Variability in Leaf Color Induced by Chlorophyll Deficiency: Transcriptional Changes in Bamboo Leaves.

The diversity of leaf characteristics, particularly leaf color, underscores a pivotal area of inquiry within plant science. The synthesis and functionality of chlorophyll, crucial for photosynthesis, largely dictate leaf coloration, with varying concentrations imparting different shades of green. Complex gene interactions regulate the synthesis and degradation of chlorophyll, and disruptions in these pathways can result in abnormal chlorophyll production, thereby affecting leaf pigmentation. This study focuses on Bambusa multiplex f. silverstripe, a natural variant distinguished by a spectrum of leaf colors, such as green, white, and green-white, attributed to genetic variations influencing gene expression. By examining the physiological and molecular mechanisms underlying chlorophyll anomalies and genetic factors in Silverstripe, this research sheds light on the intricate gene interactions and regulatory networks that contribute to leaf color diversity. The investigation includes the measurement of photosynthetic pigments and nutrient concentrations across different leaf color types, alongside transcriptomic analyses for identifying differentially expressed genes. The role of key genes in pathways such as ALA biosynthesis, chlorophyll synthesis, photosynthesis, and sugar metabolism is explored, offering critical insights for advancing research and plant breeding practices.

Comprehensive characterization of B7 family members in breast cancer: B7-H5 switch reverses breast cancer from "immuno-cold" into "immuno-hot" status.

The members of the classic B7 family regulate the immune microenvironment of several malignant tumors. However, the potential relationship between the B7 family and the breast cancer (BrCa) tumor immune microenvironment has remained elusive. In the present study, we provide a comprehensive explanation of the expression, clinical significance, mutation, and immune cell infiltration of B7 family molecules in BrCa. First, we recruited 10 patients with BrCa surgery from the Wuxi Maternal and Child Health Hospital and performed single-cell RNA sequencing (scRNA-seq) analysis to investigate the distribution of B7 family members in multiple immune cell subsets. We focused on B7-2, B7-H3, and B7-H5 molecules of the B7 family and constructed tumor microarrays by self-recruiting patients to perform multiple immunohistochemical (mIHC) analyses and study tumor expression of B7-2, B7-H3, B7-H5 and CD8+ immune cell infiltration. B7-H5 displayed a strong correlation with CD8+ immune cell infiltration. In summary, B7-H5 provides a new perspective for the identification of immunothermal subtypes of BrCa and could function as a switch to reverse BrCa from an "immunologically cold" state to an "immunologically hot" state.

A promising target for breast cancer: B7-H3.

Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint.In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.

Organocatalyzed Asymmetric Michael Addition of 3-Fluorooxindole to Vinylidene Bisphosphonates.

Both the 3-fluorooxindole and germinal bisphosphonate structural motifs are prevalent in bioactive molecules because of their associated biological activities. We describe an approach to accessing 3,3-disubstituted 3-fluorooxindoles bearing a geminal bisphosphate fragment through a highly enantioselective Michael addition reaction between 3-fluorooxindoles and vinylidene bisphosphonates. These reactions are catalyzed by a commercially available cinchona alkaloid catalyst, have a broad substrate scope concerning 3-fluorooxindoles, and provide the corresponding addition products in a yield of up to 95% with an enantiomeric excess of up to 95%. A reasonable reaction pathway to explain the observed stereochemistry is also proposed.

Application, knowledge and training needs regarding comprehensive geriatric assessment among geriatric practitioners in healthcare institutions: a cross-sectional study.

