Identification of Cuproptosis-related Gene Lipoyltransferase 1 as a Promising Biomarker in Oral Squamous Cell Carcinoma.

OBJECTIVE: To find efficient cuproptosis-related biomarkers to explore the oncogenesis and progression of oral squamous cell carcinoma (OSCC). METHODS: All the original data were downloaded from the Cancer Genome Atlas (TCGA) database. Univariate Cox analysis and Kaplan-Meier survival analysis were used to identify the gene related to survival. Tumor Immune Estimation Resource 2.0 (TIMER 2.0) was used to reveal the different expression of cuproptosis-related gene lipoyltransferase 1 (LIPT1) in various kinds of tumours. RESULTS: LIPT1, as a cuproptosis-related gene, was found to be differentially expressed in the OSCC group and the control group. It was also found to be related to the prognosis of OSCC. Pan cancer analysis showed LIPT1 was also involved in various kinds of tumours. CONCLUSION: All the results demonstrate that the cuproptosis-related gene LIPT1 is highly involved in the oncogenesis and progression of OSCC. These findings give new insight for further research into the cuproptosis-related biomarkers in OSCC.

Isolation, whole genome sequencing and application of a broad-spectrum Salmonella phage.

Salmonella is considered as one of the most common zoonotic /foodborne pathogens in the world. The application of bacteriophages as novel antibacterial agents in food substrates has become an emerging strategy. Bacteriophages have the potential to control Salmonella contamination.We have isolated and characterized a broad-spectrum Salmonella phage, SP154, which can lyse 9 serotypes, including S. Enteritidis, S. Typhimurium, S. Pullorum, S. Arizonae, S. Dublin, S. Cholerasuis, S. Chester, S. 1, 4, [5], 12: i: -, and S. Derby, accounting for 81.9% of 144 isolates. SP154 showed a short latent period (40 min) and a high burst size (with the first rapid burst size at 107 PFUs/cell and the second rapid burst size at approximately 40 PFUs/cell). Furthermore, SP154 activity has higher survival rates across various environmental conditions, including pH 4.0-12.0 and temperatures ranging from 4 to 50 °C for 60 min, making it suitable for diverse food processing and storage applications. Significant reductions in live Salmonella were observed in different foods matrices such as milk and chicken meat, with a decrease of up to 1.9 log10 CFU/mL in milk contamination and a 1 log10 CFU/mL reduction in chicken meat. Whole genome sequencing analysis revealed that SP154 belongs to the genus Ithacavirus, subfamily Humphriesvirinae, within the family Schitoviridae. Phylogenetic analysis based on the terminase large subunit supported this classification, although an alternate tree using the tail spike protein gene suggested affiliation with the genus Kuttervirus, underscoring the limitations of relying on a single gene for phylogenetic inference. Importantly, no virulence or antibiotic resistance genes were detected in SP154. Our research highlights the potential of using SP154 for biocontrol of Salmonella in the food industry.

Differential diagnostic value of simultaneous detection of CD69 and HLA-DR on host T and NK cells in QFT-TB assay for identifying active tuberculosis.

BACKGROUND: Interferon-gamma release assay (IGRA) for tuberculosis (TB) remains limited in its ability to discriminate between active TB (ATB) and latent TB infection (LTBI). Activation markers on host T and NK cells are currently considered to be promising markers in the diagnosis of ATB. METHODS: This prospective observational study enrolled 213 participants and the participants were divided into ATB, LTBI, other lung-related diseases (ORD), and health control (HC) groups. CD69 and HLA-DR on T and NK cells were detected in QFT-TB assay, and a composite scoring system (TB-Flow) was created for the diagnosis of ATB. RESULTS: The expression of activation markers (CD69 and HLA-DR) were significantly increased in ATB. HLA-DR on NK cells, CD69 on T cells, and QFT-TB in the differential diagnosis of ATB and HC were all of good diagnostic value (AUC>0.90). In addition, the TB-Flow greatly improved the efficiency of differential diagnosis between ATB and LTBI (AUC=0.90, 95%CI: 0.84-0.96), with sensitivity and specificity of 79.17 % (95%CI: 64.60%-89.04 %) and 88.68 % (95%CI: 76.28%-95.31 %). CONCLUSIONS: CD69 and HLA-DR on host T and NK cells are promising markers in distinguishing different TB infection status. Our blood-based TB-Flow scoring system can distinguish ATB from LTBI with good diagnostic efficacy.

