Efficacy and safety of camrelizumab, apatinib, and capecitabine combination therapy in advanced biliary tract cancer: a phase 2, nonrandomized, prospective study.

BACKGROUND: Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. METHODS: In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. CONCLUSIONS: In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting. CLINICAL TRIAL REGISTRATION: NCT04720131.

High-throughput computational materials screening of transition metal peroxides.

Semiconductor materials of abnormal stoichiometric ratio often exhibit unique properties, yet it is still a challenge to determine the structures of such materials in an efficient way. Herein, we propose a method for structurally biased screening according to the coordination numbers and the numbers of Wyckoff positions, balancing the atom local environment and the global symmetry of structures. Based on first-principles calculations, we have predicted two metastable peroxides P21/c-ScO2 and Pmmn-TiO3 with more than six coordination points. For these two structures, the most stable intrinsic defect is the oxygen vacancy (VO) at the peroxide anion (O2-2), which induces the absence of antibonding orbital formed by O2-2 near the valence band maximum. With the introduction of VO, the decrease of coordination numbers leads to charge recombination, and results in the appearance of an ordered phase TiO2.5 with stronger Ti-O orbital hybridization. The proposed method presents a promising and feasible approach for the screening of novel compounds.

HDAC6 inhibitor promotes reactive oxygen species-meditated clearance of Staphylococcus aureus in macrophage.

Staphylococcus aureus (S. aureus) pneumonia has become an increasingly important public health problem. Recent evidence suggests that epigenetic modifications are critical in the host immune defence against pathogen infection. In this study, we found that S. aureus infection induces the expression of histone deacetylase 6 (HDAC6) in a dose-dependent manner. Furthermore, by using a S. aureus pneumonia mouse model, we showed that the HDAC6 inhibitor, tubastatin A, demonstrates a protective effect in S. aureus pneumonia, decreasing the mortality and destruction of lung architecture, reducing the bacterial burden in the lungs and inhibiting inflammatory responses. Mechanistic studies in primary bone marrow-derived macrophages demonstrated that the HDAC6 inhibitors, tubastatin A and tubacin, reduced the intracellular bacterial load by promoting bacterial clearance rather than regulating phagocytosis. Finally, N-acetyl-L- cysteine, a widely used reactive oxygen species (ROS) scavenger, antagonized ROS production and significantly inhibited tubastatin A-induced S. aureus clearance. These findings demonstrate that HDAC6 inhibitors promote the bactericidal activity of macrophages by inducing ROS, an important host factor for S. aureus clearance and production. Our study identified HDAC6 as a suitable epigenetic modification target for preventing S. aureus infection, and tubastatin A as a useful compound in treating S. aureus pneumonia.

Advancing urban traffic accident forecasting through sparse spatio-temporal dynamic learning.

Traffic accidents have emerged as one of the most public health safety matters, raising concerns from both the public and urban administrators. The ability to accurately predict traffic accident not only supports the governmental decision-making in advance but also enhances public confidence in safety measures. However, the efficacy of traditional spatio-temporal prediction models are compromised by the skewed distributions and sparse labeling of accident data. To this end, we propose a Sparse Spatio-Temporal Dynamic Hypergraph Learning (SST-DHL) framework that captures higher-order dependencies in sparse traffic accidents by combining hypergraph learning and self-supervised learning. The SST-DHL model incorporates a multi-view spatiotemporal convolution block to capture local correlations and semantics of traffic accidents, a cross-regional dynamic hypergraph learning model to identify global spatiotemporal dependencies, and a two-supervised self-learning paradigm to capture both local and global spatiotemporal patterns. Through experimentation on New York City and London accident datasets, we demonstrate that our proposed SST-DHL exhibits significant improvements compared to optimal baseline models at different sparsity levels. Additionally, it offers enhanced interpretability of results by elucidating complex spatio-temporal dependencies among various traffic accident instances. Our study demonstrates the effectiveness of the SST-DHL framework in accurately predicting traffic accidents, thereby enhancing public safety and trust.

The stability of CsPb(BrxCl1-x)3 all-inorganic mixed halide perovskites.

The use of mixed halide perovskites in the preparation of blue light-emitting diodes (LEDs) is considered to be the most effective and direct approach. However, the introduction of chlorine (Cl) element might raise stability issues in the system and lead to low efficiency, thereby impeding the development of deep blue light-emitting diodes with high efficiency and stability. Determining the alloy concentration and the atomic distribution of bromine-chlorine (Br-Cl) mixed systems is essential for further application of deep blue light-emitting diodes. In this work, we have systematically investigated the stability of bromine-chlorine (Br-Cl) mixed alloy systems in various substitution configurations using high-throughput theoretical calculations. Based on this, we have examined the relationship between configuration stability and three aspects: the type of octahedra, the orientation of the octahedra and the Pb-X-Pb distortion angle in the configuration.

A negative binomial Lindley approach considering spatiotemporal effects for modeling traffic crash frequency with excess zeros.

Statistical analysis of traffic crash frequency is significant for figuring out the distribution pattern of crashes, predicting the development trend of crashes, formulating traffic crash prevention measures, and improving traffic safety planning systems. In recent years, the theory and practice for traffic safety management have shown that road crash data have characteristics such as spatial correlation, temporal correlation, and excess zeros. If these characteristics are ignored in the modeling process, it may seriously affect the fitting performance and prediction accuracy of traffic crash frequency models and even lead to incorrect conclusions. In this research, traffic crash data from rural two-way two-lane from four counties in Pennsylvania, USA was modeled considering the spatiotemporal effects of crashes. First, a negative binomial Lindley spatiotemporal effect model of crash frequency was constructed at the micro level; Simultaneously, the characteristics and problems of excess zeros and potential heterogeneity of the crash data were resolved; Finally, the effects of road characteristics on crash frequency were analyzed. The results indicate a significant spatial correlation between the crash frequency of adjacent road sections. Compared with the negative binomial model, the negative binomial Lindley model can better handle the excess zeros characteristics in traffic crash data. The model that considers both spatial correlation and temporal conditional autoregressive effects has the best fit for the observed data. In addition, for road sections that allow passing and have a speed limitation of not less than 50 miles per hour, the crash frequency corresponding to these sections is lower due to their good visibility and road conditions. The increase in average turning angle and intersection density on the horizontal curve of the road section corresponds to an increase in crash frequency.

