Connect with us

Uncategorized

Novel Neuroblastoma Driver Could Be Target for Therapeutics

Researchers identified a novel, potentially druggable pathway involved in initiating neuroblastoma tumor growth. Their studies provide what they say is…

Published

on

Researchers at the University Medicine Halle have identified a novel, feasibly druggable pathway that is involved in initiating neuroblastoma tumor growth. The scientists’ studies in human neuroblastoma samples, xenografts and in mouse models, provide what they say is the first evidence that a gene called IGF2BP1 acts as a novel driver of neuroblastoma, effectively behaving as the cancer-initiating spark. A feedforward loop involving transcriptional/post-transcriptional synergy between IGF2BP1 and MYCN then promotes  what they term “an oncogene storm” that fosters expression of 17q oncogenes such as BIRC5. The results of preclinical studies showed how IGF2BP1 inhibition (IGF2BP1i) using a small molecule BTYNB effectively extinguished this spark, and impaired tumor growth.

“If we succeed in developing a suitable molecule, this will not only be relevant for neuroblastomas,” said Stefan Hüttelmaier, PhD, director of the Institute of Molecular Medicine at University Medicine Halle.” Studies show that IGF2BP1 also plays a key role in other tumors.” Hüttelmaier is senior author of the team’s published paper in Molecular CancerIGF2BP1 induces neuroblastoma via a druggable feedforward loop with MYCN promoting 17q oncogene expression,” in which they concluded, “We reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1.”

Neuroblastomas are tumors of the nervous system. They can form in many places in the body and are the most common cause of cancer-related deaths in young children. “High-risk neuroblastoma (HRN) accounts for approximately 15% of all cancer-related death in infants and despite intensive multimodal therapy > 50% of HRN relapse,” the authors noted.

Neuroblastoma is commonly associated with genomic abnormalities including amplification of MYCN—which located on chromosome 2p—and 17q gain, which is “the most frequent (> 50%) chromosomal aberration,” the team continued. “In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1, and MYCN amplification at chromosome 2p are associated with adverse outcome,” they noted, although “genetic synergies of 2p and 17q remain largely unknown.”

The protein IGF2BP1 ensures that cells grow rapidly during embryonic development. Later on, its presence is linked to various tumors. “IGF2BP1 is de novo expressed in several cancers and shows conserved association with poor prognosis, disease progression and metastasis,” the investigators stated. However, it’s not known if IGF2BP1 is an oncogene in human cancers, how it synergizes with MYCN in neuroblastoma, and if targeting IGF2BP1 may have potential as an anticancer strategy.

For their newly reported study the researchers analyzed the genetic characteristics of the neuroblastoma tumors from 100 children, and performed extensive cell culture experiments and tests in mouse models. They found that in synergy with MYCN, IGF2BP1 initiates and promotes HRN by transcriptional/post-transcriptional feedforward regulation. “MYCN is a versatile transcriptional driver of oncogene expression,” they noted, “most prominently in MNA neuroblastoma.” Added Sven Hagemann, PhD, lead author and biochemist at the Institute of Molecular Medicine at University Medicine Halle, “In short, IGF2BP1 causes that another protein is produced in abundance. Both proteins can activate various, currently unresolved, processes at the genetic level that have a strong cancer-causing effect under these abnormal circumstances.”

Lead author Sven Hagemann is handling cell cultures. [University Medicine Halle]

The result is an out-of-control conflagration in the cell, which causes neuroblastomas to form, survive, grow and spread. “MYCN/IGF2BP1 feedforward regulation culminates in an oncogene storm, which likely contributes to severe genome destabilization.” The study has shown for the first time that IGF2BP1 on its own is enough to trigger this tumor; all of the mice in which the protein IGF2BP1 was induced developed a neuroblastoma.

Encouragingly, a small molecule called BTYNB was able to disrupt this oncogene storm, impairing tumor growth in neuroblastoma cell and xenograft models. “Consistent with devastating consequences of MYCN/IGF2BP1 synergy, our studies highlight potential therapeutic prospects of IGF2BP1i … In neuroblastoma cell and xenograft models, IGF2BP1 deletion and inhibition by the small molecule BTYNB impair tumor growth. BTYNB robustly disrupts MYCN/IGF2BP1 synergy …”  Hüttelmaier added, “It would be very promising to specifically inhibit IGF2BP1, since it is not normally produced after infancy—except in cancer cells.”

