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AstraZeneca has abandoned a phase 3 trial of its experimental immuno-oncology candidate monalizumab in head and neck cancer, after an interim analysis suggested it was unlikely to show a benefit.
The INTERLINK-1 trial was testing monalizumab – an NKG2A receptor inhibitor – in combination with EGFR-targeting antibody cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) previously treated with PD-1/PD-L1-targeted immunotherapies.
AZ licensed rights to monalizumab (formerly IPH2201) from France’s Innate Pharma in 2018, after taking an option on the drug four years earlier in a deal that included an upfront payment of $250 million plus milestone payments, including $100 million due on the start of phase 3 testing.
Shares in Innate Pharma started to slide after this morning’s announcement and were down almost 17% at the time of writing.
NKG2A is a checkpoint receptor thought to inhibit the anticancer activity of natural killer (NK) and cytotoxic CD8+ T-cells.
The results of INTERLINK-1 run counter to encouraging findings in a single-arm phase 1b/2 trial of monalizumab/cetuximab in SCHHN patients, which showed an overall response rate of 27.5% with the combination, as well as progression-free survival of five months and overall survival of more than ten months when after PD-1/PD-L1 therapy.
AZ is still testing the drug in the phase 3 PACIFIC-9 trial, looking at its PD-L1 checkpoint inhibitor Imfinzi (durvalumab) plus either monalizumab or anti-CD73 monoclonal antibody oleclumab in patients with non-small cell lung cancer (NSCLC) who have not progressed after first-line chemoradiotherapy.
It is also being tested alongside Imfinzi in phase 2 across multiple solid tumour types, including in the NeoCOAST-2 study as neoadjuvant (pre-surgery) treatment for early-stage lung cancer.
“While we are disappointed with the outcome of this study, the findings are certain to advance our understanding of the role of immunotherapy in this setting,” said Mondher Mahjoubi, Innate Pharma’s chief executive.
“We remain confident in the development program for monalizumab in lung cancer, where encouraging data has been previously reported from the randomized, Phase 2 COAST and Neo-COAST studies,” he added.
Over the weekend, we got an inside look at what it takes to become a police officer.
JET 24/FOX 66/YourErie.com‘s own Chelsea Swift took the Regional Physical Agility Test among 70 other potential officers.
Here is more on her experience.
As local law enforcement agencies work to recruit more officers, we had the opportunity to speak with those interested in the job while learning more about the application process.
As police departments across the state and nation are looking to recruit more officers, we took a look at the application process for people in the region.
Alongside 70 applicants, Swift took the Northwest Pennsylvania Regional Police Consortium Test.
“The first year we did the consortium was 2017 and we had almost 140 applicants every year. It’s consistently dropped 10, 15%,” said Joseph Makowski, NWPAR Training Coordinator.
Makowski explained that the consortium test allows applicants to be eligible for nearly 30 local police departments.
He said that nearly 70% passed the Physical Agility Test this year.
“If you prepare for this test a month or two in advance, you’re gonna pass this test. It’s not incredibly hard. They do validation studies to say what these test batteries can prove for your physical ability to do this job,” said Makowski.
The physical test starts with a 15 and a half inch vertical jump. While Swift passed this part of the test, some people said that the difficulty is overlooked and people miss the mark.
Participants must then complete 30 sit ups followed by a 300 meter run in under 60 seconds.
Swift said that she may have overestimated her upper body strength while failing to complete the necessary 25 push ups.
Last is the mile and a half run in which participants must complete in under 15 minutes and 54 seconds.
The City of Erie Police chief said that despite a lower turnout, he is encouraged by the makeup of the group.
“This is definitely a year with less people trying out, but we’re also seeing much more diversity in the class, so it’s a supply and take. But it looks like there’d be some great officers,” said Chief Dan Spizarny, City of Erie Police.
Xavier Woods said that he’s wanted to be a cop his whole life and encourages others to take the test.
Woods said that he recognizes the city’s effort to recruit minorities.
“I think they are doing a good job of reaching out to people just to have the confidence to say ‘hey, I want to supply this job a try, you know go for it.’ I’m just taking an opportunity today to see if I can fulfill my dream,” said Xavier Woods, Taking Police Test.
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Resean Thrower said more recently he believes he became interested in becoming an officer. He said that he sees the benefit of a more diverse complement including having more women in the department.
“What career can I have to help shape my community? Where I came from, if I think a lot of young African American see a Prep hooper, go to an officer, I think that would help us out tremendously in Erie. Having different backgrounds will help shutdown some altercations that way people can feel more comfortable,” said Resean Thrower, Taking Police Test.
After the physical test, officers took the written component. Those who passed both tests will be put on a list for potentially 28 local departments.
NEW YORK – When it comes to measuring DNA mismatch repair deficiency or microsatellite instability to guide immunotherapy decisions for patients, the College of American Pathologists (CAP) now recommends healthcare providers carefully choose which assay to perform and, in certain cancers, prioritize immunohistochemistry and PCR approaches over next-generation sequencing.
