Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR.

Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).

Association between the triglyceride-glucose index and cognitive impairment in China: a community population-based cross-sectional study.

INTRODUCTION: Insulin resistance (IR) is a feature of metabolic syndrome and plays an important role in cognitive impairment (CI). The triglyceride-glucose (TyG) index is a convenient and cost-effective surrogate for assessing IR. This study aimed to assess the association between the TyG index and CI. METHODS: This community population-based cross-sectional study used a cluster-sampling methodology. All participants underwent the education-based Mini-Mental State Examination (MMSE), and those with CI were identified using standard thresholds. The fasting blood triglyceride and glucose levels were measured in the morning, and the TyG index was calculated as ln (½ fasting triglyceride level [mg/dL] × fasting blood glucose level [mg/dL]). Multivariable logistic regression and subgroup analysis were used to assess the relationship between the TyG index and CI. RESULTS: This study included 1484 subjects, of which 93 (6.27%) met the CI criteria. Multivariable logistic regression showed that CI incidence increased by 64% per unit increase in the TyG index (odds ratio [OR] = 1.64, 95% confidence interval [CI]: 1.02-2.63, p = 0.042). CI risk was 2.64-fold higher in the highest TyG index quartile compared to the lowest TyG index quartile (OR = 2.64, 95% CI: 1.19-5.85, p = 0.016). Finally, interaction analysis showed that sex, age, hypertension, and diabetes did not significantly affect the association between the TyG index and CI. CONCLUSION: The present study suggested that an elevated TyG index was associated with a higher CI risk. Subjects with a higher TyG index should manage and treat at an early stage to alleviate the cognitive decline.

Effects of aluminum (Al) stress on the isoprenoid metabolism of two Citrus species differing in Al-tolerance.

Isoprenoid metabolism and its derivatives took part in photosynthesis, growth regulation, signal transduction, and plant defense to biotic and abiotic stresses. However, how aluminum (Al) stress affects the isoprenoid metabolism and whether isoprenoid metabolism plays a vital role in the Citrus plants in coping with Al stress remain unclear. In this study, we reported that Al-treatment-induced alternation in the volatilization rate of monoterpenes (α-pinene, ß-pinene, limonene, α-terpinene, γ-terpinene and 3-carene) and isoprene were different between Citrus sinensis (Al-tolerant) and C. grandis (Al-sensitive) leaves. The Al-induced decrease of CO2 assimilation, maximum quantum yield of primary PSII photochemistry (Fv/Fm), the lower contents of glucose and starch, and the lowered activities of enzymes involved in the mevalonic acid (MVA) pathway and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway might account for the different volatilization rate of isoprenoids. Furthermore, the altered transcript levels of genes related to isoprenoid precursors and/or derivatives metabolism, such as geranyl diphosphate (GPP) synthase (GPPS) in GPP biosynthesis, geranylgeranyl diphosphate synthase (GGPPS), chlorophyll synthase (CHS) and GGPP reductase (GGPPR) in chlorophyll biosynthesis, limonene synthase (LS) and α-pinene synthase (APS) in limonene and α-pinene synthesis, respectively, might be responsible for the different contents of corresponding products in C. grandis and C. sinensis. Our data suggested that isoprenoid metabolism was involved in Al tolerance response in Citrus, and the alternation of some branches of isoprenoid metabolism could confer different Al-tolerance to Citrus species.

Predictors of gastrointestinal bleeding in patients with acute coronary syndrome and the optimal duration of dual antiplatelet therapy.

Background: This study aims to estimate the risk factors of gastrointestinal (GI) bleeding in patients with acute coronary syndrome (ACS) and to evaluate the optimal duration of dual antiplatelet therapy (DAPT). Materials and Methods: We enrolled 1266 patients with ACS in a telephone follow-up program to determine whether any of the patients were hospitalized for GI bleeding. We collected baseline data, laboratory tests, electrocardiograms, and echocardiography covering all ACS patients. Multivariable regression was performed to adjust for confounders and predictors of GI bleeding. At the same time, the optimal duration of DAPT for ACS patients was evaluated. Results: A total of 1061 ACS patients were included in the study. After 13-68 months, 48 patients (4.5%) were hospitalized for GI bleeding. The risk of GI bleeding was significantly increased in patients treated with DAPT for more than 18 months (hazard ratio 12.792, 5.607-29.185, P < 0.01). Receiver Operating Characteristic curve showed that the duration of DAPT using a cutoff of 14.5 months resulted in a sensitivity of 66.7% and a specificity of 77%. Conclusion: In patients with ACS, DAPT time are the main risk factors of GI bleeding. The optimal duration of DAPT is 14.5 months.

