Integrated multi-omics analyses revealed the association between rheumatoid arthritis and colorectal cancer: MYO9A as a shared gene signature and an immune-related therapeutic target.

BACKGROUND: Our study aims to explore the relationship, shared gene signature, and the underlying mechanisms that connect rheumatoid arthritis (RA) to colorectal cancer (CRC). METHODS: Mendelian randomization (MR) analysis was conducted to assess the causality between RA and CRC. Summary statistic data-based Mendelian randomization (SMR) leveraging eQTL data was employed to identify the CRC-related causal genes. Integrated analyses of single-cell RNA sequencing and bulk RNA sequencing were employed to comprehensively investigate the shared gene signature and potential mechanisms underlying the pathogenesis of both RA and CRC. Predictive analysis of the shared hub gene in CRC immunotherapy response was performed. Pan-cancer analyses were conducted to explore the potential role of MYO9A in 33 types of human tumors. RESULTS: MR analysis suggested that RA might be associated with a slight increased risk of CRC (Odds Ratio = 1.04, 95% Confidence Interval = 1.01-1.07, P = 0.005). SMR analysis combining transcriptome analyses identified MYO9A as a causal gene in CRC and a shared gene signature in both RA and CRC. MYO9A may contribute to tumor suppression, while downregulation of MYO9A may impact CRC tumorigenesis by disrupting epithelial polarity and architecture, resulting in a worse prognosis in CRC. Additionally, MYO9A shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Pan-cancer analyses demonstrated MYO9A may have a protective role in the occurrence and progression of various human cancers. CONCLUSION: RA might be associated with a slight increased risk of CRC. MYO9A is a shared gene signature and a potential immune-related therapeutic target for both CRC and RA. Targeting the MYO9A-mediated loss of polarity and epithelial architecture could be a novel therapeutic approach for CRC.

Study on blood pressure rhythm in hypertensive patients withdeficiency syndrome and a random forest model for predicting hypertension withdeficiency syndrome.

OBJECTIVE: To investigate blood pressure rhythm (BPR) in Yin deficiency syndrome of hypertension (YDSH) patients and develop a random forest model for predicting YDSH. METHODS: Our study was consistent with technical processes and specification for developing guidelines of Evidence-based Chinese medicine clinical practice (T/CACM 1032-2017). We enrolled 234 patients who had been diagnosed with primary hypertension without antihypertensive medications prior to the enrollment. All participants were divided into Yin deficiency group (YX, n = 74) and non-Yin deficiency group (NYX, n = 160). Participants were professionally grouped by three experienced chief Traditional Chinese Medicine (TCM) physicians according to four examinations (i.e., inspection, listening and smelling, inquiry and palpation). We collected data on 24 h ambulatory blood pressure monitoring (ABPM) and YDSH rating scale. We divided 24 h of a day into 12 two-hour periods [Chen-Shi (7:00-9:00), Si-Shi (9:00-11:00), Wu-Shi (11:00-13:00), Wei-Shi (13:00-15:00), Shen-Shi (15:00-17:00), You-Shi (17:00-19:00), Xu-Shi (19:00-21:00), Hai-Shi (21:00-23:00), Zi-Shi (23:00-1:00), Chou-Shi (1:00-3:00), Yin-Shi (3:00-5:00), Mao-Shi (5:00-7:00)] according to the theory of "midnight-midday ebb flow". We used random forest to build the diagnostic model of YDSH, with whether it was Yin deficiency syndrome as the outcome. RESULTS: Compared with NYX group, YX group had more female participants with older age, lower waist circumference, body mass index (BMI), diastolic blood pressure (DBP), and smoking and drinking rate (all P ＜ 0.05). The YDSH rating scores of YX group [28.5 (21.0-36.0)] were significantly higher than NYX group [13.0 (8.0-22.0)] (P < 0.001), and the typical symptoms of YX group included vexing heat in the chest, palms and soles, dizziness, dry eyes, string-like and fine pulse, soreness and weakness of lumbus and knees, palpitations, reddened cheeks, and tinnitus (all P < 0.05). The ratio of non-dipper hypertension in YX group was higher than in NYX group (56.9% vs 44.4%, P = 0.004). Compared with NYX group, 24 h DBP standard deviation (SD), nighttime DBP SD, Si-Shi DBP, Si-Shi mean arterial pressure (MAP), Hi-Shi systolic blood pressure (SBP), Hi-Shi DBP, Hi-Shi MAP, Zi-Shi SBP, Zi-Shi DBP, Zi-Shi MAP, Chou-Shi SBP SD, Chou-Shi DBP SD, Chou-Shi SBP coefficient of variation (CV) were lower in YX group (all P ＜ 0.05). Binary Logistic Regression analysis showed that the diagnosis of YDSH was positively correlated with age, heart rate, YDSH rating scores, and four TCM symptoms including vexing heat in the chest, palms and soles, string-like and fine pulse, soreness and weakness of lumbus and knees, and reddened cheeks (all P ＜ 0.05), but was negatively correlated with smoking (P﹥0.05). In addition, the diagnosis of YDSH was positively correlated with daytime SBP SD, nighttime SBP SD, nighttime SBP CV, and Hi-Shi SBP CV, but was negatively correlated with 24 h SBP CV, daytime DBP SD, nighttime DBP SD, and Hi-Shi DBP (all P ＜ 0.05). Hi-Shi SBP CV had independent and positive correlation with the diagnosis of YDSH after adjusting the variables of age, gender, course of hypertension, BMI, waist circumference, SBP, DBP, heart rate, smoking and drinking (P = 0.029). Diagnostic model of YDSH was established and verified based on the random forest. The results showed that the calculation accuracy, specificity and sensitivity were 77.3%, 77.8% and 76.9%, respectively. CONCLUSION: The BPR was significantly attenuated in YDSH patients, including lower 24 h DBP SD and nighttime DBP SD, and Hi-Shi SBP CV is independently correlated with the diagnosis of YDSH. The prediction accuracy of diagnosis model of YDSH based on the random forest was good, which could be valuable for clinicians to differentiate YDSH and non-Yin deficiency patients for more effective hypertensive treatment of TCM.