The guidelines, published last week in the Archives of Pathology and Laboratory Medicine, are meant to help oncologists and pathologists accurately determine their patients' eligibility for immune checkpoint inhibitors, including Merck's Keytruda (pembrolizumab), which in 2017 garnered tissue-agnostic US Food and Drug Administration approval for advanced, refractory solid tumors that are MSI-high or mismatch repair deficient (dMMR).
While the agency often approves biomarker-defined treatments simultaneously with a companion diagnostic that can identify the intended use population, in granting tumor-agnostic approval to Keytruda, the agency left it up to oncologists to decide how they wanted to identify patients with MSI-high or dMMR tumors. This has caused substantial confusion and inconsistency across the field over the last five years, according to Russell Broaddus, chair of pathology and laboratory medicine at the University of North Carolina at Chapel Hill.
"It's been all over the place," Broaddus said of the diagnostic landscape for determining MSI and dMMR for immune checkpoint inhibitor eligibility. "People were equating all of the different assays, almost saying, 'Oh, it doesn't matter what assay you use; it's all microsatellite instability, and any assay will detect it.'"
According to Broaddus, lead author of the new CAP guidelines, the idea that assays are interchangeable is "pretty close to being true" in colorectal cancer and certain adenocarcinomas of the gastrointestinal tract. "But when you look at cancer types outside of the GI tract, that statement starts falling apart pretty quickly," he said. In particular, he hammered home CAP's position that, beyond colorectal cancer, the evidence just isn't there yet to support using broad-based NGS tests to detect dMMR.
"It may be dissatisfying to many people, but one of the big messages to come out of this guideline is that these assays are not all interchangeable," Broaddus said.
IHC vs. PCR vs. NGS: Which to use?
The new CAP guidelines are the culmination of a yearslong review process in which a multidisciplinary panel of pathologists, clinicians, oncologists, genetic counselors, guidelines methodologists, and patient advocates met eight times and defined the scope of the guideline, drafted the recommendations, responded to feedback and comments, and evaluated the evidence from a systematic review of the published literature.
A total of 103 articles were included in the data extraction and qualitative analysis, and hundreds of other studies were considered as background references for the panelists' discussions. The Association of Molecular Pathologists (AMP), the American Society of Clinical Oncology (ASCO), and the patient advocacy group Fight Colorectal Cancer collaborated with CAP on the guidelines.
In evaluating the available assays, the panel considered IHC for the mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 as well as PCR-based MSI testing and MSI testing by NGS for the detection of DNA mismatch repair defects.
Ultimately, the group came up with six evidence-based guideline statements surrounding assay choice and three good practice statements to help the field evaluate patients' dMMR and MSI status. The good practice statements are key suggestions based on studies and data outside the scope of the formal systematic evidence review.
The first guideline strongly recommends that, for patients with colorectal cancer, pathologists should use IHC to determine MMR and/or PCR to determine MSI. Though these methods are preferred, an NGS assay that has been validated for dMMR could also be used to determine MSI status for checkpoint inhibitor eligibility in this cancer type. In this case, the expert panelists wrote that the NGS assay "must be validated against MMR-IHC or MSI by PCR and must show equivalency."
The second guideline focuses on patients with gastroesophageal or small bowel cancer. In this case, the experts said MMR-IHC or MSI by PCR should be used over MSI by NGS. Of note, esophageal squamous cell carcinoma was not included in this recommendation.
In the third guideline, the experts focused on endometrial cancer patients, strongly recommending the use of MMR-IHC as opposed to MSI by PCR or NGS.
The fourth guideline deals with cancer types other than colorectal, gastroesophageal, small bowel, and endometrial cancers. For these other cancer types, the guideline acknowledges that the optimal approach has not been established and that, in the process of considering the best test to use, oncologists and pathologists should note that "assays must be adequately validated for the specific cancer type being tested with careful consideration of performance characteristics of MMR-IHC and MSI by NGS or PCR for the detection of DNA mismatch repair defects."
This recommendation, Broaddus acknowledged, is more of a spotlight on a large knowledge gap than it is a specific recommendation. Broad NGS panels might be appealing for oncologists trying to assess as much molecular information from a tumor as possible at one time, but that convenience shouldn't outweigh the fact that, for a lot of cancer types, there isn't enough evidence to show that NGS accurately determines dMMR or MSI status.
"You need to recognize that if you do NGS, you may not capture high levels of MSI for other cancer types, especially outside the GI tract," he said. "But if you're capturing other cancer types, you may miss patients who would otherwise be eligible for immunotherapy."
The fifth guideline says that tumor mutational burden should not be considered a surrogate for detecting dMMR status. The FDA in 2020 also approved a tissue-agnostic indication for Keytruda in advanced, refractory solid tumor patients with TMB of at least 10 mutations per megabase. "If a tumor is identified as TMB-high, pathologists may perform IHC and/or MSI by PCR to determine if high TMB is secondary to mismatch repair deficiency," the panelists wrote.
"What people will do is say, 'Oh, TMB is the same as high levels of microsatellite instability,'" Broaddus said. "And for colorectal cancer, there's a lot of overlap. But for other cancer types, the overlap is slim."
