Machine learning modeling of patient health signals informs long-term survival on immune checkpoint inhibitor therapy.

System-level patient health signals, as captured by treatment-emergent adverse events (TEAEs), might contain correlates of immune checkpoint inhibitor (ICI) therapy response. Using all TEAEs and a novel machine learning modeling approach, we derived a composite signature predictive of, and potentially specific to, the response to the anti-PD-L1 ICI durvalumab in patients with non-small-cell lung cancer (NSCLC). We trained on data from the durvalumab arm and chemotherapy arm in the MYSTIC clinical trial and tested on data from four independent durvalumab-containing NSCLC trials using only the first 60 days' TEAEs. We directly compared our signature performance against that of three different definitions of immune-related adverse events. Only our signature was predictive and identified longer survivors in patients treated with durvalumab but not in patients treated with chemotherapy or placebo. It also identified durvalumab-treated long survivors with stable disease at their first RECIST evaluation and a set of PD-L1-negative long survivors.

Morphogenic, molecular, and cellular adaptations for unidirectional airflow in the chicken lung.

Unidirectional airflow in the avian lung enables gas exchange during both inhalation and exhalation. The underlying developmental process and how it deviates from that of the bidirectional mammalian lung are poorly understood. Sampling key developmental stages with multiscale 3D imaging and single-cell transcriptomics, we delineate morphogenic, molecular, and cellular features that accommodate the unidirectional airflow in the chicken lung. Primary termini of hyper-elongated branches are eliminated via proximal-short and distal-long fusions, forming parabronchi. Neoform termini extend radially through parabronchial smooth muscle to form gas-exchanging alveoli. Supporting this radial alveologenesis, branch stalks halt their proximalization, defined by SOX9-SOX2 transition, and become SOX9 low parabronchi. Primary and secondary vascular plexi interface with primary and neoform termini, respectively. Single-cell and Stereo-seq spatial transcriptomics reveal a third, chicken-specific alveolar cell type expressing KRT14, hereby named luminal cells. Luminal, alveolar type 2, and alveolar type 1 cells sequentially occupy concentric zones radiating from the parabronchial lumen. Our study explores the evolutionary space of lung diversification and lays the foundation for functional analysis of species-specific genetic determinants.

Biallelic RXFP2 variants lead to congenital bilateral cryptorchidism and male infertility, supporting a role of RXFP2 in spermatogenesis.

STUDY QUESTION: Does RXFP2 disruption impair male fertility? SUMMARY ANSWER: We identified biallelic variants in RXFP2 in patients with male infertility due to spermatogenic arrest at the spermatid stage, supporting a role of RXFP2 in human spermatogenesis, specifically in germ cell maturation. WHAT IS KNOWN ALREADY: Since RXFP2, the receptor for INSL3, plays a crucial role in testicular descent during prenatal development, biallelic variants lead to bilateral cryptorchidism, as described in four families to date. While animal models have also suggested a function in spermatogenesis, the postnatal functions of RXFP2 and its ligand INSL3, produced in large amounts by the testes from puberty throughout adulthood, are largely unknown. STUDY DESIGN, SIZE, DURATION: A family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism underwent clinical, endocrinological, histological, genomic, in vitro cellular, and in silico investigations. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endocrinological and histological findings were correlated with publicly available single-cell RNA sequencing (scRNA-seq) data. The genomic defects have been characterized using long-read sequencing and validated with in silico modeling and an in vitro cyclic AMP reporter gene assay. MAIN RESULTS AND THE ROLE OF CHANCE: An intragenic deletion of exon 1-5 of RXFP2 (NM_130806.5) was detected in trans with a hemizygous missense variant c.229G>A, p.(Glu77Lys). The p.(Glu77Lys) variant caused no clear change in cell surface expression or ability to bind INSL3, but displayed absence of a cAMP signal in response to INSL3, indicating a loss-of-function. Testicular biopsy in the proband showed a maturation arrest at the spermatid stage, corresponding to the highest level of RXFP2 expression in scRNA-seq data, thereby providing a potential explanation for the impaired fertility. LIMITATIONS, REASONS FOR CAUTION: Although this is so far the only study of human cases that supports the role of RXFP2 in spermatogenic maturation, this is corroborated by several animal studies that have already demonstrated a postnatal function of INSL3 and RXFP2 in spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS: This study corroborates RXFP2 as gene implicated in autosomal recessive congenital bilateral cryptorchidism due to biallelic variants, rather than autosomal-dominant cryptorchidism due to monoallelic RXFP2 variants. Our findings also support that RXFP2 is essential in human spermatogenesis, specifically in germ cell maturation, and that biallelic disruption can cause male infertility through spermatogenic arrest at the spermatid stage. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Bellux Society for Pediatric Endocrinology and Diabetology (BELSPEED) and supported by a Research Foundation Flanders (FWO) senior clinical investigator grant (E.D.B., 1802220N) and a Ghent University Hospital Special Research Fund grant (M.C., FIKO-IV institutional fund). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Antithrombotic utilization, adverse events, and associations with treatment outcomes in multiple myeloma: pooled analysis of three clinical trials.

