A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for alpelisib.

In this study, we delved into the safety profile of alpelisib, an FDA-approved treatment for hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer, and PIK3CA-Related Overgrowth Spectrum (PROS). Despite its approval, real-world, long-term safety data is lacking. Our research scrutinizes the FDA database to assess alpelisib 's safety. We retrospectively analyzed data from April 2019 to June 2023 using four algorithms. Among 7,609,450 reports, 6692 implicated alpelisib as the primary suspected drug, uncovering adverse events (AEs) across 26 organ systems. Notably, we identified 21 previously unlisted AEs. Furthermore, differences in AEs emerged between patients with PIK3CA-mutated breast cancer and those with PROS. This study provides vital insights for healthcare professionals to navigate AEs in clinical practice and informs future research for enhancing alpelisib 's safety profile.

The effect of Fu's subcutaneous needling in treating knee osteoarthritis patients: A randomized controlled trial.

BACKGROUND: Fu's subcutaneous needling (FSN) is an acupuncture technique for the treatment of soft tissue diseases. Knee osteoarthritis often involves lower limb muscles. This study aimed to observe and compare the clinical efficacy of Fu's subcutaneous acupuncture and electroacupuncture in the treatment of patients with knee osteoarthritis. METHODS: 62 patients with early or medial stage of knee osteoarthritis were randomly divided into the FSN therapy group or the electroacupuncture(EA) therapy group (1:1). The Lysholm score, range of motion, and equilibrium function were observed over a 3-month follow-up period. A total of 60 participants completed the study. RESULTS: Over the 3 months of follow-up, both treatment regimens showed equally favorable results on all prognostic measures compared with their respective baseline data (P<0.05). Compared with the EA group, the FSN group had a significantly greater improvement in claudication, joint stability, swelling, pain, and ROM after treatment (P<0.05). At 3 months after treatment, the FSN group revealed better scores of claudication, joint stability, swelling, walking up stairs, squatting, pain, ROM, and equilibrium function (forward and backward movement speed, left and right movement speed, movement ellipse area, movement length) compared to the EA group (all P<0.05). CONCLUSIONS: This study showed that FSN can significantly improve the pain symptoms, joint stability, and joint function of patients with knee osteoarthritis, and the clinical efficacy can be maintained at least 3 months after treatment.

Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage.

It is generally thought that under basal conditions, neurons produce ATP mainly through mitochondrial oxidative phosphorylation (OXPHOS), and glycolytic activity only predominates when neurons are activated and need to meet higher energy demands. However, it remains unknown whether there are differences in glucose metabolism between neuronal somata and axon terminals. Here, we demonstrated that neuronal somata perform higher levels of aerobic glycolysis and lower levels of OXPHOS than terminals, both during basal and activated states. We found that the glycolytic enzyme pyruvate kinase 2 (PKM2) is localized predominantly in the somata rather than in the terminals. Deletion of Pkm2 in mice results in a switch from aerobic glycolysis to OXPHOS in neuronal somata, leading to oxidative damage and progressive loss of dopaminergic neurons. Our findings update the conventional view that neurons uniformly use OXPHOS under basal conditions and highlight the important role of somatic aerobic glycolysis in maintaining antioxidant capacity.

A Bi-LSTM and multihead attention-based model incorporating radiomics signatures and radiological features for differentiating the main subtypes of lung adenocarcinoma.

Background: The radiological features of computed tomography (CT) images and the sequence of radiomics signatures in continuous slices of lung CT lesions are helpful in identifying subtypes of lung adenocarcinoma. A model based on bidirectional long short-term memory (Bi-LSTM) and multihead attention can learn the rules of this sequence well. Methods: In this study, 421 patients with 427 lesions confirmed as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (IAC) were recruited from three hospitals. The radiomics signatures of the identified lesion regions in each CT image were extracted using 'PyRadiomics' software, and the corresponding radiological features were subsequently documented and collected. Then, the top 100 features were extracted by the minimum redundancy maximum relevance (mRMR) feature ranking method. A model based on the radiological and imaging features was established to classify the lesions using Bi-LSTM and multihead attention. The diagnostic performance of the model was measured by the area under the curve (AUC) of the receiver operating characteristic (ROC). Results: The model combined radiological features and radiomics signatures. The AUCs of the model in the training, testing, and validation groups were 0.985, 0.94 and 0.981, respectively, and the accuracy was 0.92, 0.976 and 0.91, respectively. In addition, we trained two other models [convolutional neural network (CNN) + multihead attention, long short-term memory (LSTM) + multihead attention] and compared them using the testing dataset. The precision of the two models was 0.89 and 0.88, respectively, and the accuracy was 0.88 and 0.87, respectively. Conclusions: Bi-LSTM and multihead attention based on radiomics signatures and radiological features provide a way to distinguish AIS, MIA, and IAC.

