Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro–in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB₁)-selective, cannabinoid receptor type 2 (CB₂)-selective, and CB₁/CB₂ mixed agonists in the cisplatin CIPN model, using both male and female mice. CB₁ selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB₂ agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB₁ selective agonism decreasing plasma estradiol while CB₂ selective agonism increased plasma estradiol. Chronic administration of a mixed CB₁/CB₂ agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB₂ acting compound while selective CB₁ agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects.

Chronic hypertension leads to injury and fibrosis in major organs. Fibroblast activation protein (FAP) is one of key molecules in tissue fibrosis, and ⁶⁸Ga-labeled FAP inhibitor-46 (FAPI46) PET is a recently developed method for evaluating FAP. The aim of this study was to evaluate FAP expression and fibrosis in a hypertension model and to test the feasibility of ⁶⁸Ga-FAPI46 PET in hypertension. Methods: Hypertension was induced in mice by angiotensin II infusion for 4 wk. ⁶⁸Ga-FAPI46 biodistribution studies and PET scanning were conducted at 1, 2, and 4 wk after hypertension modeling, and uptake in the major organs was measured. The FAP expression and fibrosis formation of the heart and kidney tissues were analyzed and compared with ⁶⁸Ga-FAPI46 uptake. Subgroups of the hypertension model underwent angiotensin receptor blocker administration and high-dose FAPI46 blocking, for comparison. As a preliminary human study, ⁶⁸Ga-FAPI46 PET images of lung cancer patients were analyzed and compared between hypertension and control groups. Results: Uptake of ⁶⁸Ga-FAPI46 in the heart and kidneys was significantly higher in the hypertension group than in the sham group as early as week 1 and decreased after week 2. The uptake was specifically blocked in the high-dose blocking study. Immunohistochemistry also revealed FAP expression in both heart and kidney tissues. However, overt fibrosis was observed in the heart, whereas it was absent from the kidneys. The angiotensin receptor blocker–treated group showed lower uptake in the heart and kidneys than did the hypertension group. In the pilot human study, renal uptake of ⁶⁸Ga-FAPI46 significantly differed between the hypertension and control groups. Conclusion: In hypertension, FAP expression is increased in the heart and kidneys from the early phases and decreases over time. FAP expression appears to represent fibrosis activity preceding or underlying fibrotic tissue formation. ⁶⁸Ga-FAPI46 PET has potential as an effective imaging method for evaluating FAP expression in progressive fibrosis by hypertension.

The role of somatostatin receptor (SSTR) PET/CT, using ⁶⁸Ga-based tracers or [⁶⁴Cu]Cu-DOTATATE (⁶⁴Cu-DOTATATE), in the management of patients with neuroendocrine neoplasm (NEN) is guided by appropriate use criteria (AUC). In this study, we performed systematic analyses of referral patterns and image findings of routine ⁶⁴Cu-DOTATATE PET/CT scans to support AUC development. Methods: We included all clinical routine ⁶⁴Cu-DOTATATE PET/CT scans performed between April 10, 2018 (start of clinical use), and May 2, 2022, at Copenhagen University Hospital–Rigshospitalet. We reviewed the referral text and image report of each scan and classified the indication according to clinical scenarios as listed in the AUC. Results: In total, 1,290 patients underwent 2,249 ⁶⁴Cu-DOTATATE PET/CT scans. Monitoring of patients with NEN seen both on conventional imaging and on SSTR PET without clinical evidence of progression was the most common indication (defined as "may be appropriate" in the AUC) and accounted for 703 (31.3%) scans. Initial staging after NEN diagnosis ("appropriate" in the AUC) and restaging after curative-intent surgery ("may be appropriate" in the AUC) accounted for 221 (9.8%) and 241 (10.7%) scans, respectively. Selection of patients eligible for peptide receptor radionuclide therapy ("appropriate" in the AUC) and restaging after peptide receptor radionuclide therapy completion ("appropriate" in the AUC) accounted for 95 (4.2%) and 115 (5.1%) scans, respectively. The number of scans performed for indications not defined in the AUC was 371 (16.5%). Image result analysis revealed no disease in 669 scans (29.7%), stable disease in 582 (25.9%), and progression in 461 (20.5%). In 99 of the 461 (21.5%) scans, progression was detected on PET but not on CT. Conclusion: Our study provided real-life data that may contribute to support development of ⁶⁴Cu-DOTATATE/SSTR PET/CT guidelines including AUC. Some scenarios listed as "may be appropriate" in the current AUC were frequent in our data. Monitoring of patients with NEN without clinical evidence of progression was the most frequent indication for ⁶⁴Cu-DOTATATE PET/CT, in which disease progression was detected in more than one third, and a large proportion was visible by PET only. We therefore conclude that this scenario could potentially be classified as appropriate.