BACKGROUND: This study aimed to investigate the actual application, knowledge, and training needs of comprehensive geriatric assessment (CGA) among geriatric practitioners in China. METHODS: A total of 225 geriatric practitioners attending the geriatric medicine or geriatric nursing training were recruited for this cross-sectional study. The questionnaire included demographics, healthcare institution characteristics, the actual application, knowledge, training needs, and barriers to CGA and geriatric syndromes (GS). RESULTS: Physicians and nurses were 57.3% and 42.7%, respectively. 71.1% were female, with a median age was 35 years. Almost two-thirds (140/225) of geriatric practitioners reported exposure to CGA in their clinical practice. The top five CGA evaluation items currently used were malnutrition risk (49.8%), fall risk (49.8%), activity of daily living (48.0%), pain (44.4%), and cognitive function (42.7%). Median knowledge scores for the management procedures of GS ranged from 2 to 6. Physicians identified medical insurance payment issues (29.5%) and a lack of systematic specialist knowledge and technology (21.7%) as the two biggest barriers to practicing geriatrics. Nurses cited a lack of systematic specialist knowledge and technology (52.1%) as the primary barrier. In addition, physicians and nurses exhibited significant differences in their knowledge of CGA-specific evaluation items and management procedures for GS (all P < 0.05). However, there were no significant differences in their training needs, except for polypharmacy. CONCLUSIONS: The rate of CGA application at the individual level, as well as the overall knowledge among geriatric practitioners, was not adequate. Geriatric education and continuous training should be tailored to address the specific roles of physicians and nurses, as well as the practical knowledge reserves, barriers, and training needs they face.

Timing of early water intake post-general anaesthesia: a systematic review and meta-analysis.

BACKGROUND: Early water intake has gained widespread attention considering enhanced recovery after surgery (ERAS). In the present systematic evaluation and meta-analysis, we assessed the effects of early water intake on the incidence of vomiting and aspiration in adult patients who received general anaesthesia on regaining consciousness during the resuscitation period. OBJECTIVE: To systematically analyse the results of randomised controlled trials on early postoperative water intake in patients who underwent different types of surgery under general anaesthesia, both at home and abroad, to further explore the safety and application of early water intake and provide an evidence-based foundation for clinical application. DESIGN: Systematic review and meta-analysis. METHODS: To perform the systematic evaluation and meta-analysis, we searched the Web of Science, CINAHL, Embase, PubMed, Cochrane Library, Sinomed, China National Knowledge Infrastructure (CNKI), Wanfang, and Vipshop databases to identify randomised controlled trial studies on early water intake in adult patients who received general anaesthesia. RESULTS: Herein, we included 10 publications with a total sample size of 5131 patients. Based on statistical analysis, there was no statistically significant difference in the incidence of vomiting (odds ratio [OR] = 0.81; 95% confidence interval [CI] [0.58-1.12]; p = 0.20; I-squared [I2] = 0%) and aspiration (OR = 0.78; 95%CI [0.45-1.37]; p = 0.40; I2 = 0%) between the two groups of patients on regaining consciousness post-general anaesthesia. CONCLUSION: Based on the available evidence, early water intake after regaining consciousness post-anaesthesia did not increase the incidence of adverse complications when compared with traditional postoperative water abstinence. Early water intake could effectively improve patient thirst and facilitate the recovery of gastrointestinal function.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

The heterogeneity of tumour immune microenvironment revealing the CRABP2/CD69 signature discriminates distinct clinical outcomes in breast cancer.

