Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study.

PURPOSE: Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC. METHODS: In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment. RESULTS: Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm. CONCLUSION: In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

Chiral bisphosphine Ph-BPE ligand: a rising star in asymmetric synthesis.

Chiral 1,2-bis(2,5-diphenylphospholano)ethane (Ph-BPE) is a class of optimal organic bisphosphine ligands with C2-symmetry. Ph-BPE with its excellent catalytic performance in asymmetric synthesis has attracted much attention of chemists with increasing popularity and is growing into one of the most commonly used organophosphorus ligands, especially in asymmetric catalysis. Over two hundred examples have been reported since 2012. This review presents how Ph-BPE is utilized in asymmetric synthesis and how powerful it is as a chiral ligand or even a catalyst in a wide range of reactions including applications in the total synthesis of bioactive molecules.

Female reproductive factors, exogenous hormone use, and incident chronic kidney disease and end-stage renal disease.

CONTEXT: Younger women have a slower progressive loss of kidney function than age-matched men and the sex advantage diminishes after menopause, suggesting a role for female hormones in the development of kidney diseases. OBJECTIVE: To examine the relationships of numerous reproductive factors and exogenous hormone use with long-term risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in women. METHODS: A total of 260,108 women without prevalent CKD and ESRD were included. The relationships of various reproductive factors and exogenous hormone use with incident CKD and ESRD were assessed, with multivariable adjustment for potential confounders. RESULTS: During a median of ∼12.5 years of follow-up, 8,766 CKD and 554 ESRD cases were identified. Younger age at first live birth, hysterectomy or bilateral oophorectomy before 50 years old, menopausal before 45 years old, and menopausal hormone therapy (MHT) initiated before 50 years old was associated with a higher risk of CKD. The relationships of these factors with ESRD were generally consistent with those for CKD. Each 5-year increment in menopausal age was associated with an 11% lower risk of CKD (HR = 0.89; 95% CI: 0.87, 0.91) and a 13% lower risk of ESRD (HR = 0.87; 95% CI: 0.79, 0.95). Each 5-year delay in starting MHT was associated with a 13% lower risk of CKD (HR = 0.87; 95% CI: 0.84, 0.90) and a 15% lower risk of ESRD (HR = 0.85; 95% CI: 0.73, 0.99). CONCLUSION: Several reproductive characteristics reflecting shorter cumulative exposure to endogenous estrogen or premature exposure to exogenous hormones are associated with a greater risk of CKD and ESRD in women, supporting a potential role of female hormones in renal pathophysiology.

Phosphine-Catalyzed Stereospecific and Enantioselective Desymmetrizative [3+2] Cycloaddition of MBH Carbonates and N-(2-tert-Butylphenyl)maleimides.

Herein, we report an l-valine-derived amide phosphine-catalyzed [3+2] cyclization of MBH carbonates and N-(2-tert-butylphenyl)maleimides via asymmetric desymmetrization. Bicyclic N-aryl succinimide derivatives bearing three continuous chiral centers with a remote C-N atropisomeric chirality were constructed stereospecifically and enantioselectively. A wide variety of MBH carbonates could be employed in this process to deliver highly optically pure succinimide derivatives in moderate to excellent yields.

Inhibition of Mettl3 ameliorates osteoblastic senescence by mitigating m6A modifications on Slc1a5 via Igf2bp2-dependent mechanisms.