This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of ¹⁸F-labeled fibroblast activation protein inhibitor ([¹⁸F]AlF-NOTA-FAPI-04, denoted as ¹⁸F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent ¹⁸F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On ¹⁸F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUV_max (area under the curve [AUC], 0.87; P = 0.0026), SUV_peak (AUC, 0.89; P = 0.0017), SUV_mean (AUC, 0.88; P = 0.0021), TBR_max (AUC, 0.86; P = 0.0031), and TBR_mean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%–81.82% and specificities of 83.33%–100%. Changes in SUV_max (AUC, 0.81; P = 0.0116), SUV_peak (AUC, 0.82; P = 0.0097), SUV_mean (AUC, 0.81; P = 0.0116), and TBR_mean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: ¹⁸F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants.

Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"].

BACKGROUND AND PURPOSE:

Low-field 64 mT portable brain MRI has recently shown diagnostic promise for MS. This study aimed to evaluate the utility of portable MRI (pMRI) in assessing dissemination in space (DIS) in patients presenting with optic neuritis and determine whether deploying pMRI in the MS clinic can shorten the time from symptom onset to MRI.

BACKGROUND AND PURPOSE:

Prediction of aneurysm instability is crucial to guide treatment decisions and to select appropriate patients with unruptured intracranial aneurysms (IAs) for preventive treatment. High-resolution 4D MR flow imaging and 3D quantification of aneurysm morphology could offer insights and new imaging markers for aneurysm instability. In this cross-sectional study, we aim to identify 4D MR flow imaging markers for aneurysm instability by relating hemodynamics in the aneurysm sac to 3D morphologic proxy parameters for aneurysm instability.

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.

T-lymphoblastic lymphoma (T-LLy) is the most common lymphoblastic lymphoma in children and often presents with a mediastinal mass. Lymphomatous suprarenal masses are possible but rare. Here, we discuss the case of a previously healthy 3-yr-old male who presented with mediastinal T-LLy with bilateral suprarenal masses. Following initial treatment, surgical biopsy of persisting adrenal masses revealed bilateral neuroblastoma (NBL). A clinical genetics panel for germline cancer predisposition did not identify any pathogenic variants. Combination large panel (864 genes) profiling analysis in the context of a precision oncology study revealed two novel likely pathogenic heterozygous variants: SMARCA4 c.1420-1G > T p.? and EZH2 c.1943G > C p.(Ile631Phefs*44). Somatic analysis revealed potential second hits/somatic variants in EZH2 (in the T-LLy) and a segmental loss in Chromosome 19p encompassing SMARCA4 (in the NBL). Synchronous cancers, especially at a young age, warrant genetic evaluation for cancer predisposition; enrollment in a precision oncology program assessing germline and tumor DNA can fulfill that purpose, particularly when standard first-line genetic testing is negative and in the setting of tumors that are not classic for common cancer predisposition syndromes.

Background

In an evolving landscape of practices and policies, reviewing and incorporating the latest scientific evidence is necessary to ensure optimal clinical management for people with opioid use disorder. We provide a synopsis of the 2024 update of the 2018 National Guideline for the Clinical Management of Opioid Use Disorder, from the Canadian Research Initiative in Substance Matters.

The Respiratory Intensive Care Assembly of the European Respiratory Society gathered in Berlin to organise the third Respiratory Failure and Mechanical Ventilation Conference in February 2024. The conference covered key points of acute and chronic respiratory failure in adults. During the 3-day conference ventilatory strategies, patient selection, diagnostic approaches, treatment and health-related quality of life topics were addressed by a panel of international experts. In this article, lectures delivered during the event have been summarised by early career members of the Assembly and take-home messages highlighted.

NATWEST has moved to reduce the UK Government’s stake in the bank after buying back a significant tranche of shares from the Treasury in what it described as a “another important milestone”, it was announced this morning.

Emergency services were called to the Glebe Place area of the town

There's not a ton of news right now, which isn't a big surprise considering the current challenges of making games. Instead we deep dive into our current games, with Jonathan, Josh, Kelley and Peter leading the charge. Anna Marie and Chris share hosting duties to wrap up this week's panel.

