Machine learning-based identification of biomarkers and drugs in immunologically cold and hot pancreatic adenocarcinomas.

BACKGROUND: Pancreatic adenocarcinomas (PAADs) often exhibit a "cold" or immunosuppressive tumor milieu, which is associated with resistance to immune checkpoint blockade therapy; however, the underlying mechanisms are incompletely understood. Here, we aimed to improve our understanding of the molecular mechanisms occurring in the tumor microenvironment and to identify biomarkers, therapeutic targets, and potential drugs to improve PAAD treatment. METHODS: Patients were categorized according to immunologically hot or cold PAAD subtypes with distinct disease outcomes. Cox regression and weighted correlation network analysis were performed to construct a novel gene signature, referred to as 'Downregulated in hot tumors, Prognostic, and Immune-Related Genes' (DPIRGs), which was used to develop prognostic models for PAAD via machine learning (ML). The role of DPIRGs in PAAD was comprehensively analyzed, and biomarker genes able to distinguish PAAD immune subtypes and predict prognosis were identified by ML. The expression of biomarkers was verified using public single-cell transcriptomic and proteomic resources. Drug candidates for turning cold tumors hot and corresponding target proteins were identified via molecular docking studies. RESULTS: Using the DPIRG signature as input data, a combination of survival random forest and partial least squares regression Cox was selected from 137 ML combinations to construct an optimized PAAD prognostic model. The effects and molecular mechanisms of DPIRGs were investigated by analysis of genetic/epigenetic alterations, immune infiltration, pathway enrichment, and miRNA regulation. Biomarkers and potential therapeutic targets, including PLEC, TRPV1, and ITGB4, among others, were identified, and the cell type-specific expression of the biomarkers was validated. Drug candidates, including thalidomide, SB-431542, and bleomycin A2, were identified based on their ability to modulate DPIRG expression favorably. CONCLUSIONS: By combining multiple ML algorithms, we developed a novel prognostic model with excellent performance in PAAD cohorts. ML also proved to be powerful for identifying biomarkers and potential targets for improved PAAD patient stratification and immunotherapy.

Tumor Mutation Burden-Related Histopathologic Features for Predicting Overall Survival in Gliomas Using Graph Deep Learning.

Tumor mutation burden (TMB) is a potential biomarker for evaluating the prognosis and response to immune checkpoint inhibitors, but its costly and time-consuming method of measurement limits its widespread application. This study aimed to identify the TMB-related histopathologic features from hematoxylin and eosin slides and explore their prognostic value in gliomas. TMB-related features were detected using a graph convolutional neural network from whole-slide images of patients from The Cancer Genome Atlas data set (619 patients), and the correlation between features and TMB was evaluated in an external validation set (237 patients). TMB-related features were used for predicting overall survival (OS) of patients to investigate whether these features have potential for prognostic prediction. Moreover, biological pathways underlying the prognostic value of the features were further explored. Histopathologic features derived from whole-slide images were significantly associated with patient TMB (P = 0.007 in the external validation set). TMB-related features showed excellent performance for OS prediction, and patients with lower-grade gliomas could be further stratified into different risk groups according to the features (P = 0.00013; hazard ratio, 4.004). Pathways involved in the cell cycle and execution of immune response were enriched in patients with higher OS risk. The TMB-related features could be used to estimate TMB and aid in prognostic risk stratification of patients with glioma with dysregulated biological pathways.

Aristolochia mimics stink bugs to repel vertebrate herbivores via TRPA1 activation.