Although patients with high TMB may now be eligible for Keytruda regardless of their dMMR or MSI status, the point that Broaddus and colleagues emphasized is that high TMB, while it may be a sign of dMMR or MSI-high status in some cases, is not the same biomarker as the other two.
Finally, in the sixth guideline, the experts noted that, if testing a patient for immune checkpoint inhibitor eligibility reveals a mismatch repair deficiency consistent with Lynch syndrome, it is strongly recommended that pathologists communicate this finding to the patient's treating physician since this is an inherited syndrome that increases the risk of other cancers.
Dealing with uncertainty
The three good practice statements in the published guideline document center on what oncologists and pathologists should do in the event of interpretation or discordance issues. This is an important point particularly with regard to IHC — the test that the experts recommended first in a number of the guidelines — since the method can, in some cases, produce varied results according to pathologists' individual interpretations.
"The good thing about IHC is that it's more universal and more clinical labs run it," Broaddus said. "But the bad thing is that there can be some subjectivity to it, and it does require some training to interpret." In the long term, Broaddus said that pathology training programs should include more formal training in how to interpret IHC assays.
In the meantime, the good practice statements included in the new CAP guidelines provide some guidance in terms of handling discrepancies. The first says that, in the event of discordant results, pathologists should interpret any evidence of either dMMR by IHC or MSI by NGS or PCR as a positive result, thus making patients eligible for the immunotherapy. "Discordant results should be reviewed to ensure that the discordance is not due to an interpretive error," the statement reads.
The second good practice statement says that, should any of the methods considered produce an indeterminate result, pathologists should perform an alternative technique or repeat that same technique on a different tumor block. "Laboratories should have a robust peer review process for indeterminate cases," it says.
Finally, the third good practice statement recommends that, in the event of a clonal loss by MMR-IHC, "pathologists should perform MSI by PCR specifically in a dissected area of tumor that has IHC loss of MMR protein."
'A living document'
While the CAP guidelines as they exist today are admittedly vague for those cancer types outside of the colorectal and GI tract tumors specifically addressed, Broaddus emphasized that the committee hopes to change that with future updates. In fact, built into the guidelines is a plan to review and revise the guideline every four years, or earlier if new high-quality evidence emerges.
"It’s kind of meant to be like the Constitution … a living, breathing document," Broaddus said. "And there are areas that I'm hoping we can update five years from now with more literature."
In the meantime, for the cancers beyond those addressed — for which the current guideline says there isn't enough evidence to recommend a specific type of assay for dMMR or MSI status at the moment — Broaddus said, "it's not entirely unreasonable to test a patient sequentially [with the different options] if you have the patience to do that."
And what will it take to address the dearth of evidence supporting a clear assay choice for these other cancer types? Better tumor-specific analyses in basket trials, Broaddus said. In particular, studies used to support NGS tests as a method of MSI or dMMR assessment often don't report results by individual cancer type, nor do they report how patients respond to immunotherapy according to the test method that was used to determine their eligibility.
"What assay did you run and what was the end result for the patient? That, to me, is the real data that's missing," he said. "A theme of this guideline is, more than anything, the call to action to start working to provide this evidence."
Broaddus was also careful to point out that liquid biopsy approaches were not among the assays considered in this CAP guideline. "To me, the liquid biopsy approaches are still on the experimental side, especially for this application," he said, noting that the approach does have clear value for other precision oncology applications, such as looking for a specific mutation in shed DNA for a patient with a tumor that's hard to reach with a biopsy. But for determining patients' immunotherapy eligibility with dMMR or MSI status, blood-based approaches are still experimental in CAP's view.
Another question that fell outside of the scope of the new CAP guidelines was whether specific assays — not just specific types of assays — were preferred over others.
"We did not get that much into the weeds," he said, adding that many clinical laboratories use very effective lab-developed tests to assess dMMR and MSI status, leaving it unclear whether FDA-approved commercial assays have a leg up for this particular use case.
Broaddus and colleagues hope that the publication will help shape the way the field approaches evidence generation to fill the gaps in knowledge that the CAP guidelines body has identified. "What I would like to see is some really organized efforts to help fill these gaps," Broaddus said. "Because these [checkpoint inhibitors] are not just incremental survival improvements. These are long-term survivals and potential cures [and] when the treatment is that good, it's really incumbent on us to find the best biomarker for it."
SINGAPORE: Over five months, a manager for Parkway Shenton misappropriated more than S$634,000 from payments collected from travellers at Woodlands Checkpoint for COVID-19 tests.
Jacob Quek Kuan Liat, 41, was sentenced to three-and-a-half years' jail on Friday (Jul 29) after pleading guilty to an amalgamated charge of criminal breach of trust by an employee.
The offences took place more than half a year after Quek started working as a checkpoint manager for the healthcare provider in June 2020.
One of his responsibilities was to collect the payments from travellers arriving from Malaysia for COVID-19 polymerase chain reaction tests.
Each PCR test cost S$160. The cash proceeds from the night shift and day shift would be collated and handed over for banking into Parkway Shenton's account.
