Connect with us


Multimodal sequencing achieves high-quality results from small volumes of frozen tumor specimens

New York, NY—January 18, 2023—Researchers at Columbia Engineering and Columbia University Irving Medical Center have invented a new RNA sequencing…



New York, NY—January 18, 2023—Researchers at Columbia Engineering and Columbia University Irving Medical Center have invented a new RNA sequencing method that achieves high-quality results from small volumes of frozen tumor specimens. They demonstrated the success of their technique in two clinical studies that profiled dozens of tumor samples, both those archived and those freshly collected, to understand how they respond to anti-tumor therapy. The paper was published January 9, 2023, by Nature Genetics.

Credit: Yiping Wang/CUIMC

New York, NY—January 18, 2023—Researchers at Columbia Engineering and Columbia University Irving Medical Center have invented a new RNA sequencing method that achieves high-quality results from small volumes of frozen tumor specimens. They demonstrated the success of their technique in two clinical studies that profiled dozens of tumor samples, both those archived and those freshly collected, to understand how they respond to anti-tumor therapy. The paper was published January 9, 2023, by Nature Genetics.

Using RNA sequencing to measure gene expression at the resolution of single cells has been one of the most transformative tools for studying cancer tissues over the past decade. By examining the RNA of individual cells, researchers can better understand the diversity of cells within a tumor, as well as how these tumor cells grow and interact with immune cells. These are important factors for understanding the hallmarks of cancer progression and the resistance of cancer to therapy–both key to the development of new cancer treatments.

Major challenge

A major barrier to the widespread adoption of single-cell RNA sequencing in traditional clinical workflows has been the volume of fresh tissue required–substantially more than what is routinely collected for clinical purposes. And the need for fresh tissue means that samples must be immediately analyzed once collected. These requirements have significantly limited the scientific analyses that can be done on patient samples. 

Successful new technique 

Focused on overcoming these barriers, the Columbia team created a new sequencing method that delivered top results from a small amount of frozen tumor specimens. Usually collected during clinical trials and stored in biobanks, these specimens may include tissues from rare cancers and patients with unique histories or risk factors. The new technique’s ability to sequence these types of specimens greatly increases the number and variety of tumor samples available for scientific analysis.

“We are very excited about this work and its potential,” said  Elham Azizi, assistant professor of biomedical engineering and Herbert and Florence Irving Assistant Professor of Cancer Data Research at the Irving Institute for Cancer Dynamics, who co-supervised this study with Benjamin Izar, assistant professor of medicine at the Herbert Irving Comprehensive Cancer Center

“The ability to work from frozen samples opens the door to multi-institutional collaborations that will propel the discovery of biomarkers and drug targets. It also gives us the opportunity to apply cutting-edge computational techniques in the analysis and integration of the unlocked clinical data,” Azizi explained. 

Izar added  “And because our method requires only a minute amount of tissue, the remainder of the sample may be used for additional studies. This really is a win-win for researchers, clinicians, and, most importantly, our patients.”

Study’s results broaden understanding of cancer progression

The new study led by Yiping Wang, Joy Fan, and Johannes Melms, trainees in the Izar and Azizi Labs, generated results from single-cell RNA sequencing, single-cell T-cell receptor sequencing, whole genome sequencing, and spatial RNA-sequencing (an innovative RNA-sequencing method that preserves the tumor architecture in situ)–all performed on the same samples. With the ability to bridge multiple modalities of cancer data, the researchers provided a comprehensive view of the genetic alterations, cellular functions, immune cell dynamics, and spatial localization of cells in the context of the patient tissue. These improvements significantly broadened their understanding of cancer progression and resistance mechanisms.

Next steps 

The team is now applying their novel experimental and computational techniques to analyze larger clinical cohorts. The data enables them to better study disease progression and examine the impact of therapies in clinical trials in melanoma as well as other cancer types. 