BACKGROUND: It has been acknowledged that the tumour immune microenvironment (TIME) plays a critical role in determining therapeutic responses and clinical outcomes in breast cancer (BrCa). Thus, the identification of the TIME features is essential for guiding therapy and prognostic assessment for BrCa. METHODS: The heterogeneous cellular composition of the TIME in BrCa by single-cell RNA sequencing (scRNA-seq). Two subtype-special genes upregulated in the tumour-rich subtype and the immune-infiltrating subtype were extracted, respectively. The CRABP2/CD69 signature was established based on CRABP2 and CD69 expression, and its predictive values for the clinical outcome and the neoadjuvant chemotherapy (NAT) responses were validated in multiple cohorts. Moreover, the oncogenic role of CRABP2 was explored in BrCa cells. RESULTS: Based on the heterogeneous cellular composition of the TIME in BrCa, the BrCa samples could be divided into the tumour-rich subtype and the immune-infiltrating subtype, which exhibited distinct prognosis and chemotherapeutic responses. Next, we extracted CRABP2 as the biomarker for the tumour-rich subtype and CD69 as the biomarker for the immune-infiltrating subtype. Based on the CRABP2/CD69 signature, BrCa samples were re-divided into three subtypes, and the CRABP2highCD69low subtype exhibited the worst prognosis and the lowest chemotherapeutic response, while the CRABP2lowCD69high subtype showed the opposite results. Furthermore, CARBP2 functioned as a novel oncogene in BrCa, which promoted tumour cell proliferation, migration, and invasion, and CRABP2 inhibition triggered the activation of cytotoxic T lymphocytes (CTLs). CONCLUSION: The CRABP2/CD69 signature is significantly associated with the TIME features and could effectively predict the clinical outcome. Also, CRABP2 is determined to be a novel oncogene, which could be a therapeutic target in BrCa.

Sex disparity of cerebral white matter hyperintensity in the hypertensive elderly: The Shanghai Changfeng study.

White matter hyperintensity (WMH) is associated with vascular hemodynamic alterations and reflects white matter injury. To date, the sex difference of tract-specific WMH and the relationship between high blood pressure (BP) and tract-specific WMH remain unclear. We recruited 515 subjects from the Shanghai Changfeng study (range 53-89 years, mean age 67.33 years). Systolic and diastolic blood pressure (SBP and DBP) were collected and used to calculate pulse pressure (PP). Magnetic resonance T1 and T2 FLAIR images were acquired to measure WMH and calculate WMH index. The ANCOVA test was performed to test the difference between sexes, and the linear regression model was used to examine the associations between BP and WMH index. Men showed higher WMH index than women in all white matter tracts (p < .001, respectively) except for the bilateral superior longitudinal fasciculus (SLF) and its left temporal part (tSLF). High SBP and PP was associated with a lower WMH index on the left corticospinal tract (CST), SLF, tSLF and right cingulum in hippocampus (p ≤ .001, respectively) in women, while high DBP was associated with a higher WMH index on the bilateral CST (left p < .001; right p = .001), left inferior longitudinal fasciculus (p < .001) and inferior fronto-occipital fasciculus (p = .002) in men. Men tend to have more WMH compared to women. A high SBP/PP relates to a lower WMH burden in women. This suggests that women could benefit from higher blood pressure in older age.

Enantioselective Synthesis of Diarylmethylamines through the Aza-Friedel-Crafts Reaction of 1,3,5-Trialkoxy Benzenes and N-Sulfonyl Aldimines Catalyzed by BINOL-Derived Disulfonimides.

A 1,1'-bi-2-naphthol (BINOL)-derived disulfonimide (DSI)-catalyzed enantioselective aza-Friedel-Crafts reaction between 1,3,5-trialkoxy benzenes and N-sulfonyl aldimines gives direct access to a series of chiral diarylmethylamines in good yields and good to excellent enantioselectivities (up to 97% ee). This reaction provides a useful protocol for the direct synthesis of diarylmethylamine derivatives.