Between Jan 28, 2021 and Jun 16, 2021, Quek misappropriated the proceeds to sustain his gambling addiction, using it to place football bets.
He would then return money to Parkway Shenton if he won. He made more than S$180,000 in voluntary restitution this way.
The offences were discovered when Quek turned himself in at a neighbourhood police centre on Jun 22, 2021.
The prosecutor asked for 42 to 45 months' jail, highlighting the substantial amount of money that Quek misappropriated.
The judge said it was aggravating that Quek stole the money to feed his gambling addiction.
But he also noted that Quek had surrendered himself to the police, paid back about 30 per cent of the stolen money, and signed an agreement to repay the rest after his release.
The punishment for criminal breach of trust as an employee is up to 15 years' jail and a fine.
Security researchers from Check Point have spotted 10 malicious packages on Python Package Index (PyPI), the primary Python package index used by Python developers.
The first of them was Ascii2text, a malicious package that mimicked the popular art package by name and description.
“Interestingly, [threat actors] were smart enough to copy the entire project description without the release part, preventing users from realizing this is a fake package,” Check Point wrote.
Ascii2text would work by downloading a script that gathered passwords stored in web browsers like Google Chrome, Microsoft Edge, Brave, Opera and Yandex Browser.
In its advisory, Check Point also mentioned Pyg-utils, Pymocks and PyProto2, three separate packages with the common goal of stealing users' AWS credentials.
The Test-async and Zlibsrc libraries also appear in the report. According to Check Point, both of them would obtain and execute potentially malicious code during installation.
An additional trio of malicious packages is mentioned by Check Point: Free-net-vpn, Free-net-vpn2 and WINRPCexploit – all of which are capable of stealing user credentials and environment variables.
Finally, the advisory mentions Browserdiv, a malicious package whose aim was to steal installers' credentials by collecting and sending them to a predefined Discord webhook.
“Interestingly, while according to its naming it seems to target web design-related programming (browser, div), according to its description the package motivation is to enable the use of selfbots inside Discord,” Check Point wrote.
Once the security researchers identified these malicious users and packages, they reportedly alerted PyPI via their official website.
“Following our disclosure, PyPI removed these packages,” the advisory concluded.
Unfortunately, this is not the first time that malicious open-source packages are spotted on the PyPI repository. In November 2021, the JFrog Security research team revealed it had discovered 11 new malware packages with over 40,000 downloads from PyPI.
To reduce the presence of malicious packages on PyPI, the repository’s team started enforcing a two-factor authentication (2FA) policy for projects categorized as “critical” in July.
Imugene Ltd (ASX:IMU, OTC:IUGNF) and cancer research and treatment organisation City of Hope in the US have dosed the first patient in cohort 3 of the phase I clinical trial of oncolytic virotherapy candidate, CHECKvacc (CF33-hNIS-antiPDL1).
The first-in-human, phase 1, single-centre, dose escalation study of CHECKvacc is recruiting patients with triple negative breast cancer (TNBC).
CF33-hNIS-antiPDL1 is an immune checkpoint inhibitor armed chimeric vaccinia poxvirus from the lab of CF33 inventor Professor Yuman Fong, Sangiacomo family chair in surgical oncology at City of Hope, and a noted expert in the oncolytic virus field.
Oncolytic viruses (OVs) are designed to both selectively kill tumour cells and activate the immune system against cancer cells, with the potential to Boost clinical response and survival.
The purpose of the study is to evaluate the safety and initial evidence of efficacy of intra-tumoural administration of CF33-hNIS-antiPDL1 against metastatic TNBC.
The current trial design will involve a dose escalation, followed by an expansion to 12 patients at the final dose, which will be the recommended phase 2 dose (RP2D).
Imugene MD & CEO Leslie Chong said: “We are pleased with the continued progress being made in this trial as we dose the first patient in cohort 3.
“From cohorts 1 & 2 we’ve continued to see early positive results in oncolytic virus infection and replication in the TNBC tumours and importantly there remains no observed toxicity.
“CHECKvacc has the potential to Boost clinical response and survival in this indication where there are currently no meaningful treatments, and we are eager to deliver on that.”
Trek has revised its popular Checkpoint gravel bike, introducing a new geometry that lets the bike be taken further off the beaten track.
The range has expanded too. The Checkpoint SL range sits in between the racy SLR range and the aluminium ALR bikes.
Cyclist contributor Ben Delaney found the Checkpoint SLR 9 to be all the bike a gravel racer could need, provided their pockets are deep enough, but I’d argue the Checkpoint SL range is the best overall proposition for most gravel riders.
The Checkpoint SL 6 on test is capable of fast, aggressive riding but also has the versatility to be used for adventurous riding on technical terrain.
Its geometry overhaul, combined with high-quality component selection, makes it great to ride on nearly all terrain, and its IsoSpeed decoupler system delivers impressive seated comfort.
The gravel bike market is continuing to develop at a fast pace and what was seen as forward-thinking design perhaps only just a couple of years ago now seems unfeasibly conservative.