Comparison between MRI-negative and positive results and the predictors for a poor prognosis in patients with idiopathic acute transverse myelitis.

BACKGROUND: Idiopathic acute transverse myelitis (IATM) is a focal inflammatory disorder of the spinal cord that results in motor, sensory, and autonomic dysfunction. However, the comparative analysis of MRI-negative and MRI-positive in IATM patients were rarely reported. OBJECTIVES: The purpose of this study was to compare MRI-negative with MRI-positive groups in IATM patients, analyze the predictors for a poor prognosis, thus explore the relationship between MRI-negative and prognosis. METHODS: We selected 132 patients with first-attack IATM at the First Affiliated Hospital of Nanchang University from May 2018 to May 2022. Patients were divided into MRI-positive and MRI-negative group according to whether there were responsible spinal MRI lesions, and good prognosis and poor prognosis based on whether the EDSS score ≥ 4 at follow-up. The predictive factors of poor prognosis in IATM patients was analyzed by logistic regression models. RESULTS: Of the 132 patients, 107 first-attack patients who fulfilled the criteria for IATM were included in the study. We showed that 43 (40%) patients had a negative spinal cord MRI, while 27 (25%) patients were identified as having a poor prognosis (EDSS score at follow-up ≥ 4). Compared with MRI-negative patients, the MRI-positive group was more likely to have back/neck pain, spinal cord shock and poor prognosis, and the EDSS score at follow-up was higher. We also identified three risk factors for a poor outcome: absence of second-line therapies, high EDSS score at nadir and a positive MRI result. CONCLUSIONS: Compared with MRI-negative group, MRI-positive patients were more likely to have back/neck pain, spinal cord shock and poor prognosis, with a higher EDSS score at follow-up. The absence of second-line therapies, high EDSS score at nadir, and a positive MRI were risk factors for poor outcomes in patients with first-attack IATM. MRI-negative patients may have better prognosis, an active second-line immunotherapy for IATM patients may improve clinical outcome.

Role of oxidative stress in the concurrent development of osteoporosis and tendinopathy: Emerging challenges and prospects for treatment modalities.

Both osteoporosis and tendinopathy are widely prevalent disorders, encountered in diverse medical contexts. Whilst each condition has distinct pathophysiological characteristics, they share several risk factors and underlying causes. Notably, oxidative stress emerges as a crucial intersecting factor, playing a pivotal role in the onset and progression of both diseases. This imbalance arises from a dysregulation in generating and neutralising reactive oxygen species (ROS), leading to an abnormal oxidative environment. Elevated levels of ROS can induce multiple cellular disruptions, such as cytotoxicity, apoptosis activation and reduced cell function, contributing to tissue deterioration and weakening the structural integrity of bones and tendons. Antioxidants are substances that can prevent or slow down the oxidation process, including Vitamin C, melatonin, resveratrol, anthocyanins and so on, demonstrating potential in treating these overlapping disorders. This comprehensive review aims to elucidate the complex role of oxidative stress within the interlinked pathways of these comorbid conditions. By integrating contemporary research and empirical findings, our objective is to outline new conceptual models and innovative treatment strategies for effectively managing these prevalent diseases. This review underscores the importance of further in-depth research to validate the efficacy of antioxidants and traditional Chinese medicine in treatment plans, as well as to explore targeted interventions focused on oxidative stress as promising areas for future medical advancements.

Enantiomerically Resolvable Inherent Chirality Induced by Strong Para-Steric Hindrance in Cycloparaphenylene-Based Carbon Nanohoops.