Different biomarker ratios in peripheral blood have limited value in diagnosing periprosthetic joint infection after total joint arthroplasty: a single-center, retrospective study.

BACKGROUND: Periprosthetic joint infection (PJI) is a severe complication that can occur after total joint arthroplasty (TJA). The timely and accurate diagnosis of PJI is the key to treatment. This study investigated the diagnostic value of platelet to lymphocyte ratio (PLR), platelet count to mean platelet volume ratio (PVR), neutrophil to lymphocyte ratio (NLR) and monocyte to lymphocyte ratio (MLR) in PJI after total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: We performed a retrospective analysis of the patients who underwent revision hip or knee arthroplasty at our Institute between June 2015 and June 2020. Of the 187 patients reviewed, 168 were included in the study. According to the diagnostic criteria of the Musculoskeletal Infection Society (MSIS), 58 patients were in the PJI group, and 110 patients were in the aseptic loosening (AL) group. We recorded and compared the preoperative peripheral blood white blood cell (WBC) count, platelet count (PLT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), PLR, PVR, NLR, and MLR in both groups. The diagnostic performance of the WBC, PLT, PLR, PVR, NLR, and MLR individually and in combination with the ESR and CRP for PJI diagnosis was evaluated by receiver operating characteristic (ROC) curves, and the sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: Compared to those in the AL group, the mean WBC, PLT, ESR, CRP, PLR, PVR, NLR, and MLR in the peripheral blood of the PJI group were significantly greater (P < 0.05). The analysis of the ROC curve revealed that the ESR, CRP, PLR, PVR, NLR, and MLR in peripheral blood had moderate effectiveness in diagnosing PJI, with area under the curve (AUC) values of 0.760 (95% CI: 0.688-0.823), 0.758 (95% CI: 0.687-0.821), 0.714 (95% CI: 0.639-0.781), 0.709 (95% CI: 0.634-0.777), 0.723 (95% CI: 0.649-0.789), and 0.728 (95% CI: 0.654-0.793), respectively. Conversely, the WBC and PLT counts demonstrated poor diagnostic value for PJI, with AUC values of 0.578 (95% CI: 0.499-0.653) and 0.694 (95% CI: 0.619-0.763), respectively. The results of the prediction model calculations revealed that the combined AUC of the WBC, PLT, ESR, CRP, PLR, PVR, NLR, and MLR was the highest at 0.853 (95% CI, 0.790-0.909), indicating good value in the diagnosis of PJI, with a sensitivity of 82.8% and a specificity of 72.7%. Moreover, the novel composite of parameters improved the accuracy and reliability in diagnosing PJI compared to the traditional biomarkers ESR and CRP (P = 0.015). CONCLUSION: Our study suggested that the diagnostic value of the peripheral blood biomarkers PLR, PVR, NLR, and MLR for diagnosing PJI is limited and not superior to that of the ESR or CRP. However, when the WBC, PLT, ESR, CRP, PLR, PVR, NLR, and MLR are combined, the diagnostic performance of PJI in TJA patients can be improved.