Mimicry is the phenomenon in which one species (the mimic) closely resembles another (the model), enhancing its own fitness by deceiving a third party into interacting with it as if it were the model. In plants, mimicry is used primarily to gain fitness by withholding rewards from mutualists or deterring herbivores cost-effectively. While extensive work has been documented on putative defence mimicry, limited investigation has been conducted in the field of chemical mimicry. In this study, we used field experiments, chemical analyses, behavioural assays, and electrophysiology, to test the hypothesis that the birthwort Aristolochia delavayi employs chemical mimicry by releasing leaf scent that closely resembles stink bug defensive compounds and repels vertebrate herbivores. We show that A. delavayi leaf scent is chemically and functionally similar to the generalized defensive volatiles of stink bugs and that the scent effectively deters vertebrate herbivores, likely through the activation of TRPA1 channels via (E)-2-alkenal compounds. This study provides an unequivocal example of chemical mimicry in plants, revealing intricate dynamics between plants and vertebrate herbivores. Our study underscores the potency of chemical volatiles in countering vertebrate herbivory, urging further research to uncover their potentially underestimated importance.

Long noncoding RNA AI662270 promotes kidney fibrosis through enhancing METTL3-mediated m6 A modification of CTGF mRNA.

The sustained release of profibrotic cytokines, mainly transforming growth factor-ß (TGF-ß), leads to the occurrence of kidney fibrosis and chronic kidney disease (CKD). Connective tissue growth factor (CTGF) appears to be an alternative target to TGF-ß for antifibrotic therapy in CKD. In this study, we found that long noncoding RNA AI662270 was significantly increased in various renal fibrosis models. In vivo, ectopic expression of AI662270 alone was sufficient to activate interstitial fibroblasts and drive kidney fibrosis, whereas inhibition of AI662270 blocked the activation of interstitial fibroblasts and ameliorated kidney fibrosis in various murine models. Mechanistic studies revealed that overexpression of AI662270 significantly increased CTGF product, which was required for the role of AI662270 in driving kidney fibrosis. Furthermore, AI662270 binds to the CTGF promoter and directly interacts with METTL3, the methyltransferase of RNA N6 -methyladenosine (m6 A) modification. Functionally, AI662270-mediated recruitment of METTL3 increased the m6 A methylation of CTGF mRNA and consequently enhanced CTGF mRNA stability. In conclusion, our results support that AI662270 promotes CTGF expression at the posttranscriptional stage by recruiting METTL3 to the CTGF promoter and depositing m6 A modifications on the nascent mRNA, thereby, uncovering a novel regulatory mechanism of CTGF in the pathogenesis of kidney fibrosis.

Dearomatization of 3-Aminophenols for Synthesis of Spiro[chromane-3,1'-cyclohexane]-2',4'-dien-6'-ones via Hydride Transfer Strategy-Enabled [5+1] Annulations.

The Sc(OTf)3-catalyzed dearomative [5+1] annulations between readily available 3-aminophenols and O-alkyl ortho-oxybenzaldehydes were developed for synthesis of spiro[chromane-3,1'-cyclohexane]-2',4'-dien-6'-ones. The "two-birds-with-one-stone" strategy was disclosed by the dearomatization of phenols and direct α-C(sp3)-H bond functionalization of oxygen through cascade condensation/[1,5]-hydride transfer/dearomative-cyclization process. In addition, the antifungal activity assay and derivatizations of products were conducted to further enrich the utility of the structure.

PIK3CA mutations are associated with pathologic complete response rate to neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

BACKGROUND: Neoadjuvant treatment with a dual anti-human epidermal growth factor receptor 2 (HER2) blockade with pyrotinib and trastuzumab has been shown to be effective for HER2-positive breast cancer. METHODS: The genomic characteristics of 425 cancer-related genes from the archived tumour blocks of 50 patients enrolled in a prospective neoadjuvant pyrotinib and trastuzumab plus chemotherapy clinical trial (ChiCTR1900022293) were assessed by next-generation sequencing (NGS). The relationship between tumour biomarkers and the postoperative pathological complete response (pCR) were explored. RESULTS: Forty-five patients completed neoadjuvant chemotherapy and final surgery, of which 26 (58%) achieved a pCR. Among all driver gene mutations, PIK3CA mutation was screened out for having a significant relationship with the treatment response. The pCR rate of patients with wild-type PIK3CA was significantly higher than patients with mutated PIK3CA (80.8% vs. 26.3%; P = 0.00057), and remained significant after a multiple comparison adjustment (Padjusted = 0.024). We further evaluated the predictive value with logistic regression model of clinical features, genetic biomarkers or both, an AUC of 0.912 (95% CI: 0.827-0.997) was achieved in the integrated model. CONCLUSIONS: Our data suggest that HER2-positive breast cancers with activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy.