Biomarkers of gut barrier dysfunction and risk of hepatocellular carcinoma in the REVEAL-HBV and REVEAL-HCV cohort studies.

Gut barrier dysfunction can result in the liver being exposed to an elevated level of gut-derived bacterial products via portal circulation. Growing evidence suggests that systemic exposure to these bacterial products promotes liver diseases including hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, prospective studies have not examined the association between biomarkers of gut barrier dysfunction and HCC risk in a population of hepatitis B or C viral (HBV/HCV) carriers. We investigated whether prediagnostic, circulating biomarkers of gut barrier dysfunction were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-HBV and REVEAL-HCV cohorts from Taiwan. REVEAL-HBV included 185 cases and 161 matched controls, and REVEAL-HCV 96 cases and 96 matched controls. The biomarkers quantitated were immunoglobulin A (IgA), IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and LPS-binding protein (LBP). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarker levels and HCC were calculated using multivariable-adjusted logistic regression. A doubling of the circulating levels of antiflagellin IgA or LBP was associated with a 76% to 93% increased risk of HBV-related HCC (OR per one unit change in log2 antiflagellin IgA = 1.76, 95% CI: 1.06-2.93; OR for LBP = 1.93, 95% CI: 1.10-3.38). None of the other markers were associated with an increased risk of HBV-related or HCV-related HCC. Results were similar when cases diagnosed in the first 5 years of follow-up were excluded. Our findings contribute to understanding the interplay of gut barrier dysfunction and primary liver cancer etiology.

Effectiveness and safety of radiotherapy plus programmed death-1 inhibitors and lenvatinib in patients with advanced biliary tract carcinoma: a real-world study.

BACKGROUND: Radiotherapy (RT) may function synergistically with immunotherapy and targeted agents (TA). This study aimed to assess the effectiveness and safety of RT combined with programmed death-1 (PD-1) inhibitors and lenvatinib in patients with relapsed or refractory advanced biliary tract carcinoma (BTC). METHODS: This retrospective study included patients with relapsed or refractory advanced BTC who received RT combined with PD-1 inhibitors and lenvatinib at the Peking Union Medical College Hospital (PUMCH). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated. RESULTS: Thirty-one patients who received RT combined with PD-1 inhibitors and lenvatinib as a second- or later-line therapy were analyzed. RT sites were mainly distributed in the liver lesions (64.5%) and lymph nodes (58.1%). The ORR and DCR were 32.3% (10/31; 95% CI: 14.8-49.7) and 87.1% (27/31; 95% CI: 74.6-99.6), respectively. The median PFS (mPFS) and median OS (mOS) were 7.9 (95% CI: 7.1-8.7) and 11.7 (95% CI: 8.3-15.0) months, respectively. Subgroup analyses of this cohort included 12 and 19 patients who received concurrent and salvage (> 6 weeks after commencing PD-1 inhibitor therapy) RT, respectively. The salvage RT group had higher mOS (11.7 vs. 10.5; p = 0.75) and mPFS (7.9 vs. 6.9; p = 0.85) than the concurrent RT group; however, statistical significance was not reached. All patients experienced any-grade adverse events (AEs), and excessive PD-1 inhibitors or RT toxicity were not observed. CONCLUSIONS: RT, PD-1 inhibitors, and lenvatinib may be safely combined and have antitumor effectiveness in patients with advanced BTC.

Efficacy, safety, and prognostic factors of PD-1 inhibitors combined with lenvatinib and Gemox chemotherapy as first-line treatment in advanced intrahepatic cholangiocarcinoma: a multicenter real-world study.