ECHIDNA, a new computational tool

In parallel, the researchers are also developing an innovative computational tool for systematic integrative analysis of whole genome data and single-cell RNA sequencing, named ECHIDNA. They expect this machine learning algorithm to be key in understanding the relationship between genetic alterations (genotype) and cellular function (phenotype) in tumor cells and will apply it to a larger cohort of melanoma patients in order to characterize diverse mechanisms of treatment resistance. Future work will also include building new computational methods for integrating these data within the spatial context of the histology slice in order to characterize the spatial dynamics of tumor-immune cell interactions.

Izar noted, “In addition to understanding cancer tissue, our method also enables studying tissue response and tissue immunology in other diseases. In the past, we used an earlier version of the method presented here to study the tissue response to lethal COVID-19 infection across multiple organs. This demonstrates an example of developments originating in cancer research that can propel life science research at large.”


About the Study

JOURNAL: Nature Genetics

STUDY:  “Multi-modal single-cell and whole-genome sequencing of small, frozen clinical specimens.”

AUTHORS: Yiping Wang1,2*, Joy Linyue Fan3*, Johannes C. Melms1,4*, Amit Dipak Amin1,4, Yohanna Georgis5, Irving Barrera6, Patricia Ho1,4, Somnath Tagore1,7, Gabriel Abril-Rodríguez8, Siyu He3, Yinuo Jin3, Jana Biermann1,2, Matan Hofree6, Lindsay Caprio1,4, Simon Berhe4, Shaheer A. Khan1,5, Brian S. Henick1,5, Antoni Ribas8,9, Evan Z. Macosko6,10, Fei Chen6,11, Alison M. Taylor5,12, Gary K. Schwartz1,5, Richard D. Carvajal1,5, Elham Azizi3,5,13,#, Benjamin Izar1,2,4,5,7#

1Department of Medicine, Division of Hematology/Oncology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center
2Department of Systems Biology, Program for Mathematical Genomics, Columbia University

3Department of Biomedical Engineering, Columbia University
4Columbia Center for Translational Immunology, Columbia University Irving Medical Center

5Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University
6Broad Institute of Harvard and MIT

7Department of Systems Biology, Columbia University Irving Medical Center
8Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA)
9Parker Institute for Cancer Immunotherapy, San Francisco
10Department of Psychiatry, Massachusetts General Hospital
11Department of Stem Cell and Regenerative Biology, Harvard University

12Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA

13Irving Institute for Cancer Dynamics, Columbia University, New York, NY, USA.

FUNDING: Y.W. is supported by National Institutes of Health (NIH), National Institute of Allergy and Infectious Disease training grant (no. T32AI148099). B.I. is supported by the NIH, National Cancer Institute (NCI) (grant nos. K08CA222663, R37CA258829, R01CA266446, and U54CA225088), a Burroughs Wellcome Fund Career Award for Medical Scientists, a Velocity Fellows Award, the Louis V. Gerstner, Jr. Scholars Program and a Young Investigator Award by the Melanoma Research Alliance. R.D.C., E.A., and B.I. are supported by an NCI grant (no. R21CA263381) and a Columbia University Research Initiatives in Science & Engineering Award. E.A. was supported by an NCI grant (no. R00CA230195) and NSF grant (no. CBET-2144542). J.L.F. acknowledges support from the Columbia University Van C. Mow fellowship. G.A.-R. and A.R. are supported by the Parker Institute for Cancer Immunotherapy and an NIH grant (no. P01CA168585). A.M.T. is supported by the NCI (grant no. 5K22CA237733-03). This work was supported by an NIH/NCI Cancer Center Support grant (no. P30CA013696), the Molecular Pathology Shared Resource and its Tissue Bank at Columbia University, and the Flow-cytometry Core Facility supported by a grant (no. S10OD020056).