Deciphering complex reticulate evolution of Asian Buddleja (Scrophulariaceae): insights into the taxonomy and speciation of polyploid taxa in the Sino-Himalayan region.

BACKGROUND AND AIMS: Species of the genus Buddleja in Asia are mainly distributed in the Sino-Himalayan region and form a challenging taxonomic group, with extensive hybridization and polyploidization. A phylogenetic approach to unravelling the history of reticulation in this lineage will deepen our understanding of the speciation in biodiversity hotspots. METHODS: For this study, we obtained 80 accessions representing all the species in the Asian Buddleja clade, and the ploidy level of each taxon was determined by flow cytometry analyses. Whole plastid genomes, nuclear ribosomal DNA, single nucleotide polymorphisms and a large number of low-copy nuclear genes assembled from genome skimming data were used to investigate the reticulate evolutionary history of Asian Buddleja. Complex cytonuclear conflicts were detected through a comparison of plastid and species trees. Gene tree incongruence was also analysed to detect any reticulate events in the history of this lineage. KEY RESULTS: Six hybridization events were detected, which are able to explain the cytonuclear conflict in Asian Buddleja. Furthermore, PhyloNet analysis combining species ploidy data indicated several allopolyploid speciation events. A strongly supported species tree inferred from a large number of low-copy nuclear genes not only corrected some earlier misinterpretations, but also indicated that there are many Asian Buddleja species that have been lumped mistakenly. Divergent time estimation shows two periods of rapid diversification (8-10 and 0-3 Mya) in the Asian Buddleja clade, which might coincide with the final uplift of the Hengduan Mountains and Quaternary climate fluctuations, respectively. CONCLUSIONS: This study presents a well-supported phylogenetic backbone for the Asian Buddleja species, elucidates their complex and reticulate evolutionary history and suggests that tectonic activity, climate fluctuations, polyploidization and hybridization together promoted the diversification of this lineage.

Tubule-derived INHBB promotes interstitial fibroblast activation and renal fibrosis.

Upstream stimuli for myofibroblast activation are of considerable interest for understanding the mechanisms underlying renal fibrosis. Activin B, a member of the TGF-ß family, exists as a homodimer of inhibin subunit beta B (INHBB), but its role in renal fibrosis remains unknown. We found that INHBB expression was significantly increased in various renal fibrosis models and human chronic kidney disease specimens with renal fibrosis. Notably, the increase of INHBB occurred mainly in the tubular epithelial cells (TECs). In vivo, inhibiting INHBB blocked the activation of interstitial fibroblasts and ameliorated the renal fibrosis induced by unilateral ureteral obstruction or ischemia-reperfusion injury, while ectopic expression of INHBB in the TECs was able to activate interstitial fibroblasts and initiate interstitial fibrosis. In vitro, overexpression of INHBB in TECs led to the secretion of activin B, thereby promoting the proliferation and activation of interstitial fibroblasts through activin B/Smad signaling. Furthermore, inhibition of activin B/Smad signaling attenuated the fibrotic response caused by tubular INHBB. Mechanistically, the upregulation of INHBB depended on the transcription factor Sox9 in the injured TECs. Clinical analyses also identified a positive correlation between Sox9 and INHBB expression in human specimens, suggesting the Sox9/INHBB axis as a positive regulator of renal fibrosis. In conclusion, tubule-derived INHBB is implicated in the pathogenesis of renal fibrosis by activating the surrounding fibroblasts in a paracrine manner, thereby exhibiting as a potential therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Homochiral Chemistry Strategy To Trigger Dielectric Switching and Second-Harmonic Generation Response on Spirocyclic Derivatives.