BACKGROUND: A programmed cell death protein-1 (PD-1) inhibitor combined with lenvatinib and Gemox chemotherapy as first-line therapy demonstrated high anti-tumor activity against biliary tract cancer in phase II clinical trials. Herein, we aimed to investigate the efficacy and safety for advanced intrahepatic cholangiocarcinoma (ICC) in a multicenter real-world study. METHODS: Patients with advanced ICC who received PD-1 inhibitor combined with lenvatinib and Gemox chemotherapy were retrospectively screened at two medical centers. The primary endpoints were overall survival (OS) and progression-free survival (PFS), whereas the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors for survival were analyzed. RESULTS: Fifty-three patients with advanced ICC were included in this study. The median follow-up time was 13.7 (95% confidence interval (CI): 12.9-17.2) months. The median OS and PFS were 14.3 (95% CI: 11.3-NR) and 8.63 (95% CI: 7.17-11.6) months, respectively. The ORR, DCR, and clinical benefit rate were 52.8, 94.3, and 75.5%, respectively. In the multivariate analysis, the tumor burden score (TBS), tumor-node metastasis classification (TNM) stage, and PD-L1 expression were independent prognostic factors for OS and PFS. All patients experienced adverse events (AEs), 41.5% (22/53) experienced grade 3 or 4 AEs, including fatigue (8/53, 15.1%) and myelosuppression (7/53, 13.2%). No grade 5 AEs were reported. CONCLUSION: PD-1 inhibitors combined with lenvatinib and Gemox chemotherapy represent an effective and tolerable regimen for advanced ICC in a multicenter retrospective real-world study. TBS, TNM stage, and PD-L1 expression can be used as potential prognostic factors for OS and PFS.

Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells.

Chimeric antigen receptor (CAR) T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell-associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Among 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase, and occasionally hemophagocytosis. Development of carHLH was associated with preinfusion natural killer(NK) cell lymphopenia and higher bone marrow T-cell:NK cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK cell lymphopenia amplified preinfusion differences in those with carHLH without evidence for defects in NK cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.

Development and validation of a selenium metabolism regulators associated prognostic model for hepatocellular carcinoma.

BACKGROUND: Selenium metabolism has been implicated in human health. This study aimed to identify a selenium metabolism regulator-based prognostic signature for hepatocellular carcinoma (HCC) and validate the role of INMT in HCC. METHODS: Transcriptome sequencing data and clinical information related to selenium metabolism regulators in TCGA liver cancer dataset were analysed. Next, a selenium metabolism model was constructed by multiple machine learning algorithms, including univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses. Then, the potential of this model for predicting the immune landscape of different risk groups was evaluated. Finally, INMT expression was examined in different datasets. After knockdown of INMT, cell proliferation and colony formation assays were conducted. RESULTS: A selenium metabolism model containing INMT and SEPSECS was established and shown to be an independent predictor of prognosis. The survival time of low-risk patients was significantly longer than that of high-risk patients. These two groups had different immune environments. In different datasets, including TCGA, GEO, and our PUMCH dataset, INMT was significantly downregulated in HCC tissues. Moreover, knockdown of INMT significantly promoted HCC cell proliferation. CONCLUSIONS: The current study established a risk signature of selenium metabolism regulators for predicting the prognosis of HCC patients. INMT was identified as a biomarker for poor prognosis of HCC.

A novel framework for vegetation change characterization from time series landsat images.

Understanding terrestrial ecosystem dynamics requires a comprehensive examination of vegetation changes. Remote sensing technology has been established as an effective approach to reconstructing vegetation change history, investigating change properties, and evaluating the ecological effects. However, current remote sensing techniques are primarily focused on break detection but ignore long-term trend analysis. In this study, we proposed a novel framework based on a change detection algorithm and a trend analysis method that could integrate both short-term disturbance detection and long-term trends to comprehensively assess vegetation change. With this framework, we characterized the vegetation changes in Zhejiang Province from 1990 to 2020 using Landsat and landcover data. Benefiting from combining break detection and long-term trend analysis, the framework showcased its capability of capturing a variety of dynamics and trends of vegetation. The results show that the vegetation was browning in the plains while greening in the mountains, and the overall vegetation was gradually greening during the study period. By comparison, detected vegetation disturbances covered 57.71% of the province's land areas (accounting for 66.92% of the vegetated region) which were mainly distributed around the built-up areas, and most disturbances (94%) occurred in forest and cropland. There were two peak timings in the frequency of vegetation disturbances: around 2003 and around 2014, and the proportions of more than twice disturbances in a single location were low. The results illustrate that this framework is promising for the characterization of regional vegetation growth, including long-term trends and short-term features. The proposed framework enlightens a new direction for the continuous monitoring of vegetation dynamics.