Age-related osteoporosis is characterized by a marked decrease in the number of osteoblasts, which has been partly attributed to the senescence of cells of the osteoblastic lineage. Epigenetic studies have provided new insights into the mechanisms of current osteoporosis treatments and bone repair pathophysiology. N6-methyladenosine (m6A) is a novel transcript modification that plays a major role in cellular senescence and is essential for skeletal development and internal environmental stability. Bioinformatics analysis revealed that the expression of the m6A reading protein Igf2bp2 was significantly higher in osteoporosis patients. However, the role of Igf2bp2 in osteoblast senescence has not been elucidated. In this study, we found that Igf2bp2 levels are increased in ageing osteoblasts induced by multiple repetition and H2O2. Increasing Igf2bp2 expression promotes osteoblast senescence by increasing the stability of Slc1a5 mRNA and inhibiting cell cycle progression. Additionally, Mettl3 was identified as Slc1a5 m6A-methylated protein with increased m6A modification. The knockdown of Mettl3 in osteoblasts inhibits the reduction of senescence, whereas the overexpression of Mettl3 promotes the senescence of osteoblasts. We found that administering Cpd-564, a specific inhibitor of Mettl3, induced increased bone mass and decreased bone marrow fat accumulation in aged rats. Notably, in an OVX rat model, Igf2bp2 small interfering RNA delivery also induced an increase in bone mass and decreased fat accumulation in the bone marrow. In conclusion, our study demonstrated that the Mettl3/Igf2bp2-Slc1a5 axis plays a key role in the promotion of osteoblast senescence and age-related bone loss.

The salvage lenvatinib-based regimen provides survival benefit in patients with refractory metastatic colorectal cancer.

Salvage treatment for refractory metastatic colorectal cancer (mCRC) has yet to be identified. We aimed to evaluate the efficacy of a salvage lenvatinib-based regimen for refractory mCRC. In total, 371 patients were categorized into lenvatinib-based and non-lenvatinib-based groups. In the lenvatinib-based group, patients who received lenvatinib at a dosage of 10 mg/day were categorized into lenvatinib/chemotherapy and lenvatinib/immunotherapy subgroups. We reported overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. OS1 was used to measure the time from disease progression after TAS-102 and regorafenib treatment to death, while OS2 was used to measure the time from TAS-102 or regorafenib treatment to death. Propensity score matching analysis was employed to compare the characteristics between the lenvatinib-based and non-lenvatinib-based groups. Next-generation sequencing (NGS) information was analyzed using R software. The lenvatinib-based group exhibited longer OS than did the non-lenvatinib-based group (OS1, 11.4 vs. 3.7 months; OS2, 27.2 vs. 8.2 months). The disease control rate (DCR) and objective response rate (ORR) of the lenvatinib-based regimens were 69.4% and 6.1%, respectively. Lenvatinib/chemotherapy and lenvatinib/immunotherapy had similar PFS, OS, DCR, and ORR. The adverse effects were manageable. After propensity score matching, the lenvatinib-based group continued to exhibit significantly longer OS1 and OS2 than did the non-lenvatinib-based group. NGS analysis revealed that GNAS and KRAS alterations were associated with a worse treatment response and prolonged survival, respectively. In conclusion, a moderate-dose salvage lenvatinib-based regimen demonstrated promising clinical activity and tolerability in treating refractory mCRC.

An investigation of germline variants of HAVCR2 in subcutaneous panniculitis-like T-cell lymphoma and related lesions in a North American population.

Not available.

Quantifying changes in oxygen saturation of the internal jugular vein in vivo using deep neural networks and subject-specific three-dimensional Monte Carlo models.

Central venous oxygen saturation (ScvO2) is an important parameter for assessing global oxygen usage and guiding clinical interventions. However, measuring ScvO2 requires invasive catheterization. As an alternative, we aim to noninvasively and continuously measure changes in oxygen saturation of the internal jugular vein (SijvO2) by a multi-channel near-infrared spectroscopy system. The relation between the measured reflectance and changes in SijvO2 is modeled by Monte Carlo simulations and used to build a prediction model using deep neural networks (DNNs). The prediction model is tested with simulated data to show robustness to individual variations in tissue optical properties. The proposed technique is promising to provide a noninvasive tool for monitoring the stability of brain oxygenation in broad patient populations.

Second opinion for pulmonary and pleural cytology is valuable for patient care.