Trek’s first-generation Checkpoint was regarded as a progressive gravel bike when it first came out in 2018 (it had an adjustable rear axle and everything), yet things have shifted to such an extent that its design would be considered barely more capable than a contemporary endurance/all-road bike nowadays.
The new Checkpoint was released to address that and it does so emphatically – pushing aspects of its design like geometry more resolutely into off-road bike territory, while at the same time introducing more utility and choice to the range in general.
The new Checkpoint comes in 3 guises and each tries to cater for a different rider and set of circumstances. At the top of the tree there is the SLR, which is a stripped back, aggressive version of the design aimed at racers.
There’s the ALR too, which swaps carbon composite for aluminium and gains features like a more relaxed fit and extra mounting points, for those in need of a rugged workhorse version of the design.
Then there’s the SL, which sits somewhere in the middle. It uses Trek’s mid-tier OCLV 500 carbon construction and offers the capability to match the much of the SLR’s raciness, but also the versatility of the ALR to go for long distance adventures off road. As such, it strikes me as the ideal middle ground to suit the vast majority of riders’ needs.
The Checkpoint SL’s frameset in undeniably slick. It borrows many style cues from the Trek’s latest Domane SLR and Émonda SLR road bikes, such as the distinctive head tube, and the profiled headset top cap that accepts the cables running down from an otherwise conventional cockpit.
It also makes use of the Isospeed decoupler mechanism that Trek employs on its other platforms too.
There are now several versions of Isospeed, but the Checkpoint SL uses the device’s original arrangement: aside from its origin at the bottom bracket junction the seat tube is essentially detached from the rest of the frame, connected to the seat tube cluster by an axle mounted on bearings.
This allows the seat post and seat tube to flex fore and aft independently of the rest of the frame, without compromising on stiffness.
There are some Checkpoint-specific features that helps set the bike apart from designs like the Domane and Émonda though.
There’s a neat down tube hatch hidden underneath the bottle cage mount, a bash-guard on the down tube, a dropped driveside chainstay that helps the bike comfortably clear 45mm 700c tyres, and there are mounting points aplenty, with several on the main triangle and down the fork blades too.
You wouldn’t perhaps notice straight away though, as everything seems very nicely integrated.
Aside from the SRAM Rival eTap AXS groupset, the Checkpoint SL6 build comprises exclusively parts from Trek’s component brand Bontrager.
There was once a stigma attached to in-house componentry however the parts that Bontrager produce are a prime example of why that is largely no longer an issue.
From what I can tell the build quality is beyond reproach and the performance attributes of a lot of Bontrager’s components rival that of many specialist brands.
By keeping things in-house Trek could even design kit to work specifically with the features of the Checkpoint frameset.
For example, the cockpit is made up of a Bontrager stem and bars that create a short reach to balance the lengthened reach of the frameset.
Both components are made from aluminium and simple in design, which I like – design simplicity is an indicator that something will be easy to live with and is fundamentally good quality.
The carbon Bontrager seatpost was again unfussy and seemed to pair well with the flexible, IsoSpeed-decoupled seat tube.
The Bontrager P3 Verse Comp saddle was perhaps the only low point for me on the spec list. While the shape is nothing to fall out with, it’s bulky and its padding was too squishy.
I’d prefer to use a saddle with less padding that is more supportive, but it's an easy component to swap out. I need to recognise that it’s also highly subjective part of the build, so your results may vary, and you could well find the saddle is a good fit for you.
The wheels, however, are an excellent choice between budget and performance. The Paradigm Comp 25 design is a little weighty, but it boasts a 25mm internal rim width that supports wider gravel tyres nicely.
I’ll add that Bontrager’s snap-in rim strips are a fantastic way to set up rims tubeless, being far quicker to install than traditional tape, though they can only be used on the Bontrager wheels they come with.
The Bontrager GR1 Team Issue 40mm tyres were a similarly excellent match for the wheels. They felt grippy in dry gravel conditions, but the low-profile tread still felt supple and speedy on the road. The tan sidewall colour looks very nice too.
SRAM’s Rival eTap AXS contributes to the bike’s 9.3kg overall weight however functionally it is superb.
In its 1× XPLR guise, the 40-tooth chainring worked nicely with the 10-44 cassette to supply great range without too big a jump between each sprocket.
For the varied, predominantly off-road terrain the Checkpoint SL6 is aimed at covering it's a great set-up, even if the 1× chainring annoyingly highlights the fact Trek didn’t opt for a removable front derailleur mount. Then again that’s hardly the fault of the groupset.
Without doubt the Checkpoint’s most important feature is its new geometry. The frameset is longer at both ends: reach has grown by around 20mm, and chainstay length is up 10mm, but to keep the riding position normal shorter stems have been specced, with shorter-reach bars too.
Head tube angles have relaxed a bit, but more importantly fork rakes have dropped. Both changes combining to result in a significant increase in trail for a given tyre size.
For example, this Checkpoint SL6 with its 40mm Bontrager GR1 tyres has a trail figure of 67mm, which is pretty long.