The chemical modification of the achiral carbon nanohoops to break the symmetry will result in inherently chiral structures with interesting optical properties. Herein, we report two novel π-extended chiral macrocycles, cyclo[10]paraphenylene-pyrene ([10]CPP-2Pyrene) and cyclo[10]paraphenylene-hexa-peri-hexabenzocoronene ([10]CPP-2HBC). The large substituents on the nanohoop peripheries effectively prevented free rotation and the racemization process. The conformation of each enantiomer is stable enough to be resolved by recycling HPLC.

Single-cell transcriptome dissecting the microenvironment remodeled by PD1 blockade combined with photodynamic therapy in a mouse model of oral carcinogenesis.

Oral squamous cell carcinoma (OSCC) stands as a predominant and perilous malignant neoplasm globally, with the majority of cases originating from oral potential malignant disorders (OPMDs). Despite this, effective strategies to impede the progression of OPMDs to OSCC remain elusive. In this study, we established mouse models of oral carcinogenesis via 4-nitroquinoline 1-oxide induction, mirroring the sequential transformation from normal oral mucosa to OPMDs, culminating in OSCC development. By intervening during the OPMDs stage, we observed that combining PD1 blockade with photodynamic therapy (PDT) significantly mitigated oral carcinogenesis progression. Single-cell transcriptomic sequencing unveiled microenvironmental dysregulation occurring predominantly from OPMDs to OSCC stages, fostering a tumor-promoting milieu characterized by increased Treg proportion, heightened S100A8 expression, and decreased Fib_Igfbp5 (a specific fibroblast subtype) proportion, among others. Notably, intervening with PD1 blockade and PDT during the OPMDs stage hindered the formation of the tumor-promoting microenvironment, resulting in decreased Treg proportion, reduced S100A8 expression, and increased Fib_Igfbp5 proportion. Moreover, combination therapy elicited a more robust treatment-associated immune response compared with monotherapy. In essence, our findings present a novel strategy for curtailing the progression of oral carcinogenesis.

Reflectance confocal microscopy for plaque psoriasis therapeutic follow-up during an anti-interleukin-17A monoclonal antibody: an observational study.

Interleukin-17A therapeutic inhibitors are among the most effective treatment methods for moderate-to-severe plaque psoriasis (PP). Reflectance confocal microscopy is a non-invasive imaging technique already documented to be beneficial in evaluating the follow-up of PP under treatment with topical actives and phototherapy. This study aimed to assess the epidermal and dermal changes associated with psoriasis and its treatment with RCM during systemic secukinumab treatment in patients with moderate-to-severe PP. A pilot study was conducted to evaluate RCM as a non-invasive tool for monitoring secukinumab treatment in patients with PP. For patients receiving secukinumab treatment, lesional skin was selected for RCM imaging, which were recorded at all scheduled times. The RCM evaluation criteria were established based on the histopathological diagnostic criteria for psoriasis. The clinical severity of psoriasis was assessed utilizing the psoriasis area severity index. A total of 23 patients with PP were included in the study. Each patient received 300 mg of subcutaneous secukinumab as induction therapy at baseline and weeks 1-4, followed by maintenance therapy every four weeks. Microscopic confocal changes were observed during the treatment. The results identified early microscopic evidence of the anti-inflammatory activity of secukinumab, which was not detected during the clinical examination. RCM findings correlating with the PASI were used to observe the patient's response to treatment and were identified as follows: acanthosis and parakeratosis, presence of epidermal and dermal inflammatory cells, presence of non-edge dermal papillae, and vascularization in the papillary dermis. This study is the first to demonstrate the use of RCM as an effective tool for non-invasive monitoring of secukinumab therapeutic response at a cellular level in a clinical or research setting. Early detection of RCM parameters associated with secukinumab activity may facilitate the identification of an early treatment response. RCM appears to be capable of providing practical and helpful information regarding follow-up in patients with PP undergoing secukinumab treatment. RCM may also provide novel perspectives on the subclinical evaluation of PP's response to biological therapy.

