplace

Information about major technologies for the formulation of DNA vaccines and assessment of their relation to biotechnology, gene therapy, DNA delivery, pharmaceuticals, and biodefense companies

Comprehensive profiles of leading companies in the field as well as updates to alliance, merger, and acquisition activities, including Astellas Pharma Inc., Bristol-Myers Squibb Co., Merck & Co., Novartis AG, Pfizer Inc. and Sanofi-Aventisa

Vaccines, once a stable though unexciting sector of the pharmaceutical industry, are becoming an attractive growth opportunity. DNA vaccines are an emerging vaccine platform within this changing paradigm. DNA vaccines target a wide range of traditional pharmaceutical markets, such as cancers and allergies, as well as infectious diseases. The vaccine industry has proved that it can generate products with nontraditional applications and blockbuster potential. Products such as that from ViroCyt, now part of Sartorius Stedim Biotech, are leading the field of rapid virus quantification. DNA vaccines are poised to generate significant future market potential.

Story continues

New biotechnologies and nanotechnologies are driving DNA vaccine development. Particularly key to DNA vaccines reaching their potential are emerging delivery technologies such as electroporation (EP), innovative vaccine formats such as DNA prime-adenovector boost, and novel molecular adjuvant technologies. These technologies are providing the means for achieving the higher efficacy in humans that is required for the commercialization of DNA vaccines.

DNA vaccines have already made significant progress to date. There are three approved DNA vaccines for animal health applications and nearly 100 clinical trials underway in humans for a wide range of diseases. There is a deep pipeline of preclinical projects. A small but strategic market segment is commercial today, consisting of research tools and animal health applications.

The high growth is the result of a low starting base and a forecast introduction of several DNA vaccines late in the period. While research tools and animal health clinical applications currently dominate the market, human clinical DNA vaccines will make up the vast majority of this market through 2026.

Key Topics Covered:

Chapter 1 Introduction

Chapter 2 Summary

Chapter 3 Market Overview

Introduction

DNA Vaccine Technologies Covered in This Report

Global Market for DNA Vaccines

Forces Driving DNA Vaccine Market Growth

Life Cycle Status of DNA Vaccine Technologies

Commercial Status of DNA Vaccine Technologies

DNA Vaccine Industry

Chapter 4 DNA Vaccine Technologies

Introduction

Human Immune System

Vaccines

Evolution of Vaccines

Types of Vaccines

DNA Vaccines

Changing Vaccine Paradigm

Function and Scope of DNA Vaccines

Cancer DNA Vaccines

DNA Vaccine Technology Value Chain

Antigen Discovery

Plasmid Design

Plasmid Manufacture

Delivery Technologies

Uncomplexed pDNA

Electroporation

Liposomes

Gold Particles

Nanoparticles

Bacterial Ghosts

Bacteriophages

Viruses

Targeting Technologies

Adjuvant Technologies

DNA Vaccine Technology Needs

Chapter 5 DNA Vaccine Applications

Research Tool Applications

Clinical Application

Overview to DNA Vaccine Clinical Trials Process

Summary of DNA Vaccine Clinical Trials

Chapter 6 DNA Vaccine Industry

Vaccine Industry Structural Shifts

Industry Structure

DNA Vaccine Industry Competitors

DNA Vaccine Commercial Value Chain

DNA Vaccine Competitor Strategic Positioning

Research & Development

Chapter 7 DNA Vaccine Markets

Drivers of Growth

DNA Vaccine Markets

Market Forecasts

DNA Vaccine Research Tool Markets

DNA Vaccine Clinical Markets

DNA Vaccine Market by Region

Research Tools for DNA Vaccine Market by Region

Clinical DNA Vaccine Market by Region

Chapter 8 Impact of COVID-19

Vaccines, Treatments and Diagnostics

Vaccines

Therapeutics

Economic Impact of COVID-19

Chapter 9 Company Profiles

Astellas Pharma Inc.

Astrazeneca Plc

Bristol-Myers Squibb Co.

Gilead Sciences Inc.

Johnson & Johnson

Merck & Co.

Novartis Ag

Pfizer Inc.

Sanofi-Aventis

For more information about this report visit https://www.researchandmarkets.com/r/o8dxo1

Media Contact:

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The Worldwide DNA Vaccines Industry Should Reach $11.5 Billion by 2026 - Yahoo Finance

After the dire misery of last year, vaccines have emerged as mankinds main weapon against the COVID-19pandemic. Governments all over the world are striving to get as many people vaccinated as fast as possible.