Background: Patients with multiple myeloma (MM) are at risk of venous thromboembolism (VTE), worsened by immunomodulatory drugs. Although antithrombotics are recommended for prophylaxis, existing guidelines are suboptimal and treatment outcomes remain unclear. Objectives: This study aimed to investigate adverse events, antithrombotic utilization, and their associations with survival outcomes in patients with MM initiating multi-drug immunomodulatory combinations. Design: A posthoc analysis of individual-participant level data (IPD). Methods: IPD from three daratumumab clinical trials (MAIA, POLLUX, and CASTOR) were pooled. Adverse events incidence and antithrombotic utilization were assessed. Logistic and Cox regression were utilized to examine associations between antithrombotics use with adverse events and survival outcomes at the baseline and 6-month landmark. Results: Among 1804 patients, VTE occurred in 10%, bleeding in 14%, ischemic heart disease in 4%, and stroke in 2%. Patients with these adverse events demonstrated elevated rates of any grade ⩾3 events. Antiplatelet (primarily aspirin) and anticoagulant (primarily LMWH and direct oral anticoagulants) prescriptions have seen an increase from baseline (25% and 14%, respectively) to 6 months (35% and 31%). The primary indication for their use was prophylaxis. Anticoagulant use within 6 months was associated with reduced VTE (OR (95% CI) = 0.45 (0.26-0.77), p = 0.004), while antiplatelet use showed no associations with any evaluated adverse events. Antithrombotics and survival outcomes had no significant associations. Conclusion: This study underscores the complexities of antithrombotic therapy and adverse events in MM and highlights the need for vigilant and proactive management due to increased grade ⩾3 adverse events. While anticoagulant use was associated with reduced VTE risk, further research is needed to optimize thromboprophylaxis guidelines and explore antithrombotic efficacy and safety in patients with MM. Trial registration: MAIA (NCT02252172), POLLUX (NCT02076009), CASTOR (NCT02136134).

Blood clot prevention drugs in multiple myeloma: usage and impact on patient outcomes Aims and Purpose of the Research This study aimed to understand how blood-thinning medications are used by patients with multiple myeloma, a type of blood cancer. Specifically, we wanted to find out how often these medications are used, what side effects they might cause, and whether they are linked with how long the patients live. Background of the Research This study is important because patients with multiple myeloma often have a higher risk of blood clots, especially when they are taking certain anticancer treatments. Blood-thinning drugs are usually recommended to prevent these clots, but it's not always clear how well these drugs work or what side effects they might cause. Methods and Research Design This study looked at data from three clinical trials involving a multiple myeloma drug called daratumumab. We looked at how often side effects occurred and how often blood-thinning drugs were used. Two groups of blood thinning drugs were investigated: antiplatelets and anticoagulants. We used two types of statistical methods, called logistic and Cox regression, to see if there was a connection between the use of these blood-thinning drugs and the occurrence of side effects or survival rates at the start of the study and after six months. Results and Importance The study found that the use of blood-thinning drugs increased over time and that using anticoagulants within the first six months was linked to a lower risk of blood clots. However, blood-thinning drugs were not linked with how long the patients lived. These results are important because they can help doctors better manage the use of blood-thinning drugs in patients with multiple myeloma. The key message is that more research is needed to improve guidelines for preventing blood clots and to better understand the safety and effectiveness of blood-thinning drugs in these patients.