LASSO-derived nomogram for early identification of pediatric monogenic lupus.

BACKGROUND: Monogenic lupus is defined as systemic lupus erythematosus (SLE)/SLE-like patients with either dominantly or recessively inherited pathogenic variants in a single gene with high penetrance. However, because the clinical phenotype of monogenic SLE is extensive and overlaps with that of classical SLE, it causes a delay in diagnosis and treatment. Currently, there is a lack of early identification models for clinical practitioners to provide early clues for recognition. Our goal was to create a clinical model for the early identification of pediatric monogenic lupus, thereby facilitating early and precise diagnosis and treatment for patients. METHODS: This retrospective cohort study consisted of 41 cases of monogenic lupus treated at the Department of Pediatrics at Peking Union Medical College Hospital from June 2012 to December 2022. The control group consisted of classical SLE patients recruited at a 1:2 ratio. Patients were randomly divided into a training group and a validation group at a 7:3 ratio. A logistic regression model was established based on the least absolute shrinkage and selection operator to generate the coefficient plot. The predictive ability of the model was evaluated using receiver operator characteristic curves and the area under the curve (AUC) index. RESULTS: A total of 41 cases of monogenic lupus patients and 82 cases of classical SLE patients were included. Among the monogenic lupus cases (with a male-to-female ratio of 1:1.05 and ages of onset ranging from birth to 15 years), a total of 18 gene mutations were identified. The variables included in the coefficient plot were age of onset, recurrent infections, intracranial calcifications, growth and developmental delay, abnormal muscle tone, lymphadenopathy/hepatosplenomegaly, and chilblain-like skin rash. Our model demonstrated satisfactory diagnostic performance through internal validation, with an AUC value of 0.97 (95% confidence interval = 0.92-0.97). CONCLUSIONS: We summarized and analyzed the clinical characteristics of pediatric monogenic lupus and developed a predictive model for early identification by clinicians. Clinicians should exercise high vigilance for monogenic lupus when the score exceeds - 9.032299.

The impact of female sex hormones on cardiovascular disease: from mechanisms to hormone therapy.

Cardiovascular disease remains the leading cause of mortality in women, yet it has not raised the awareness from the public. The pathogenesis of cardiovascular disease differs significantly between females and males concerning the effect of sex hormones. Estrogen and progestogen impact cardiovascular system through genomic and non-genomic effects. Before menopause, cardiovascular protective effects of estrogens have been well described. Progestogens were often used in combination with estrogens in hormone therapy. Fluctuations in sex hormone levels, particularly estrogen deficiency, were considered the specific risk factor in women's cardiovascular disease. However, considerable heterogeneity in the impact of hormone therapy was observed in clinical trials. The heterogeneity is likely closely associated with factors such as the initial time, administration route, dosage, and formulation of hormone therapy. This review will delve into the pathogenesis and hormone therapy, summarizing the effect of female sex hormones on hypertension, pre-eclampsia, coronary heart disease, heart failure with preserved ejection fraction, and cardiovascular risk factors specific to women.

Genomic and Phenotypic Analysis of bla KPC-2 Associated Carbapenem Resistance in Klebsiella aerogenes: Insights into Clonal Spread and Resistance Mechanisms Across Hospital Departments in Beijing.