Bear Bile Powder Ameliorates LPS-Induced Acute Lung Injury by Inhibiting CD14 Pathway and Improving Intestinal Flora: Exploration of "Fei (Lung)-Dachang (Large Intestine) Interaction".

OBJECTIVE: To explore the effect of bear bile powder (BBP) on acute lung injury (ALI) and the underlying mechanism. METHODS: The chemical constituents of BBP were analyzed by ultra-high-pressure liquid chromatography-mass spectrometry (UPLC-MS). After 7 days of adaptive feeding, 50 mice were randomly divided into 5 groups by a random number table (n=10): normal control (NC), lipopolysaccharide (LPS), dexamethasone (Dex), low-, and high-dose BBP groups. The dosing cycle was 9 days. On the 12th and 14th days, 20 µL of Staphylococcus aureus solution (bacterial concentration of 1 × 10-7 CFU/mL) was given by nasal drip after 1 h of intragastric administration, and the mice in the NC group was given the same dose of phosphated buffered saline (PBS) solution. On the 16th day, after 1 h intragastric administration, 100 µL of LPS solution (1 mg/mL) was given by tracheal intubation, and the same dose of PBS solution was given to the NC group. Lung tissue was obtained to measure the myeloperoxidase (MPO) activity, the lung wet/dry weight ratio and expressions of CD14 and other related proteins. The lower lobe of the right lung was obtained for pathological examination. The concentrations of inflammatory cytokines including interleukin (IL)-6, tumour necrosis factor α (TNF-α ) and IL-1ß in the bronchoalveolar lavage fluid (BALF) were detected by enzyme linked immunosorbent assay, and the number of neutrophils was counted. The colonic contents of the mice were analyzed by 16 sRNA technique and the contents of short-chain fatty acids (SCFAs) were measured by gas chromatograph-mass spectrometer (GC-MS). RESULTS: UPLC-MS revealed that the chemical components of BBP samples were mainly tauroursodeoxycholic acid and taurochenodeoxycholic acid sodium salt. BBP reduced the activity of MPO, concentrations of inflammatory cytokines, and inhibited the expression of CD14 protein, thus suppressing the activation of NF-κB pathway (P<0.05). The lung histopathological results indicated that BBP significantly reduced the degree of neutrophil infiltration, cell shedding, necrosis, and alveolar cavity depression. Moreover, BBP effectively regulated the composition of the intestinal microflora and increased the production of SCFAs, which contributed to its treatment effect (P<0.05). CONCLUSIONS: BBP alleviates lung injury in ALI mouse through inhibiting activation of NF-κB pathway and decreasing expression of CD14 protein. BBP may promote recovery of ALI by improving the structure of intestinal flora and enhancing metabolic function of intestinal flora.

Assessment of pathogenicity and functional characterization of APPL1 gene mutations in diabetic patients.

BACKGROUND: Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) plays a crucial role in regulating insulin signaling and glucose metabolism. Mutations in the APPL1 gene have been associated with the development of maturity-onset diabetes of the young type 14 (MODY14). Currently, only two mutations [c.1655T>A (p.Leu552*) and c.281G>A p.(Asp94Asn)] have been identified in association with this disease. Given the limited understanding of MODY14, it is imperative to identify additional cases and carry out comprehensive research on MODY14 and APPL1 mutations. AIM: To assess the pathogenicity of APPL1 gene mutations in diabetic patients and to characterize the functional role of the APPL1 domain. METHODS: Patients exhibiting clinical signs and a medical history suggestive of MODY were screened for the study. Whole exome sequencing was performed on the patients as well as their family members. The pathogenicity of the identified APPL1 variants was predicted on the basis of bioinformatics analysis. In addition, the pathogenicity of the novel APPL1 variant was preliminarily evaluated through in vitro functional experiments. Finally, the impact of these variants on APPL1 protein expression and the insulin pathway were assessed, and the potential mechanism underlying the interaction between the APPL1 protein and the insulin receptor was further explored. RESULTS: A total of five novel mutations were identified, including four missense mutations (Asp632Tyr, Arg633His, Arg532Gln, and Ile642Met) and one intronic mutation (1153-16A>T). Pathogenicity prediction analysis revealed that the Arg532Gln was pathogenic across all predictions. The Asp632Tyr and Arg633His variants also had pathogenicity based on MutationTaster. In addition, multiple alignment of amino acid sequences showed that the Arg532Gln, Asp632Tyr, and Arg633His variants were conserved across different species. Moreover, in in vitro functional experiments, both the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were found to downregulate the expression of APPL1 on both protein and mRNA levels, indicating their pathogenic nature. Therefore, based on the patient's clinical and family history, combined with the results from bioinformatics analysis and functional experiment, the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were classified as pathogenic mutations. Importantly, all these mutations were located within the phosphotyrosine-binding domain of APPL1, which plays a critical role in the insulin sensitization effect. CONCLUSION: This study provided new insights into the pathogenicity of APPL1 gene mutations in diabetes and revealed a potential target for the diagnosis and treatment of the disease.

Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer-like social memory loss.

BACKGROUND: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. METHODS: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice. RESULTS: The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory. CONCLUSION: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.

Gastroesophageal reflux disease with 6 neurodegenerative and psychiatric disorders: Genetic correlations, causality, and potential molecular mechanisms.

The comorbidities between gastroesophageal reflux disease (GERD) and various neurodegenerative and psychiatric disorders have been widely reported. However, the genetic correlations, causal relationships, and underlying mechanisms linking GERD to these disorders remain largely unknown. Here, we conducted a bidirectional Mendelian randomization (MR) analysis to determine the causality between GERD and 6 neurodegenerative and psychiatric disorders. Sensitivity analyses and multivariable MR were performed to test the robustness of our findings. Linkage disequilibrium score regression was used to assess the genetic correlation between these diseases as affected by heredity. Multiple bioinformatics tools combining two machine learning algorithms were applied to further investigate the potential mechanisms underlying these diseases. We found that genetically predicted GERD significantly increased the risk of Alzheimer's disease, major depressive disorder, and anxiety disorders. There might be a bidirectional relationship between GERD and insomnia. GERD has varying degrees of genetic correlations with AD, ALS, anxiety disorders, insomnia, and depressive disorder. Bioinformatics analyses revealed the hub shared genes and the common pathways between GERD and 6 neurodegenerative and psychiatric disorders. Our findings demonstrated the complex nature of the genetic architecture across these diseases and clarified their causality, highlighting that treatments for the cure or remission of GERD may serve as potential strategies for preventing and managing neurodegenerative and psychiatric disorders.

Association between Atopic Dermatitis and Colorectal Cancer: TET2 as a Shared Gene Signature and Prognostic Biomarker.

Background: Recent studies have linked atopic dermatitis (AD) to colorectal cancer (CRC) risk. Their causality and potential molecular mechanisms remain unclear. Methods: We performed Mendelian randomization (MR) analysis to evaluate the causality between AD and CRC. Summary statistic data-based Mendelian randomization (SMR) analysis was used to identify CRC-related causal genes. Transcriptome analyses and immunohistochemical methods were applied to investigate the shared gene signature and potential mechanisms that contribute to the pathogenesis of both AD and CRC. A predictive analysis was performed to examine the shared gene signature associated with immunotherapy response in CRC. Results: MR analysis indicated a causal association between AD and a decreased risk of CRC. SMR analysis uncovered TET2 as a CRC-related causal gene, showing an inverse relationship with the risk of CRC. Transcriptome analyses identified TET2 as a shared gene signature between AD and CRC. Decreased TET2 expression is associated with impaired demethylation and worse prognosis in CRC patients. We observed ten pathways related to the inflammatory response and immune regulation that may be shared mechanisms underlying both AD and CRC. These findings were validated through single-cell analysis. TET2 shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Conclusion: There is a causal association between AD and a decreased risk of CRC. AD may influence the occurrence of CRC by modulating immune and inflammatory responses. TET2 could serve as a potential biomarker for prognosis and may be considered a novel therapeutic target for methylation and immune-related interventions.

Metabolic syndrome, its components, and gastrointestinal cancer risk: a meta-analysis of 31 prospective cohorts and Mendelian randomization study.