Combined Oxygen-enhanced MRI and perfusion imaging detect hypoxia modification from banoxantrone and atovaquone and track their differential mechanisms of action.

Oxygen-enhanced MRI (OE-MRI) has shown promise for quantifying and spatially mapping tumor hypoxia, either alone or in combination with perfusion imaging. Previous studies have validated the technique in mouse models and in patients with cancer. Here, we report the first evidence that OE-MRI can track change in tumor oxygenation induced by two drugs designed to modify hypoxia. Mechanism of action of banoxantrone and atovaquone were confirmed using in vitro experiments. Next, in vivo OE-MRI studies were performed in Calu6 and U87 xenograft tumor models, alongside [18F] FAZA PET and immunohistochemistry assays of hypoxia. Neither drug altered tumor size. Banoxantrone reduced OE-MRI hypoxic fraction in Calu6 tumors by 52.5% +/- 12.0% (p=0.008) and in U87 tumors by 29.0% +/- 15.8% (p=0.004) after 3 days treatment. Atovaquone reduced OE-MRI hypoxic fraction in Calu6 tumors by 53.4% +/- 15.3% (p=0.002) after 7 days therapy. PET and immunohistochemistry provided independent validation of the MRI findings. Finally, combined OE-MRI and perfusion imaging showed that hypoxic tissue was converted into necrotic tissue when treated by the hypoxia-activated cytotoxic prodrug banoxantrone, whereas hypoxic tissue became normoxic when treated by atovaquone, an inhibitor of mitochondrial complex III of the electron transport chain. OE-MRI detected and quantified hypoxia reduction induced by two hypoxia-modifying therapies and could distinguish between their differential mechanisms of action. These data support clinical translation of OE-MRI biomarkers in clinical trials of hypoxia-modifying agents, to identify patients demonstrating biological response and to optimize treatment timing and scheduling.

ctDNA dynamics and mechanisms of acquired resistance in patients treated with osimertinib with or without bevacizumab from the randomised phase II ETOP-BOOSTER trial.

BACKGROUND: ETOP 10-16 BOOSTER study was a randomised phase II trial of osimertinib and bevacizumab versus osimertinib in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously. METHODS: Next generation sequencing (Guardant360®) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored and molecular alterations at progression were described. RESULTS: 136 patients (88% of 155 randomised) had plasma samples at baseline (68 per arm), 110 (71%) at week 9 and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found different by smoking status (interaction p=0.046), with the effect of smoking also different by baseline EGFR T790M (interaction p=0.033), while both TP53 at baseline and tissue EGFR Exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (p=0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (p=0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arm, respectively. CONCLUSIONS: The differential effect of treatment by smoking was not explained by TP53 mutation or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected but no novel molecular alterations were identified in the combination arm.

Central nervous system metastases in advanced non-small cell lung cancer: A review of the therapeutic landscape.

Up to 40% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases. Current treatments for this subgroup of patients with advanced NSCLC include local therapies (surgery, stereotactic radiosurgery, and, less frequently, whole-brain radiotherapy), targeted therapies for oncogene-addicted NSCLC (small molecules, such as tyrosine kinase inhibitors, and antibody-drug conjugates), and immune checkpoint inhibitors (as monotherapy or combination therapy), with multiple new drugs in development. However, confirming the intracranial activity of these treatments has proven to be challenging, given that most lung cancer clinical trials exclude patients with untreated and/or progressing CNS metastases, or do not include prespecified CNS-related endpoints. Here we review progress in the treatment of patients with CNS metastases originating from NSCLC, examining local treatment options, systemic therapies, and multimodal therapeutic strategies. We also consider challenges regarding assessment of treatment response and provide thoughts around future directions for managing CNS disease in patients with advanced NSCLC.