India has administered around 65 crore doses, with around 15 crore fully vaccinated individuals and 50 crore vaccinated with a single shot. If you're one of the vaccinated, theres a lot of information out there to give an idea of what exactly happens when the COVID-19 vaccine is injected into the body.

Here we talk about what is injected via a vaccine, what happens inside the body when it responds to the jab, why many people get some common side-effects and finally, why is there a need with several COVID-19 vaccines to get a second shot.

What happens when vaccine serum is injected into the body?

By definition, vaccine is a process of acquired immunity to fight off a future infection. Vaccines contain an agent resembling the virus, bacteria or parasite causing a disease, which in the case of COVID-19 is the SARS-COV-2 virus. It is either a weakened or dead microorganism, or its toxins or a surface protein. This agent carries the virus genetical material, which can then be read by the body to formulate the immune response.

When the vaccine is injected, the agent goes into the cells of our tissues. It captures the attention of certain 'dendritic' cells, which have a specific function to monitor intruders that may have entered the body. These patrolling cells come in contact with this new never-before-seen agent and alarm the body against it.

The dendritic cells do this by reading the genetic instructions about the virus carried into the body by the vaccine agent. The information is then replicated for the immune system to read and react.The cells travel to a lymph node to identify the right cells in the body and then activates them against the virus.

Why does the vaccine give side-effects to some people?

When it comes to vaccines, most side-effects literally mean that your immune system is responding as it is supposed to. With COVID-19 vaccines, common side effects range from soreness or swelling in the arm where the vaccine was injected, fatigue, headache, fever, chills, muscular pain and nausea.

Vaccines trick the immune system in believing that an actual pathogen has entered the body as it cannot tell the difference between the actual virus and a vaccine agent. The white blood cells rush to the spot to break down the virus and antibodies then attack the debris spread around from the breakdown. This makes the spot of injection akin to a tiny battlefield.

Fatigue and soreness after receiving the vaccine shot is due to cytokines and chemokines. These substances are directing more of the immune cells from other parts of the body to the infected site. This also causes inflammation and temporary swelling in lymph nodes in the armpit area.

Why the need for a second shot?

Several of the COVID-19 vaccines, including the COVAXIN and Covishield being administered in India, need a second booster shot after some time. This is because the first shot creates neutralizing antibodies in the body that block the SARS-COV-2 virus from making one sick but this formation of protective antibodies can be short-lived. Thus, a second dose is needed in most cases to help the body generate a more robust and long-term response against illness by locking the memory of the virus.

The second shot helps the body form long-term memory-cells in addition to short-term protective antibodies. This is also why several people see much stronger side-effects after the second shot, because the body now has a stronger, faster and better-equipped immune response against the virus.

The fear of side effects might tempt many to forego the second shot, but it should be remembered that the potential effects of a COVID-19 infection could be much worse and even fatal.

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DNA Explainer: Received your COVID-19 vaccine? Know what's going on inside your body - DNA India

Results Indicate Induction of Adaptive Immune Response Against SARS-CoV-2

Company Plans Additional Development Work to Further Optimize its Vaccine Platform Through Vector Compositions, Delivery Route, Dosing and Dosing Frequency, and Use of Molecular Adjuvant

LAWRENCEVILLE, N.J., Sept. 02, 2021 (GLOBE NEWSWIRE) -- Celsion Corporation (NASDAQ: CLSN), a clinical-stage company focused on DNA-based immunotherapy and next-generation vaccines, today announced results from preclinical in vivo studies showing production of antibodies and cytotoxic T-cell response specific to the spike antigen of SARS-CoV-2 when immunizing BALB/c mice with the Companys next-generation PLACCINE DNA vaccine platform. Moreover, the antibodies to SARS-CoV-2 spike antigen prevented the infection of cultured cells in a viral neutralization assay. The production of antibodies predicts the ability of PLACCINE to protect against SARS-CoV-2 exposure, and the elicitation of cytotoxic T-cell response shows the vaccines potential to eradicate cells infected with SARS-CoV-2.

These findings demonstrate the potential immunogenicity of Celsions PLACCINE DNA vaccine, which is intended to provide broad-spectrum protection and resistance against variants by incorporating multiple viral antigens, to improve vaccine stability at storage temperatures of 4o C and above, and to facilitate cheaper and easier manufacturing. Celsion expects to report these data at the International Vaccines Conference to be held on October 19 21, 2021.

