Entropy-Driven Catalytic G-Quadruple Cycle Amplification Integrated with Ligases for Label-Free Detection of Single Nucleotide Polymorphisms.

G-Quadruplex/thioflavin (G4/THT) has become a very promising label-free fluorescent luminescent element for nucleic acid detection due to its good programmability and compatibility. However, the weak fluorescence efficiency of single-molecule G4/THT limits its potential applications. Here, we developed an entropy-driven catalytic (EDC) G4 (EDC-G4) cycle amplification technology as a universal label-free signal amplification and output system by properly programming classical EDC and G4 backbone sequences, preintegrated ligase chain reaction (LCR) for label-free sensitive detection of single nucleotide polymorphisms (SNPs). First, the positive strand LCR enabled specific transduction and preliminary signal amplification from single-base mutation information to single-strand information. Subsequently, the EDC-G4 cycle amplification reaction was activated, accompanied by the production of a large number of G4/THT luminophores to output fluorescent signals. The EDC-G4 system was proposed to address the weak fluorescence of G4/THT and obtain a label-free fluorescence signal amplification. The dual-signal amplification effect enabled the LCR-EDC-G4 detection system to accurately detect mutant target (MT) at concentrations as low as 22.39 fM and specifically identify 0.01% MT in a mixed detection pool. Moreover, the LCR-EDC-G4 system was further demonstrated for its potential application in real biological samples. Therefore, this study not only contributes ideas for the development of label-free fluorescent biosensing strategies but also provides a high-performance and practical SNP detection tool in parallel.

Lewis-Acid-Promoted Visible-Light-Mediated C(sp3)-H Bond Functionalization of Arylvinylpyridines via Diradical Hydrogen Atom Transfer.

A visible-light-induced intramolecular diradical-mediated hydrogen atom transfer (DHAT) of primary, secondary, and tertiary C(sp3)-H bonds and subsequent cyclization is described. This transformation is enabled by triplet energy transfer upon Lewis acid coordination to alkyl-substituted arylvinylpyridines and gives access to a variety of benzocyclobutenes (>40 examples, 32-96% yield). Notably, tri- and tetrasubstituted olefins with tertiary C(sp3)-H bonds effectively delivered sterically hindered products with adjacent all-carbon quaternary centers. Mechanistic evidence and density functional theory (DFT) calculations suggest that Lewis acid coordination was crucial for the success by modulating the reactivity of the diradical intermediates to unlock a challenging carbon-to-carbon DHAT and subsequent cyclization with a rather low barrier, which allows the functionalization of benzylic C(sp3)-H bonds to construct otherwise inaccessible benzocyclobutenes.

Selective Cellular Uptake and Druggability Efficacy through Functionalized Chitosan-Conjugated Polyamidoamine (PAMAM) Dendrimers.

Nanotechnology has ushered in significant advancements in drug design, revolutionizing the prevention, diagnosis, and treatment of various diseases. The strategic utilization of nanotechnology to enhance drug loading, delivery, and release has garnered increasing attention, leveraging the enhanced physical and chemical properties offered by these systems. Polyamidoamine (PAMAM) dendrimers have been pivotal in drug delivery, yet there is room for further enhancement. In this study, we conjugated PAMAM dendrimers with chitosan (CS) to augment cellular internalization in tumor cells. Specifically, doxorubicin (DOX) was initially loaded into PAMAM dendrimers to form DOX-loaded PAMAM (DOX@PAMAM) complexes via intermolecular forces. Subsequently, CS was linked onto the DOX-loaded PAMAM dendrimers to yield CS-conjugated PAMAM loaded with DOX (DOX@CS@PAMAM) through glutaraldehyde crosslinking via the Schiff base reaction. The resultant DOX@CS@PAMAM complexes were comprehensively characterized using Fourier-transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Notably, while the drug release profile of DOX@CS@PAMAM in acidic environments was inferior to that of DOX@PAMAM, DOX@CS@PAMAM demonstrated effective acid-responsive drug release, with a cumulative release of 70% within 25 h attributed to the imine linkage. Most importantly, DOX@CS@PAMAM exhibited significant selective cellular internalization rates and antitumor efficacy compared to DOX@PAMAM, as validated through cell viability assays, fluorescence imaging, and flow cytometry analysis. In summary, DOX@CS@PAMAM demonstrated superior antitumor effects compared to unconjugated PAMAM dendrimers, thereby broadening the scope of dendrimer-based nanomedicines with enhanced therapeutic efficacy and promising applications in cancer therapy.