Frame geometry is not often something that gets tweaked so significantly and it could be considered a bold move by Trek to change the recipe of the first-generation Checkpoint, given that it was considered to be such a well-rounded bike.
However, gravel bikes have only been getting more capable off-road so it is understandable that Trek has modified the bike in such a way, particularly when the result is so successful.
That longer wheelbase and slacker handling geometry has all been done with stability in mind, and the effect was noticeable in off-road conditions.
The long trail figure meant that the front of the bike was more inclined to understeer when nearing the limit of grip on loose ground, as opposed to simply washing out without warning, giving me more of a chance to correct things and remain upright.
Likewise, over rocks the Checkpoint’s front wheel ate big off-centre strikes that would cause other quicker-handling bikes to jerk off line. While the bike could never be described as any more than sedate on the road, the short 90mm stem and short-reach bars kept the handling from trending towards sluggishness.
The Checkpoint’s balance of geometry and componentry has been expertly judged by Trek in my opinion.
The Checkpoint’s long dimensions and 9.3kg weight meant it didn’t have the turn of speed that some gravel bikes do buts its oversize tube profiles meant it felt sturdy if not sprightly under acceleration.
In fact, I’d say it’s one of the bulkiest bikes in its category. The oversize headset bearings mean the head tube is broad and the natty storage compartment in the down tube means that is similarly girthy.
Trek’s sensible use of a T47 bottom bracket means the BB junction is large and even the seat stays are unusually substantial.
It's Trek’s use of the Isospeed decoupler mechanism that means it can build to such proportions with no penalty to ride quality.
It frees the seat tube and seat post up to flex along their entire combined length, so with such a long member through which to dissipate vibration and neutralise big bumps, the device is highly effective at improving comfort.
I have some niggles with a couple of finishing details – the headset port that accepts the hydraulic hoses into the frame isn’t watertight, and the front derailleur hanger, not being removable, is an eyesore – but broadly speaking Trek’s Checkpoint is a well-specced and highly capable machine to go gravel riding on.
|Weight||9.3kg (size 56)|
|Sizes available||49, 52, 54, 56, 58, 61|
|Levers||SRAM Rival eTap AXS|
|Brakes||SRAM Rival AXS|
|Rear derailleur||SRAM Rival eTap AXS|
|Crankset||SRAM Rival AXS 1×, 40t|
|Bottom bracket||Sram DUB T47|
|Cassette||SRAM XG-1251, 10-44|
|Chain||SRAM Rival AXS|
|Wheels||Bontrager Paradigm Comp 25|
|Tyres||Bontrager GR1 Team Issue, 40mm|
|Bar||Bontrager Elite Gravel, 42cm|
|Stem||Bontrager Pro, 90mm|
|Saddle||Bontrager P3 Verse Comp|
The Endurance 3 bib shorts are mid-level offering from Castelli that get the most important things right. Despite costing significantly less than Castelli’s top bib shorts they use the same Progetto X2 Air Seamless chamois, which is very comfortable.
The panel shaping of the body fabric is a little less finessed, meaning a few more seams than you’d find higher up the range, but I never found I noticed them during my rides.
I particularly like the Endurance 3’s Giro3 hem gripper design, which is a wide band comprising thin elastic strands that stay put, but don’t cut in.
Products reviewed by Cyclist are independently selected and tested by our editorial team. Cyclist may earn an affiliate commission if you make a purchase through a retailer link. Read our reviews policy.
The £11,250 Checkpoint SLR 9 is a no-holds barred gravel race bike. It uses a higher-tier carbon layup than the SL – OCLV 700 versus 500 – and a revised Isospeed design to shed weight, and its spec list is universally excellent.
Trek’s Checkpoint ALR 5 is its most accessible at £2,150. The frame is made from Trek’s 300 Series Alpha aluminium and it has the adjustable rear axle of the previous Checkpoint so users can alter its geometry or boost its maximum tyre size.
Review photos: Lizzie Crabb, product photos: Trek Bikes
On Tuesday 1806 vehicles were stopped in Whanganui, with drivers undertaking an alcohol screening test. Photo / Supplied
Almost 2000 drivers were stopped at a police checkpoint on Tuesday morning in Whanganui, and none were over the alcohol limit, drawing praise from local traffic officers.
It was the second iteration of "Operation Ethos", a police initiative running random checkpoint days throughout the year across the whole of the police's central North Island region.
In total, 8157 vehicles in the region were stopped with drivers undertaking breath tests, 1806 of which were in Whanganui.
Whanganui Area Commander Ross Grantham said three checkpoints across Whanganui were set up.
At the Whanganui checkpoints, 12 infringement notices were issued for traffic offences, and two referrals were made to support people with licensing issues.
"Three breath screening tests showed alcohol present, but all were under the limit which was good to see."
Grantham said Tuesday's operation was a success.
"We want every driver and their passengers to get where they are going safely.
"Simply, that means driving to the conditions, keep to the speed limit, wear your seatbelt, don't drink and drive, and leave your phone alone because 'mate, it can wait'."
During the first operation on June 9, 932 vehicles were stopped.