DJ-1 promotes osteosarcoma progression through activating CDK4/RB/E2F1 signaling pathway.

Osteosarcoma (OS) is a primary malignant tumor of the bone characterized by poor prognosis due to chemotherapy resistance and high recurrence rates. DJ-1 (PARK7) is known as an oncogene and its abnormal expression is related to the poor prognosis of various types of malignant tumors. It was found in this study that upregulated expression of DJ-1 was closely correlated with the prognosis of OS patients by promoting the proliferation, migration and chemotherapy resistance of OS cells in vitro through regulating the activity of CDK4 but not through the oxidation mechanism or AKT pathway. The combination of DJ-1 and CDK4 promoted RB phosphorylation, leading to the dissociation of E2F1 into the nucleus to regulate the expression of cell cycle-related genes. The tumor xenograft mouse model demonstrated that DJ-1 knockout suppressed tumor growth in vivo. All these findings indicate that DJ-1 can affect the occurrence and progression of OS by regulating the CDK/RB/E2F1axis, suggesting a novel therapeutic opportunity for OS patients.

DJ-1 inhibits glutathione degradation by downregulating CHAC1 expression in astrocytes.

The PARK7 gene, which encodes DJ-1 protein, is the causative gene of autosomal recessive early-onset Parkinson's disease. DJ-1 has many biological functions, including regulating glutathione (GSH) levels. However, the molecular mechanism by which DJ-1 regulates GSH levels in astrocytes remains unclear. With high throughput sequencing, we discovered that DJ-1 knockout could significantly upregulate the expression of ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1). We demonstrate that DJ-1 can bind with the basic leucine zipper domain of activating transcription factor 3 (ATF3) through bimolecular fluorescence complementation. Besides, DJ-1 inhibits ATF3 binding to the CHAC1 promoter and downregulates the expression of CHAC1 to reduce GSH degradation. Our research suggests that the loss of DJ-1 in astrocytes promotes the degradation of GSH, leading neurons more vulnerable to oxidative damage. It provides a theoretical basis for developing drugs targeting DJ-1 and GSH in the brain.

Establishment and Validation of an Interferon-Stimulated Genes (ISGs) Prognostic Signature in Pan-cancer Patients: A Multicenter, Real-world Study.

Our study aims at developing an interferon-stimulated genes (ISGs) signature that could predict overall survival (OS) in cancer patients, which enrolled a total of 5643 pan-cancer patients. Linear models for microarray data method analysis were conducted to identify the differentially expressed prognostic genes in the global ISGs family. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival analysis were used to test the efficiency of a multi-gene signature in predicting the prognosis of pan-cancer patients. The prognostic performance and potential biological function of gene signature were verified by quantitative real-time PCR in a pan-cancer independent cohort. Three ISGs genes were finally identified to build a classifier, a specific risk score formula, with which patients were classified into the low- or high-risk groups. Time-dependent ROC analyses proved prognostic accuracy. Then, its prognostic value was validated in seven external validation series. A nomogram was constructed to guide the individualized treatment of patients with lung adenocarcinoma. Biological pathway and tumor immune infiltration analysis showed that the signature might cause poor prognosis by blocking NK cell activation. Finally, the signature in our centers was confirmed by real-time quantitative PCR. A robust ISGs-related feature was discovered to effectively classify pan-cancer patients into subgroups with different OS.

Enhanced soil erosion threatens fluvial tufa landscapes after an Ms 7.0 earthquake in the Jiuzhaigou World Heritage Site, southwestern China.