The post RPG Cast – Episode 542: “Hell House? Hold My Beer” appeared first on RPGamer.

It’s a slightly more potty mouthed cast than usual, as Alice joins Peter, Kelley, Anna Marie and Chris to discuss what the cast has been playing for the week. Anna Marie’s 5-hour rule resurfaces and we explore what crazy black holes Chris has been down this week, alongside the news and your feedback.

The post RPG Cast – Episode 543: “Go Find Gnome, Dumb***” appeared first on RPGamer.

Things are looking grim: we get thrown out cars, assassinated for our kingdoms, drowned underwater, and struck out. If you’re scratching your head, don’t worry! Everything will make sense once you listen to this week’s podcast.

The post RPG Cast – Episode 544: “You Will NOT Bucket Shame Me” appeared first on RPGamer.

With many media events getting pushed back, the news is a little trim this week. But we still manage to pull together our basket of zany personalities for a podcast we hope brings a smile to your face.

The post RPG Cast – Episode 545: “Did You Infect My Game With Harvest Moon?” appeared first on RPGamer.

Before we go pre-order all the games from Steve, we get a podcast up for you. Chris and Kelley complain about Civ 6 on Switch. Johnathan rages in some streets. And Josh is trying to find where to turn all his sidequests into. Ok, we're off to go be feline couriers.

The post RPG Cast – Episode 546: “Sugar Coated Turd” appeared first on RPGamer.

The best way to predict the review score of a game is to play a demo of it. So never trouble another for what you can do yourself. For every minute you are playing you lose sixty seconds of ignorance. And without Pokémon tooth brushing games, life would be a mistake.

The post RPG Cast – Episode 547: “Cancer Inducing External Hardrive” appeared first on RPGamer.

New Game Plus Expo comprises the bulk of this week’s news, while the crew ponders their love and hate for Phantasy Star Online 2. Just what has Anna Marie been playing the last two weeks? You’ll have to listen to the episode to find out!

The post RPG Cast – Episode 548: “Do Not Karen on Me” appeared first on RPGamer.

The RPG Cast has dived head first into #JRPGJuly in our now playing, but since the new month has rolled over, that also means new bugs and fish to catch in Animal Crossing as well! We've got a slew of editorial content to discuss and a smattering of news. Stay safe during the holiday weekend!

The post RPG Cast – Episode 549: “What’s in Your Cranny?” appeared first on RPGamer.

Jonathan Stringer joins this week and helps Major Tomcat recruit Kelley and Chris for a PC RPG. Chris will likely just hack the planet instead. Kelley, meanwhile, will tend to her cat's bad habits.

The post RPG Cast – Episode 554: “Cat Smoker Meow” appeared first on RPGamer.

There's one cat in the mouse, but five folks on the cast. Alex apologizes for rocks. Kelley learns things by watching mew. Chris is watching RPGmaniacs. Anna Marie has started embalming ship girls. And Pascal flips coins to decide whether or not to open a site indexing body mutilation in films.

The post RPG Cast – Episode 564: “Paws Is Best Lederhosen” appeared first on RPGamer.

Kelley gets a sweet message from her husband, while Josh is not convinced he wants to play the Untitled Groose Game. Anna Marie is warned off of spitting in Chris's briefs and calling it rain, and somehow we manage to get through two weeks of news including two big presentations!

The post RPG Cast – Episode 574: “We’re a Real Site in Our Hearts” appeared first on RPGamer.

Kelley reviews a game in cats, Josh mourns the Moe, Chris gets to say Gugnir again, and Jonathan gets surpassed by his own progeny.

The post RPG Cast – Episode 576: “4K VRR LCD versus CRT” appeared first on RPGamer.

Anna Marie wonders why we can't be friends. Jonathan becomes a Marbula One fan. Kelley engages "pants off, games on" mode. And Chris learns that the only person he's cheating is himself...and his dire gryphon.

The post RPG Cast – Episode 584: “A Crater Sized Hole Filled with Funko Pops!” appeared first on RPGamer.

It's been a week full of news, some exciting, some alarming. Chris breaks the site...repeatedly. Kelley comes to terms with the fact mowing the lawn is hard in real life. Josh explains Japanese tabloid scandals. Anna Marie assigns a tedious task to Pascal.