Detective Inspector Neil Forlong said two drivers were well over the legal alcohol limit.
On Tuesday 2716 vehicles were stopped in Manawatū and 3635 in Taranaki.
Seventy infringement notices were issued across the police central district to drivers for offences such as failing to wear a seatbelt, using cellphones while driving and careless driving.
Two drivers were forbidden from driving for licence offences and two disqualified drivers were apprehended.
Inspector Ashley Gurney was pleased that no one was found driving drunk.
"It seemed central district motorists were getting the message," Gurney said.
"So overall, we are really pleased with our community."
Gurney said police would continue to run Operation Ethos across the district in the coming months, to ensure the safety of all road users.
"Members of the public should expect to see us and to be stopped at any time."
Forlong said the idea behind Operation Ethos was to involve non-specialist road policing staff to concentrate on road policing through checkpoints.
"Road policing is a responsibility of all police, not just the highway patrol or dedicated road police."
MacPherson has devoted his laboratory to rectifying the dearth of small cell lung cancer research and lack of treatment advancements. After Congress passed the 2013 Recalcitrant Cancer Act, which mandated more research focus on treatment-resistant cancers like SCLC, the NCI put together an SCLC consortium, which MacPherson joined.
He and his team used SCLC cells floating in patients’ blood to set up patient-derived xenografts, or PDX, models in which human tumor tissue grows in mice. These allow the group to test potential therapies on human SCLC tissue growing in an environment that more closely mimics a patient than a lab dish ever could. MacPherson’s work on SCLC became one of the four clinically focused lung cancer research projects in the Hutch’s NCI-funded Specialized Program of Research Excellence in lung cancer. The SPORE initiative is designed to accelerate the timeline from basic science breakthrough to clinical advancement.
As scientists put more effort into untangling the biology of SCLC, it became clear that there are several “flavors” of the disease, MacPherson said.
Different tumors carry different key mutations. And the pattern of genes that are turned on or off also varies between tumors. Investigators outlined a highly neuroendocrine, or NE, SCLC type, which has stronger neural and hormonal features than other tumor types, and an inflamed type, which shows signs of heightened immune activity. These types were also linked to prognosis: NE tumors tend to be more aggressive, while inflamed tumors often have a better prognosis.
MacPherson turned his attention to molecules that regulate DNA packaging, which can change which genes are on or off and affect tumor behavior. One regulator of DNA packaging is a molecule called LSD1. In a prior study, MacPherson and his team had tested an LSD1 inhibitor against SCLC patient-derived tumor tissue growing in immunocompromised mice, a PDX model derived from a chemo-resistant tumor, which melted away. Though other models didn’t respond as dramatically, the investigators saw that the LSD1 inhibitor suppressed NE features and turned up expression of a gene called Notch in every PDX model they tested it against.
At the time, other researchers began reporting on characteristics of SCLC tumors that respond to immunotherapy. They reported reduced NE features and higher levels of Notch.
“And that’s exactly what LSD1 inhibition was doing [in the lab],” MacPherson said.
This prompted the researchers to test whether they could make SCLC tumors sensitive to immunotherapy by using an LSD1 inhibitor to ramp down their NE qualities and ramp up Notch.
This time, the researchers used mice with fully functional immune systems and mouse SCLC tumors engineered to better simulate human SCLC features. (Mouse immune systems will reject human tissue, making it impossible to create a human PDX model in standard immunocompetent mice.)
They then tested whether an LSD1 inhibitor called bomedemstat, provided by Imago Biosciences, improved responses to an immune checkpoint inhibitor. Immune checkpoint inhibitors work by blocking molecular brakes that keep tumor-attacking immune cells called T cells in check. Treatment with the checkpoint inhibitor did not reduce tumor growth compared to untreated tumors. Bomedemstat on its own reduced tumor size a little. Together, bomedemstat and the immunotherapy drug kept tumor growth strongly in check.
The team also found that significantly more immune cells made their way into tumors in doubly treated mice than in mice left untreated or given either treatment alone.
Additionally, the researchers revealed a key cellular change that helped explain bomedemstat’s immune-amplifying capabilities. They found that bomedemstat treatment boosted levels of a molecule that T cells can use to “see” the mutations lurking within tumor cells. Tumors that lack this molecule essentially hide from T cells, so turning this molecule back on could keep small cell tumors from flying under the immune system’s radar.
MacPherson noted that a study from another group in New York, published last month, found similar results.
The laboratory results were so exciting — and meshed so well with clinical findings — that Hiatt and MacPherson have already opened a clinical trial in collaboration with Dr. Rafael Santana-Davila at the University of Washington. Imago Bioscience will provide bomedemstat to patients but is not funding or overseeing the trial. Two participants have enrolled so far.
In the current standard of care, patients with SCLC receive treatment in two phases: an initial phase of chemotherapy plus an immune checkpoint inhibitor, followed by a second phase of checkpoint inhibitor alone to maintain tumor regression. The trial will add bomedemstat to the maintenance phase to see if this drug can extend the length of time before a patient’s disease progresses or recurs. The scientists will compare data from patients on the trial to historical data to measure bomedemstat’s effect.