Association between oral infections, triglyceride-glucose index, and in-stent restenosis.

OBJECTIVES: To investigate oral infections in patients suffering in-stent restenosis (ISR) and non-ISR and analyze the possible correlation between the oral infection and triglyceride-glucose (TyG) index, a clinical surrogate indicator of insulin resistance (IR). MATERIALS AND METHODS: A cross-sectional design was used, in which 586 patients with acute coronary syndrome who underwent coronary angiography 6-24 months after coronary stent implantation were recruited. The modified total dental index (TDI) was used to evaluate the status of oral inflammation. RESULTS: In both univariate analyses, TDI scores [3 (1.5, 4.5) vs. 2.5 (1.5, 4.0), p < 0.01] and a multivariate regression model (OR = 1.202, 95% CI = 1.085-1.333, p < 0.01), the TDI significantly correlated with ISR. The TyG index was positively associated with ISR (OR = 1.766, 95% CI = 1.055-2.957, p < 0.05). Correlation analysis showed that TDI was positively correlated with TyG index (r = 0.190, p < 0.01). Using linear regression analysis, higher TDI scores were significantly associated with IR (95% CI = 0.029-0.063, p < 0.01). CONCLUSIONS: Oral infections and TyG index were independently and positively correlated with ISR in patients with acute coronary syndrome. Oral inflammatory burden assessed by TDI score was associated with IR.

Virulence Variability and Genetic Diversity in Blumeria graminis f. sp. hordei in Southeastern and Southwestern China.

Powdery mildew is a key airborne foliar disease of barley in southeastern and southwestern China. Barley varieties usually partially or wholly lose resistance to the pathogen Blumeria graminis (DC.) f. sp. hordei 3 to 5 years after release due to the frequent acquirements of new virulences in the pathogen population. However, no B. graminis f. sp. hordei virulence detection has been carried out in the recent decade and, thus, no information is available on the present virulence components and major pathotypes in epidemic regions. Twenty-one near-isogenic lines of Pallas were selected to detect B. graminis f. sp. hordei virulence variation, with 97 pathotypes identified from the isolates collected from 2015 to 2019. The virulence complexities ranged from 1 to 12, with 1.5 isolates on average assigned per pathotype, suggesting a natural trait of high pathotype diversity and low virulence complexity in the Chinese B. graminis f. sp. hordei populations. Eleven high-virulence pathotypes were detected in the traditional barley-growing regions in Yunnan and Zhejiang. Six virulent pathotypes to resistance gene mlo-5 were detected only in the two traditional epidemic regions, with a virulence frequency (VF) of 4.8% (7 of 147). Compared with the results from a decade ago, VFs for resistance alleles Mla3, mlo-5, Mla6 + Mla14, Mla7 + Mlk, Mlg + MlCP, and Mla13 + MlRu3 + MlaRu4 increased from 0 to 0.7 to 25.8%. Isolates from Yunnan and Zhejiang had similar virulence profiles, which differed from those identified in Tibet. In addition, genetic diversities differed in the isolate groups collected from Tibet, Yunnan, and Zhejiang.

The link between different infection forms of Porphyromonas gingivalis and acute myocardial infarction: a cross-sectional study.