INTRODUCTION: Thoracic cytology can be challenging due to limited procured material or overlapping morphology between benign and malignant entities. In such cases, expert consultation might be sought. This study aimed to characterize all pulmonary and pleural cytology consult cases submitted to our practice and provide recommendations on approaching difficult cases. MATERIALS AND METHODS: All thoracic (pulmonary and pleural) cytology cases submitted for expert consultation to the University of Michigan (MLabs) from 2013 to mid-2022 were reviewed. Cases where cytology was only part of a hematopathology or surgical pathology consult were excluded. Patient demographics, specimen location, procedure performed, referring diagnosis, and our diagnoses were recorded for each case. Diagnoses were categorized according to the Papanicolaou Society of Cytopathology recommendations for pulmonary and effusion cytology. Discordant diagnoses were stratified as major or minor. Data was analyzed using chi-square analysis and logistic models. RESULTS: We received 784 thoracic cytology consult cases, including 530 exfoliative samples and 307 fine-needle aspirations. The most common anatomic locations sampled were the bronchial wall (n = 194, 23%), lung nodule (n = 322, 38%), and pleura (n = 296, 35%). 413 cases had a diagnostic discrepancy (48.3%), with 274 (66%) minor and 139 (34%) major discrepancies. By location, pleural effusion specimens had the highest probability of a discrepant diagnosis (P = 0.003). By specimen type, fine-needle aspiration samples were significantly more likely to have a discrepant diagnosis (P = 0.06). CONCLUSION: Nearly half of the thoracic cytology cases submitted for expert second opinion had diagnostic discrepancies. Consequently, consulting a tertiary medical care center with cytopathology expertise for challenging thoracic cytology diagnoses is beneficial.

Unlocking Single Particle Anisotropy in Real-Time for Photoelectrochemistry Processes at the Nanoscale.

The key to rationally and rapidly designing high-performance materials is the monitoring and comprehension of dynamic processes within individual particles in real-time, particularly to gain insight into the anisotropy of nanoparticles. The intrinsic property of nanoparticles typically varies from one crystal facet to the next under realistic working conditions. Here, we introduce the operando collision electrochemistry to resolve the single silver nanoprisms (Ag NPs) anisotropy in photoelectrochemistry. We directly identify the effect of anisotropy on the plasmonic-assisted electrochemistry at the single NP/electrolyte interface. The statistical collision frequency shows that heterogeneous diffusion coefficient among crystal facets facilitates Ag NPs to undergo direction-dependent mass transfer toward the gold ultramicroelectrode. Subsequently, the current amplitudes of transient events indicate that anisotropy enables variations in dynamic interfacial electron transfer behaviors during photothermal processes. The results presented here demonstrate that the measurement precision of collision electrochemistry can be extended to the sub-nanoparticle level, highlighting the potential for high-throughput material screening with comprehensive kinetics information at the nanoscale.

Anomalous Structural Transformation of Cu(I) Clusters into Multifunctional CuAg Nanoclusters.

We report an anomalous structural transformation of a Cu(I) cluster into two different types of copper-silver (CuAg) alloy nanoclusters. Different from previous reports, we demonstrate that under specifically designed reaction conditions, the Ag-doping could induce a substantial growth of the starting Cu15 and a Ag13Cu20 nanocluster was obtained via the unexpected insertion of an Ag13 kernel inside the Cu(I)-S shell. Ag13Cu20 demonstrates high activity to initiate the photopolymerization of previously hard-to-print inorganic polymers in 3D laser microprinting. Interestingly, a slight modification of the reaction condition leads to the formation of another Ag18-xCuxS (8≤x) nanocluster templated by a central S2- anion, which possesses a unique electronic structure compared to conventional template-free CuAg nanoclusters. Overall, this work unveils the intriguing doping chemistry of Cu clusters, as well as their capability to create different types of alloy nanoclusters with previously unobtainable structures and multifunctionality.

Furosemide and Ductus Arteriosus Closure in Very-Low-Birth-Weight Preterm Infants: A Comprehensive Retrospective Study.