Identification and validation of diagnostic biomarkers for intrahepatic cholestasis of pregnancy based on untargeted and targeted metabolomics analyses of urine metabolite profiles.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a prevalent pregnancy-specific complication that presents with maternal itching and elevated serum bile acid levels. ICP is associated with unfavorable pregnancy outcomes, severely decreasing the pregnant woman's quality of life. Timely identification of ICP is crucial for effective management and improved outcomes. METHODS: We collected urine samples from 8 patients with ICP and 8 healthy individuals. We used Liquid Chromatography-Mass Spectrometry (LC-MS) to detect metabolite expression levels, then conducted a series of bioinformatic analyses to explore the potential biological meanings of differentially expressed metabolites, and preliminarily discovered several candidate biomarkers. To validate these candidate biomarkers, we performed Gas Chromatography-Mass Spectrometry (GC-MS) detection and analyzed their diagnostic values using receiver operating characteristic (ROC) curve. RESULTS: Untargeted metabolomics data showed that 6129 positive peaks and 6218 negative peaks were extracted from each specimen. OPLS-DA analysis and the heat map for cluster analysis showed satisfactory capability in discriminating ICP specimens from controls. Subsequent analysis extracted 64 significantly differentially expressed metabolites, which could be potential biomarkers for diagnosis of ICP. Based on the KEGG enrichment analyses, six candidate biomarkers were preliminarily identified. Two most promising biomarkers (3-hydroxypropionic acid and uracil) were validated by targeted metabolomics analyses with the area under the curve (AUC) of 0.920 and 0.850 respectively. CONCLUSION: Based on preliminary screening from untargeted metabolomics and subsequent validation through targeted metabolomics, 3-hydroxypropionic acid and uracil were identified as promising diagnostic biomarkers for ICP.

The Relationship between Skeletal Muscle Mass and Bone Mass at Different Sites in Older Adults.

INTRODUCTION: It has been well recognized that sarcopenia is closely related with osteoporosis, while the relationship between bone mass at different sites and muscle mass remains largely unexplored. This study aims to explore the relationship between bone mass at different sites and skeletal muscle mass in older adults. METHODS: A total of 228 patients over 65 years old were enrolled in this study, and then 180 valid participants with accessible dual-energy X-ray absorptiometry (DXA) scanning data and absence of malignant tumors, mobility disorders, serious liver and kidney disease, and cardiac insufficiency were selected (138 male and 42 female). These individuals were further divided into control group and low skeletal muscle mass index (SMI) group. DXA scanning was used to access skeletal muscle mass and bone mass. SMI or body mass index was defined as appendicular muscle mass or weight divided by squared height, respectively. Low SMI <7.0 kg/m2 in male or <5.4 kg/m2 in female was defined as low SMI; while the bone density score at or below 2.5 standard deviations (T-score) below normal peak bone values, was regarded as osteoporosis. RESULTS: The average age of enrolled patients was 82.72 years; the ratios of osteoporosis, low SMI, and low SMI with osteoporosis were 48.8%, 23.3%, and 15.0%, respectively. Compared with the control group, the prevalence of osteoporosis was higher, and the total bone mass and bone mass at various sites including limbs, spine, and pelvis, were all lower in low SMI group. Correlation analysis showed that SMI was positively related with total bone mass and bone mass at various sites. Covariance analysis showed that only total bone mass and appendicular bone mass decreased with decreasing SMI. After multiple adjustment, osteoporosis was positively related with the prevalence of low SMI, as evidenced by logistic regression analysis (odds ratio = 1.33, 95% confidential interval: 1.04-3.24, p = 0.045). Furthermore, compared with the highest quartile of appendicular bone mass, the lowest quartile was related with the increasing prevalence of low SMI (odds ratio = 7.29, 95% confidential interval: 1.21-67.45, p = 0.042). CONCLUSION: Compared with the other sites, the bone mass reduction at limbs of older adults was positively associated with skeletal muscle loss. It may be more beneficial to increase bone mass at the limbs for improved sarcopenia prevention and therapy. Further investigations are needed to explore the effects of other confounders (e.g., energy, calcium and vitamin D intake, and physical activity) on the osteoporosis and sarcopenia in older adults.

Liposomal Doxorubicin: the Sphingomyelin/Cholesterol System Significantly Enhances the Antitumor Efficacy of Doxorubicin.