The trial is also designed to help scientists learn more about biological features of SCLC tumors that correlate with how well the drug combination works.
“We always want to do a better job of identifying who benefits the most from standard treatments or from new treatments,” Hiatt said. “But probably even more importantly, [we need to identify] who's not going to benefit at all and would need a totally different strategy.”
So the trial team will also monitor cancer DNA found in patients’ blood (also known as a liquid biopsy) to see if they can uncover molecular markers that distinguish tumors that respond from those that don’t (and perhaps also hint at the molecular basis for a response). With Hutch colleague Dr. Gavin Ha, the team is developing a test that can look at patterns in DNA packaging proteins to glean information about the molecular state of the tumors.
“There’s also a lot to understand about how LSD1 inhibition is augmenting the immune response,” MacPherson said. “The next steps are to tease out its impact on the immune system more broadly and detail the molecular mechanisms involved.”
The team’s clinical ties strengthen their laboratory work, they said. His clinical experience informs what questions he tackles and how he designs his experiments, Hiatt said.
“It’s very rewarding to go back to the lab to try to come up with new strategies that could theoretically be helpful for these patients,” he said.
The laboratory studies were supported by funding from the Fred Hutch Lung SPORE. The ongoing clinical trial is funded by Fred Hutchinson Cancer Center.
HONOLULU (KHON2) — A district contract security manager for Allied Universal is calling for patience at Lihue Airport following recent arrests of travelers causing disturbances. He’s also shining a light on the dedicated airport law enforcement team that continue to be professional while working under unfavorable conditions.
“The men and women of the airport security and police detail are tasked with first showing restraint and aloha. Sometimes that is put to the test,” said Charlie Iona.
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“There is a threshold that once it is crossed, then action must be taken,” he continued. “They do take a lot, but many have gone through extensive training that you normally don’t experience especially in the security industry.“
Iona said sometimes they do run into problems with travelers being impatient, then one thing leads to another. When it gets out of hand and they become aggressive, an arrest will usually occur. According to Kauai Police Department, two arrests were made in late July for disorderly conduct.
On July 29, a 37-year-old Kaneohe resident was arrested after he was accused of yelling profanities and racial slurs toward an airline employee. An airport police officer escorted the passenger from the plane as he continued to yell and scream at everyone in the vicinity, causing a disturbance. Police said he was arrested and charged with disorderly conduct and harassment. His total bail for both charges was $2,000.
On July 31, a 58-year-old resident of Miami Beach, Florida, was also arrested for disorderly conduct after police said he was “recklessly creating a risk of alarming members of the public by engaging in violent or tumultuous behavior.” He was charged with disorderly conduct; bail was set at $50.
Though Iona would like to see more improvements at the airport, he said it’s all about the footprint of where it’s located.
“When you have only so much area to work with, that plays a role on what can and cannot be done,” he explained. “A more open environment leads to better temperament in my opinion.”
Just like on the other islands, Lihue Airport has seen its share of long lines getting through the checkpoint, which was especially bad more than a week ago when there were two broken X-ray machines. A Transportation Security Administration spokesperson told KHON2 on Monday that the units have both been repaired and are fully operational now.
In addition to the lines, there have been issues of no parking at the airport.
On Saturday, Aug. 6, the Hawaii Department of Transportation sent out an advisory that morning about the full parking lot, saying the best course was to be dropped off.
DOT said the problems weren’t Turo-related, just “a busy day.”
According to Iona, this type of activity goes up and down based on the number of flights departing Lihue Airport.
“With the increase in flights and the larger aircrafts being used, that will determine the number of travelers we expect to see at the airport at any given time,” he said.
On Tuesday, TSA added that the busiest times at the security checkpoint are driven by the flight departure schedules determined by the airlines.
“When there is a concentrated number of flight departures over a short period of time, there will be intervals when the number of departing passengers may exceed the capacity of the TSA security checkpoint,” said Lorie Dankers, TSA spokesperson. “This is why it is essential that travelers arrive early and prepared to allow for completion of every step of the travel process from curb to gate.”
Iona would like to thank tourists for visiting and hopes they had a wonderful experience. He also asks that they be patient in crowded situations.“Paying to have TSA PreCheck, if you are a frequent traveler, helps the wait time because you are expressed through a PreCheck line that normally does not have a crowd,” he said.
On Tuesday, Dankers clarified that you don’t have to be a frequent traveler for the program, which allows travelers to be eligible for a different type of screening through the security checkpoint.
“Eligible TSA PreCheck travelers do not need to remove shoes, belts, light outerwear, laptops, electronics larger than a cell phone or travel-size liquids from carry-on luggage,” she said.
In July, 95% of travelers eligible for TSA PreCheck waited five minutes or less to be screened at airports nationwide. Another perk is they generally have the least amount of physical contact during the security screening process. For more information on the program, click here.
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“Eventually you will get to your destination,” said Iona, “and like anything else, there are steps to take and one of it being going through the TSA checkpoints, whether it’s busy or not.”