Aging aggravates aortic aneurysm and dissection via miR-1204-MYLK signaling axis in mice.

The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates ß-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-ß signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.

Simultaneous quantification of baloxavir marboxil and its active metabolite in human plasma using UHPLC-MS/MS: Application to a human pharmacokinetic study with different anticoagulants.

Baloxavir marboxil (BXM) is a cap-dependent nucleic acid endonuclease inhibitor, which exerts its antiviral effects after being metabolized to its active form baloxavir acid (BXA). Ethylenediamine tetra-acetic acid (EDTA) and heparin are the two most used anticoagulants in clinical blood sample collection to estimate drug levels in plasma. However, compared to heparin plasma, there is a lack of clinical pharmacokinetic data of BXA using EDTA anticoagulant tubes for blood collection. In the present study, an efficient, rapid, and sensitive ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for simultaneous quantification of BXM and its active metabolite BXA in human plasma with its isotopic baloxavir-d5 (BXA-d5) as internal standard (IS). Plasma samples (50 µL) were undergone using acetonitrile containing 0.1 % formic acid a precipitant. Chromatographic separation was achieved by a Waters XBridge®C8 (2.1 mm × 50 mm, 2.5 µm) column. The gradient mobile phase was 0.1 % formic acid in water (A, pH 2.8) and 0.1 % formic acid in acetonitrile (B) and delivered at a flow rate of 0.6 mL/min for 4.5 min. BXM and BXA were monitored using a positive electrospray triple quadrupole mass spectrometer (TRIPLE QUAD™ 6500+) via multiple reaction monitoring mode. The mass-to-charge ratios (m/z) were 572.2→247.0, 484.2→247.0 and 489.2→252.0 for BXM, BXA, and BXA-d5 (IS). Calibration curves exhibited excellent linearity in the range of 0.1-10 ng/mL for BXM (r2 > 0.996), and 0.3-300 ng/mL for BXA (r2 > 0.998). Within-run and between-run precisions in coefficients of variations were less than 11.62 % for BXM and less than 7.47 % for BXA, and accuracies in relative error were determined to be within -7.78 % to 5.70 % for BXM and -6.67 % to 8.56 % for BXA. Extraction recovery efficiency was 92.76 % for BXM, 95.32 % for BXA, and 99.26 % for BXA-d5, respectively. The matrix effect of BXM and BXA was in line with the requirements, where the relative deviation of the accuracy was less than 6.67 % and the precision was less than 6.69 %. The validated efficient and simple UHPLC-MS/MS method was successfully used in the pharmacokinetic study of BXM and BXA in healthy human volunteers with K2EDTA and heparin tubes for blood collection. EDTA might compete with BXA for chelating metal ions and thereby decrease the plasma ratio in whole blood, leading to approximately 50 % lower measurement of pharmacokinetic parameters as compared with those obtained from heparin plasma anticoagulant tubes.

Self-Sustained-Release Strategy Realizes Colloid Oriented Assembly to Fabricate Prussian Blue with Hierarchical Structure.