Doxorubicin (DOX) has a cytotoxic effect on many tumor cells; however, its clinical application is limited owing to its strong side effects. Although Doxil® reduces the cardiotoxicity of free DOX, it has also introduced a new dose-limiting toxicity. In a previous study, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified onto the surface of DOX-loaded liposomes to target tumor-associated macrophages (TAMs), further improving the efficacy of DOX-loaded liposomes over that of Doxil®. Meanwhile, the good retention characteristics and promising antitumor ability of sphingomyelin/cholesterol (SM/CH) system for water-soluble drugs have attracted wide attention. Therefore, we aimed to use SA-CH as the target and hydrogenated soybean phosphatidylcholine (HSPC) or egg sphingomyelin (ESM) as the membrane material to develop a more stable DOX-loaded liposome with stronger antitumor activity. The liposomes were evaluated for particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release, long-term storage, cytotoxicity, cellular uptake, pharmacokinetics, tumor targetability, and in vivo antitumor activity. In the liposomes prepared using HSPC/CH, sialic acid (SA) modification considerably increased the accumulation of DOX-loaded liposomes in the tumor, thus exerting a better antitumor effect. However, SA modification in DOX-ESL (SA-CH-modified DOX-loaded liposomes prepared by ESM/CH) destroyed the strong retention effect of the ESM/CH system on DOX, resulting in a reduced antitumor effect. Notably, DOX-ECL (DOX-loaded liposome prepared by ESM/CH) had the optimal storage stability, lowest toxicity, and optimal antitumor effect due to better drug retention properties. Thus, the ESM/CH liposome of DOX is a potential drug delivery system. Sketch of the effect of two DOX-loaded liposomes with hydrogenated soybean phospholipid (HSPC) and egg sphingomyelin (ESM) as lipid membrane material and surface-modified SA derivative on tumor growth inhibition.

Rehmannioside D mitigates disease progression in rats with experimental-induced diminished ovarian reserve via Forkhead Box O1/KLOTHO axis.

This study aims to explore the impact of Rehmannioside D (RD) on ovarian functions of rats with diminished ovarian reserve (DOR) and its underlying mechanisms of action. A single injection of cyclophosphamide was performed to establish a DOR rat model, and fourteen days after the injection, the rats were intragastrically administrated with RD for two weeks. Rat estrus cycles were tested using vaginal smears. Ovarian tissues were histologically evaluated, the number of primordial, mature, and atretic follicles was calculated, and the apoptotic rate of granulosa cells. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels were determined by ELISA assays. Protein levels of Forkhead Box O1 (FOXO1), KLOTHO, Bcl-2, and Bax were investigated in ovarian tissues of DOR rats. The binding between FOXO1 and KLOTHO was verified by ChIP assay. High-dose administration of RD into DOR rats improved their estrus cycles, increased ovarian index, enhanced the number of primordial and mature follicles, reduced the number of atretic follicle number, and ovarian granulosa cell apoptosis in addition to inhibiting FSH and LH levels and upregulating E2 expression. FOXO1 and KLOTHO were significantly suppressed in DOR rats. FOXO1 knockdown partially suppressed the protective effects of RD on DOR rats, and KLOTHO overexpression could restore RD-induced blockade of DOR development despite knocking down FOXO1. FOXO1 antibody enriched KLOTHO promoter, and the binding between them was reduced in DOR group compared to that in sham group. RD improved ovarian functions in DOR rats and diminished granulosa cell apoptosis via the FOXO1/KLOTHO axis.

Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity.