The team has now successfully tested such a molecule in close cooperation with the Institute of Pharmacy at Martin Luther University Halle-Wittenberg. “Our drug candidate has so far shown no adverse effects in initial preclinical trials and can be used as the basis of further developments. In the future, the targeted treatment of neuroblastomas could prevent patients from experiencing the severe side effects of chemotherapy,” says Hüttelmaier. However, it will take a few more years to clarify unresolved questions before clinical trials can begin. It is unclear, for example, why IGF2BP1 is present in the first place, or how the drug can best be delivered to where it is needed in the body.

Professor Hüttelmaier has been studying the protein IGF2BP1 for more than 20 years: “We began by studying neurons until we suddenly stumbled upon the fact that this protein is particularly prevalent in cancer.” Based on clinical data, Professor Hüttelmaier’s team was able to demonstrate in 2015 that IGF2BP1 plays a role in the development of neuroblastomas. “We have now succeeded in uncovering further pieces of evidence and, for the first time, we have identified a possible therapeutic approach. If we succeed in developing a suitable molecule, this will not only be relevant for neuroblastomas. Studies show that IGF2BP1 also plays a key role in other tumors.”

In their paper the team concluded, “Our studies unravel that impairing IGF2BP1-RNA association by the small molecules BTYNB disrupts this oncogene storm and provides benefits in combined treatment with MYC/N inhibition via BRD inhibitors, most prominently Mivebresib, as well as inhibitors of MYCN/IGF2BP1-driven oncogenes like BIRC5.”

The post Novel Neuroblastoma Driver Could Be Target for Therapeutics appeared first on GEN - Genetic Engineering and Biotechnology News.

Read More

Continue Reading

Uncategorized

February Employment Situation

By Paul Gomme and Peter Rupert The establishment data from the BLS showed a 275,000 increase in payroll employment for February, outpacing the 230,000…

Published

on

By Paul Gomme and Peter Rupert

The establishment data from the BLS showed a 275,000 increase in payroll employment for February, outpacing the 230,000 average over the previous 12 months. The payroll data for January and December were revised down by a total of 167,000. The private sector added 223,000 new jobs, the largest gain since May of last year.

Temporary help services employment continues a steep decline after a sharp post-pandemic rise.

Average hours of work increased from 34.2 to 34.3. The increase, along with the 223,000 private employment increase led to a hefty increase in total hours of 5.6% at an annualized rate, also the largest increase since May of last year.

The establishment report, once again, beat “expectations;” the WSJ survey of economists was 198,000. Other than the downward revisions, mentioned above, another bit of negative news was a smallish increase in wage growth, from $34.52 to $34.57.

The household survey shows that the labor force increased 150,000, a drop in employment of 184,000 and an increase in the number of unemployed persons of 334,000. The labor force participation rate held steady at 62.5, the employment to population ratio decreased from 60.2 to 60.1 and the unemployment rate increased from 3.66 to 3.86. Remember that the unemployment rate is the number of unemployed relative to the labor force (the number employed plus the number unemployed). Consequently, the unemployment rate can go up if the number of unemployed rises holding fixed the labor force, or if the labor force shrinks holding the number unemployed unchanged. An increase in the unemployment rate is not necessarily a bad thing: it may reflect a strong labor market drawing “marginally attached” individuals from outside the labor force. Indeed, there was a 96,000 decline in those workers.

Earlier in the week, the BLS announced JOLTS (Job Openings and Labor Turnover Survey) data for January. There isn’t much to report here as the job openings changed little at 8.9 million, the number of hires and total separations were little changed at 5.7 million and 5.3 million, respectively.

As has been the case for the last couple of years, the number of job openings remains higher than the number of unemployed persons.

Also earlier in the week the BLS announced that productivity increased 3.2% in the 4th quarter with output rising 3.5% and hours of work rising 0.3%.

The bottom line is that the labor market continues its surprisingly (to some) strong performance, once again proving stronger than many had expected. This strength makes it difficult to justify any interest rate cuts soon, particularly given the recent inflation spike.

Read More

Continue Reading

Uncategorized

Mortgage rates fall as labor market normalizes

Jobless claims show an expanding economy. We will only be in a recession once jobless claims exceed 323,000 on a four-week moving average.

Published

on

Everyone was waiting to see if this week’s jobs report would send mortgage rates higher, which is what happened last month. Instead, the 10-year yield had a muted response after the headline number beat estimates, but we have negative job revisions from previous months. The Federal Reserve’s fear of wage growth spiraling out of control hasn’t materialized for over two years now and the unemployment rate ticked up to 3.9%. For now, we can say the labor market isn’t tight anymore, but it’s also not breaking.