The controlled self-assembly of nanomaterials has been a great challenge in nanosynthesis, especially for hierarchical architectures with high complexity. Particularly, the structural design of Prussian blue (PB) series materials with robustness and fast nucleation is even more difficult. Herein, a self-sustained-release strategy based on the slow release of metal ions from coordination ions is proposed to guide the assembly of PB crystals. The key to this strategy is the slow release by ligand, which can create ultra-low concentrations of metal ions so as to provide the possibility to realize the surface charge manipulation of PB primary colloids. By adding electrolyte or changing the polarity of the solution, the surface charge regulation of PB colloid is realized, and the PB hierarchical structures with branch fractal structure (PB-BS), octahedral fractal structure, and spherical fractal structure are effectively constructed. This work not only achieves the designability of the PB structure, but also synchronizes the functionalization during the PB assembly growth process by in situ encapsulation of the effective catalytic active component L-Ascorbic acid. As a result, the assembled PB-BS exhibits greatly enhanced catalytic activity and selectivity in styrene oxidation with the selectivity of oxidized styrene increasing from 35.6% (PB) to 80.5% (PB-BS).

A Clinical Bacterial Dataset for Deep Learning in Microbiological Rapid On-Site Evaluation.

Microbiological Rapid On-Site Evaluation (M-ROSE) is based on smear staining and microscopic observation, providing critical references for the diagnosis and treatment of pulmonary infectious disease. Automatic identification of pathogens is the key to improving the quality and speed of M-ROSE. Recent advancements in deep learning have yielded numerous identification algorithms and datasets. However, most studies focus on artificially cultured bacteria and lack clinical data and algorithms. Therefore, we collected Gram-stained bacteria images from lower respiratory tract specimens of patients with lung infections in Chinese PLA General Hospital obtained by M-ROSE from 2018 to 2022 and desensitized images to produce 1705 images (4,912 × 3,684 pixels). A total of 4,833 cocci and 6,991 bacilli were manually labelled and differentiated into negative and positive. In addition, we applied the detection and segmentation networks for benchmark testing. Data and benchmark algorithms we provided that may benefit the study of automated bacterial identification in clinical specimens.

The gut microbial composition in polycystic ovary syndrome with hyperandrogenemia and its association with steroid hormones.

Background: Polycystic ovary syndrome (PCOS) is characterized by excess androgens, ovulatory dysfunction, and polycystic ovaries. The mechanisms underlying ovulatory and metabolic disorders in PCOS remain elusive, hampering therapeutic development. Enhanced metabolic health correlates with increased microbiota gene content and microbial diversity. We aimed to explore the impact of gut microbiota and serum steroids on PCOS regulation associated with androgen excess. Methods: The fecal samples of patients with hyperandrogenic PCOS (n = 14) and control group with PCOS (n = 14) were analyzed by 16S rRNA gene sequencing. The peripheral venous blood of all subjects was collected to detect serum hormones. The association between gut microbiota and serum hormones was analyzed with the R language. Results: Our findings reveal that the hyperandrogenic PCOS group exhibits lower richness and diversity of gut microbiota compared to the control group. Characteristic genera in PCOS patients with hyperandrogenism include Bifidobacterium, Enterobacteriaceae_unclassified, Streptococcus, Saccharimonadaceae, Enterococcus, and Eubacterium_nodatum_group. Five hormones, including 5ß-androsterone, deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, and cortexolone, emerge as potential serum biomarkers for identifying patients with hyperandrogenic-PCOS (HA-PCOS). Furthermore, a lower vitamin D3 level may act as a susceptibility factor, suggesting that vitamin D3 supplementation could serve as a potential intervention for PCOS with hyperandrogenism. Conclusion: Specific fecal microbiota and serum steroids may be used as characteristic markers for clinical diagnosis of hyperandrogenic-PCOS. This research enhances our understanding of the intricate interplay among hormones, gut microbiota, and hyperandrogenemia in patients with PCOS.

Two-Dimensional Deep Learning Frameworks for Drug-Induced Cardiotoxicity Detection.