Biokinetics of Americium-241 in the euryhaline diamond sturgeon Acipenser gueldenstaedtii following its uptake from water or food.

Americium-241 whole body and internal biokinetics were experimentally investigated in the euryhaline diamond sturgeon Acipenser gueldenstaedtii during its uptake from water and food, in fresh (FW) and brackish water (BW; 9 psu). Whole-body uptake rates of 241Am from water and subsequent depuration rates were quantified over 14 and 28 days, respectively, and assimilation efficiency (AE) of 241Am from diet (chironomid) was determined over 28 days. FW reduced the biological half-life of 241Am following aqueous uptake by an order of magnitude. In contrast BW greatly reduced 241Am assimilation efficiency (AE) from diet (chironomid) by several orders of magnitude (from an AE of 8.5% (FW) down to 0.003% (BW)). Hence, salinity per se is indicated as a major environmental variable in determining the radiological exposure of A. gueldenstaedtii to 241Am. During aqueous exposure BW appreciably increased 241Am activity concentrations in most body components, but aqueous or dietary exposure pathway at either salinity did not determine marked differences in how 241Am was distributed among six body components. The highly mineralized skin of A. gueldenstaedtii recurred as a major repository of 241Am in all experimental treatments, as high as 50% among body components, due to its internal transfer from diet, surface adsorption and/or active absorption from water. The indicated prominence of the aqueous, compared to the dietary, exposure pathway for 241Am accumulation by A. gueldenstaedtii suggests its radiological exposure would be enhanced by BW as it leads to its greater long-term retention, due to a much longer biological half-life.

Measuring repeatability of dynamic contrast-enhanced MRI biomarkers improves evaluation of biological response to radiotherapy in lung cancer.

OBJECTIVES: To measure dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) biomarker repeatability in patients with non-small cell lung cancer (NSCLC). To use these statistics to identify which individual target lesions show early biological response. MATERIALS AND METHODS: A single-centre, prospective DCE-MRI study was performed between September 2015 and April 2017. Patients with NSCLC were scanned before standard-of-care radiotherapy to evaluate biomarker repeatability and two weeks into therapy to evaluate biological response. Volume transfer constant (Ktrans), extravascular extracellular space volume fraction (ve) and plasma volume fraction (vp) were measured at each timepoint along with tumour volume. Repeatability was assessed using a within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment effects on biomarkers were estimated using mixed-effects models. RC limits of agreement revealed which individual target lesions changed beyond that expected with biomarker daily variation. RESULTS: Fourteen patients (mean age, 67 years +/- 12, 8 men) had 22 evaluable lesions (12 primary tumours, 8 nodal metastases, 2 distant metastases). The wCV (in 8/14 patients) was between 9.16% to 17.02% for all biomarkers except for vp, which was 42.44%. Cohort-level changes were significant for Ktrans and ve (p < 0.001) and tumour volume (p = 0.002). Ktrans and tumour volume consistently showed the greatest number of individual lesions showing biological response. In distinction, no individual lesions had a real change in ve despite the cohort-level change. CONCLUSION: Identifying individual early biological responders provided additional information to that derived from conventional cohort cohort-level statistics, helping to prioritise which parameters would be best taken forward into future studies. CLINICAL RELEVANCE STATEMENT: Dynamic contrast-enhanced magnetic resonance imaging biomarkers Ktrans and tumour volume are repeatable and detect early treatment-induced changes at both cohort and individual lesion levels, supporting their use in further evaluation of radiotherapy and targeted therapeutics. KEY POINTS: Few literature studies report quantitative imaging biomarker precision, by measuring repeatability or reproducibility. Several DCE-MRI biomarkers of lung cancer tumour microenvironment were highly repeatable. Repeatability coefficient measurements enabled lesion-specific evaluation of early biological response to therapy, improving conventional assessment.

Oxygen-enhanced MRI detects incidence, onset and heterogeneity of radiation-induced hypoxia modification in HPV-associated oropharyngeal cancer.