BACKGROUND AND AIM: Cohort studies have linked metabolic syndrome (MetS) to gastrointestinal (GI) cancer risk. We aimed to evaluate the associations between MetS, its components, and combinations of MetS components with eight GI cancers risk. METHODS: We conducted a systematic search of prospective cohort studies and performed a meta-analysis. Subgroup analyses regarding diagnostic criteria, sex, cancer sites, histological subtypes, ethnic groups, and studies adjusted for alcohol consumption were carried out. Mendelian randomization (MR) was employed to evaluate the causality between 17 MetS-related traits and eight GI cancers among Europeans and Asians separately. RESULTS: Meta-analyses of 31 prospective studies indicated that MetS was significantly associated with an increased risk of colorectal cancer (CRC) (RR [95% CI] = 1.13 [1.12-1.15]), esophageal cancer (EC) (RR [95% CI] = 1.17 [1.03-1.32]), gallbladder cancer (GBC) (RR [95% CI] = 1.37[1.10-1.71]), liver cancer (LC) (RR [95% CI] = 1.46 [1.29-1.64]), and pancreatic cancer (PaC) (RR [95% CI] = 1.25 [1.20-1.30]), but not gastric cancer (GC) (RR [95% CI] = 1.11 [0.96-1.28]). Regarding the associations between MetS components and GI cancers risk, the following associations showed statistical significance: obesity-CRC/LC/EC/, hypertriglyceridemia-LC/PaC, reduced high-density lipoprotein (HDL)-CRC/LC/GC/PaC, hyperglycemia-CRC/LC/PaC, and hypertension-CRC/LC/EC/PaC. Sex-specific associations were observed between individual MetS components on GI cancers risk. Among the top three common combinations in both sexes, obesity + HTN + hyperglycemia had the strongest association with CRC risk (RR [95% CI] = 1.54 [1.49-1.61] for males and 1.27 [1.21-1.33] for females). MR analyses revealed causality in 16 exposure-outcome pairs: waist-to-hip ratio/BMI/HbA1c-CRC; BMI/childhood obesity/waist circumference/T2DM/glucose-EC; BMI/waist circumference/cholesterol-LC; cholesterol/childhood obesity/waist circumference/HbA1c-PaC; and HbA1c-GBC. These results were robust against sensitivity analyses. CONCLUSIONS: Since MetS is reversible, lifestyle changes or medical interventions targeting MetS patients might be potential prevention strategies for GI cancers.

Electroacupuncture at Sensitized Acupoints Relieves Somatic Referred Pain in Colitis Rats by Inhibiting Sympathetic-Sensory Coupling to Interfere with 5-HT Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To investigate whether electroacupuncture (EA) at sensitized acupoints could reduce sympathetic-sensory coupling (SSC) and neurogenic inflammatory response by interfering with 5-hydroxytryptamine (5-HT)ergic neural pathways to relieve colitis and somatic referred pain, and explore the underlying mechanisms.@*METHODS@#Rats were treated with 5% dextran sodium sulfate (DSS) solution for 7 days to establish a colitis model. Twelve rats were randomly divided into the control and model groups according to a random number table (n=6). According to the "Research on Rat Acupoint Atlas", sensitized acupoints and non-sensitized acupoints were determined. Rats were randomly divided into the control, model, Zusanli-EA (ST 36), Dachangshu-EA (BL 25), and Xinshu (BL 15) groups (n=6), as well as the control, model, EA, and EA + GR113808 (a 5-HT inhibitor) groups (n=6). The rats in the control group received no treatment. Acupuncture was administered on 2 days after modeling using the stimulation pavameters: 1 mA, 2 Hz, for 30 min, with sparse and dense waves, for 14 consecutive days. GR113808 was injected into the tail vein at 5 mg/kg before EA for 10 min for 7 consecutive days. Mechanical sensitivity was assessed with von Frey filaments. Body weight and disease activity index (DAI) scores of rats were determined. Hematoxylin and eosin staining was performed to observe colon histopathology. SSC was analyzed by immunofluorescence staining. Immunohistochemical staining was performed to detect 5-HT and substance P (SP) expressions. The calcitonin gene-related peptide (CGRP) in skin tissue and tyrosine hydroxylase (TH) protein levels in DRG were detected by Western blot. The levels of hyaluronic acid (HA), bradykinin (BK), prostaglandin I2 (PGI2) in skin tissue, 5-HT, tryptophan hydroxylase 1 (TPH1), serotonin transporters (SERT), 5-HT 3 receptor (5-HT3R), and 5-HT 4 receptor (5-HT4R) in colon tissue were measured by enzyme-linked immunosorbent assay (ELISA).@*RESULTS@#BL 25 and ST 36 acupoints were determined as sensitized acupoints, and BL 15 acupoint was used as a non-sensitized acupoint. EA at sensitized acupoints improved the DAI score, increased mechanical withdrawal thresholds, and alleviated colonic pathological damage of rats. EA at sensitized acupoints reduced SSC structures and decreased TH and CGRP expression levels (P<0.05). Furthermore, EA at sensitized acupoints reduced BK, PGI2, 5-HT, 5-HT3R and TPH1 levels, and increased HA, 5-HT4R and SERT levels in colitis rats (P<0.05). GR113808 treatment diminished the protective effect of EA at sensitized acupoints in colitis rats (P<0.05).@*CONCLUSION@#EA at sensitized acupoints alleviated DSS-induced somatic referred pain in colitis rats by interfering with 5-HTergic neural pathway, and reducing SSC inflammatory response.