The identification of drug-induced cardiotoxicity remains a pressing challenge with far-reaching clinical and economic ramifications, often leading to patient harm and resource-intensive drug recalls. Current methodologies, including in vivo and in vitro models, have severe limitations in accurate identification of cardiotoxic substances. Pioneering a paradigm shift from these conventional techniques, our study presents two deep learning-based frameworks, STFT-CNN and SST-CNN, to assess cardiotoxicity with markedly improved accuracy and reliability. Leveraging the power of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a more human-relevant cell model, we record mechanical beating signals through impedance measurements. These temporal signals were converted into enriched two-dimensional representations through advanced transformation techniques, specifically short-time Fourier transform (STFT) and synchro-squeezing transform (SST). These transformed data are fed into the proposed frameworks for comprehensive analysis, including drug type classification, concentration classification, cardiotoxicity classification, and new drug identification. Compared to traditional models like recurrent neural network (RNN) and 1-dimensional convolutional neural network (1D-CNN), SST-CNN delivered an impressive test accuracy of 98.55% in drug type classification and 99% in distinguishing cardiotoxic and noncardiotoxic drugs. Its feasibility is further highlighted with a stellar 98.5% average accuracy for classification of various concentrations, and the superiority of our proposed frameworks underscores their promise in revolutionizing drug safety assessments. With a potential for scalability, they represent a major leap in drug safety assessments, offering a pathway to more robust, efficient, and human-relevant cardiotoxicity evaluations.

STIL facilitates the development and malignant progression of triple-negative breast cancer through activation of Fanconi anemia pathway via interacting with KLF16.

BACKGROUND: STIL is an important cell cycle-regulating protein specifically recruited to the mitotic centrosome to promote the replication of centrioles in dividing cells. However, the potential role of STIL in the regulation of the biological functions of triple-negative breast cancer remains still unclear. METHODS: We screened for differentially expressed STIL in the Cancer Genome Atlas database. The expression of STIL protein in 10 pairs of breast cancer tissues and adjacent normal tissues was further assessed by western blotting. Functionally, the knockdown and overexpression of STIL have been used to explore the effects of STIL on breast cancer cell proliferation, migration, and invasion. Mechanistically, RNA-seq, dual-luciferase reporter assay, chromatin immunoprecipitation assay, mass spectrometry, immunoprecipitation assay, and DNA pull-down assay were performed. RESULTS: Breast cancer tissues and cells have higher STIL expression than normal tissues and cells. STIL knockdown impairs breast cancer cell growth, migration, and invasion, whereas STIL overexpression accelerates these processes. STIL promotes breast cancer progression by regulating FANCD2 expression, and exploration of its molecular mechanism demonstrated that STIL interacts with KLF16 to regulate the expression of FANCD2. CONCLUSIONS: Collectively, our findings identified STIL as a critical promoter of breast cancer progression that interacts with KLF16 to regulate Fanconi anemia pathway protein FANCD2. In summary, STIL is a potential novel biomarker and therapeutic target for breast cancer.

Spatiotemporal architecture of immune cells and cancer-associated fibroblasts in high-grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSOC), the deadliest form of ovarian cancer, is typically diagnosed after it has metastasized and often relapses after standard-of-care platinum-based chemotherapy, likely due to advanced tumor stage, heterogeneity, and immune evasion and tumor-promoting signaling from the tumor microenvironment. To understand how spatial heterogeneity contributes to HGSOC progression and early relapse, we profiled an HGSOC tissue microarray of patient-matched longitudinal samples from 42 patients. We found spatial patterns associated with early relapse, including changes in T cell localization, malformed tertiary lymphoid structure (TLS)-like aggregates, and increased podoplanin-positive cancer-associated fibroblasts (CAFs). Using spatial features to compartmentalize the tissue, we found that plasma cells distribute in two different compartments associated with TLS-like aggregates and CAFs, and these distinct microenvironments may account for the conflicting reports about the role of plasma cells in HGSOC prognosis.

Application of telemedicine system for older adults postoperative patients in community: a feasibility study.