In an effort to establish a suite of platform technologies, we have produced and characterized a family of DNA vaccine vectors expressing one or more SARS-CoV-2 surface antigens or proteins with or without immune modifiers or agents to improve vaccine quality, said Khursheed Anwer, PhD, Celsions Executive Vice President and Chief Science Officer. In addition, we are developing an intramuscular vaccine based on a specialized synthetic delivery system that yields high levels of viral proteins to generate the desired immune response. This formulation does not require a separate delivery device, such as electroporation, for administration. We are pleased with the immunogenicity data from our recent preclinical studies and plan to continue to share progress from ongoing in vivo studies intended to further optimize the PLACCINE DNA vaccine activity through vector design, delivery route, dose levels and dosing frequency, as well as adjuvant quality. If successful, our immediate goal is to validate our program with IND-enabling studies.

Michael H. Tardugno, Celsions Chairman, President and Chief Executive Officer, said, Our DNA-based vaccine is designed to improve the breadth of immune response by targeting multiple antigens of a pathogen or multiple mutants of the same antigen. The findings we are reporting today are encouraging and demonstrate that the immune response to the PLACCINE DNA vaccine is consistent with our vaccine design goals. We look forward to sharing our progress as we conduct further studies to optimize vector design, dosing and delivery with the goal of filing an Investigational New Drug application with the U.S. Food and Drug Administration early next year.

Importantly, based on our experience with GEN-1, our DNA plasmid immunotherapy, we fully expect that our platform will be both cost-effective and scalable, allowing for stability across a reasonable and readily achievable temperature range that addresses global vaccine storage and distribution needs. A successful proof of concept using mRNA vaccines as a standard will provide Celsion with the scientific basis to launch a vaccine program to address a range of unaddressed serious infectious diseases, Mr. Tardugno added.

About the PLACCINE platform

PLACCINE is Celsions proprietary plasmid and DNA delivery technology and the subject of a provisional patent application that covers a broad range of next-generation DNA vaccines. An adaptation of the Companys TheraPlas technology, PLACCINE is a DNA vaccine technology platform characterized by a single plasmid DNA with multiple coding regions. The plasmid vector is designed to express multiple pathogen antigens along with a potent immune modifier. It is delivered via a synthetic delivery system and has the potential to be easily modified to create vaccines against a multitude of infectious diseases, addressing:

About Celsion Corporation

Celsion is a fully integrated, clinical stage biotechnology company focused on advancing a portfolio of innovative cancer treatments, including immunotherapies and DNA-based therapies; and a platform for the development of nucleic acid vaccines currently focused on SARS-CoV2. The companys product pipeline includes GEN-1, a DNA-based immunotherapy for the localized treatment of ovarian cancer. ThermoDox, a proprietary heat-activated liposomal encapsulation of doxorubicin, is under investigator-sponsored development for several cancer indications. Celsion also has two platform technologies for the development of novel nucleic acid-based immunotherapies and other anti-cancer DNA or RNA therapies. Both are novel synthetic, non-viral vectors with demonstrated capability in nucleic acid cellular transfection. For more information on Celsion, visit http://www.celsion.com.

Forward-Looking Statements

Forward-looking statements in this news release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, statements relating to the offering and the use of proceeds therefrom, unforeseen changes in the course of research and development activities and in clinical trials; the uncertainties of and difficulties in analyzing interim clinical data, particularly in small subgroups that are not statistically significant; FDA and regulatory uncertainties and risks; the significant expense, time and risk of failure of conducting clinical trials; the need for Celsion to evaluate its future development plans; possible acquisitions or licenses of other technologies, assets or businesses; possible actions by customers, suppliers, competitors or regulatory authorities; and other risks detailed from time to time in the Celsion's periodic filings with the Securities and Exchange Commission. Celsion assumes no obligation to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise.

CONTACTS:

Celsion CorporationJeffrey W. ChurchExecutive Vice President and CFO609-482-2455jchurch@celsion.com

LHA Investor RelationsKim Sutton Golodetz212-838-3777kgolodetz@lhai.com

Excerpt from:
Celsion Reports T-cell and B-cell Response from In Vivo Studies with its PLACCINE DNA Vaccine Platform - GlobeNewswire

If in space, no one can hear you scream, then what happens when DNA silently breaks in microgravity? Spoiler alert: it heals itself.