The key labor data line in this expansion is the weekly jobless claims report. Jobless claims show an expanding economy that has not lost jobs yet. We will only be in a recession once jobless claims exceed 323,000 on a four-week moving average.

From the Fed: In the week ended March 2, initial claims for unemployment insurance benefits were flat, at 217,000. The four-week moving average declined slightly by 750, to 212,250


Below is an explanation of how we got here with the labor market, which all started during COVID-19.

1. I wrote the COVID-19 recovery model on April 7, 2020, and retired it on Dec. 9, 2020. By that time, the upfront recovery phase was done, and I needed to model out when we would get the jobs lost back.

2. Early in the labor market recovery, when we saw weaker job reports, I doubled and tripled down on my assertion that job openings would get to 10 million in this recovery. Job openings rose as high as to 12 million and are currently over 9 million. Even with the massive miss on a job report in May 2021, I didn’t waver.

Currently, the jobs openings, quit percentage and hires data are below pre-COVID-19 levels, which means the labor market isn’t as tight as it once was, and this is why the employment cost index has been slowing data to move along the quits percentage.  

2-US_Job_Quits_Rate-1-2

3. I wrote that we should get back all the jobs lost to COVID-19 by September of 2022. At the time this would be a speedy labor market recovery, and it happened on schedule, too

Total employment data

4. This is the key one for right now: If COVID-19 hadn’t happened, we would have between 157 million and 159 million jobs today, which would have been in line with the job growth rate in February 2020. Today, we are at 157,808,000. This is important because job growth should be cooling down now. We are more in line with where the labor market should be when averaging 140K-165K monthly. So for now, the fact that we aren’t trending between 140K-165K means we still have a bit more recovery kick left before we get down to those levels. 




From BLS: Total nonfarm payroll employment rose by 275,000 in February, and the unemployment rate increased to 3.9 percent, the U.S. Bureau of Labor Statistics reported today. Job gains occurred in health care, in government, in food services and drinking places, in social assistance, and in transportation and warehousing.

Here are the jobs that were created and lost in the previous month:

IMG_5092

In this jobs report, the unemployment rate for education levels looks like this:

  • Less than a high school diploma: 6.1%
  • High school graduate and no college: 4.2%
  • Some college or associate degree: 3.1%
  • Bachelor’s degree or higher: 2.2%
IMG_5093_320f22

Today’s report has continued the trend of the labor data beating my expectations, only because I am looking for the jobs data to slow down to a level of 140K-165K, which hasn’t happened yet. I wouldn’t categorize the labor market as being tight anymore because of the quits ratio and the hires data in the job openings report. This also shows itself in the employment cost index as well. These are key data lines for the Fed and the reason we are going to see three rate cuts this year.

Read More

Continue Reading

Uncategorized

Inside The Most Ridiculous Jobs Report In History: Record 1.2 Million Immigrant Jobs Added In One Month

Inside The Most Ridiculous Jobs Report In History: Record 1.2 Million Immigrant Jobs Added In One Month

Last month we though that the January…

Published

on

Inside The Most Ridiculous Jobs Report In History: Record 1.2 Million Immigrant Jobs Added In One Month

Last month we though that the January jobs report was the "most ridiculous in recent history" but, boy, were we wrong because this morning the Biden department of goalseeked propaganda (aka BLS) published the February jobs report, and holy crap was that something else. Even Goebbels would blush. 

What happened? Let's take a closer look.

On the surface, it was (almost) another blockbuster jobs report, certainly one which nobody expected, or rather just one bank out of 76 expected. Starting at the top, the BLS reported that in February the US unexpectedly added 275K jobs, with just one research analyst (from Dai-Ichi Research) expecting a higher number.

Some context: after last month's record 4-sigma beat, today's print was "only" 3 sigma higher than estimates. Needless to say, two multiple sigma beats in a row used to only happen in the USSR... and now in the US, apparently.

Before we go any further, a quick note on what last month we said was "the most ridiculous jobs report in recent history": it appears the BLS read our comments and decided to stop beclowing itself. It did that by slashing last month's ridiculous print by over a third, and revising what was originally reported as a massive 353K beat to just 229K,  a 124K revision, which was the biggest one-month negative revision in two years!

Of course, that does not mean that this month's jobs print won't be revised lower: it will be, and not just that month but every other month until the November election because that's the only tool left in the Biden admin's box: pretend the economic and jobs are strong, then revise them sharply lower the next month, something we pointed out first last summer and which has not failed to disappoint once.

