Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: A multicenter, retrospective cohort study.

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.

Individuals with autism spectrum disorder have altered visual encoding capacity.

Perceptual anomalies in individuals with autism spectrum disorder (ASD) have been attributed to an imbalance in weighting incoming sensory evidence with prior knowledge when interpreting sensory information. Here, we show that sensory encoding and how it adapts to changing stimulus statistics during feedback also characteristically differs between neurotypical and ASD groups. In a visual orientation estimation task, we extracted the accuracy of sensory encoding from psychophysical data by using an information theoretic measure. Initially, sensory representations in both groups reflected the statistics of visual orientations in natural scenes, but encoding capacity was overall lower in the ASD group. Exposure to an artificial (i.e., uniform) distribution of visual orientations coupled with performance feedback altered the sensory representations of the neurotypical group toward the novel experimental statistics, while also increasing their total encoding capacity. In contrast, neither total encoding capacity nor its allocation significantly changed in the ASD group. Across both groups, the degree of adaptation was correlated with participants' initial encoding capacity. These findings highlight substantial deficits in sensory encoding-independent from and potentially in addition to deficits in decoding-in individuals with ASD.

The Difference in Ir-Catalyzed C(sp2)-H and C(sp3)-H Bond Activation Assisted by a Directing Group: Cyclometalation via Cis- or Trans-Chelation?

Iridium-catalyzed C-H borylation of aromatic and aliphatic hydrocarbons assisted by a directing group was theoretically investigated. Density functional theory (DFT) calculations revealed both Ir-catalyzed C(sp2)-H and C(sp3)-H borylations via an IrIII/IrV catalytic cycle, where the tetra-coordinated (C, N)IrIII(Bpin)2 complex with two vacant sites is an active species. Dramatically, the orientation of cyclometalation for C(sp2)-H bond activation assisted by a directing group is different from the C(sp3)-H one. The activation energy (ΔG°‡ = 28.5 kcal mol-1) of the C(sp2)-H bond via trans-chelation to form cyclometalation is lower than that (41.4 kcal mol-1) via cis-chelation. In contrast, the ΔG°‡ (26.6 kcal mol-1) of the C(sp3)-H bond via cis-chelation to form cyclometalation is lower than that (34.3 kcal mol-1) via trans-chelation. In addition, the rate-determining step of Ir-catalyzed C(sp2)-H borylation is oxidative addition of the C(sp2)-H bond, while that of C(sp3)-H analogues is hydride migration. Such differences arise from not only the differences in the steric hindrance of the C(sp2) and secondary C(sp3) atoms but also the differences in the trans effect and steric effect of the two vacant sites of active species. These findings were expected to facilitate further studies on the design and synthesis of innovative ligands for Ir-catalyzed C-H borylation.

Integrated chromosomal instability and tumor microbiome redefined prognosis-related subtypes of pancreatic cancer.

BACKGROUND: Pancreatic cancer is a common malignancy with poor prognosis and limited treatment. Here we aimed to investigate the role of host chromosomal instability (CIN) and tumor microbiome in the prognosis of pancreatic cancer patients. METHODS: One hundred formalin-fixed paraffin-embedded (FFPE) pancreatic cancer samples were collected. DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing (WGS) via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector. RESULTS: Samples are tested according to the procedure of ultrasensitive chromosomal aneuploidy detector (UCAD). We excluded 2 samples with failed quality control, 1 patient lost to follow-up and 6 dead in the perioperative period. The final 91 patients were admitted for the following analyses. Thirteen (14.3%) patients with higher CIN score had worse overall survival (OS) than those with lower CIN score. The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses. Patients with high human herpesvirus (HHV)-7 and HHV-5 DNA reads exhibited worse OS. Furthermore, we classified 91 patients into 3 subtypes. Patients with higher CIN score (n =13) had the worst prognosis (median OS 6.9 mon); patients with lower CIN score but with HHV-7/5 DNA load (n = 24) had worse prognosis (median OS 10.6 mon); while patients with lower CIN score and HHV-7/5 DNA negative (n = 54) had the best prognosis (median OS 21.1 mon). CONCLUSIONS: High CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer. The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.

Prior Expectations in Visual Speed Perception Predict Encoding Characteristics of Neurons in Area MT.

Bayesian inference provides an elegant theoretical framework for understanding the characteristic biases and discrimination thresholds in visual speed perception. However, the framework is difficult to validate because of its flexibility and the fact that suitable constraints on the structure of the sensory uncertainty have been missing. Here, we demonstrate that a Bayesian observer model constrained by efficient coding not only well explains human visual speed perception but also provides an accurate quantitative account of the tuning characteristics of neurons known for representing visual speed. Specifically, we found that the population coding accuracy for visual speed in area MT ("neural prior") is precisely predicted by the power-law, slow-speed prior extracted from fitting the Bayesian observer model to psychophysical data ("behavioral prior") to the point that the two priors are indistinguishable in a cross-validation model comparison. Our results demonstrate a quantitative validation of the Bayesian observer model constrained by efficient coding at both the behavioral and neural levels.SIGNIFICANCE STATEMENT Statistical regularities of the environment play an important role in shaping both neural representations and perceptual behavior. Most previous work addressed these two aspects independently. Here we present a quantitative validation of a theoretical framework that makes joint predictions for neural coding and behavior, based on the assumption that neural representations of sensory information are efficient but also optimally used in generating a percept. Specifically, we demonstrate that the neural tuning characteristics for visual speed in brain area MT are precisely predicted by the statistical prior expectations extracted from psychophysical data. As such, our results provide a normative link between perceptual behavior and the neural representation of sensory information in the brain.

Transportome Malfunctions and the Hallmarks of Pancreatic Cancer.