Purpose: This study conducted an phenotypic and whole-genome sequencing analysis with Klebsiella aerogenes to elucidate its clinical epidemiological characteristics, antimicrobial resistance (AMR) phenotype, biofilm formation ability and hemolytic activity testing, AMR genes and phylogenetic relationships, so as to provide a further understanding of the intra-hospital strain transmission. Methods: Samples were collected from a hospital in Beijing between 2020 and 2022. All strains underwent bacterial identification, antimicrobial susceptibility testing (AST) using the VITEK-2 compact system. Biofilm formation ability and hemolytic activity were tested. Second-generation sequencing was applied to all strains, with those carrying the bla KPC gene were selected for third-generation sequencing. Whole-genome analysis identified resistance genes, plasmid types, MLST typing, and phylogenetic relationships. Plasmids were assembled to detect plasmid structures and AMR gene location. Results: Among the 42 K. aerogenes isolates, 21 were carbapenem-resistant K. aerogenes (CRKA). All strains exhibited strong biofilm formation and no hemolytic activity. Most were sourced from sputum (83.3%). CRKA demonstrated extensive resistance to antibiotics, particularly ß-lactamase inhibitors and Cefotetan. This resistance pattern was closely associated with the presence of an IncFII(pHN7A8) plasmid, which carried multiple resistance genes, including bla KPC-2, bla CTX-M-65, bla TEM-1, rmtB and a large number of mobile elements. The majority of CRKA strains clustered within the same branch of the phylogenetic tree, exhibiting minimal single nucleotide polymorphism (0-13 SNPs) differences, and they shared the same sequence type (ST292), resistance genes, and plasmids, originating from different departments, suggesting clonal transmission among the hospital. Conclusion: Our research reveals that the clonal transmission of CRKA occurs across various departments within the hospital. The widespread resistance observed in CRKA, attributed to the presence of bla KPC and ESBLs genes, underscores the need for heightened vigilance to prevent the further dissemination of CRKA within the hospital and, potentially, throughout the wider community.

Multi-omics analysis and experimental validation of the value of monocyte-associated features in prostate cancer prognosis and immunotherapy.

Background: Monocytes play a critical role in tumor initiation and progression, with their impact on prostate adenocarcinoma (PRAD) not yet fully understood. This study aimed to identify key monocyte-related genes and elucidate their mechanisms in PRAD. Method: Utilizing the TCGA-PRAD dataset, immune cell infiltration levels were assessed using CIBERSORT, and their correlation with patient prognosis was analyzed. The WGCNA method pinpointed 14 crucial monocyte-related genes. A diagnostic model focused on monocytes was developed using a combination of machine learning algorithms, while a prognostic model was created using the LASSO algorithm, both of which were validated. Random forest and gradient boosting machine singled out CCNA2 as the most significant gene related to prognosis in monocytes, with its function further investigated through gene enrichment analysis. Mendelian randomization analysis of the association of HLA-DR high-expressing monocytes with PRAD. Molecular docking was employed to assess the binding affinity of CCNA2 with targeted drugs for PRAD, and experimental validation confirmed the expression and prognostic value of CCNA2 in PRAD. Result: Based on the identification of 14 monocyte-related genes by WGCNA, we developed a diagnostic model for PRAD using a combination of multiple machine learning algorithms. Additionally, we constructed a prognostic model using the LASSO algorithm, both of which demonstrated excellent predictive capabilities. Analysis with random forest and gradient boosting machine algorithms further supported the potential prognostic value of CCNA2 in PRAD. Gene enrichment analysis revealed the association of CCNA2 with the regulation of cell cycle and cellular senescence in PRAD. Mendelian randomization analysis confirmed that monocytes expressing high levels of HLA-DR may promote PRAD. Molecular docking results suggested a strong affinity of CCNA2 for drugs targeting PRAD. Furthermore, immunohistochemistry experiments validated the upregulation of CCNA2 expression in PRAD and its correlation with patient prognosis. Conclusion: Our findings offer new insights into monocyte heterogeneity and its role in PRAD. Furthermore, CCNA2 holds potential as a novel targeted drug for PRAD.

GPAT3 is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma.