Purpose: In response to the growing challenges posed by an aging society, a telemedicine system was developed specifically for older adults postoperative patients, and its effectiveness was thoroughly investigated. Methods: Between May 2020 and May 2022, a total of 88 older adults postoperative patients were enrolled and randomly allocated into an experimental group and a control group. The experimental group received telemedicine services after discharge, while the control group received conventional medical services following the traditional protocol. One month after discharge, various indicators were evaluated for both groups, including number of visits, medical expenditures, postoperative recovery, anxiety, depression and satisfaction. Results: The number of visits and medical expenditures of the experimental group were less than those of the control group [1 (0, 1) vs. 1 (1, 2), Z = -3.977, p < 0.001; 25.25 (0.00, 277.40) yuan vs. 174.65 (49.63, 446.10) yuan, Z = -2.150, p = 0.032]. In both groups, there were 2 cases of incision infection, respectively. No significant difference was observed between the two groups (Fisher χ2, p = 0.259). In both groups, there was no instance of incision bleeding, incision dehiscence, readmission, or reoperation. Additionally, there was no significant difference in physical status between the two groups at discharge and after discharge (66.06 ± 8.92 vs. 65.45 ± 7.39 t = 0.287, p = 0.775; 73.33 ± 9.97 vs. 70.91 ± 7.50, t = 1.202, p = 0.235). And there was no significant difference in the change of physical status between the two groups after discharge [10.00 (0.00, 10.00) vs. 5.00 (0.00, 10.00), Z = -1.077, p = 0.281]. There was no significant difference in body weight change between the two groups after discharge [1.05 (0.38, 1.60) Kg vs. 0.80 (0.50, 1.43) Kg, Z = -0.265, p = 0.791]. There was no significant difference in the levels of anxiety and depression between the two groups at discharge (45.64 ± 8.10 vs. 44.60 ± 8.24, t = 0.520, p = 0.604, 48.33 ± 8.46 vs. 47.50 ± 6.85, t = 0.418, p = 0.677). But the levels of anxiety and depression in the experimental group were lower than those in the control group after discharge (34.92 ± 7.38 vs. 39.03 ± 8.42, t = -2.183, p = 0.032, 37.86 ± 7.29 vs. 41.93 ± 7.13, t = -2.281, p = 0.025); The change of anxiety level and depression level of the experimental group were more than those of the control group [-10.00 (-11.25, -8.75) vs. -5.00 (-7.81, -3.75), Z = -5.277, p < 0.001; -10.00 (-12.50, -7.50) vs. -5.00 (-7.75, -3.44), Z = -4.596, p < 0.001]. The level of satisfaction regarding medical services, daily care, and psychological comfort was higher in the experimental group compared to the control group [3 (3, 3.25) vs. 2 (1, 2), Z = -5.931, p < 0.001; 3 (3, 4) vs. 3 (2, 3), Z = -2.286, p = 0.022; 2 (1, 3) vs. 1 (0.75, 2), Z = -2.081, p = 0.037]. Conclusion: In the context of an aging society, telemedicine system can offer improved healthcare to older adults postoperative patients. This includes benefits such as reducing number of visits, saving medical expenditures, enhancing psychological comfort and daily care.

Circulation immune cell landscape in canonical pathogenesis of colorectal adenocarcinoma by CyTOF analysis.

Current studies on the immune microenvironment of colorectal cancer (CRC) were mostly limited to the tissue level, lacking relevant studies in the peripheral blood, and failed to describe its alterations in the whole process of adenocarcinoma formation, especially of adenoma carcinogenesis. Here, we constructed a large-scale population cohort and used the CyTOF to explore the changes of various immune cell subsets in peripheral blood of CRC. We found monocytes and basophils cells were significantly higher in adenocarcinoma patients. Compared with early-stage CRC, effector CD4+T cells and naive B cells were higher in patients with lymph node metastasis, whereas the basophils were lower. We also performed random forest algorithm and found monocytes play the key role in carcinogenesis. Our study draws a peripheral blood immune cell landscape of the occurrence and development of CRC at the single-cell level and provides a reference for other researchers.

The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells.

The antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment.

EFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death.