Ion channels and transporters (ICT) play important roles in almost all basic cellular processes. During last decades, abundant evidences have been provided that ICT (e.g., Ca2+ and K+ channels) are notable for regulating physiological pancreatic duct cellular function and deregulation of ICT is closely associated with the widely accepted hallmarks of pancreatic ductal adenocarcinoma (PDAC) such as proliferation, apoptosis resistance, invasion, and metastasis. Hence this review focuses on the role of ICT malfunctions in context with the hallmarks of PDAC. After briefly introducing epidemiology and history of molecular oncology of PDAC and summarizing the recent studies on molecular classification systems, we focus then on the exocrine pancreas as a very active secretory gland which considerably impacts the changes in the ion transport system (the transportome) upon malignant transformation. We highlight multiplicity of ICT members (H+ transporters, Ca2+, K+, Na+ and Cl- channels) and their functional impact in PDAC. We also present some selective therapeutic options to interfere with transportome functions and thereby with key mechanisms of malignant progression. This will hopefully contribute to a better clinical outcome based on improved therapeutic strategies for this still extremely deadly disease.

High-Efficiency 3D DNA Walker Immobilized by a DNA Tetrahedral Nanostructure for Fast and Ultrasensitive Electrochemical Detection of MiRNA.

Herein, by directly limiting the reaction space, an ingenious three-dimensional (3D) DNA walker (IDW) with high walking efficiency is developed for rapid and sensitive detection of miRNA. Compared with the traditional DNA walker, the IDW immobilized by the DNA tetrahedral nanostructure (DTN) brings stronger kinetic and thermodynamic favorability resulting from its improved local concentration and space confinement effect, accompanied by a quite faster reaction speed and much better walking efficiency. Once traces of target miRNA-21 react with the prelocked IDW, the IDW could be largely activated and walk on the interface of the electrode to trigger the cleavage of H2 with the assistance of Mg2+, resulting in the release of amounts of methylene blue (MB) labeled on H2 from the electrode surface and the obvious decrease of the electrode signal. Impressively, the IDW reveals a conversion efficiency as high as 9.33 × 108 in 30 min with a much fast reaction speed, which is at least five times beyond that of typical DNA walkers. Therefore, the IDW could address the inherent challenges of the traditional DNA walker easily: slow walking speed and low efficiency. Notably, the IDW as a DNA nanomachine was utilized to construct a sensitive sensing platform for rapid miRNA-21 detection with a limit of detection (LOD) of 19.8 aM and realize the highly sensitive assay of biomarker miRNA-21 in the total RNA lysates of cancer cell. The strategy thus helps in the design of a versatile nucleic acid conversion and signal amplification approach for practical applications in the areas of biosensing assay, DNA nanotechnology, and clinical diagnosis.

Optical vector fields with kaleidoscopic quasicrystal structures by multiple beam interference.

An easily accessible approach is proposed to create structured beams with various quasicrystal structures and polarization distributions based on multi-beam interference. By controlling the azimuthally-dependent polarization for Q evenly and circularly distributed beams to be interfered, the intensity and polarization structures for the generated quasicrystal field with Q-fold rotational symmetry are flexibly adjusted. Using the diffraction theory for interfering Q vector Gaussian beams, an analytical wave function is derived to reconstruct the polarization-resolved intensities and the distributions of Stokes parameters measured in the experiment. With good agreement between the numerical and experimental results, the derived wave function is further employed to characterize the propagation-variant states of polarization, providing fundamentally important information for the vector quasicrystal beams.

Lewis Acid-Catalyzed Remote Site-Selective Ring Deconstruction of Cyclobuteno[a]naphthalene-4-ones to Access Unsymmetric 1,1-Diarylated Olefins.

A catalytic site-selective ring deconstruction of cyclobuteno[a]naphthalene-4-ones with alcohols is reported, enabling the direct production of a wide range of unsymmetric 1,1-diarylated olefins with good yields and complete regioselectivity. The late-stage application of these resulting terminal olefins demonstrates great possibilities to apply this strategy to complex molecules. The protocol features good functional group compatibility, broad substrate scope, and controllable site selectivity.

Optimal timing of surgery for gastric cancer after neoadjuvant chemotherapy: a systematic review and meta-analysis.

BACKGROUND: Following neoadjuvant chemotherapy, surgical resection is one of the most preferred treatment options for locally advanced gastric cancer patients. However, the optimal time interval between chemotherapy and surgery is unclear. This review aimed to identify the optimal time interval between neoadjuvant chemotherapy and surgery for advanced gastric cancer. METHODS: Beginning on November 12, 2022, we searched the PubMed, Cochrane Library, Web of Science databases, and Embase.com databases for relevant English-language research. Two authors independently screened the studies, assessed their quality, extracted the data, and analyzed the results. The primary goal was to investigate the relationship between the time interval to surgery (TTS) and long-term survival outcomes for patients. This study has been registered with PROSPERO (CRD42022365196). RESULTS: After an initial search of 4880 articles, the meta-analysis review ultimately included only five retrospective studies. Ultimately, this meta-analysis included 1171 patients, of which 411 patients had TTS of < 4 weeks, 507 patients had TTS of 4-6 weeks, and 253 patients had TTS of > 6 weeks. In survival analysis, patients with TTS of > 6 weeks had poorer overall survival outcomes than patients with TTS of 4-6 weeks (HR = 1.34, 95% CI: 1.03-1.75, P = 0.03). No significant differences were found in terms of disease-free survival the groups. CONCLUSION: Based on the current clinical evidence, patients with locally advanced gastric cancer may benefit better with a TTS of 4-6 weeks; however, this option still needs additional study.