Efficacy and safety of paclitaxel albumin assisted platinum chemotherapy in the treatment of recurrent and metastatic cervical cancer based on tumor factors and inflammatory status / 中国临床药理学与治疗学

AIM: To investigate the efficacy and safety of paclitaxel albumin assisted platinum chemotherapy in the treatment of recurrent and metastatic cervical cancer based on tumor factors and inflammatory status. METHODS: A total of 100 patients with recurrent and metastatic cervical cancer in our hospital from January 2020 to January 2023 were randomly divided into two groups: 50 patients in the control group were treated with paclitaxel-assisted nedaplatin regimen, and 50 patients in the study group were treated with paclitaxel-assisted nedaplatin regimen. The short-term efficacy, tumor factors, inflammatory factors, relapse-metastasis related indexes, quality of life, functional status and adverse reactions were compared between the two groups. RESULTS: The total remission rate of the study group (72.00%) was higher than that of the control group (48.00%) (P0.05), but the total incidence of adverse reactions (12.00%) was lower than that of the control group (32.00%) (P<0.05). CONCLUSION: Paclitaxel albumin-assisted nedaplatin has a reliable effect in the treatment of recurrent and metastatic cervical cancer, which can further reduce the level of tumor factors, relieve inflammation, and has high safety.

Analysis of chemical constituents and components absorbed into plasma of Ardisia crenata based on UPLC-QE-HF-MS/MS / 中国药房

OBJECTIVE To analyze the chemical constituents and components absorbed into plasma of the extract of Ardisia crenata and to elucidate its possible pharmacodynamic material basis. METHODS Overall， 12 rats were randomly assigned to the blank group （n＝6） and A. crenata group （n＝6） by the paired comparison method. The drug was administered once daily in the morning and afternoon for three days. Serum samples were prepared from serum after redosing on 4th day. The UPLC-QE-HF-MS/ MS was used to analyze and identify the chemical constituents in A. crenata extract and serum samples. Compound Discoverer 3.0 was employed for retention time correction， peak identification， and peak extraction. According to the secondary mass spectrometry information， the Thermo mzCloud online and Thermo mzVault local databases， referring to the relevant literature and control quality spectrum information were used to preliminarily identify the chemical constituents and components absorbed into plasma of A. crenata. RESULTS A total of 34 compounds were identified from the extract of A. crenata， mainly coumarins， flavonoids， organic acids， amino acids， including bergenin， quercetin， gallic acid， L-pyroglutamic acid， etc. Besides， 5 components absorbed into plasma were identified from serum samples: L-pyroglutamic acid， syringic acid， bergenin， cinnabar root saponin A， and mycophenolic acid. CONCLUSIONS L-pyroglutamic acid， syringic acid， bergenin， cinnabar root saponin A， and mycophenolic acid may act as the pharmacodynamic material basis of A. crenata.

Thiacalix[4]arene-Protected Silver Nanoclusters Encapsulating Different Two-Electron Superatom Oligomers.

The subvalent silver kernel represents the nascent state of silver cluster formation, yet the growth mechanism has long been elusive. Herein, two silver nanoclusters (Ag30 and Ag34) coprotected by TC4A4- (H4TC4A = p-tert-butylthiacalix[4]arene) and TBPMT- (TBPMTH = 4-tert-butylbenzenemethanethiol) containing 6e and 4e silver kernels are synthesized and characterized. The trimer of the 2e superatom Ag14 kernel in Ag30 is built from a central Ag6 octahedron sandwiched by two orthogonally oriented Ag5 trigonal bipyramids through sharing vertexes, whereas a double-octahedral Ag10 kernel in Ag34 is a dimer of 2e superatoms. They manifest disparate polyhedron fusion growth patterns at the beginning of the silver cluster formation. Their excellent solution stabilities are contributed by the multisite and multidentate coordination fashion of TC4A4- and the special valence electron structures. This work demonstrates the precise control of silver kernel growth by the solvent strategy and lays a foundation for silver nanocluster application in photothermal conversion.