Ductus arteriosus closure may be delayed in preterm infants, and prostaglandin, a vasodilator, can affect ductal patency. Furosemide can increase renal prostaglandin synthesis, so its net effect on patent ductus arteriosus (PDA) is uncertain. Our goal is to explore the relationship between furosemide and spontaneous ductal closure in very-low-birth-weight preterm infants. Our treatment for PDA involves fluid restriction initially and furosemide administration for hemodynamically significant PDA until closure is confirmed by the echocardiogram. We enrolled 105 infants from 1 January 2019 to 30 June 2022 and evaluated the impact of furosemide on ductal closure, including exposure duration and cumulative dose. There is no correlation between furosemide exposure and spontaneous ductal closure (p = 0.384). Furosemide exposure does not delay the postmenstrual age at which spontaneous ductal closure occurs (p = 0.558). The time for spontaneous ductal closure is positively associated with furosemide prescription days (coefficient value = 0.547, p = 0.026) and negatively with gestational age (coefficient value = -0.384, p = 0.062). The prescription of furosemide does not impact the probability or time duration of ductus arteriosus spontaneous closure. The cumulative dose of furosemide has minimal impact on ductal closure. The correlation between furosemide exposure duration and ductal patency duration is likely due to our treatment protocol, with gestational age being a significant factor.

Widespread reductions in cortical thickness following ketamine abuse.

BACKGROUND: Esketamine is a version of ketamine that has been approved for treatment-resistant depression, but our previous studies showed a link between non-medical use of ketamine and brain structural and functional alterations, including dorsal prefrontal grey matter reduction among chronic ketamine users. In this study, we sought to determine cortical thickness abnormalities following long-term, non-medical use of ketamine. METHODS: We acquired structural brain images for patients with ketamine use disorder and drug-free healthy controls. We used FreeSurfer software to measure cortical thickness for 68 brain regions. We compared cortical thickness between the 2 groups using analysis of covariance with covariates of age, gender, educational level, smoking, drinking, and whole-brain mean cortical thickness. RESULTS: We included images from 95 patients with ketamine use disorder and 169 controls. Compared with healthy controls, patients with ketamine use disorder had widespread decreased cortical thickness, with the most extensive reductions in the frontal (including the dorsolateral prefrontal cortex) and parietal (including the precuneus) lobes. Increased cortical thickness was not observed among ketamine users relative to comparison participants. Estimated total lifetime ketamine consumption was correlated with reductions in the right inferior parietal and the right rostral middle frontal cortical thickness. LIMITATIONS: We conducted a retrospective cross-sectional study, but longitudinal studies are needed to further validate decreased cortical thickness after nonmedical use of ketamine. CONCLUSION: This study provided evidence that, compared with healthy controls, chronic ketamine users have widespread reductions in cortical thickness. Our study underscores the importance of the long-term effects of ketamine on brain structure and serves as a reference for the antidepressant use of ketamine.

AGR2-mediated unconventional secretion of 14-3-3ε and α-actinin-4, responsive to ER stress and autophagy, drives chemotaxis in canine mammary tumor cells.