This is what a CRISPR experiment that won the Genes in Space 6 contest SYFY WIRE was at the recent launchof the Genes in Space 8 experiment to the ISS found out. DNA damage or breakage can mean the potential for degenerative diseases such as cancer, but the fact that it can also self-repair (and in microgravity!) has enormous implications for medical treatments above and below Earths atmosphere.

Genes in Space picks the brains of teen scientists in grades 7 through 12 to come up with a DNA analysis experiment that can be carried out in the ISS U.S. National Lab, which has really become more like a molecular laboratory in space. Aarthi Vijayakumar, Michelle Sung, Rebecca Li, and David Li were the winners who wanted to know if broken DNA could heal in zero-G.

Along with NASA microbiologists Sarah Rommel and Sarah Wallace, the students recently published a study in PLOS ONE.

We have the capabilities to extract, amplify, purify, prepare sequencing libraries, and sequence nucleic acids onboard the ISS, Wallace told SYFY WIRE. While we have come a long way, there is still a lot that could advance the work further.

You cant just pack up an experiment and launch it to the ISS as is. Wallace and Rommel, in collaboration with biologist Emily Gleason of miniPCR and the Genes in Space Program, needed to create custom kits that took both the conditions in space and safety of the crew into account. Everything in those kits must undergo a tough toxicological assessment to make sure the astronauts are not being exposed to anything dangerous almost 250 miles from the ground. If something happens, astronauts cant just wash their hands or roll the window down.

The ISS, as Wallace sees it, is a semi-closed system. Anything that is brought in from outside could possibly be a hazard, which is why scientists much make sure that whatever is on a payload will not endanger astronauts or mess with life support systems. Procedures also need to be streamlined. There is not that much crew time to go around, since the crew have multiple experiments to manage and also take care of other tasks, such as going on spacewalks to resolve maintenance issues. Everything in a kit needs to be packaged for one convenient use.

The end result is a custom kit that has everything the astronauts need to perform the experiment we have planned, said Wallace. We use a lot of things from commercial kits, but we also use reagents we make in our labs, so it really is similar to what molecular labs on Earth are doing.

There is a huge advantage to going through with the entire experiment in space rather than just breaking the DNA on Earth and sending it up to the ISS to see whether it can be repaired. Not everything used in a lab on terra firma can transition to microgravity. At least CRISPR (which is really an acronym for Clustered Regularly Insterspaced Short Palindromic Repeats) does. It replicates an immune response in which bacteria copy DNA sequences to RNA, which sends a protein to cut the DNA. CRISPR can break DNA in a specific place without random damage.

"It has been hypothesized that DNA is more likely to be repaired by the error prone method in microgravity than it is on Earth, but there hasn't been a good way to study this before now." Gleason also told SYFY WIRE. "The students wanted to know ifDNA is repaired differently in microgravity andproposed using the CRISPR/Cas9 system to damage DNA so that we could study how it was repaired in space."

Astronauts created breaks in both strands of the double helix and waited to see what would happen. Our bodies do repair DNA on their own, but would these genes, taken from yeast, be salvageable in space? Replicating these processes in space was previously prevented by technical and safety risks that have now been worked out. After the DNA had repaired itself, it was sequenced to make sure that all its components had gone back to where they belonged. The methods used on the ISS arent limited to space, something Wallace is excited about.

I believe that there is massive potential for this type of portable method in the diagnostic space, she said. There are many potential applications of these methods and technology, ranging from environmental monitoring, pathogen identification, revealing antimicrobial resistance, and so much more.

Wallace and her team are currently working on a collaboration that will optimize an ISS method to see what kinds of microbes are crawling around in hospital rooms, since antibiotic resistance is an issue that (especially in this pandemic era) threatens healthcare. The miniPCR tech that is being used on the ISS has already been used in COVID-19 diagnostics, andGleason also looks forward to updates that will be made to the ISS lab and Genes in Space.

"There's so much that can be done with the tools and procedures already on the ISS," she said. "Genes in space has plans to add flurorescence visulaization and cell-free protein synthesis technology next year."

This goes to show that studies done in microgravity this can go from Earth to space and back again.

See more here:
CRISPR just proved genes can self-heal in space for the first time ever - SYFY WIRE

Background: The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis.

Methods and findings: We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point.

Conclusions: utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

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Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort...