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By Pooja Toshniwal Paharia Jun 11 2024 Reviewed by Lily Ramsey, LLM

In a recent study published in Cancer Discovery, researchers developed and validated a blood-based, cell-free deoxyribonucleic acid (cfDNA) fragmentome assay for lung cancer detection, which, if the results were positive, would be followed by low-dose computed tomography (LDCT).

Study:  Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection . Image Credit: MMD Creative/Shutterstock.com Introduction

Lung cancer is a major death cause, and yearly screening is crucial. However, chest LDCT has low adoption due to patient barriers like inadequate awareness, radiation concerns, and limited availability.

Other challenges include poor smoking history recording, a lack of defined practices, and specialist follow-up.

A blood-based lung malignancy screening test, like the fragmentome technique, could increase screening rates by analyzing specific chromatin configurations in peripheral blood. About the study

In the present DELFI-L101 study, researchers developed a hematological test using machine learning to analyze DNA fragmentomes and identify individuals at risk of lung cancer. Individuals testing positive would undergo LDCT.

Beginning March 2021, the researchers enrolled 958 individuals aged 50–80 with ≥20 pack-years of smoking across 47 United States (US) facilities. Eligibility features resembled the LDCT screening criteria of the 2015 National Health Interview Survey (NHIS).

They excluded individuals with cancer therapy within one year, a history of hematologic malignancy or myelodysplasia, organ tissue transplantation, blood product transfusion within 120 days of enrollment, pregnancy, and participation in other trials.

The team divided the study participants into three groups: A (lung cancer), B (non-cancer controls), and C (cancer other than lung cancer). Related StoriesResearch reveals new pathways for treating never-smoker lung cancerCanada's plan to eliminate cervical cancer by 2040: HPV-based screening and vaccination keyLung cancer screening yields early diagnoses and increased cure rates in veterans

The American Joint Committee on Cancer's Cancer Staging Manual (AJCC) criteria ascertained the disease stage. Changes in cfDNA fragmentation patterns (fragmentomes) in blood revealed genomic and chromatin features of lung cancer.

The researchers trained the classifier on 576 cases and controls before validating it on another 382 cases and controls.

They used whole genome sequences from the training dataset to assess fragmentations in 504 non-overlapping-type 5.0 MB sections with strong mappability. Each region included 80,000 pieces and covered a genome size of 2.50 GB.

The team examined genome-wide alterations to Hi-C open-type (A compartment) and closed-type (B compartment) chromatin.

They created the classifier using principal component analysis (PCA) and logistic regressions, incorporating chromosomal arm-level changes, cfDNA fractions derived from the mitochondrial genome, and cfDNA fragment length distributions.

The researchers performed Monte Carlo simulations on 15 million individuals under three scenarios: Base Scenario: Current practices without hematological screening. Low Scenario: 10% uptake of hematological screening for individuals eligible for pulmonary cancer screening but not subjected to low-dose CT in the first year, increasing to 25% in five years. High Scenario: 20% uptake of hematological screening for the same group in the first year, increasing to 50% in five years. Results

The researchers observed 58% test specificity, 84% sensitivity, and 99.8% negative predictive value (NPV). Applying the rest to the screening-eligible group with 0.7% lung cancer prevalence, the number needed to screen (NNS) was 143.

Study validations showed negative and positive results related to NNS with LDCT imaging to detect 414 and 76 cases, respectively, yielding a 5.5 relative risk value. The positive predictive value (PPV) was almost double that of the LDCT qualifying requirements alone.

The cfDNA fragmentomes of lung squamous cell carcinoma (LUSC) patients comprised a component resembling cfDNA profiles from non-cancer individuals and another resembling A/B-type compartments noted in LUSC tissues.

Non-cancer individuals showed cfDNA patterns approximating lymphoblastoid Hi-C findings. Within common locations, fragmentations among samples provided by individuals with cancer presence and absence were similar.

Lung cancer patients had increased cell-free DNA representations fpr 1q, 3q, 5p, 8q, and 12p, as well as lower 1p, 3p, 4q, 5q, 10q, and 17p levels. Their cfDNA fragmentations differed from controls, revealing more closely packed chromatin in cfDNA of closed LUSC spaces, while lymphoblastoid reference regions showed the reverse impact.

At the cut-off of 0.2, ten-fold cross-validation with ten repeats within the training population yielded 50% overall specificity and sensitivities of 75%, 90%, 96%, and 97% for stages I, II, III, and IV, respectively. Sensitivity was constant across ages, with younger people having higher specificity. Using the 2015 NHIS data yielded 80% sensitivity and 58% specificity.

From the ‘base’ scenario (24,489 cases), lung cancer cases identified by screening increased to 63,523 (the ‘low’ scenario) and 100,346 (the ‘high’ scenario). In contrast, stage I cases increased by 4.80% and 9.70%, while stage IV diagnoses decreased by 4.20% and 8.70%, respectively.

In total, 4,720 deaths from lung malignancies could be averted in the ‘base’ scenario, 7,652 in the ‘low’ scenario, and 14,264 deaths in the ‘high’ scenario. LDCT use in screening could reduce the number of tests required to identify lung cancers from 202 (‘base’ scenario) to 150 (‘low’ scenario) and 139 (‘high’ scenario). Conclusion

Based on the study findings, the DNA fragmentome assay provides a novel, accurate, affordable, blood-based tool for initial lung cancer evaluation with LDCT follow-ups.

The assay could contribute to preventing lung cancer-related deaths, with moderate adoption rates possibly lowering late-stage diagnoses and fatalities. Journal reference:

Peter Mazzone et al., (2024) Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection, Cancer Discov (2024), doi: https://doi.org/10.1158/2159-8290.CD-24-0519.https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-24-0519/745696/Clinical-validation-of-a-cell-free-DNA-fragmentome?searchresult=1

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Sports

Shocks at No. 1 — and No. 2?! Winners, losers and takeaways from MLB draft Day 1

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Shocks at No. 1 -- and No. 2?! Winners, losers and takeaways from MLB draft Day 1

The first day of the 2025 MLB draft is complete! The Washington Nationals selected Eli Willits with the No. 1 pick, opting for the prep shortstop — who might be more likely to sign below slot — in a draft with no clear-cut top prospect. And there were plenty of other intriguing selections as the first three rounds unfolded Sunday night.

The Seattle Mariners had to have been thrilled to have Kiley McDaniel’s No. 1-ranked prospect, Kade Anderson, fall to them at No. 3, and Ethan Holliday was selected at No. 4 by his famous father’s former squad the Colorado Rockies.

We asked ESPN baseball insiders Alden Gonzalez, Jesse Rogers and David Schoenfield to break down their favorite and most head-scratching moves of the draft’s first night, as well as to predict which players will bring the most to their new teams in the long term.


A lot of us were thrown for a loop by the first two selections. What do you make of the Nationals taking Ethan Willits at No. 1 and the Angels picking Tyler Bremner at No. 2?

Gonzalez: I was stunned on both accounts. Though there was definitely some uncertainty around the Nationals’ approach, especially since the firing of GM Mike Rizzo, I didn’t see anybody, anywhere, projecting Willits to be their choice at No. 1 overall. But the Angels drafting Bremner was an even bigger risk. Kiley had him 18th in his latest ranking. Six pitchers were ranked ahead of him. But Bremner might be someone who can rise and impact their major league roster quickly, and the Angels are always looking for that.

Rogers: The first two picks really summed up the uncertainty of the entire draft. The Nationals’ faith in a 17-year-old will be tested over the coming years, but the pick will likely save them some money for later in this draft and give Willits time to grow. The same can be said of many of the top picks: They’re going to need time. There are far fewer sure things this year — though Bremner could be the exception. The Angles love to graduate their players quickly, and as a college arm, he could see the majors sooner rather than later. Like Willits, this could also be a cost-saving move for later spending.

Schoenfield: In a draft that not only lacked a sure-thing No. 1 overall pick but was viewed as weaker at the top than those of recent years, it’s perhaps not a huge surprise that the Nationals and Angels used their picks to strike likely underslot deals with Willits and Bremner, giving them money to spend later in the draft — which they can use on high school prospects who might have slipped, trying to buy them out from going to college. It’s a strategy teams have used with success over the years, so the drafts for the Nationals and Angels will have to be viewed in their totality and not just focused on these two players.


What was your favorite pick of the night — and which one had you scratching your head?

Gonzalez: The Rockies have done a lot of things wrong over these last few … uh, decades. But it was really cool to see them take Ethan Holliday at No. 4 after his father, Matt, starred in Colorado for so long. Outside of the top two picks, Ethan Conrad going 17th to the Cubs was my biggest surprise of the night. Kiley had him ranked 30th; others had him falling out of the first round entirely. There’s uncertainty coming off shoulder surgery. But Conrad, 21, put up a 1.238 OPS in 97 plate appearances before his season ended prematurely in March. And the dearth of college bats probably influenced a slight reach here.

Rogers: I’m loving Billy Carlson to the White Sox at No. 10. Though they lost 121 games last season, Chicago couldn’t pick higher than this spot per CBA rules — but the Sox might have gotten a top-five player. Carlson’s defense will play extremely well behind a sneaky good and young pitching staff that should keep the ball on the ground in the long term. Meanwhile, with the pick of the litter when it came to hitters — college outfielders and high school kids as well — the Pirates took a high school pitcher at No. 6. Seth Hernandez could be great, but they need hitting. A lot of it.

Schoenfield: The Mariners reportedly wanted LSU left-hander Kade Anderson all along, but they certainly couldn’t have been expecting to get him with the third pick. (Keep in mind that the Mariners were lucky in the first place to land the third pick in the lottery, so they added some good fortune on top of good luck.) They get the most polished college pitcher in the draft, one who should move quickly — and perhaps make it a little easier for Jerry Dipoto to dip into his farm system and upgrade the big league roster at the trade deadline. Even though I understand why the Angels did it, Bremner still seems a little questionable. With the second pick, you want to go for a home run, and the consensus is that Holliday or even Anderson is more likely to be a more impactful major leaguer. Bremner’s lack of a third plus pitch is an issue, and you have to wonder if the Angels are relying too much on his control — which, yes, should allow him to get to the majors — and ignoring the possible lack of upside.


Who is the one player you’d like to plant your flag on as the biggest steal of this draft?

Gonzalez: Seth Hernandez, who went sixth to the Pirates and should someday share a rotation with Paul Skenes and Jared Jones. High school pitchers are incredibly risky, especially when taken so early in the draft. But Hernandez is a great athlete who already throws hard, boasts a plus changeup and showed improvement with his breaking ball this spring. He’ll go the Hunter Greene route, from standout high school pitcher to major league ace.

Rogers: Jamie Arnold will look like a steal at No. 11, especially when he debuts in the majors well before many of the players taken around him. I’m not worried about the innings drop in 2025 — not when he was striking out 119 hitters and walking just 27. The A’s need to polish him up but will be pleased by how consistent he’ll be. You can’t go wrong with a college lefty from an ACC school — at least, the A’s didn’t.

Schoenfield: I’m going with Billy Carlson with the 10th pick — with the admitted caveat that the White Sox haven’t exactly been stellar at developing hitters. But Carlson looks like an elite defensive shortstop with plus power, and that alone can make him a valuable major leaguer. If the hit tool comes along, we’re looking at a potential star. OK, he’s Bobby Witt Jr. lite? That’s still an All-Star player.


What’s your biggest takeaway from Day 1 of this draft?

Gonzalez: The Nationals throwing a wrench into the proceedings by selecting Willits. It was a surprising choice, but in their minds an easy one. Interim general manager Mike DeBartolo called Willits the best hitter and best fielder available. And in a draft devoid of can’t-miss, high-impact talent, Willits is no doubt a solid pick — a polished hitter who should stick at shortstop and might consistently hit 20 homers and steal 20 bases at a premium position. He also might come under slot, allowing flexibility later in the draft. But his selection is what allowed Anderson to reach the Mariners at No. 3 and prompted the Rockies to draft Holliday at No. 4, among other dominoes. It set a really interesting tone.

Rogers: Things change quickly in baseball. Whereas college hitters are usually the safest bets early in the draft, this year high school position players dominated. (And they all play shortstop, at least for now.) Athleticism has returned to baseball, and draft rooms are acting accordingly.

Schoenfield: I’m agreeing with Jesse. The selection of that many prep shortstops stood out — and they all seem to hit left-handed and run well, and some of them have big power potential and a cannon for an arm. Look, the hit tool is the most important and the hardest to scout and project, so not all these kids are going to make it, but their potential is exciting and, to Jesse’s point, their wide range of tools is showing that baseball is still drawing top athletes to the sport.

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Business

Economists say the cost of living crisis is over – here’s why many households disagree

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Economists say the cost of living crisis is over - here's why many households disagree

Talk to economists and they will tell you that the cost of living crisis is over.

They will point towards charts showing that while inflation is still above the Bank of England’s 2% target, it has come down considerably in recent years, and is now “only” hovering between 3% and 4%.