PURPOSE: Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced (OE)-MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in HPV-associated oropharyngeal head and neck squamous cell cancer (HNSCC). EXPERIMENTAL DESIGN: 27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy then at weeks 2 and 4 (W2, W4) into therapy. Two pre-treatment scans assessed biomarker within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modelling. Responding lesions were identified by comparing HVMRI change to RC limits of agreement (LOA). RESULTS: OE-MRI identified hypoxia in all lesions. HVMRI wCV was 24.6% and RC LOA were -45.7% to 84.1%. Cohort median pre-treatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both p < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients. CONCLUSIONS: Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in HPV-associated oropharyngeal carcinoma.

A platform to deliver single and bi-specific Cas9/guide RNA to perturb genes in vitro and in vivo.

Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.

Mutant induced neurons and humanized mice enable identification of Niemann-Pick C1 proteostatic therapies.

Therapeutics that rescue folding, trafficking, and function of disease-causing missense mutants are sought for a host of human diseases, but efforts to leverage model systems to test emerging strategies have met with limited success. Such is the case for Niemann-Pick type C1 disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, progressive neurodegeneration, and early death. NPC1, a multipass transmembrane glycoprotein, is synthesized in the endoplasmic reticulum and traffics to late endosomes/lysosomes, but this process is often disrupted in disease. We sought to identify small molecules that promote folding and enable lysosomal localization and functional recovery of mutant NPC1. We leveraged a panel of isogenic human induced neurons expressing distinct NPC1 missense mutations. We used this panel to rescreen compounds that were reported previously to correct NPC1 folding and trafficking. We established mo56-hydroxycholesterol (mo56Hc) as a potent pharmacological chaperone for several NPC1 mutants. Furthermore, we generated mice expressing human I1061T NPC1, a common mutation in patients. We demonstrated that this model exhibited disease phenotypes and recapitulated the protein trafficking defects, lipid storage, and response to mo56Hc exhibited by human cells expressing I1061T NPC1. These tools established a paradigm for testing and validation of proteostatic therapeutics as an important step towards the development of disease-modifying therapies.

Asymmetric Dynamics Drive Catalytic Activation of the Hsp90 Chaperone.

The Hsp90 chaperone is an ATPase enzyme composed of two copies of a three-domain subunit. Hsp90 stabilizes and activates a diverse array of regulatory proteins. Substrates are bound and released by the middle domain through a clamping cycle involving conformational transitions between a dynamic open state and a compact conformationally restricted closed state. Intriguingly, the overall ATPase activity of dimeric Hsp90 can be asymmetrically enhanced through a single subunit when Hsp90 is bound to a cochaperone or when Hsp90 is composed of one active and one catalytically defunct subunit as a heterodimer. To explore the mechanism of asymmetric Hsp90 activation, we designed a subunit bearing N-terminal ATPase mutations that demonstrate increased intra- and interdomain dynamics. Using intact Hsp90 and various N-terminal and middle domain constructs, we blended 19F NMR spectroscopy, molecular dynamics (MD) simulations, and ATPase assays to show that within the context of heterodimeric Hsp90, the conformationally dynamic subunit stimulates the ATPase activity of the normal subunit. The contrasting dynamic properties of the subunits within heterodimeric Hsp90 provide a mechanistic framework to understand the molecular basis for asymmetric Hsp90 activation and its importance for the biological function of Hsp90.

Asymptomatic Rectal Bacterial Pathogens Show Large Prospective Relationships With HIV Incidence in a Cohort of Young Sexual and Gender Minorities: Implications for STI Screening and HIV Prevention.