COI: B.I. has received consulting fees from Volastra Therapeutics Inc, Merck, AstraZeneca, and Janssen Pharmaceuticals and has received research funding to Columbia University from Alkermes, Arcus Biosciences, Checkmate Pharmaceuticals, Compugen, Immunocore, and Synthekine. G.A.-R. has received honoraria from consulting with Arcus Biosciences. A.R. has received honoraria from consulting with Amgen, Bristol Myers Squibb, Chugai, Genentech, Merck, Novartis, Roche, and Sanofi, is or has been a member of the scientific advisory board, and holds stock in Arcus, Compugen, CytomX, Highlight, ImaginAb, Isoplexis, Kite-Gilead, Lutris, Merus, PACT, RAPT, Synthekine, and Tango Therapeutics. A.M.T. receives research support from Ono Pharmaceuticals. B.S.H. participated in advisory boards for AstraZeneca and Ideaya. R.D.C. is a consultant for Alkermes, Bristol Myers Squibb, Castle Biosciences, Delcath, Eisai, Hengrui, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Sanofi Genzyme, Sorrento Therapeutics and Trisalus, serves on clinical/scientific advisory boards for Aura Biosciences, Chimeron, and Rgenix Research, and has received research funding to Columbia University from Amgen, Astellis, AstraZeneca, BioMed Valley, Bolt, Bristol Myers Squibb, Corvus, Cstone, Foghorn, Ideaya, Immatics, Immunocore, InxMed, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron, and Roche/Genentech. B.I. and J.C.M. filed a patent describing the generation of high-quality single-cell genomics data from frozen tissues. The remaining authors declare no competing interests.



DOI:  10.1038/s41588-022-01268-9 


Read More

Continue Reading


Lower mortgage rates fueling existing home sales

To understand why we had such a beat in sales, you only need to go back to Nov. 9, when mortgage rates started to fall from 7.37% to 5.99%.



Existing home sales had a huge beat of estimates on Tuesday. This wasn’t shocking for people who follow how I track housing data. To understand why we had such a beat in sales, you only need to go back to Nov. 9, when mortgage rates started to fall from 7.37% to 5.99%.

During November, December and January, purchase application data trended positive, meaning we had many weeks of better-looking data. The weekly growth in purchase application data during those months stabilized housing sales to a historically low level.

For many years I have talked about how rare it is that existing home sales trend below 4 million. That is why the historic collapse in demand in 2022 was one for the record books. We understood why sales collapsed during COVID-19. However, that was primarily due to behavior changes, which meant sales were poised to return higher once behavior returned to normal.

In 2022, it was all about affordability as mortgage rates had a historical rise. Many people just didn’t want to sell their homes and move with a much higher total cost for housing, while first-time homebuyers had to deal with affordability issues.

Even though mortgage rates were falling in November and December, positive purchase application data takes 30-90 days to hit the sales data. So, as sales collapsed from 6.5 million to 4 million in the monthly sales data, it set a low bar for sales to grow. This is something I talked about yesterday on CNBC, to take this home sale in context to what happened before it. 

Because housing data and all economics are so violent lately, we created the weekly Housing Market Tracker, which is designed to look forward, not backward.

From NAR: Total existing-home sales – completed transactions that include single-family homes, townhomes, condominiums and co-ops – vaulted 14.5% from January to a seasonally adjusted annual rate of 4.58 million in February. Year-over-year, sales fell 22.6% (down from 5.92 million in February 2022).

As we can see in the chart above, the bounce is very noticeable, but this is different than the COVID-19 lows and massive rebound in sales. Mortgage rates spiked from 5.99% to 7.10% this year, and that produced one month of negative forward-looking purchase application data, which takes about 30-90 days to hit the sales data.

So this report is too old and slow, but if you follow the tracker, you’re not slow. This is the wild housing action I have talked about for some time and why the Housing Market Tracker becomes helpful in understanding this data.

The last two weeks have had positive purchase application data as mortgage rates fell from 7.10% down to 6.55%; tomorrow, we will see if we can make a third positive week. One thing to remember about purchase application data since Nov. 9, 2022 is that it’s had a lot more positive data than harmful data. 

However, the one-month decline in purchase application data did bring us back to levels last seen in 1995 recently. So, the bar is so low we can trip over.

One of the reasons I took off the savagely unhealthy housing market label was that the days on the market are now above 30 days. I am not endorsing, nor will I ever, a housing market that has days on the market at teenager levels. A teenager level means one of two bad things are happening:

1. We have a massive credit boom in housing which will blow up in time because demand is booming, similar to the run-up in the housing bubble years.