BACKGROUND: Porphyromonas gingivalis (Pg) is one of the keystone pathogens involved in periodontitis. The present study aimed to observe the relationship among different infection forms of Pg, systemic inflammation, and acute myocardial infarction (AMI). METHODS: A total of 382 patients diagnosed with AMI and 78 patients without coronary heart disease (CHD) were included in the study. DNA from exfoliated oral cells, circulating cell-free DNA (cfDNA), and genomic DNA (gDNA) from blood samples were extracted. The qPCR method was employed to detect Pg infection. Clinical characteristics, inflammatory parameters, and severity of coronary artery lesions of the patients were analyzed and compared. RESULTS: Both the oral colonization and distant invasion of Pg correlated positively with systemic inflammation. Multivariate logistic regression analysis suggested that Pg positivity in gDNA was correlated with the risk of AMI [Model 1 (odds ratio (OR) = 1.917, 95% confidence interval (CI) 1.108-3.315), Model 2 (OR = 1.863, 95% CI 1.064-3.262), and Model 3 (OR = 1.853, 95% CI 1.042-3.295); p < 0.05]. Pg positivity in cfDNA and gDNA was related to the severity of coronary artery lesions (cfDNA-positive cases, adjusted OR = 1.577, p < 0.05; gDNA-positive cases, adjusted OR = 1.976, p < 0.01). CONCLUSIONS: The distant invasion and colonization of Pg were the risk factors of AMI. They also affected the severity of CHD, indicating that periodontitis severity and distant invasion of periodontal pathogens were related to CHD. The presence of Pg was likely able to drive systemic inflammation, suggesting that there was an inflammatory relationship between periodontitis and AMI.

A real-world study of the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer.

BACKGROUND: Anti-PD-1 antibodies plus lenvatinib therapeutic regimens have demonstrated a relatively high antitumor response in many solid cancers; however, the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer (GBC) has not been reported. METHODS: Advanced GBC patients who received anti-PD-1 antibodies plus lenvatinib were retrospectively screened. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), PD-L1 expression and safety were evaluated to identify efficacy biomarkers. RESULTS: A total of 31 GBC patients were included in this study. After a median follow-up of 8 months and 23 deaths were observed. The median PFS was 5.0 months (95% CI: 4.1-8.0 months), and the median OS was 11.3 months (95% CI: 7.5-20.9 months). Overall, the ORR was 32.3%, the DCR was 83.9%, and the CBR was 41.9%. Moreover, after treatment, 3 patients received conventional surgery, in which 1 patient achieved a pathological complete response. All patients (100%) experienced adverse events (AEs), and 58.1% of the patients experienced grade 3 AEs. The most commonly observed grade 3 AEs included fatigue (5/31, 16.1%), decreased appetite (5/31, 16.1%), hypertension (4/31, 12.9%) and bilirubin elevation (4/31, 12.9%). Subgroup analysis revealed that positive PD-L1 expression maybe associate with a longer PFS. CONCLUSION: Anti-PD-1 antibodies plus lenvatinib represent an effective and tolerable therapy for patients with advanced gallbladder cancer.

Altered brain structural and functional connectivity in schizotypy.

BACKGROUND: Schizotypy refers to schizophrenia-like traits below the clinical threshold in the general population. The pathological development of schizophrenia has been postulated to evolve from the initial coexistence of 'brain disconnection' and 'brain connectivity compensation' to 'brain connectivity decompensation'. METHODS: In this study, we examined the brain connectivity changes associated with schizotypy by combining brain white matter structural connectivity, static and dynamic functional connectivity analysis of diffusion tensor imaging data and resting-state functional magnetic resonance imaging data. A total of 87 participants with a high level of schizotypal traits and 122 control participants completed the experiment. Group differences in whole-brain white matter structural connectivity probability, static mean functional connectivity strength, dynamic functional connectivity variability and stability among 264 brain sub-regions of interests were investigated. RESULTS: We found that individuals with high schizotypy exhibited increased structural connectivity probability within the task control network and within the default mode network; increased variability and decreased stability of functional connectivity within the default mode network and between the auditory network and the subcortical network; and decreased static mean functional connectivity strength mainly associated with the sensorimotor network, the default mode network and the task control network. CONCLUSIONS: These findings highlight the specific changes in brain connectivity associated with schizotypy and indicate that both decompensatory and compensatory changes in structural connectivity within the default mode network and the task control network in the context of whole-brain functional disconnection may be an important neurobiological correlate in individuals with high schizotypy.