So why does the cost of living still feel like such a pressing issue for so many households? The short answer is because, depending on how you define it, it never ended.

Economists like to focus on the change in prices over the past year, and certainly on that measure inflation is down sharply, from double-digit levels in recent years.

But if you look over the past four years then the rate of change is at its highest since the early 1990s.

But even that understates the complexity of economic circumstances facing households around the country.

For if you want a sense of how current financial conditions really feel in people’s pockets, you really ought to offset inflation against wages, and then also take account of the impact of taxes.

More on Cost Of Living

That is a complex exercise – in part because no two households’ experience is alike.

But recent research from the Resolution Foundation illustrates some of the dynamics going on beneath the surface, and underlines that for many households the cost of living crisis is still very real indeed.

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UK inflation slows to 3.4%

The place to begin here is to recall that perhaps the best measure of economic “feelgood factor” is to subtract inflation and taxes from people’s nominal pay.

You end up with a statistic showing your real household disposable income.

Consider the projected pattern over the coming years. For a household earning £50,000, earnings are expected to increase by 10% between 2024/25 and 2027/28.

Subtract inflation projected over that period and all of a sudden that 10% drops to 2.5%.

Now subtract the real increase in payments of National Insurance and taxes and it’s down to 0.2%.

Now subtract projected council tax increases and all of a sudden what began as a 10% increase is actually a 0.1% decrease.

Read more:
UK economy figures ‘not as bad as they look’, analysts say
More options than ever for savers to beat inflation

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Will we see tax rises in next budget?

Of course, the degree of change in your circumstances can differ depending on all sorts of factors. Some earners (especially those close to tax thresholds, which in this case includes those on £50,000) feel the impact of tax changes more than others.

Pensioners and those who own their homes outright benefit from a comparatively lower increase in housing costs in the coming years than those paying mortgages and (especially) rent.

Nor is everyone’s experience of inflation the same. In general, lower-income households pay considerably more of their earnings on essentials, like housing costs, food and energy. Some of those costs are going up rapidly – indeed, the UK faces higher power costs than any other developed economy.

But the ultimate verdict provides some clear patterns. Pensioners can expect further increases in their take-home pay in the coming years. Those who own their homes outright and with mortgages can likely expect earnings to outpace extra costs. But others are less fortunate. Those who rent their homes privately are projected to see sharp falls in their household income – and children are likely to see further falls in their economic welfare too.

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Environment

E-quipment highlight: Perkins TracStar battery electric power unit

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E-quipment highlight: Perkins TracStar battery electric power unit

The off-highway equipment experts at Perkins and McElroy have teamed up to develop a plug-and-play battery electric power unit designed to help equipment OEMs and upfitters to seamlessly transition from diesel to battery electric power.

Designed to occupy the same space as the companies’ diesel-engined power units, Perkins dropped its new battery power unit into the similarly new McElroy TracStar 900i pipe fusion machine (specialized equipment used to join thermoplastic pipes like HDPE or polypropylene by heat-welding them end-to-end to form a continuous length pf pipe).

Perkins’ battery electric power unit replaces the company’s proprietary 134 hp, 3.6 liter 904 Series Tier V diesel engine, enabling units that are already deployed to be quickly upgraded to electric power – and helping trade allies and development partners to easily retrofit existing equipment in order to add zero-emission options to their operational fleet.

“We’re actively helping customers navigate the shift in power system requirements, with a range of advanced power systems including electric, diesel-electric and alternative fuel compatible engines,” says Jaz Gill, vice president, global sales, marketing at Perkins. “When it comes to the innovative fully integrated battery electric power unit, it can be ‘dropped in’ to a machine to replace a diesel engine. The system consists of a Perkins battery along with inverters, motors and on-board chargers – all packaged up into a compact drop-in system to support seamless transition from diesel to electric for our customers looking to make that move.”

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McElroy believes that an electric, emissions-free power unit like this one will open new opportunities and applications for its customers.

“Their team has done a phenomenal job of integrating their battery electric system into our TracStar 900i,” explains McElroy President and CEO Chip McElroy. “We’re really excited to see what the market thinks about this concept.”

Development of the battery electric powered pipe fusion machine was completed in about nine months. Future Perkins-powered electric equipment running the 904 diesel (small excavators, telehandlers, pumps, and gensets) could be developed even more quickly. You can find out more in the company’s promo video, below.

Perkins electric power unit


SOURCE | IMAGES: McElroy, Perkins.

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