Using three European and two Chinese genome-wide association studies (GWAS), we investigated the performance of genetic risk scores (GRSs) for predicting the susceptibility and severity of systemic lupus erythematosus (SLE), using renal disease as a proxy for severity. We used four GWASs to test the performance of GRS both cross validating within the European population and between European and Chinese populations. The performance of GRS in SLE risk prediction was evaluated by receiver operating characteristic (ROC) curves. We then analyzed the polygenic nature of SLE statistically. We also partitioned patients according to their age-of-onset and evaluated the predictability of GRS in disease severity in each age group. We found consistently that the best GRS in the prediction of SLE used SNPs associated at the level of P < 1e-05 in all GWAS data sets and that SNPs with P-values above 0.2 were inflated for SLE true positive signals. The GRS results in an area under the ROC curve ranging between 0.64 and 0.72, within European and between the European and Chinese populations. We further showed a significant positive correlation between a GRS and renal disease in two independent European GWAS (Pcohort1 = 2.44e-08; Pcohort2 = 0.00205) and a significant negative correlation with age of SLE onset (Pcohort1 = 1.76e-12; Pcohort2 = 0.00384). We found that the GRS performed better in the prediction of renal disease in the 'later onset' compared with the 'earlier onset' group. The GRS predicts SLE in both European and Chinese populations and correlates with poorer prognostic factors: young age-of-onset and lupus nephritis.

Angiotensin-converting enzyme 2 identifies immuno-hot tumors suggesting angiotensin-(1-7) as a sensitizer for chemotherapy and immunotherapy in breast cancer.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is known as a tumor suppressor and lowly expressed in most cancers. The expression pattern and role of ACE2 in breast cancer (BC) have not been deeply elucidated. METHODS: A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). The correlation of ACE2 expression and immunological characteristics in the BC tumor microenvironment (TME) was evaluated. The role of ACE2 in predicting the response to therapeutic options was estimated. Moreover, the pharmacodynamic effect of angiotensin-(1-7) (Ang-1-7), the product of ACE2, on chemotherapy and immunotherapy was evaluated on the BALB/c mouse BC model. In addition, the plasma samples from BC patients receiving neoadjuvant chemotherapy were collected and subjected to the correlation analysis of the expression level of Ang-1-7 and the response to neoadjuvant chemotherapy. RESULTS: ACE2 was lowly expressed in BC tissues compared with that in adjacent tissues. Interestingly, ACE2 was shown the highest correlation with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, immune checkpoints, and tumor mutation burden (TMB) in BC. In addition, a high level of ACE2 indicated a low response to endocrine therapy and a high response to chemotherapy, anti-ERBB therapy, antiangiogenic therapy and immunotherapy. In the mouse model, Ang-1-7 sensitized mouse BC to the chemotherapy and anti-PD-1 immunotherapy, which revealed its significant anti-tumor effect. Moreover, a high plasma level of Ang-1-7 was associated with a better response to neoadjuvant chemotherapy. CONCLUSIONS: ACE2 identifies immuno-hot tumors in BC, and its enzymatic product Ang-1-7 sensitizes BC to the chemotherapy and immunotherapy by remodeling the TME.

Ligustrazine Attenuates Liver Fibrosis by Targeting miR-145 Mediated Transforming Growth Factor-ß/Smad Signaling in an Animal Model of Biliary Atresia.

To investigate therapeutic target for ligustrazine during liver fibrosis in an ethanol-induced biliary atresia rat model and transforming growth factor-ß (TGF-ß) induced hepatic stellate cell activation cell model, and the underlying mechanism, a total of 30 rats were randomly assigned into five groups (n = 6 per group): control, sham, ethanol-induced biliary atresia model, model plus pirfenidone, and model plus ligustrazine groups. The liver changes were assessed using H&E and Masson staining and transmission electron microscopy. Expression of miR-145 and mRNA and protein levels of TGF-ß/smads pathway-related proteins were detected. HSC-T6 cells were infected with LV-miR or rLV-miR-145 in the presence or absence of SMAD3 inhibitor SIS3 and treated with 2.5 ng/ml TGF-ß1 and then with ligustrazine. Collected cells were subjected to detect the expression of miR-145 and mRNA and protein expression levels of TGF-ß/smads pathway-related proteins. Ligustrazine rescued liver fibrogenesis and pathology for ethanol-caused bile duct injury, revealed by decreased α-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Further experiments showed that ligustrazine inhibited intrinsic and phosphorylated Smad2/3 protein expression and modification. Similar results were obtained in cells. In addition, ligustrazine altered miR-145 expression in both animal and cell models. Lentivirus mediated miR-145 overexpression and knockdown recombinant virus showed that miR-145 enhanced the TGF-ß/Smad pathway, which led to hepatic stellate cell activation, and ligustrazine blocked this activation. This work validated that ligustrazine-regulated miR-145 mediated TGF-ß/Smad signaling to inhibit the progression of liver fibrosis in a biliary atresia rat model and provided a new therapeutic strategy for liver fibrosis. SIGNIFICANCE STATEMENT: With an ethanol-induced biliary atresia rat model, ligustrazine was found to rescue liver fibrogenesis and pathology for ethanol caused bile duct injury, revealed by decreased α-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Furthermore, we found ligustrazine upregulated miR-145 expression and inhibited TGF-ß/SMAD signaling pathway both in vivo and in vitro. In addition, overexpression and knockdown of miR-145 confirmed that miR-145 is involved in the ligustrazine inhibition of liver fibrosis through the TGF-ß/SMAD signaling pathway.

