Primary Ewing's sarcoma of the uterine cervix: a case report and review of the literature.

BACKGROUND: Ewing's sarcoma (ES) is an aggressive cancer of bone and soft tissue, most of which tend to occur in the bone. Extraosseous Ewing's sarcoma (EES) of the cervix is extremely rare. CASE PRESENTATION: In the present work, we reported a 39-year-old cervical EES patient with a 2.5*2.1*1.8 cm tumor mass. According to previous literatures, our case is the smallest tumor found in primary cervical ES ever. The patient initially came to our hospital due to vaginal bleeding, and then the gynecological examination found a neoplasm between the cervical canal and partially in the external cervical orifice. The diagnosis of EES was confirmed below: Hematoxylin & Eosin staining (H&E) revealed small round blue malignant cells in biopsy specimens. Immunohistochemistry (IHC) showed the positive staining for CD99, NKX2.2, and FLI1. Disruption of EWSR1 gene was found by fluorescence in situ hybridization (FISH), and the EWSR1-FLI1 gene fusion was determined by next-generation sequencing (NGS). The patient received laparoscopic wide hysterectomy, bilateral adnexectomy, pelvic lymphadenectomy, and postoperative adjuvant chemotherapy and remained disease free with regular follow-up for 1 year. CONCLUSIONS: Through a systematic review of previously reported cervical ES and this case, we highlighted the importance of FISH and NGS for the accuracy of ESS diagnosis, which could assist on the optimal treatment strategy. However, due to the rarity of the disease, there is no standard treatment schemes. Investigation on molecular pathological diagnosis and standardization of treatment regimens for cervical ES are critical to patients' prognosis.

Neutrophil-to-lymphocyte ratio associated with renal function in type 2 diabetic patients.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a leading risk factor for the development and progression of chronic kidney disease (CKD). However, an accurate and convenient marker for early detection and appropriate management of CKD in individuals with T2DM is limited. Recent studies have demonstrated a strong correlation between the neutrophil-to-lymphocyte ratio (NLR) and CKD. Nonetheless, the predictive value of NLR for renal damage in type 2 diabetic patients remains understudied. AIM: To investigate the relationship between NLR and renal function in T2DM patients. METHODS: This study included 1040 adults aged 65 or older with T2DM from Shanghai's Community Health Service Center. The total number of neutrophils and lymphocytes was detected, and NLR levels were calculated. CKD was defined as an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m². Participants were divided into four groups based on NLR levels. The clinical data and biochemical characteristics were compared among groups. A multivariate logistic regression model was used to analyze the association between NLR levels and CKD. RESULTS: Significant differences were found in terms of sex, serum creatinine, blood urea nitrogen, total cholesterol, and low-density lipoprotein cholesterol among patients with T2DM in different NLR groups (P < 0.0007). T2DM patients in the highest NLR quartile had a higher prevalence of CKD (P for trend = 0.0011). Multivariate logistic regression analysis indicated that a high NLR was an independent risk factor for CKD in T2DM patients even after adjustment for important clinical and pathological parameters (P = 0.0001, odds ratio = 1.41, 95% confidence intervals: 1.18-1.68). CONCLUSION: An elevated NLR in patients with T2DM is associated with higher prevalence of CKD, suggesting that it could be a marker for the detection and evaluation of diabetic kidney disease.

Effect of 5:2 Regimens: Energy-Restricted Diet or Low-Volume High-Intensity Interval Training Combined With Resistance Exercise on Glycemic Control and Cardiometabolic Health in Adults With Overweight/Obesity and Type 2 Diabetes: A Three-Arm Randomized Controlled Trial.

OBJECTIVE: We aimed to examine the effects of a 5:2 diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS: The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (-0.72, 95% CI -0.95 to -0.48) compared with the control group (-0.37, 95% CI -0.60 to -0.15) (diet vs. control -0.34, 95% CI -0.58 to -0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (-0.46, 95% CI -0.70 to -0.23) did not significantly differ from the control group (exercise vs. control -0.09, 95% CI -0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS: These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control.

Giving birth after fertility-sparing treatment for primary leiomyosarcoma of the fallopian tube.

Primary leiomyosarcoma of the fallopian tube (PLFT) is an extremely rare gynecological malignancy that has only been described in case reports. Fertility-sparing treatment for PLFT has not been reported previously. A 24-year-old nulligravida woman was diagnosed with stage IC1 PLFT in the right fallopian tube after experiencing right lower quadrant pain for 2 weeks. She underwent laparoscopic right salpingectomy to preserve fertility followed by adjuvant chemotherapy with gemcitabine/docetaxel. She subsequently became pregnant spontaneously, delivering a term baby 27 months after treatment. This appears to be the only report of the use of fertility-preserving treatment for PLFT. The success of the treatment provides valuable information on the preservation of fertility in young women with PLFT.

Development and Validation of an ADA-Tolerant Assay for Quantification of an Exatecan-Based ADC in Monkey Plasma.