Molecular typing and prognostic risk models for ovarian cancer: a study based on cell differentiation trajectory.

Ovarian cancer is a heterogeneous disease with different molecular phenotypes. We performed molecular typing of ovarian cancer using cell differentiation trajectory analysis and proposed a prognostic risk scoring model. Using the copy number variation provided by inferCNV, we identified malignant tumor cells. Then, ovarian cancer samples were divided into four subtypes based on differentiation-related genes (DRGs). There were significant differences in survival rates, clinical features, tumor microenvironment scores, and the expression levels of ICGs among the subtypes. Based on nine DRGs, a prognostic risk score model was generated (AUC at 1 year: 0.749; 3 years: 0.651). Then we obtained a nomogram of the prognostic variable combination, including risk scores and clinicopathological characteristics, and predicted the 1-, 3- and 5-year overall survival. Finally, we explored some issues of immune escape using the established risk model. Our study demonstrates the significant influence of cell differentiation on predicting prognosis in OV patients and provides new insights for OV treatment and potential immunotherapeutic strategies.

Monoarsine-protected icosahedral cluster [Au13(AsPh3)8Cl4]+: comparative studies on ligand effect and surface reactivity with its stibine analogue.

Ligand shells of gold nanoclusters play important roles in regulating their molecular and electronic structures. However, the similar but distinct impacts of the homologous analogues of the protecting ligands remain elusive. The C2v symmetric monoarsine-protected cluster [Au13(AsPh3)8Cl4]+ (Au13As8) was facilely prepared by direct reduction of (Ph3As)AuCl with NaBH4. This cluster is isostructural with its previously reported stibine analogue [Au13(SbPh3)8Cl4]+ (Au13Sb8), enabling a comparative study between them. Au13As8 exhibits a blue-shifted electronic absorption band, and this is probably related to the stronger π-back donation interactions between the Au13 core and AsPh3 ligands, which destabilize its superatomic 1P and 1D orbitals. In comparison to the thermodynamically less stable Au13Sb8, Au13As8 achieves a better trade-off between catalytic stability and activity, as demonstrated by its excellent catalytic performance towards the aldehyde-alkyne-amine (A3) coupling reaction. Moreover, the ligand exchange reactions between Au13As8 with phosphines, as exemplified by PPh3 and Ph2P(CH2)2PPh2, suggest that Au13As8 may be a good precursor cluster for further cluster preparation through the "cluster-to-cluster" route.

Effects of Particulate Matter on the Risk of Gestational Hypertensive Disorders and Their Progression.

Associations between particulate matter (PM) and gestational hypertensive disorders (GHDs) are well documented, but there is no evidence on the associations between PM and GHD progression, especially among those with assisted reproductive technology (ART) conceptions. To explore the effects of PM on the risk of GHDs and their progression among pregnant women with natural or ART conception, we enrolled 185,140 pregnant women during 2014-2020 in Shanghai and estimated the associations during different periods using multivariate logistic regression. During the 3 months of preconception, 10 µg/m3 increases in PM concentrations were associated with increased risks of gestational hypertension (GH) (PM2.5: aOR = 1.076, 95% CI: 1.034-1.120; PM10: aOR = 1.042, 95% CI: 1.006-1.079) and preeclampsia (PM2.5: aOR = 1.064, 95% CI: 1.008-1.122; PM10: aOR = 1.048, 95% CI: 1.006-1.092 ) among women with natural conception. Furthermore, for women with ART conceptions who suffered current GHD, 10 µg/m3 increases in PM concentrations in the third trimester elevated the risk of progression (PM2.5: aOR = 1.156, 95% CI: 1.022-1.306 ; PM10: aOR = 1.134, 95% CI: 1.013-1.270). In summary, women with natural conception should avoid preconceptional PM exposure to protect themselves from GH and preeclampsia. For women with ART conceptions suffering from GHD, it is necessary to avoid PM exposure in late pregnancy to prevent the disease from progressing.