The post RPG Cast – Episode 594: “The Queen Needs a Monster Rig” appeared first on RPGamer.

It's the RPGCast trio bringing you another week of mild insanity. Kelley struggles because Japanese names are hard. Chris wants to take all the cats camping, but Anna Marie swiftly vetoes the idea. The dad jokes arrive in full force, and everyone's thinking about vacations.

The post RPG Cast – Episode 604: “Press 5 for More Rune Factory” appeared first on RPGamer.

Kelley finds out that Alice is made of Lego. Josh asks if his cat even lifts, bro. Chris puts everything into the Final Fantasy XVI bucket. And everyone gets KEMCO shamed.

The post RPG Cast – Episode 614: “The Burned Pirated Disc Is a Feature” appeared first on RPGamer.

Chris wants an OP fox with mods. Matt wears a turnip and marries a twelve year old. And Josh goes off to read the new J.R.R. Martin time loop book.

The post RPG Cast – Episode 624: “Kirby Is the New Elden Ring” appeared first on RPGamer.

Anna gets her tentacle on, but doesn't notice any performance issues. Chris learns what a wheelbarrow is while putting his sink on the ceiling. And Kelley covers Vahn with cats and steals the unexpected Dragon Age: Inquisition!

The post RPG Cast – Episode 634: “That Bea Arthur Wig Gives Me a +5 to Int” appeared first on RPGamer.

Chris's 3DS battery is swol. Johnathan educates us on the retro market. Kelley poopsocks like a three-legged kitten. While Josh waxes poetic about his Madden otome dating sim.

The post RPG Cast – Episode 640: “Does Your Task Bar Need Fiber?” appeared first on RPGamer.

Chris takes his horse in for an oil change. Kelley droplifts bootleg amiibos at Target. Josh fantasizes about Nopon Tom Cruise.

The post RPG Cast – Episode 641: “It’s a Vestigial Wheel” appeared first on RPGamer.

Chris is not an automated phone system. Josh has been delayed until 2023. And Kelley gets cases for her Star Wars cases.

The post RPG Cast – Episode 642: “We Are Not Bringing Up Your Cat Fountain” appeared first on RPGamer.

Congested Kelley goes HONK! Chris runs over old people in GTA while distracting Anna Marie with Octopath. RPGamer tip of the week: If your game has more than 12 currencies, it's main stream.

The post RPG Cast – Episode 643: “Kinky Chemical Engineer” appeared first on RPGamer.

Kelley watches the American Sailor Moon pilot acid trip fever dream. Tam is going off to get 800 glamour shots. Chris gets carded while trying to buy a Mara.

The post RPG Cast – Episode 644: “Is That a Demon Machine Making a Pizza?” appeared first on RPGamer.

Kelley hoards all the PS5s. Chris needs a build for the I'm Bad playstyle. And Josh gets treatment for his cat's demon tapeworm.

The post RPG Cast – Episode 645: “Rob Zombie’s Drag-Gula Lost” appeared first on RPGamer.

Kelley carries her Vita with her, but then realizes she can't play the games in public. Josh practices his dramatic Yakuza shirt ripping skills. And Chris uses an AI to generate a new Soul Hackers map.

The post RPG Cast – Episode 646: “You Have to Butter Your Sphinx” appeared first on RPGamer.

Kelley is creeped out by grown men in diapers. Josh can't name a kaiju that isn't Godzilla or Mothra. And Chris gets an Elden Pacifier since he's never happy.

The post RPG Cast – Episode 647: “Stellar Eve for When You Don’t Feel Fresh” appeared first on RPGamer.

Chris bangs his crotch on a keyboard. Kelley plays Alice Simulator on her not-laptop for portable gaming. And Robert makes the hard decision of filet mignon or 3 day old McDonalds.

The post RPG Cast – Episode 648: “Flawless Were-Cat Loaf” appeared first on RPGamer.

Kelley is a complicated person when it comes to PC gaming. Josh is a quiet English man, slightly constipated. And Chris takes a Steam Deck to the face.

The post RPG Cast – Episode 649: “Away With You, Stadia!” appeared first on RPGamer.

It's Extra Life Weekend baby! Phil puts Chris in a closet while Anna states that it's not because she's Canadian, it's because she's a cheap bitch. Meanwhile, the treasure chest looks back at Kelley with an expression that says "...Bruh."

The post RPGCast – Episode 654: “You Canadian” appeared first on RPGamer.