Background: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency. Lipid metabolic disorder plays an important role in hepatocarcinogenesis. However, whether and how lipid metabolic reprogramming regulates sorafenib resistance of HCC cells remains vague. Methods: Sorafenib resistant HCC cells were established by continuous induction. UHPLC-MS/MS, proteomics, and flow cytometry were used to assess the lipid metabolism. ChIP and western blot were used to reflect the interaction of signal transducer and activator of transcription 3 (STAT3) with glycerol-3-phosphate acyltransferase 3 (GPAT3). Gain- and loss-of function studies were applied to explore the mechanism driving sorafenib resistance of HCC. Flow cytometry and CCK8 in vitro, and tumor size in vivo were used to evaluate the sorafenib sensitivity of HCC cells. Results: Our metabolome data revealed a significant enrichment of triglycerides in sorafenib-resistant HCC cells. Further analysis using proteomics and genomics techniques demonstrated a significant increase in the expression of GPAT3 in the sorafenib-resistant groups, which was found to be dependent on the activation of STAT3. The restoration of GPAT3 resensitized HCC cells to sorafenib, while overexpression of GPAT3 led to insensitivity to sorafenib. Mechanistically, GPAT3 upregulation increased triglyceride synthesis, which in turn stimulated the NF-κB/Bcl2 signaling pathway, resulting in apoptosis tolerance upon sorafenib treatment. Furthermore, our in vitro and in vivo studies revealed that pan-GPAT inhibitors effectively reversed sorafenib resistance in HCC cells. Conclusions: Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.

Cinnamaldehyde targets SarA to enhance ß-lactam antibiotic activity against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a current global public health problem due to its increasing resistance to the most recent antibiotic therapies. One critical approach is to develop ways to revitalize existing antibiotics. Here, we show that the phytogenic compound cinnamaldehyde (CIN) and ß-lactam antibiotic combinations can functionally synergize and resensitize clinical MRSA isolates to ß-lactam therapy and inhibit MRSA biofilm formation. Mechanistic studies indicated that the CIN potentiation effect on ß-lactams was primarily the result of inhibition of the mecA expression by targeting the staphylococcal accessory regulator sarA. CIN alone or in combination with ß-lactams decreased sarA gene expression and increased SarA protein phosphorylation that impaired SarA binding to the mecA promoter element and downregulated virulence genes such as those encoding biofilm, α-hemolysin, and adhesin. Perturbation of SarA-mecA binding thus interfered with PBP2a biosynthesis and this decreased MRSA resistance to ß-lactams. Furthermore, CIN fully restored the anti-MRSA activities of ß-lactam antibiotics in vivo in murine models of bacteremia and biofilm infections. Together, our results indicated that CIN acts as a ß-lactam adjuvant and can be applied as an alternative therapy to combat multidrug-resistant MRSA infections.

Effect of negative remodeling of the side branch ostium on the efficacy of a two-stent strategy for distal left main bifurcation lesions: an intravascular ultrasound study.

OBJECTIVES: To investigate whether negative remodeling (NR) detected by intravascular ultrasound (IVUS) of the side branch ostium (SBO) would affect in-stent neointimal hyperplasia (NIH) at the one-year follow-up and the clinical outcome of target lesion failure (TLF) at the long-term follow-up for patients with left main bifurcation (LMb) lesions treated with a two-stent strategy. METHODS: A total of 328 patients with de novo true complex LMb lesions who underwent a 2-stent strategy of percutaneous coronary intervention (PCI) treatment guided by IVUS were enrolled in this study. We divided the study into two phases. Of all the patients, 48 patients who had complete IVUS detection pre- and post-PCI and at the 1-year follow-up were enrolled in phase I analysis, which aimed to analyze the correlation between NR and in-stent NIH at SBO at the 1-year follow-up. If the correlation was confirmed, the cutoff value of the remodeling index (RI) for predicting NIH ≥ 50% was analyzed next. The phase II analysis focused on the incidence of TLF as the primary endpoint at the 1- to 5-year follow-up for all 328 patients by grouping based on the cutoff value of RI. RESULTS: In phase I: according to the results of a binary logistic regression analysis and receiver operating characteristic (ROC) analysis, the RI cutoff value predicting percent NIH ≥ 50% was 0.85 based on the ROC curve analysis, with a sensitivity of 85.7%, a specificity of 88.3%, and an AUC of 0.893 (0.778, 1.000), P = 0.002. In phase II: the TLR rate (35.8% vs. 5.3%, P < 0.0001) was significantly higher in the several NR (sNR, defined as RI ≤ 0.85) group than in the non-sNR group. CONCLUSION: The NR of LCxO is associated with more in-stent NIH post-PCI for distal LMb lesions with a 2-stent strategy, and NR with RI ≤ 0.85 is linked to percent NIH area ≥ 50% at the 1-year follow-up and more TLF at the 5-year follow-up.