BACKGROUND: Canine mammary tumors (CMTs) in intact female dogs provide a natural model for investigating metastatic human cancers. Our prior research identified elevated expression of Anterior Gradient 2 (AGR2), a protein disulfide isomerase (PDI) primarily found in the endoplasmic reticulum (ER), in CMT tissues, highly associated with CMT progression. We further demonstrated that increased AGR2 expression actively influences the extracellular microenvironment, promoting chemotaxis in CMT cells. Unraveling the underlying mechanisms is crucial for assessing the potential of therapeutically targeting AGR2 as a strategy to inhibit a pro-metastatic microenvironment and impede tumor metastasis. METHODS: To identify the AGR2-modulated secretome, we employed proteomics analysis of the conditioned media (CM) from two CMT cell lines ectopically expressing AGR2, compared with corresponding vector-expressing controls. AGR2-regulated release of 14-3-3ε (gene: YWHAE) and α-actinin 4 (gene: ACTN4) was validated through ectopic expression, knockdown, and knockout of the AGR2 gene in CMT cells. Extracellular vesicles derived from CMT cells were isolated using either differential ultracentrifugation or size exclusion chromatography. The roles of 14-3-3ε and α-actinin 4 in the chemotaxis driven by the AGR2-modulated CM were investigated through gene knockdown, antibody-mediated interference, and recombinant protein supplement. Furthermore, the clinical relevance of the release of 14-3-3ε and α-actinin 4 was assessed using CMT tissue-immersed saline and sera from CMT-afflicted dogs. RESULTS: Proteomics analysis of the AGR2-modulated secretome revealed increased abundance in 14-3-3ε and α-actinin 4. Ectopic expression of AGR2 significantly increased the release of 14-3-3ε and α-actinin 4 in the CM. Conversely, knockdown or knockout of AGR2 expression remarkably reduced their release. Silencing 14-3-3ε or α-actinin 4 expression diminished the chemotaxis driven by AGR2-modulated CM. Furthermore, AGR2 controls the release of 14-3-3ε and α-actinin 4 primarily via non-vesicular routes, responding to the endoplasmic reticulum (ER) stress and autophagy activation. Knockout of AGR2 resulted in increased α-actinin 4 accumulation and impaired 14-3-3ε translocation in autophagosomes. Depletion of extracellular 14-3-3ε or α-actinin 4 reduced the chemotaxis driven by AGR2-modulated CM, whereas supplement with recombinant 14-3-3ε in the CM enhanced the CM-driven chemotaxis. Notably, elevated levels of 14-3-3ε or α-actinin 4 were observed in CMT tissue-immersed saline compared with paired non-tumor samples and in the sera of CMT dogs compared with healthy dogs. CONCLUSION: This study elucidates AGR2's pivotal role in orchestrating unconventional secretion of 14-3-3ε and α-actinin 4 from CMT cells, thereby contributing to paracrine-mediated chemotaxis. The insight into the intricate interplay between AGR2-involved ER stress, autophagy, and unconventional secretion provides a foundation for refining strategies aimed at impeding metastasis in both canine mammary tumors and potentially human cancers.

The efficacy of nutritional screening indexes in predicting the incidence of osteosarcopenia and major osteoporotic fracture in the elderly.

INTRODUCTION: The effect of nutritional status on osteosarcopenia (OS) and major osteoporotic fracture (MOF) among the elderly is still unclear. So we aimed to compare the efficacy of the Mini-Nutrition Assessment-Short Form (MNA-sf), the Geriatric Nutritional Risk Index (GNRI) and Controlling Nutritional Status (CONUT) for predicting OS and MOF among the elderly. MATERIALS AND METHODS: A total of 409 participants were enrolled in this prospective study. Blood biochemical indexes, nutritional status, and bone- and muscle-related examinations were assessed at initial visit to the outpatient. Participants were divided into 4 groups: (1) control; (2) osteopenia/osteoporosis; (3) sarcopenia; (4) osteosarcopenia, and then followed for 5 years, recording the occurrence time of MOF. RESULTS: The frequency values of osteopenia/osteoporosis, sarcopenia, and OS, at baseline, were respectively 13.4, 16.1, and 12% among the study samples. Correlation analysis showed that nutritional status scores were associated with body mass index, handgrip strength, albumin, bone mineral density, and physical functions. According to multivariate models, poor nutritional status was significantly associated with a higher risk of OS and MOF (P < 0.05). Survival analysis showed that the MOF rate in malnutrition group was significantly higher than normal nutrition group (P < 0.05). The receiver operator characteristic curve shows that the value of MNA-sf to diagnose OS and MOF is greater (P < 0.05). CONCLUSION: The poor nutritional status was associated with a higher risk of both OS and MOF. MNA-sf showed a superior diagnostic power for OS and MOF among the elderly. Early nutrition assessments and interventions may be key strategies to prevent OS and fractures.