TNF acts as one pathogenic driver for inducing intestinal epithelial cell (IEC) death and substantial intestinal inflammation. How the IEC death is regulated to physiologically prevent intestinal inflammation needs further investigation. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin and suppresses Cofilin phosphorylation, thus blocking TNF receptor I (TNFR1) internalization to inhibit IEC apoptosis and consequently protecting intestine from inflammation. Our findings deepen the understanding of EFHD2 as the key regulator of membrane receptor trafficking, providing insight into death receptor signals and autoinflammatory diseases.

INHBA(+) cancer-associated fibroblasts generate an immunosuppressive tumor microenvironment in ovarian cancer.

Effective targeting of cancer-associated fibroblasts (CAFs) is hindered by the lack of specific biomarkers and a poor understanding of the mechanisms by which different populations of CAFs contribute to cancer progression. While the role of TGFß in CAFs is well-studied, less attention has been focused on a structurally and functionally similar protein, Activin A (encoded by INHBA). Here, we identified INHBA(+) CAFs as key players in tumor promotion and immunosuppression. Spatiotemporal analyses of patient-matched primary, metastatic, and recurrent ovarian carcinomas revealed that aggressive metastatic tumors enriched in INHBA(+) CAFs were also enriched in regulatory T cells (Tregs). In ovarian cancer mouse models, intraperitoneal injection of the Activin A neutralizing antibody attenuated tumor progression and infiltration with pro-tumorigenic subsets of myofibroblasts and macrophages. Downregulation of INHBA in human ovarian CAFs inhibited pro-tumorigenic CAF functions. Co-culture of human ovarian CAFs and T cells revealed the dependence of Treg differentiation on direct contact with INHBA(+) CAFs. Mechanistically, INHBA/recombinant Activin A in CAFs induced the autocrine expression of PD-L1 through SMAD2-dependent signaling, which promoted Treg differentiation. Collectively, our study identified an INHBA(+) subset of immunomodulatory pro-tumoral CAFs as a potential therapeutic target in advanced ovarian cancers which typically show a poor response to immunotherapy.

Plin2 inhibits autophagy via activating AKT/mTOR pathway in non-small cell lung cancer.

Perilipin 2 (Plin2) is known to be dysregulated in several human malignancies, which facilitates cancer progression. Recent studies have found that the abnormal expression of Plin2 is associated with poor prognosis of non-small cell lung cancer (NSCLC). However, the specific role of Plin2 and its underlying mechanism remain unclear. This study revealed that Plin2 expression was low in NSCLC tissues, and its relatively higher expression indicated larger tumor size and poorer prognosis. In vitro experiments proved that Plin2 promoted NSCLC cellular proliferation and inhibited autophagy by activating the AKT/mTOR pathway. Meanwhile, treatment with the AKT phosphorylation promoter or inhibitor neutralized the influence of Plin2 depletion or over-expression on proliferation and autophagy, respectively. In vivo study showed that Plin2 stimulated subcutaneous tumorigenesis of NSCLC cells in nude mice. Collectively, this study clarified the carcinogenic role of Plin2 and its molecular mechanism in NSCLC progression, which may facilitate a targeted therapy in the future.

mTOR inhibitor introduce disitamab vedotin (RC48-ADC) rechallenge microtubule-chemotherapy resistance in HER2-low MBC patients with PI3K mutation.

This study aimed to explore the efficacy and potential mechanisms of rechallenge therapy with microtubule-targeting agents (MTAs) in patients with HER2-low metastatic breast cancer (MBC). We performed a systematic review to investigate the rechallenge treatment concept in the field of HER2-low MBC treatment and utilized a series of cases identified in the literature to illustrate the concept. Here we reported two clinical cases of HER2-low MBC patients whose disease progressed after prior treatment with MTAs such as docetaxel and vincristine. When rechallenged with disitamab vedotin ((RC48-antibody-drug conjugate (ADC), a monomethyl auristatin (MMAE) MTA)), both patients achieved a partial response and the final progression-free survival (PFS) was 13.5 and 9 months, respectively. Genomic profiling detected a PIK3CA H1047R mutation in the patients. The patients were treated with everolimus before being rechallenged with RC48, which may lead to a better response. This study further summarizes and analyzes the potential mechanism of the PI3K-AKT signaling pathway in MTA resistance and reveals that the PIK3CA H1047R mutation may be a potential molecular marker for the efficacy prediction of mTOR inhibitors, providing new insights and potential therapeutic strategies for the application of MTAs to MBC patients.