Unraveling the role of tumor sidedness in prognosis of stage II colon cancer.

Background: Stage II colon cancer has varying risks for metastasis, and treatment strategies depend on molecular and clinicopathological features. While tumor-sidedness is a well-accepted prognostic factor for stage III/IV colon cancer, its role in stage II is controversial. Understanding its effect in stage II is crucial for improving treatment strategies. Methods: We analyzed clinical and follow-up data of colon cancer from the Surveillance, Epidemiology, and End Results database (2004-2017). Patients were divided into a primary study cohort (2010-2017) and a validation cohort (2004-2009). The baseline characteristics between right-sided colon cancer (RCC) and left-sided colon cancer (LCC) groups were compared. Moreover, the effect of tumor size on cancer-specific survival (CSS) was evaluated using Kaplan-Meier analysis. Results: The study involved 87,355 patients in the study cohort and 65,858 in the validation cohort. Of the study cohort, 52.3% were diagnosed with RCC. The median age was 64 years old, with 48.5% females and 76.8% of white people. In addition, stage II RCC showed better CSS compared with LCC (5-year CSS 88.0% vs 85.5%, P < 0.001), while stage III/IV RCC demonstrated poorer outcomes. Multivariate Cox regression analysis identified that the right-sidedness was a positive prognostic factor in stages I/II but negative in stages III (HR 1.10, P < 0.001) and IV (HR 1.26, P < 0.001). Chemotherapy rates decreased in RCC, particularly in stage II (RCC vs LCC: 16.2% vs 28.5%, P < 0.001). Subgroup analysis, stratified by T3/T4 stages and chemotherapy status, further highlighted better survival outcomes in RCC. Conclusions: RCC is associated with a significantly better prognosis in stage II. The importance of considering tumor-sidedness in clinical decision-making and the design of future clinical trials should be emphasized.

Identifying the Spatial Architecture That Restricts the Proximity of CD8+ T Cells to Tumor Cells in Pancreatic Ductal Adenocarcinoma.

The anti-tumor function of CD8+ T cells is dependent on their proximity to tumor cells. Current studies have focused on the infiltration level of CD8+ T cells in the tumor microenvironment, while further spatial information, such as spatial localization and inter-cellular communication, have not been defined. In this study, co-detection by indexing (CODEX) was designed to characterize PDAC tissue regions with seven protein markers in order to identify the spatial architecture that regulates CD8+ T cells in human pancreatic ductal adenocarcinoma (PDAC). The cellular neighborhood algorithm was used to identify a total of six conserved and distinct cellular neighborhoods. Among these, one unique spatial architecture of CD8+ T and CD4+ T cell-enriched neighborhoods enriched the majority of CD8+ T cells, but heralded a poor prognosis. The proximity analysis revealed that the CD8+ T cells in this spatial architecture were significantly closer to themselves and the CD4+ T cells than to the tumor cells. Collectively, we identified a unique spatial architecture that restricted the proximity of CD8+ T cells to tumor cells in the tumor microenvironment, indicating a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner and providing new insights into the biology of PDAC.

NAMPT-targeting PROTAC and nicotinic acid co-administration elicit safe and robust anti-tumor efficacy in NAPRT-deficient pan-cancers.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the biosynthesis of nicotinamide adenine dinucleotide (NAD+), making it a potential target for cancer therapy. Two challenges hinder its translation in the clinic: targeting the extracellular form of NAMPT (eNAMPT) remains insufficient, and side effects are observed in normal tissues. We previously utilized proteolysis-targeting chimera (PROTAC) to develop two compounds capable of simultaneously degrading iNAMPT and eNAMPT. Unfortunately, the pharmacokinetic properties were inadequate, and toxicities similar to those associated with traditional inhibitors arose. We have developed a next-generation PROTAC molecule 632005 to address these challenges, demonstrating exceptional target selectivity and bioavailability, improved in vivo exposure, extended half-life, and reduced clearance rate. When combined with nicotinic acid, 632005 exhibits safety and robust efficacy in treating NAPRT-deficient pan-cancers, including xenograft models with hematologic malignancy and prostate cancer and patient-derived xenograft (PDX) models with liver cancer. Our findings provide clinical references for patient selection and treatment strategies involving NAMPT-targeting PROTACs.

Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC.

Inflammasome activity is important for the immune response and is instrumental in numerous clinical conditions. Here we identify a mechanism that modulates the central Caspase-1 and NLR (Nod-like receptor) adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). We show that the function of ASC in assembling the inflammasome is controlled by its modification with SUMO (small ubiquitin-like modifier) and identify that the nuclear ZBTB16 (zinc-finger and BTB domain-containing protein 16) promotes this SUMOylation. The physiological significance of this activity is demonstrated through the reduction of acute inflammatory pathogenesis caused by a constitutive hyperactive inflammasome by ablating ZBTB16 in a mouse model of Muckle-Wells syndrome. Together our findings identify an further mechanism by which ZBTB16-dependent control of ASC SUMOylation assembles the inflammasome to promote this pro-inflammatory response.