2. We simply don’t have enough products for homebuyers, creating forced bidding in a low-inventory environment. 

Guess which one we had post 2020? Look at the purchase application data above — we never had a credit boom. Look at the Inventory data below. Even with the collapse in home sales and the first real rebound, total active listings are still below 1 million.

From NAR: Total housing inventory registered at the end of February was 980,000 units, identical to January & up 15.3% from one year ago (850,000). Unsold inventory sits at a 2.6-month supply at the current sales pace, down 10.3% from January but up from 1.7 months in February ’22. #NAREHS

However, with that said, the one data line that I love, love, love, the days on the market, is over 30 days again, and no longer a teenager like last year, when the housing market was savagely unhealthy.

From NAR: First-time buyers were responsible for 27% of sales in January; Individual investors purchased 18% of homes; All-cash sales accounted for 28% of transactions; Distressed sales represented 2% of sales; Properties typically remained on the market for 34 days.

Today’s existing home sales report was good: we saw a bounce in sales, as to be expected, and the days on the market are still over 30 days. When the Federal Reserve talks about a housing reset, they’re saying they did not like the bidding wars they saw last year, so the fact that price growth looks nothing like it was a year ago is a good thing.

Also, the days on market are on a level they might feel more comfortable in. And, in this report, we saw no signs of forced selling. I’ve always believed we would never see the forced selling we saw from 2005-2008, which was the worst part of the housing bubble crash years. The Federal Reserve also believes this to be the case because of the better credit standards we have in place since 2010. 

Case in point, the MBA‘s recent forbearance data shows that instead of forbearance skyrocketing higher, it’s collapsed. Remember, if you see a forbearance crash bro, hug them, they need it.

Today’s existing home sales report is backward looking as purchase application data did take a hit this year when mortgage rates spiked up to 7.10%. We all can agree now that even with a massive collapse in sales, the inventory data didn’t explode higher like many have predicted for over a decade now.

I have stressed that to understand the housing market, you need to understand how credit channels work post-2010. The 2005 bankruptcy reform laws and 2010 QM laws changed the landscape for housing economics in a way that even today I don’t believe people understand.

However, the housing market took its biggest shot ever in terms of affordability in 2022 and so far in 2023, and the American homeowner didn’t panic once. Even though this data is old, it shows the solid footing homeowners in America have, and how badly wrong the extremely bearish people in this country were about the state of the financial condition of the American homeowner.

Read More

Continue Reading


SVB contagion: Australia purportedly asks banks to report on crypto

Australia’s prudential regulator has purportedly told banks to improve reporting on crypto assets and provide daily updates.



Australia’s prudential regulator has purportedly told banks to improve reporting on crypto assets and provide daily updates.

Australia’s prudential regulator has purportedly asked local banks to report on cryptocurrency transactions amid the ongoing contagion of Silicon Valley Bank’s (SVB) collapse.

The Australian Prudential Regulation Authority (APRA) has started requesting banks to declare their exposures to startups and crypto-related companies, the Australian Financial Review reported on March 21.

The regulator has ordered banks to improve their reporting on crypto assets and provide daily updates to the APRA, the Financial Review notes, citing three people familiar with the matter. The agency is aiming to obtain more information and insight into banking exposures into crypto as well as associated risks, the sources said.

The new measures are apparently part of the APRA’s increased supervision of the banking sector in the aftermath of recent massive collapses in the global banking system. On March 19, UBS Group agreed to buy its ailing competitor Credit Suisse for $3.2 billion after the latter collapsed over the weekend. The takeover became one of the latest failures in the banking industry following the collapses of SVB and Silvergate.

Barrenjoey analyst Jonathan Mott reportedly told clients in a note that the situation “remains stable” for Australian banks but warned confidence could be quickly disrupted, putting pressure on bank margins.