The B7H4-PDL1 classifier stratifies immuno-phenotype in cervical cancer.

BACKGROUND: It has been revealed that B7H4 is negatively correlated with PDL1 and identifies immuno-cold tumors in glioma. However, the application of the B7H4-PDL1 classifier in cancers has not been well testified. METHODS: A pan-cancer analysis was conducted to evaluate the immunological role of B7H4 using the RNA-sequencing data downloaded from the Cancer Genome Atlas (TCGA). Immunohistochemistry (IHC) and multiplexed quantitative immunofluorescence (QIF) were performed to validate the primary results revealed by bioinformatics analysis. RESULTS: The pan-cancer analysis revealed that B7H4 was negatively correlated with PDL1 expression and immune cell infiltration in CeCa. In addition, patients with high B7H4 exhibited the shortest overall survival (OS) and relapse-free survival (RFS) while those with high PDL1 exhibited a better prognosis. Multiplexed QIF showed that B7H4 was mutually exclusive with PDL1 expression and the B7H4-high group exhibited the lowest CD8 + T cell infiltration. Besides, B7H4-high predicted highly proliferative subtypes, which expressed the highest Ki67 antigen. Moreover, B7H4-high also indicated a lower response to multiple therapies. CONCLUSIONS: Totally, the B7H4-PDL1 classifier identifies the immunogenicity and predicts proliferative subtypes and limited therapeutic options in CeCa, which may be a convenient and feasible biomarker in clinical practice.

Enantioselective synthesis of 2-indolyl methanamine derivatives through disulfonimide-catalyzed Friedel-Crafts C2-alkylation of 3-substituted indoles with imines.

An asymmetric Friedel-Crafts C2-alkylation between 3-substituted indoles and imines catalyzed by chiral BINOL-derived disulfonimides (DSIs) has been developed. This reaction tolerated a wide range of 3-substituted indoles and imines, affording a series of chiral 2-indolyl methanamine derivatives in good yields with good to excellent enantioselectivities (up to 98% ee). This is a useful protocol for the direct synthesis of 2-indolyl methanamine derivatives. It is worth noting that increasing the temperature in this reaction could result in a better enantioselectivity, making it different from the other common organocatalytic systems.

In(OTf)3-catalyzed N-α phosphonylation of N,O-acetals with triethyl phosphite.

A practical approach to α-aminophosphonates has been developed through an In(OTf)3-catalyzed N-α phosphonylation of N,O-acetals with triethyl phosphite 7. Indoline and isoindoline N,O-acetals 6a-6j and 9a-9j and chain N,O-acetals 11a-11p were subjected to a Lewis acid catalyzed N-α phosphonylation process. As a result, the desired α-aminophosphonates 8a-8j, 10a-10j and 12a-12p were obtained in moderate to good yields.