Stem cell division and its critical role in mammary gland development and tumorigenesis: current progress and remaining challenges.

The origin of breast cancer (BC) has traditionally been a focus of medical research. It is widely acknowledged that BC originates from immortal mammary stem cells (MaSCs) and that these stem cells participate in two division modes: symmetric cell division (SCD) and asymmetric cell division (ACD). Although both of these modes are key to the process of breast development and their imbalance is closely associated with the onset of BC, the molecular mechanisms underlying these phenomena deserve in-depth exploration. In this review, we first outline the molecular mechanisms governing ACD/SCD and analyze the role of ACD/SCD in various stages of breast development. We describe that the changes in telomerase activity, the role of polar proteins, and the stimulation of ovarian hormones subsequently lead to two distinct consequences: breast development or carcinogenesis. Finally, gene mutations, abnormalities in polar proteins, modulation of signal-transduction pathways, and alterations in the microenvironment disrupt the balance of breast cancer stem cells (BCSCs) division modes and cause BC. Important regulatory factors such as mammalian Inscuteable (mInsc), Numb, Eya1, PKCα, PKCθ, p53, and IL-6 also play significant roles in regulating pathways of ACD/SCD and may constitute key targets for future research on stem cell division, breast development, and tumor therapy.

Two-sample Mendelian randomization studies revealed a causal relationship between insulin use and osteoporosis: An observational study.

OBJECTIVE: To investigate causal associations between diabetes, insulin treatment and osteoporosis using LDSC analysis with a 2-way Mendelian randomization study. METHODS: LDSC analysis was used to estimate the likelihood-scale heritability of the genome-wide association study used with genetic correlation between the 2 genome-wide association study used. Then a 2-sample Mendelian randomization study was performed using 3 methods including inverse variance weighted, MR Egger, and weighted median. RESULTS: The genetic correlation between diabetes, insulin treatment (h2_Z = 3.70, P = 2.16e-4), osteoporosis (h2_Z = 4.93, h2_p = 8.13e-7) and genes was significant. There was a significant genetic correlation (rg = 0.122, P = 0.0211). There was a causal association between diabetes, insulin treatment and osteoporosis [P = 0.003754, OR (95%CI) = 0.998876 (0.998116-0.999636)], while no causal association existed between osteoporosis and insulin use (P = 0.998116-0.999636) causal association existed (P = 0.333244). CONCLUSION: There was a strong genetic correlation between diabetes, insulin treatment and osteoporosis, a causal association between diabetes, insulin treatment and osteoporosis, and no causal association between osteoporosis and diabetes, insulin treatment.

An insight into trichomes-deficiency and trichomes-rich black teas by comparative metabolomics: The impact of oxidized trichomes on metabolic profiles and infusion color.