Targeting cathepsin S promotes activation of OLF1-BDNF/TrkB axis to enhance cognitive function.

BACKGROUND: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions. METHODS: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss-/- mice, Ctss+/+ mice and Ctss+/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions. RESULTS: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis. CONCLUSION: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.

Treatment strategies for progressive immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: case series.

Not available.

Toward Accurate Quantum Mechanical Thermochemistry: (1) Extensible Implementation and Comparison of Bond Additivity Corrections and Isodesmic Reactions.

Obtaining accurate enthalpies of formation of chemical species, ΔHf, often requires empirical corrections that connect the results of quantum mechanical (QM) calculations with the experimental enthalpies of elements in their standard state. One approach is to use atomization energy corrections followed by bond additivity corrections (BACs), such as those defined by Petersson et al. or Anantharaman and Melius. Another approach is to utilize isodesmic reactions (IDRs) as shown by Buerger et al. We implement both approaches in Arkane, an open-source software that can calculate species thermochemistry using results from various QM software packages. In this work, we collect 421 reference species from the literature to derive ΔHf corrections and fit atomization energy corrections and BACs for 15 commonly used model chemistries. We find that both types of BACs yield similar accuracy, although Anantharaman- and Melius-type BACs appear to generalize better. Furthermore, BACs tend to achieve better accuracy than IDRs for commonly used model chemistries, and IDRs can be less robust because of the sensitivity to the chosen reference species and reactions. Overall, Anantharaman- and Melius-type BACs are our recommended approach for achieving accurate QM corrections for enthalpies.

TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti-PD-1 tumor immunotherapy.

The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.

Associations of urinary polycyclic aromatic hydrocarbon (PAH) metabolites and their mixture with thyroid hormone concentration during pregnancy in the LIFECODES cohort: A repeated measures study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are endocrine disruptors resulting from incomplete combustion. Pregnancy represents a particularly vulnerable period to such exposures, given the significant influence of hormone physiology on fetal growth and pregnancy outcomes. Maternal thyroid hormones play crucial roles in fetal development and pregnancy outcomes. However, limited studies have examined gestational PAH exposure and maternal thyroid hormones during pregnancy. METHODS: Our study included 439 women enrolled in the LIFECODES birth cohort in Boston, aiming to explore the relationship between urinary PAH metabolites and thyroid hormones throughout pregnancy. Urine samples for PAH metabolite analysis and plasma samples for thyroid hormone were measured up to four visits throughout gestation. Single pollutant analyses employed linear mixed effect models to investigate individual associations between each PAH metabolite and thyroid hormone concentration. Sensitivity analyses were conducted to assess potential susceptibility windows and fetal-sex-specific effects of PAH exposure. Mixture analyses utilized quantile g-computation to evaluate the collective impact of eight PAH metabolites on thyroid hormone concentrations. Additionally, Bayesian kernel machine regression (BKMR) was employed to explore potential non-linear associations and interactions between PAH metabolites. Subject-specific random intercepts were incorporated to address intra-individual correlation of serial measurements over time in both single pollutant and mixture analyses. RESULTS: Our findings revealed positive trends in associations between PAH metabolites and thyroid hormones, both individually and collectively as a mixture. Sensitivity analyses indicated that these associations were influenced by the study visit and fetal sex. Mixture analyses suggested non-linear relationships and interactions between different PAH exposures. CONCLUSIONS: This comprehensive investigation underscores the critical importance of understanding the impact of PAH exposures on thyroid hormone physiology during pregnancy. The findings highlight the intricate interplay between environmental pollutants and human pregnancy physiology, emphasizing the need for targeted interventions and public health policies to mitigate adverse outcomes associated with prenatal PAH exposure.