Background: We estimated the predictive value of rectal (bacterial sexually transmitted infection [bSTI]) pathogen detection for future HIV seroconversion among young adult sexual and gender minorities (YSGMs) assigned male at birth (AMAB). Methods: Data were collected between March 2018 and August 2022 from RADAR, a longitudinal cohort study of YSGMs AMAB living in the Chicago metropolitan area (n = 1022). Rates of rectal bSTIs and the proportion of self-reported rectal bSTI symptoms are reported. We examined whether the presence of rectal bSTIs predicted HIV seroconversion using generalized estimating equations (GEEs). Results: Participants tested reactive for rectal Mycoplasma genitalium (MGen), Neisseria gonorrhoeae (NG), and Chlamydia trachomatis (CT) at a rate of 20.8 (95% CI, 18.4-23.5), 6.5 (95% CI, 5.0-8.2), and 8.4 (95% CI, 6.8-10.3) cases per 100 persons, respectively. There were no statistically significant pairwise differences in self-reported rectal bSTI symptoms between participants with self-collected swabs testing nonreactive vs reactive for rectal MGen (χ2 = 0.04; P = .84), NG (χ2 = 0.45; P = .37), or CT (χ2 = 0.39; P = .46). In multivariate GEE analysis, rectal NG (adjusted odds ratio, 5.11; 95% CI, 1.20-21.77) was a statistically significant predictor of HIV seroconversion after controlling for other bSTIs, demographics, and sexual risk behavior. Conclusions: Our findings provide a robust longitudinal estimation of the relationship between primarily asymptomatic rectal NG nucleic acid detection and HIV infection. These findings highlight the importance of asymptomatic screening for bSTIs and targeting biobehavioral intervention to prevent HIV infection among YSGMs with rectal bSTI agents detected.

CD8+ T cells exacerbate AD-like symptoms in mouse model of amyloidosis.

Alzheimer's disease (AD) is linked to toxic Aß plaques in the brain and activation of innate responses. Recent findings however suggest that the disease may also depend on the adaptive immunity, as B cells exacerbate and CD8+ T cells limit AD-like pathology in mouse models of amyloidosis. Here, by artificially blocking or augmenting CD8+ T cells in the brain of 5xFAD mice, we provide evidence that AD-like pathology is promoted by pathogenic, proinflammatory cytokines and exhaustion markers expressing CXCR6+ CD39+CD73+/- CD8+ TRM-like cells. The CD8+ T cells appear to act by targeting disease associated microglia (DAM), as we find them in tight complexes with microglia around Aß plaques in the brain of mice and humans with AD. We also report that these CD8+ T cells are induced by B cells in the periphery, further underscoring the pathogenic importance of the adaptive immunity in AD. We propose that CD8+ T cells and B cells should be considered as therapeutic targets for control of AD, as their ablation at the onset of AD is sufficient to decrease CD8+ T cells in the brain and block the amyloidosis-linked neurodegeneration.

Catheter ablation for atrial fibrillation in patients with significant mitral regurgitation: A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is commonly associated with cardiac structural abnormalities including mitral regurgitation (MR). Contemporary guidelines recommend consideration of early rhythm control strategies including catheter ablation (CA) for AF. However, the long-term efficacy of CA is highly variable across studies and patient populations, and the effect of coexisting MR on AF recurrence remains unclear. OBJECTIVE: A systematic review and meta-analysis was performed to determine the impact of significant MR (defined as ≥moderate) on AF recurrence rate after CA and whether CA for AF is associated with significant changes in the severity of MR. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases for all English-language studies published to December 31, 2023, was performed. RESULTS: A total of 17 studies (N = 2624 patients) were retained for meta-analysis. The pooled recurrence proportion of AF after CA in patients with baseline significant MR was 36% (95% CI, 27%-46%) compared with 27% (14%-41%) in patients without. The pooled hazard ratio (95% CI) for AF recurrence after CA in the presence of significant MR was 2.47 (1.52-4.01; P < .001; Egger test P value, .0583). The pooled proportion of patients who witnessed MR improvement to nonsignificant (ie,

Talc and human cancer: a systematic review of the experimental animal and mechanistic evidence.