Tea trichomes were regarded as an essential evaluation index for reflecting tea flavor quality in terms of aroma and influence on infusion color. This study reveals the impact of golden oxidized trichomes on the color, volatile and non-volatile metabolites of black teas through comparative metabolomics combined quantitative analysis on hongbiluo (trichomes-deficiency black teas), hongjinluo (trichomes-rich black teas), and trichomes (from hongjinluo). Forty-six volatile components were detected using headspace solid-phase microextraction gas chromatography-mass spectrometry, while the results suggested that the contribution of trichomes to black teas is limited. A total of 60 marker non-volatile compounds were identified, including catechins, catechin oxidation products, flavonoid glycosides, organic acids, hydrolysable tannins and amino acids. Notably, p-coumaroyl-kaempferol glucosides, and catechin dimers demonstrated high levels in independent trichomes and showed a positive correlation with the brightness and yellow hue of black tea infusions, specifically kaempferol 3-O-di-(p-coumaroyl)-hexoside. Furthermore, results from fractional extraction analysis of separated trichomes provided that N-ethyl-2-pyrrolidinone-substituted epicatechin gallates, acylated kaempferol glycosides, and chromogenic catechins dimers, such as theaflavins, were primary color contributors in oxidized trichomes. Especially, we found that epicatechin gallate (ECG) and its derivates, 3'-O-methyl-ECG and N-ethyl-2-pyrrolidinone-substituted ECG, highly accumulated in trichomes, which may be associated with the varieties of hongbiluo and hongjinluo black teas. Eventually, addition tests were applied to verify the color contribution of trichome mixtures. Our findings employed comprehensive information revealing that golden oxidized trichomes contributed significantly to the brightness and yellow hue of black tea infusion, but their contribution to the aroma and metabolic profile is limited. These findings may contribute to the effective modulation of the infusion color during black tea production by regulating the proportion of tea trichomes or screening trichomes-rich or deficiency varieties.

Prediction of the short-term efficacy and recurrence of photodynamic therapy in the treatment of oral leukoplakia based on deep learning.

BACKGROUND: The treatment of oral leukoplakia (OLK) with aminolaevulinic acid photodynamic therapy (ALA-PDT) is widespread. Nonetheless, there is variation in efficacy. Therefore, this study constructed a model for predicting the short-term efficacy and recurrence of OLK after ALA-PDT. METHODS: The short-term efficacy and recurrence of ALA-PDT were calculated by statistical analysis, and the relevant influencing factors were analyzed by Logistic regression and COX regression model. Finally, prediction models for total response (TR) rate, complete response (CR) rate and recurrence in OLK patients after ALA-PDT treatment were established. Features from pathology sections were extracted using deep learning autoencoder and combined with clinical variables to improve prediction performance of the model. RESULTS: The logistic regression analysis showed that the non-homogeneous (OR: 4.911, P: 0.023) OLK and lesions with moderate to severe epithelial dysplasia (OR: 4.288, P: 0.042) had better short-term efficacy. The area under receiver operating characteristic curve (AUC) of CR, TR and recurrence predict models after the ALA-PDT treatment of OLK patients is 0.872, 0.718, and 0.564, respectively. Feature extraction revealed an association between inflammatory cell infiltration in the lamina propria and recurrence after PDT. Combining clinical variables and deep learning improved the performance of recurrence model by more than 30 %. CONCLUSIONS: ALA-PDT has excellent short-term efficacy in the management of OLK but the recurrence rate was high. Prediction model based on clinicopathological characteristics has excellent predictive effect for short-term efficacy but limited effect for recurrence. The use of deep learning and pathology images greatly improves predictive value of the models.

Development of machine learning models for patients in the high intrahepatic cholangiocarcinoma incidence age group.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis and is understudied. Based on the clinical features of patients with ICC, we constructed machine learning models to understand their importance on survival and to accurately determine patient prognosis, aiming to develop reference values to guide physicians in developing more effective treatment plans. METHODS: This study used machine learning (ML) algorithms to build prediction models using ICC data on 1,751 patients from the SEER (Surveillance, Epidemiology, and End Results) database and 58 hospital cases. The models' performances were compared using receiver operating characteristic curve analysis, C-index, and Brier scores. RESULTS: A total of eight variables were used to construct the ML models. Our analysis identified the random survival forest model as the best for prognostic prediction. In the training cohort, its C-index, Brier score, and Area Under the Curve values were 0.76, 0.124, and 0.882, respectively, and it also performed well in the test cohort. Kaplan-Meier survival analysis revealed that the model could effectively determine patient prognosis. CONCLUSIONS: To our knowledge, this is the first study to develop ML prognostic models for ICC in the high-incidence age group. Of the ML models, the random survival forest model was best at prognosis prediction.