Tufa is a porous freshwater deposit comprising primarily calcite (CaCO3) and organic matter. Massive tufa depositions can spread for up to several kilometers, forming tufa landscapes that have been recognized as national parks and World Heritage Sites. Previous studies have suggested that enhanced soil erosion owing to human activities (e.g., deforestation and agriculture) is one of the major causes of fluvial tufa decline in many places worldwide. In 2017, an Ms 7.0 earthquake occurred in Jiuzhaigou, which greatly increased soil erosion in the catchment. We compared the water chemistry and tufa deposition before and after the earthquake to understand the impact of soil erosion on tufa landscapes in Jiuzhaigou. After the earthquake, we found that high turbidity greatly reduced the aesthetic value of the lakes. Enhanced soil erosion increased NO3-, dissolved organic carbon (DOC), and PO43- concentrations in surface water, which may worsen the problems of increased algal biomass and marsh development. Enhanced soil erosion reduced alkalinity, HCO3-, and the saturation index of calcite (SIc), thereby decreasing the potential to generate new calcite. Enhanced soil erosion may also increase the annual tufa deposition rates by increasing the soil and organic materials in the sediment. In addition, the tufa sediment affected by enhanced soil erosion was loose, highly porous, and contained numerous diatoms. This study provides observational data to explain the impact mechanisms of soil erosion on tufa landscapes and assess the necessity and achievements of artificial soil erosion control.

Antioxidant potential of Pediococcus pentosaceus strains from the sow milk bacterial collection in weaned piglets.

BACKGROUND: In modern animal husbandry, breeders pay increasing attention to improving sow nutrition during pregnancy and lactation to favor the health of neonates. Sow milk is a main food source for piglets during their first three weeks of life, which is not only a rich repository of essential nutrients and a broad range of bioactive compounds, but also an indispensable source of commensal bacteria. Maternal milk microorganisms are important sources of commensal bacteria for the neonatal gut. Bacteria from maternal milk may confer a health benefit on the host. METHODS: Sow milk bacteria were isolated using culturomics followed by identification using 16S rRNA gene sequencing. To screen isolates for potential probiotic activity, the functional evaluation was conducted to assess their antagonistic activity against pathogens in vitro and evaluate their resistance against oxidative stress in damaged Drosophila induced by paraquat. In a piglet feeding trial, a total of 54 newborn suckling piglets were chosen from nine sows and randomly assigned to three treatments with different concentrations of a candidate strain. Multiple approaches were carried out to verify its antioxidant function including western blotting, enzyme activity analysis, metabolomics and 16S rRNA gene amplicon sequencing. RESULTS: The 1240 isolates were screened out from the sow milk microbiota and grouped into 271 bacterial taxa based on a nonredundant set of 16S rRNA gene sequencing. Among 80 Pediococcus isolates, a new Pediococcus pentosaceus strain (SMM914) showed the best performance in inhibition ability against swine pathogens and in a Drosophila model challenged by paraquat. Pretreatment of piglets with SMM914 induced the Nrf2-Keap1 antioxidant signaling pathway and greatly affected the pathways of amino acid metabolism and lipid metabolism in plasma. In the colon, the relative abundance of Lactobacillus was significantly increased in the high dose SMM914 group compared with the control group. CONCLUSION: P. pentosaceus SMM914 is a promising probiotic conferring antioxidant capacity by activating the Nrf2-Keap1 antioxidant signaling pathway in piglets. Our study provided useful resources for better understanding the relationships between the maternal microbiota and offspring. Video Abstract.

Direct conversion of syngas into aromatics over a bifunctional catalyst: inhibiting net CO2 release.

Tandem catalysis via methanol intermediate is a promising route for the direct conversion of syngas into aromatics. However, the simultaneous formation of CO2 is a serious problem. Here, we demonstrate that CO2 was formed by the water-gas shift (WGS) reaction (CO + H2O → CO2 + H2) over a ZnO-ZrO2/H-ZSM-5 catalyst, and the net CO2 formation could be inhibited without affecting the formation of aromatics by co-feeding CO2.

Opportunities for biodiversity gains under the world's largest reforestation programme.