To be fair, not every aspect of the jobs report was stellar (after all, the BLS had to give it some vague credibility). Take the unemployment rate, after flatlining between 3.4% and 3.8% for two years - and thus denying expectations from Sahm's Rule that a recession may have already started - in February the unemployment rate unexpectedly jumped to 3.9%, the highest since February 2022 (with Black unemployment spiking by 0.3% to 5.6%, an indicator which the Biden admin will quickly slam as widespread economic racism or something).

And then there were average hourly earnings, which after surging 0.6% MoM in January (since revised to 0.5%) and spooking markets that wage growth is so hot, the Fed will have no choice but to delay cuts, in February the number tumbled to just 0.1%, the lowest in two years...

... for one simple reason: last month's average wage surge had nothing to do with actual wages, and everything to do with the BLS estimate of hours worked (which is the denominator in the average wage calculation) which last month tumbled to just 34.1 (we were led to believe) the lowest since the covid pandemic...

... but has since been revised higher while the February print rose even more, to 34.3, hence why the latest average wage data was once again a product not of wages going up, but of how long Americans worked in any weekly period, in this case higher from 34.1 to 34.3, an increase which has a major impact on the average calculation.

While the above data points were examples of some latent weakness in the latest report, perhaps meant to give it a sheen of veracity, it was everything else in the report that was a problem starting with the BLS's latest choice of seasonal adjustments (after last month's wholesale revision), which have gone from merely laughable to full clownshow, as the following comparison between the monthly change in BLS and ADP payrolls shows. The trend is clear: the Biden admin numbers are now clearly rising even as the impartial ADP (which directly logs employment numbers at the company level and is far more accurate), shows an accelerating slowdown.

But it's more than just the Biden admin hanging its "success" on seasonal adjustments: when one digs deeper inside the jobs report, all sorts of ugly things emerge... such as the growing unprecedented divergence between the Establishment (payrolls) survey and much more accurate Household (actual employment) survey. To wit, while in January the BLS claims 275K payrolls were added, the Household survey found that the number of actually employed workers dropped for the third straight month (and 4 in the past 5), this time by 184K (from 161.152K to 160.968K).

This means that while the Payrolls series hits new all time highs every month since December 2020 (when according to the BLS the US had its last month of payrolls losses), the level of Employment has not budged in the past year. Worse, as shown in the chart below, such a gaping divergence has opened between the two series in the past 4 years, that the number of Employed workers would need to soar by 9 million (!) to catch up to what Payrolls claims is the employment situation.

There's more: shifting from a quantitative to a qualitative assessment, reveals just how ugly the composition of "new jobs" has been. Consider this: the BLS reports that in February 2024, the US had 132.9 million full-time jobs and 27.9 million part-time jobs. Well, that's great... until you look back one year and find that in February 2023 the US had 133.2 million full-time jobs, or more than it does one year later! And yes, all the job growth since then has been in part-time jobs, which have increased by 921K since February 2023 (from 27.020 million to 27.941 million).

Here is a summary of the labor composition in the past year: all the new jobs have been part-time jobs!

But wait there's even more, because now that the primary season is over and we enter the heart of election season and political talking points will be thrown around left and right, especially in the context of the immigration crisis created intentionally by the Biden administration which is hoping to import millions of new Democratic voters (maybe the US can hold the presidential election in Honduras or Guatemala, after all it is their citizens that will be illegally casting the key votes in November), what we find is that in February, the number of native-born workers tumbled again, sliding by a massive 560K to just 129.807 million. Add to this the December data, and we get a near-record 2.4 million plunge in native-born workers in just the past 3 months (only the covid crash was worse)!

The offset? A record 1.2 million foreign-born (read immigrants, both legal and illegal but mostly illegal) workers added in February!

Said otherwise, not only has all job creation in the past 6 years has been exclusively for foreign-born workers...

Source: St Louis Fed FRED Native Born and Foreign Born

... but there has been zero job-creation for native born workers since June 2018!

This is a huge issue - especially at a time of an illegal alien flood at the southwest border...

... and is about to become a huge political scandal, because once the inevitable recession finally hits, there will be millions of furious unemployed Americans demanding a more accurate explanation for what happened - i.e., the illegal immigration floodgates that were opened by the Biden admin.

Which is also why Biden's handlers will do everything in their power to insure there is no official recession before November... and why after the election is over, all economic hell will finally break loose. Until then, however, expect the jobs numbers to get even more ridiculous.

Tyler Durden Fri, 03/08/2024 - 13:30

Read More

Continue Reading

Trending