The potential carcinogenicity of talc has been evaluated in many studies in humans and experimental animals published in the scientific literature over the last several decades, with a number of these studies reporting no associations between talc exposure and any type of cancer. In order to fully understand the current state of the science regarding the potential for talc to induce human cancers, we conducted a comprehensive and systematic review of the available experimental animal and mechanistic evidence (in conjunction with a systematic review of the epidemiology evidence in a companion analysis) to evaluate whether it supports talc as being carcinogenic to humans. We considered study quality and its impact on the interpretation of results and evaluated all types of cancer and all exposure routes. We also evaluated the evidence on the potential for talc to migrate in the body to potential tumor sites. We identified seven experimental animal carcinogenicity studies and 11 mechanistic studies of talc to systematically review. We found that several of the experimental animal carcinogenicity studies of talc have limitations that preclude their sensitivity to detect increases in tumor incidence. Regardless, the studies cover multiple exposure routes, species, and exposure durations, and none indicate that talc is a carcinogen in experimental animals except in rats under conditions of extremely high exposure that likely resulted in lung particle overload, a nonspecific effect of high exposures to poorly soluble particles, and not from any carcinogenic properties of talc. Lung particle overload leading to lung tumor formation has only been observed in rats and not in any other species, including humans. The mechanistic studies indicate that talc is not genotoxic or mutagenic, but can induce some effects that could be events on a possible pathway to carcinogenicity, mainly at high exposures or in in vitro studies with exposures of unclear relevance in vivo, but these effects are not consistent across studies and cell types. This systematic review of the experimental animal carcinogenicity and mechanistic evidence for talc indicates that an association between talc exposure and cancer is not expected in humans. Talc carcinogenicity is not plausible in any species except rats, and only when the exposure conditions are high enough to induce lung particle overload, which is not relevant to human exposures.

Modulating the gut microbiome in non-small cell lung cancer: Challenges and opportunities.

Despite the efficacy of immunotherapy in non-small cell lung cancer (NSCLC), the majority of the patients experience relapse with limited subsequent treatment options. Preclinical studies of various epithelial tumors, such as melanoma and NSCLC, have shown that harnessing the gut microbiome resulted in improvement of therapeutic responses to immunotherapy. Is this review, we summarize the role of microbiome, including lung and gut microbiome in the context of NSCLC, provide overview of the mechanisms of microbiome in efficacy and toxicity of chemotherapies and immunotherapies, and address current ongoing clinical trials for NSCLC including fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs).

Phosphor Ceramic Composite for Tunable Warm White Light.

Composite phosphor ceramics for warm white LED lighting were fabricated with K2SiF6:Mn4+ (KSF) as both a narrowband red phosphor and a translucent matrix in which yellow-emitting Y3Al5O12:Ce3+ (YAG) particles were dispersed. The emission spectra of these composites under blue LED excitation were studied as a function of YAG loading and thickness. Warm white light with a color temperature of 2716 K, a high CRI of 92.6, and an R9 of 77.6 was achieved. A modest improvement in the thermal conductivity of the KSF ceramic of up to 9% was observed with the addition of YAG particles. In addition, a simple model was developed for predicting the emission spectra based on several parameters of the composite ceramics and validated with the experimental results. The emission spectrum can be tuned by varying the dopant concentrations, thickness, YAG loading, and YAG particle size. This work demonstrates the utility of KSF/YAG composite phosphor ceramics as a means of producing warm white light, which are potentially suitable for higher-drive applications due to their increased thermal conductivity and reduced droop compared with silicone-dispersed phosphor powders.

Sustainability pathways for perovskite photovoltaics.

Solar energy is the fastest-growing source of electricity generation globally. As deployment increases, photovoltaic (PV) panels need to be produced sustainably. Therefore, the resource utilization rate and the rate at which those resources become available in the environment must be in equilibrium while maintaining the well-being of people and nature. Metal halide perovskite (MHP) semiconductors could revolutionize PV technology due to high efficiency, readily available/accessible materials and low-cost production. Here we outline how MHP-PV panels could scale a sustainable supply chain while appreciably contributing to a global renewable energy transition. We evaluate the critical material concerns, embodied energy, carbon impacts and circular supply chain processes of MHP-PVs. The research community is in an influential position to prioritize research efforts in reliability, recycling and remanufacturing to make MHP-PVs one of the most sustainable energy sources on the market.