Reforestation is a critical means of addressing the environmental and social problems of deforestation. China's Grain-for-Green Program (GFGP) is the world's largest reforestation scheme. Here we provide the first nationwide assessment of the tree composition of GFGP forests and the first combined ecological and economic study aimed at understanding GFGP's biodiversity implications. Across China, GFGP forests are overwhelmingly monocultures or compositionally simple mixed forests. Focusing on birds and bees in Sichuan Province, we find that GFGP reforestation results in modest gains (via mixed forest) and losses (via monocultures) of bird diversity, along with major losses of bee diversity. Moreover, all current modes of GFGP reforestation fall short of restoring biodiversity to levels approximating native forests. However, even within existing modes of reforestation, GFGP can achieve greater biodiversity gains by promoting mixed forests over monocultures; doing so is unlikely to entail major opportunity costs or pose unforeseen economic risks to households.

Invasive mouse gastric adenocarcinomas arising from Lgr5+ stem cells are dependent on crosstalk between the Hedgehog/GLI2 and mTOR pathways.

Gastric adenocarcinoma is the third most common cause of cancer-related death worldwide. Here we report a novel, highly-penetrant mouse model of invasive gastric cancer arising from deregulated Hedgehog/Gli2 signaling targeted to Lgr5-expressing stem cells in adult stomach. Tumor development progressed rapidly: three weeks after inducing the Hh pathway oncogene GLI2A, 65% of mice harbored in situ gastric cancer, and an additional 23% of mice had locally invasive tumors. Advanced mouse gastric tumors had multiple features in common with human gastric adenocarcinomas, including characteristic histological changes, expression of RNA and protein markers, and the presence of major inflammatory and stromal cell populations. A subset of tumor cells underwent epithelial-mesenchymal transition, likely mediated by focal activation of canonical Wnt signaling and Snail1 induction. Strikingly, mTOR pathway activation, based on pS6 expression, was robustly activated in mouse gastric adenocarcinomas from the earliest stages of tumor development, and treatment with rapamycin impaired tumor growth. GLI2A-expressing epithelial cells were detected transiently in intestine, which also contains Lgr5+ stem cells, but they did not give rise to epithelial tumors in this organ. These findings establish that deregulated activation of Hedgehog/Gli2 signaling in Lgr5-expressing stem cells is sufficient to drive gastric adenocarcinoma development in mice, identify a critical requirement for mTOR signaling in the pathogenesis of these tumors, and underscore the importance of tissue context in defining stem cell responsiveness to oncogenic stimuli.

Transgenic expression of interferon-γ in mouse stomach leads to inflammation, metaplasia, and dysplasia.

Gastric adenocarcinoma is one of the leading causes of cancer mortality worldwide. It arises through a stepwise process that includes prominent inflammation with expression of interferon-γ (IFN-γ) and multiple other pro-inflammatory cytokines. We engineered mice expressing IFN-γ under the control of the stomach-specific H(+)/K(+) ATPase ß promoter to test the potential role of this cytokine in gastric tumorigenesis. Stomachs of H/K-IFN-γ transgenic mice exhibited inflammation, expansion of myofibroblasts, loss of parietal and chief cells, spasmolytic polypeptide expressing metaplasia, and dysplasia. Proliferation was elevated in undifferentiated and metaplastic epithelial cells in H/K-IFN-γ transgenic mice, and there was increased apoptosis. H/K-IFN-γ mice had elevated levels of mRNA for IFN-γ target genes and the pro-inflammatory cytokines IL-6, IL-1ß, and tumor necrosis factor-α. Intracellular mediators of IFN-γ and IL-6 signaling, pSTAT1 and pSTAT3, respectively, were detected in multiple cell types within stomach. H/K-IFN-γ mice developed dysplasia as early as 3 months of age, and 4 of 39 mice over 1 year of age developed antral polyps or tumors, including one adenoma and one adenocarcinoma, which expressed high levels of nuclear ß-catenin. Our data identified IFN-γ as a pivotal secreted factor that orchestrates complex changes in inflammatory, epithelial, and mesenchymal cell populations to drive pre-neoplastic progression in stomach; however, additional alterations appear to be required for malignant conversion.