Primary Surgery Followed by Selective Chemoradiotherapy Versus Preoperative Chemoradiotherapy Followed by Surgery for Locally Advanced Rectal Cancer: A Randomized Clinical Trial.

PURPOSE: The aim of this work was to determine whether locally advanced rectal cancer (LARC) with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiation therapy treatment. METHODS AND MATERIALS: This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6 to 12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathologic [CRM] circumferential margins were subjected to chemoradiotherapy [CRT] and those with negative CRM underwent adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients underwent subsequent surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS). RESULTS: A total of 275 patients were randomly assigned to the intervention (n = 140) and control (n = 135) groups, in which 33.57% and 28.15% patients were at clinical T4 stage and 85.92% and 80.45% patients were at "bad" or "ugly" risk in the intervention and control groups, respectively. There were 2 patients (1.52%) and 1 patient (0.77%) with positive CRM in the intervention and control groups, respectively (P > .05). The non-adherence rates for the intervention and control groups were 3.6% and 23.7%, respectively. After a median follow-up of 34.6 months (IQR, 18.2-45.7), 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were 6 patients (4.4%) with local recurrence in the intervention group and none in the control group, which led to the termination of the trial. The 3-year DFS rate was 81.82% in the intervention group (95% CI, 78.18%-85.46%) and 85.37% in the control group (95% CI, 81.75%-88.99%), with a difference of -3.55% (95% CI, -3.71% to -3.39%; hazard ratio, 1.76; 95% CI, 0.94-3.30). In the per-protocol data set, the difference between 3-year DFS rates was -5.44% (95% CI, -5.63% to -5.25%; hazard ratio, 2.02; 95% CI, 1.01-4.06). CONCLUSIONS: Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy compared with preoperative CRT followed by surgery and cannot be recommended for patients with LARC.

Spatial distribution, sources, and direct radiative effect of carbonaceous aerosol along a transect from the Arctic Ocean to Antarctica.

Carbonaceous aerosols (CA) have a high impact on air quality and climate. However, the composition and spatial variability of CA in the marine boundary layer (MBL) remain understudied, especially in the remote regions. Here, atmospheric organic carbon (OC) and elemental carbon (EC) measurements using DRI Model 2001 Thermal/Optical Carbon Analyzer in the MBL were performed during the Chinese Antarctic (2019-2020) and Arctic (2021) research expedition, spanning about 160 latitudes. Due to varying intensities of atmospheric transport from the continents, a significant latitudinal gradient in OC and EC was observed. OC exhibited the highest concentration over the coastal East Asia (CEA), with a mean of 4324 ng m-3 (358-18027 ng m-3), followed by the Arctic Ocean (AO). Similar OC levels were detected over the Southern Ocean (SO) and the Antarctic Ice Sheet (AIS). Similarly, the highest EC was also observed over CEA, with a mean of 867 ng m-3 (71-3410 ng m-3), followed by AO and SO, while the lowest EC appeared over the AIS, with a mean of 30 ng m-3 (2-70 ng m-3). The lower Char-EC/Soot-EC ratios over AO and CEA compared to SO and AIS indicated that fossil fuel combustion contributed more to EC over AO and CEA, while biomass burning played a more significant role in EC levels over SO and AIS. The high OC/EC ratio over AIS was associated with an extremely low EC level and the formation of secondary OC over AIS. SBDART model results suggested that EC had a net warming effect on the atmospheric column, with the highest direct radiative effects (DRE) over AO (5.50 ± 0.15 W m-2, corresponding a heating rate of 0.15 K day-1) and the lowest DRE over SO (1.35 ± 0.04 W m-2, corresponding a heating rate of 0.04 K day-1).