Related: Silvergate, SBV collapse ‘definitely good’ for Bitcoin, Trezor exec says

“Our channel checks indicate deposits are not being withdrawn from smaller institutions in any size, and capital and liquidity buffers are strong,” Mott said, adding:

“But this is a crisis of confidence and credit spreads and cost of capital will continue to rise. At a minimum, this will add to the margin pressure the banks are facing, while credit quality will continue to deteriorate.”

The news comes soon after the Australian Banking Association launched a cost of living inquiry to study the impact of the COVID-19 pandemic and geopolitical tensions on Australians. The inquiry followed an analysis of the rising inflation suggesting that more than 186 banks in the United States are at risk of a similar shutdown if depositors decide to withdraw all funds.

Read More

Continue Reading


Delta Move Is Bad News For Southwest, United Airlines Passengers

Passengers won’t be happy about this, but there’s nothing they can do about it.



Passengers won't be happy about this, but there's nothing they can do about it.

Airfare prices move up and down based on two major things -- passenger demand and the cost of actually flying the plane. In recent months, with covid rules and mask mandates a thing of the past, demand has been very heavy.

Domestic air travel traffic for 2022 rose 10.9% compared to the prior year. The nation's air traffic in 2022 was at 79.6% of the full-year 2019 level. December 2022 domestic traffic was up 2.6% over the year-earlier period and was at 79.9% of December 2019 traffic, according to The International Air Transport Association (IATA).

“The industry left 2022 in far stronger shape than it entered, as most governments lifted COVID-19 travel restrictions during the year and people took advantage of the restoration of their freedom to travel. This momentum is expected to continue in the New Year,” said IATA Director General Willie Walsh.

And, while that's not a full recovery to 2019 levels, overall capacity has also not recovered. Total airline seats available actually sits "around 18% below the 2019 level," according to a report from industry analyst OAG.

So, basically, the drop in passengers equals the drop in capacity meaning that planes are flying full. That's one half of the equation that keeps airfare prices high and the second one looks bad for anyone planning to fly in the coming years.

Image source: Getty Images.

Airlines Face One Key Rising Cost

While airlines face some variable costs like fuel, they also must account for fixed costs when setting airfares. Personnel are a major piece of that and the pandemic has accelerated a pilot shortage. That has given the unions that represent pilots the upper hand when it comes to making deals with the airlines.

The first domino in that process fell when Delta Airlines (DAL) - Get Free Report pilots agreed to a contract in early March that gave them an immediate 18% increase with a total of a 34% raise over the four-year term of the deal.

"The Delta contract is now the industry standard, and we expect United to also offer their pilots a similar contract," investment analyst Helane Becker of Cowen wrote in a March 10 commentary, Travel Weekly reported.

US airfare prices have been climbing. They were 8.3% above pre-pandemic levels in February, according to Consumer Price Index, but they're actually below historical highs.

Southwest and United Airlines Pilots Are Next

Airlines have very little negotiating power when it comes to pilots. You can't fly a plane without pilots and the overall shortage of qualified people to fill those roles means that, within reason, United (UAL) - Get Free Report and Southwest Airlines  (LUV) - Get Free Report, both of which are negotiating new deals with their pilot unions, more or less have to equal (or improve on) the Delta deal.

The actual specifics don't matter much to consumers, but the takeaway is that the cost of hiring pilots is about to go up in a very meaningful way at both United and Southwest. That will create a situation where all major U.S. airlines have a higher cost basis going forward.

Lower fuel prices could offset that somewhat, but raises are not going to be unique to pilots. Southwest also has to make a deal with its flight attendants and, although they don't have the same leverage as the pilots, they have taken a hard line.   

The union, which represents Southwest’s 18,000 flight attendants, has been working without a contract for four years. It shared a statement on its Facebook page detailing its position Feb. 20.

"TWU Local 556 believes strongly in making this airline successful and is working to ensure this company we love isn’t run into the ground by leadership more concerned about shareholders than about workers and customers. Management’s methodology of choosing profits at the expense of the operation and its workforce has to change, because the flying public is also tired of the empty apologies that flight attendants have endured for years."

Read More

Continue Reading