Shared and distinct reward neural mechanisms among patients with schizophrenia, major depressive disorder, and bipolar disorder: an effort-based functional imaging study.

Unwillingness to exert effort for rewards has been found in patients with schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), but the underlying shared and distinct reward neural mechanisms remain unclear. This study aimed to compare the neural correlates of such impairments across different diagnoses. The neural responses in an effort-expenditure for reward task (EEfRT) were assessed in 20 SCZ patients, 23 MDD patients, 17 BD patients, and 30 healthy controls (HC). The results found shared activation in the cingulate gyrus, the medial frontal gyrus, and the middle frontal gyrus during the EEfRT administration. Compared to HC, SCZ patients exhibited stronger variations of functional connectivity between the right caudate and the left amygdala, the left hippocampus and the left putamen, with increase in reward magnitude. In MDD patients, an enhanced activation compared to HC in the right superior temporal gyrus was found with the increase of reward magnitude. The variations of functional connectivity between the caudate and the right cingulate gyrus, the left postcentral gyrus and the left inferior parietal lobule with increase in reward magnitude were weaker than that found in HC. In BD patients, the degree of activation in the left precuneus was increased, but that in the left dorsolateral prefrontal cortex was decreased with increase in reward probability compared to HC. These findings demonstrate both shared and distinct reward neural mechanisms associated with EEfRT in patients with SCZ, MDD, and BD, implicating potential intervention targets to alleviate amotivation in these clinical disorders.

Novel cellular therapies for hepatobiliary malignancies.

BACKGROUND: The mortalities of hepatobiliary malignancies are high. With the failure of conventional chemotherapy and unsatisfactory outcome of molecular targeted drugs, immune-based therapy has become a new focus of research in hepatobiliary cancers treatment. DATA SOURCES: We performed a PubMed search with relevant articles published up to May 2022 and the following keywords: cellular immunotherapy, hepatobiliary cancer, antigen receptor T cell therapy, and receptor-engineered T cell. Information of clinical trials was obtained from https://clinicaltrials.gov/. RESULTS: Cell therapies for hepatobiliary malignancies are at early stage of development. The current review showed that cellular therapies are safe and feasible in patients. These findings provide an important platform for future lager scale clinical trials on immunotherapy in patients with hepatobiliary malignancies. CONCLUSIONS: With the continuous advances of cellular immunotherapy, the combination of cellular immunotherapy with surgery, chemotherapy and radiotherapy will be new therapeutic strategies for patients with hepatobiliary cancer.

Correction: Bacillus anthracis Spore Surface Protein BclA Mediates Complement Factor H Binding to Spores and Promotes Spore Persistence.

[This corrects the article DOI: 10.1371/journal.ppat.1005678.].

Impacts of Soil NOx Emission on O3 Air Quality in Rural California.

Nitrogen oxides (NOx) are a key precursor in O3 formation. Although stringent anthropogenic NOx emission controls have been implemented since the early 2000s in the United States, several rural regions of California still suffer from O3 pollution. Previous findings suggest that soils are a dominant source of NOx emissions in California; however, a statewide assessment of the impacts of soil NOx emission (SNOx) on air quality is still lacking. Here we quantified the contribution of SNOx to the NOx budget and the effects of SNOx on surface O3 in California during summer by using WRF-Chem with an updated SNOx scheme, the Berkeley Dalhousie Iowa Soil NO Parameterization (BDISNP). The model with BDISNP shows a better agreement with TROPOMI NO2 columns, giving confidence in the SNOx estimates. We estimate that 40.1% of the state's total NOx emissions in July 2018 are from soils, and SNOx could exceed anthropogenic sources over croplands, which accounts for 50.7% of NOx emissions. Such considerable amounts of SNOx enhance the monthly mean NO2 columns by 34.7% (53.3%) and surface NO2 concentrations by 176.5% (114.0%), leading to an additional 23.0% (23.2%) of surface O3 concentration in California (cropland). Our results highlight the cobenefits of limiting SNOx to help improve air quality and human health in rural California.