Consensus on diagnostic criteria for deficiency syndrome in hypertension: a modified Delphi study.

OBJECTIVE: To reach consensus on the diagnostic criteria for deficiency syndrome in hypertension (YDSH) patients by a modified Delphi method. METHODS: Our study was consistent with T/CACM 1032-2017. The methodology of RAND/UCLA appr-opriateness was used to develop consensus guidance statements. A nationwide panel of experienced clinical experts from 19 provinces was constructed. These experts were all prominent in Traditional Chinese Medicine (TCM) of cardiovascular diseases. This con-sensus process consisted of two rounds of ques-tionnaires and a final round of consultation to analyze the weight score of each item. Moreover, the data extraction process is carried out independently by third-party researchers (LIANG Junya, SUN Yang, and DU Xiaona). When there is disagreement in all three rounds, the expert panel group (odd number) are invited to vote, and the one with more votes wins. In the questionnaires, participants were asked to rate the appropriateness of each syndrome item using a nine-point Likert scale. The consensus was defined as a panel median rating 1-3 or 7-9 without disagreement. And then the diagnostic criteria of YDSH were formed according to the weight score in the final round. RESULTS: Twenty-eight experts (84.8%) participated in the first round, and thirty-one (93.9%) finished the second round. After two rounds, the consensus of YDSH was reached on 11 items (25.6%), including symptoms, signs, and pulse condition. Twenty-one experts (63.6%) com-pleted the final round in which they used a grading system for each item. Red tongue with scanty fur had the highest weighting (22.8%), followed by heat in the palms and soles (20.1%). CONCLUSIONS: The consensus-based diagnostic criteria for YDSH, formed by a modified Delphi method, can be widely incorporated in TCM. A further clinical study will be conducted to analyze the diagnosis value and cut-off score of our YDSH criteria.

The information-motivation-behavioral skills (IMB) model of antiretroviral therapy (ART) adherence among people living with HIV in Shanghai.

The Information-Motivation-Behavioral skills (IMB) model of antiretroviral therapy (ART) adherence was applied in people living with HIV/AIDS in Shanghai, China to understand how adherence-related information, motivation and behavioral skills would affect ART adherence. The LifeWindows Information-Motivation-Behavioral Skills ART Adherence Questionnaire (LW-IMB-AAQ) was translated into Chinese and used. The IMB model was then implemented by testing standardized path estimates with standard model fitness indices in the participants. 426 participants from 11 community centres in Putuo district of Shanghai were recruited, of which 95.3% reported a high level of adherence (>95% adherence). The fitness indices of the final adjusted model were χ2 = 6.110, df = 7, p = 0.527(>0.05), CFI = 1.000(>0.9) and RMSEA = 0.000 (<0.08). In the model, information, which was separated into two sections (the perceived effect of ART on health and knowledge about ART medication), had an indirect effect on the ART adherence through behavioral skills, while motivation did not have such an effect. Neither information nor motivation had a direct effect on ART adherence. In addition, motivation was related to the two sections of information. The feasibility of the IMB model of ART adherence is verified by its application to predictive of adherence-related behaviors among HIV+ patients in this study.

Transient neurogenesis in ischemic cortex from Sox2+ astrocytes.

The adult cortex has long been regarded as non-neurogenic. Whether injury can induce neurogenesis in the adult cortex is still controversial. Here, we report that focal ischemia stimulates a transient wave of local neurogenesis. Using 5'-bromo-2'-deoxyuridine labeling, we demonstrated a rapid generation of doublecortin-positive neuroblasts that died quickly in mouse cerebral cortex following ischemia. Nestin-CreER-based cell ablation and fate mapping showed a small contribution of neuroblasts by subventricular zone neural stem cells. Using a mini-photothrombotic ischemia mouse model and retrovirus expressing green fluorescent protein labeling, we observed maturation of locally generated new neurons. Furthermore, fate tracing analyses using PDGFRα-, GFAP-, and Sox2-CreER mice showed a transient wave of neuroblast generation in mild ischemic cortex and identified that Sox2-positive astrocytes were the major neurogenic cells in adult cortex. In addition, a similar upregulation of Sox2 and appearance of neuroblasts were observed in the focal ischemic cortex of Macaca mulatta. Our findings demonstrated a transient neurogenic response of Sox2-positive astrocytes in ischemic cortex, which suggests the possibility of inducing neuronal regeneration by amplifying this intrinsic response in the future.