Organic-inorganic hybrid materials with switchable properties have significant potential applications in intelligent devices. There are some conventional ways to obtain optical and/or electric multiple responses, such as asymmetric design, chirality, doping, and structural dimension in hybrid materials. Among them, the homochirality strategy is one of the best ways to regulate the molecular structure and symmetry, thereby ensuring second-harmonic generation (SHG) and dielectric dual response characteristics. Here, we report a homochiral design strategy to obtain noncentrosymmetric [R-(HASD)][Cd(SCN)3] (HASD = 7-hydroxy-5-azaspiro[4.5]decan) and [S-(HASD)][Cd(SCN)3]; [Rac-(HASD)][Cd(SCN)3] was also synthesized as a comparative experiment to illustrate the relationship between structural chirality and physical properties. With the help of homochiral regulation, the SHG response is excited and dielectric phase transition temperature (Tc) is also highly improved. In addition, both the optical SHG and dielectric phase change show an optical/electric switchable response. This work is of great significance for the further exploration of multifunctional molecular switching materials through homochiral chemistry.

Value of bedside echocardiography in predicting persistent patency of the ductus arteriosus during the early postnatal period in very low birth weight infants. / ç”ŸåŽæ—©æœŸåºŠæ—å¿ƒè„è¶ å£°é¢„æµ‹æžä½Žå‡ºç”Ÿä½“é‡å„¿åŠ¨è„‰å¯¼ç®¡æŒç»­å¼€æ”¾çš„ç ”ç©¶.

OBJECTIVES: To study the value of bedside echocardiography in predicting persistent patency of the ductus arteriosus during the early postnatal period in very low birth weight (VLBW) infants. METHODS: A retrospective analysis was performed for 51 VLBW infants who were admitted from March 2020 to June 2021, with an age of ≤3 days and a length of hospital stay of ≥14 days. According to the diameter of patent ductus arteriosus (PDA) on days 14 and 28 after birth, the infants were divided into three groups: large PDA group (PDA diameter ≥2 mm), small PDA group (PDA diameter <2 mm), and PDA closure group (PDA diameter =0 mm). The echocardiographic parameters measured at 72 hours after birth were compared among the three groups. The receiver operating characteristic (ROC) curve was used to evaluate the value of the echocardiographic parameters in predicting persistent patency of the ductus arteriosus (PDA≥2 mm) at the ages of 14 and 28 days. RESULTS: On day 14 after birth, there were 17 infants in the large PDA group, 11 in the small PDA group, and 23 in the PDA closure group. On day 28 after birth, there were 14 infants in the large PDA group, 9 in the small PDA group, and 26 in the PDA closure group. There were significant differences in gestational age, birth weight, rate of pulmonary surfactant use, and incidence rate of hypotension among the three groups (P<0.05). PDA diameter, end-diastolic velocity of the left pulmonary artery, left ventricular output, and left ventricular output/superior vena cava flow ratio measured at 72 hours after birth were associated with persistent patency of the ductus arteriosus at the ages of 14 and 28 days (P<0.05), and the ratio of the left atrium to aorta diameter was associated with persistent patency of the ductus arteriosus at the age of 28 days (P<0.05). The ROC curve analysis showed that the area under the curve that the PDA diameter measured at 72 hours after birth predicting the persistent patency of the ductus arteriosus at the ages of 14 and 28 days was the largest (0.841 and 0.927 respectively), followed by end-diastolic velocity of the left pulmonary artery, with the area under the curve of 0.793 and 0.833 respectively. CONCLUSIONS: The indicators obtained by beside echocardiography at 72 hours after birth, especially PDA diameter and end-diastolic velocity of the left pulmonary artery, can predict persistent patency of the ductus arteriosus at the ages of 14 and 28 days in VLBW infants, which provides a basis for the implementation of early targeted treatment strategy for PDA.