BACKGROUND: The development of an anti-drug antibody (ADA)-tolerant pharmacokinetic (PK) assay is important when the drug exposure is irrelevant to toxicity in the presence of ADA. We aimed to develop and validate an ADA-tolerant assay for an exatecan-based antibody-drug conjugate (ADC) in monkey plasma. RESULTS: The assay tolerated 5.00 µg/mL of ADA at 12 µg/mL of ADC. Its accuracy and precision results satisfied the acceptance criteria. Furthermore, the assay was free from hook and matrix effects and exhibited good dilutional linearity. Additionally, the ADC in plasma samples was stable under different storage conditions. METHOD: An ADA-tolerant ADC assay was configured with an anti-payload antibody for capture, and a drug-target protein combined with a horseradish peroxidase (HRP)-labeled antibody against a drug-target-protein tag for detection. Samples were firstly acidified to dissociate drug and ADA complexes, and to convert the carboxylate form to the lactone form of exatecan molecules; then, the ADAs in the samples were removed with a naked antibody-coated microplate. The treated samples were further incubated with coated anti-payload antibody and captured ADC molecules were quantified by the detection reagent. The developed assay was optimized and validated against regulatory guidelines. CONCLUSIONS: The assay met both methodological and sample-related ADA tolerance requirements, and was applicable to a nonclinical study in cynomolgus monkeys.

CircFKBP3 absence alleviates oxygen glucose deprivation-induced function loss of human brain microvascular endothelial cells in vitro via governing the miR-766-3p/TRAF3 axis.

BACKGROUND: Brain microvascular endothelial cell (BMEC) functions loss is a key event in the development of ischemic stroke, which may be affected by the dysregulation of circular RNAs (circRNAs). We aimed to unveil the role of circRNA FKBP Prolyl Isomerase 3 (circFKBP3) in cell models of ischemic stroke. METHODS: Cell models of ischemic stroke were constructed in human BEMCs (HBMECs) with the treatment of oxygen glucose deprivation (OGD). Quantitative real-time PCR (qPCR) and western blotting were conducted for expression analysis of circFKBP3, miR-766-3p and TNF receptor associated factor 3 (TRAF3). CCK-8, transwell, wound healing, flow cytometry, tube formation and ELISA assays were implemented to monitor cell viability, migration, apoptosis, angiogenesis and inflammation production. The putative binding relationship between miR-766-3p and circFKBP3 or TRAF3 was validated by dual-luciferase, RIP and pull-down assays. RESULTS: CircFKBP3 expression was elevated in OGD-treated HBMECs. OGD suppressed HBMEC viability, migration, angiogenesis, and provoked cell apoptosis and inflammation production, while knockdown of circFKBP3 attenuated these effects. CircFKBP3 interacted with miR-766-3p, and circFKBP3 absence-repressed HBMEC function loss and inflammation were recovered by miR-766-3p inhibition. CircFKBP3 targeted miR-766-3p to regulate TRAF3 expression. MiR-766-3p enrichment-repressed HBMEC function loss and inflammation were recovered by TRAF3 overexpression. CONCLUSION: CircFKBP3 absence alleviated OGD-induced function loss and inflammatory responses of HBMECs via governing the miR-766-3p/TRAF3 axis.

CircFKBP3 expression is elevated in OGD-treated HBMECs.OGD-induced HBMEC function loss and inflammation are alleviated by circFKBP3 absence.CircFKBP3 directly targets miR-766-3p to regulate TRAF3 expression.

Combination of transbronchial cryobiopsy based clinic-radiologic-pathologic strategy and metagenomic next-generation sequencing for differential diagnosis of rapidly progressive diffuse parenchymal lung diseases.

Background: The complicated spectrum of rapidly progressive diffused parenchymal lung diseases (RP-DPLD) creates obstacles to the precise diagnosis and treatment. We evaluated the differential diagnostic value of transbronchial cryobiopsy (TBCB) based clinic-radiologic-pathologic (CRP) strategy combined with bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) in RP-DPLD patients. Methods: RP-DPLD patients who underwent the diagnostic strategy of TBCB-based CRP combined with BALF mNGS at Shanghai East Hospital from May 2020 to Oct 2022 were retrospectively analyzed. Clinical characteristics were summarized, including demographic data, high-resolution computed tomography (HRCT) findings, histopathology of TBCB and microbiological results. Diagnostic value of the combined strategy, as well as the sensitivity, specificity, and positive detection rates of mNGS were evaluated. Results: A total of 115 RP-DPLD patients were enrolled, with a mean age of 64.4 years old and a male proportion of 54.8%. The pulmonary imaging findings in most patients were complex and diverse, with all patients showing bilateral lung diffuse lesions in HRCT, and progressively aggravated imaging changes within one month. After combining TBCB-based CRP strategy with mNGS, all participants received a corresponding diagnosis with 100% diagnostic yield. In these patients, 58.3% (67/115) were diagnosed with noninfectious RP-DPLD and 41.7% (48/115) with infection-related RP-DPLD. There were 86.1% of cases with known etiology according to the DPLD classification. BALF mNGS and traditional pathogen detection methods were performed in all patients, the positive detection rates were 50.4% (58/115) and 32.2% (37/115), respectively. Meanwhile, the mNGS showed significantly higher sensitivity and negative predictive value than the traditional pathogen detection methods for the diagnosis of infection-related RP-DPLD (100% vs 60.4% (p<0.001), 100% vs 75.6% (p<0.001), respectively). Among noninfectious RP-DPLD patients, the true negative rate of mNGS was 85.1% (57/67). All patients had their treatment regimen modified and the 30-day mortality was 7.0%. Conclusion: The novel strategy of TBCB-based CRP combined with mNGS provided dependable and sufficient evidence for the diagnosis, meanwhile further improved the accuracy of RP-DPLD treatment, as well as the prognosis of patients. Our results highlight the significant value of combined strategy in determining whether the RP-DPLD patients were infection associated or not.

Single-cell dissection of cervical cancer reveals key subsets of the tumor immune microenvironment.

The tumor microenvironment (TME) directly determines patients' outcomes and therapeutic efficiencies. An in-depth understanding of the TME is required to improve the prognosis of patients with cervical cancer (CC). This study conducted single-cell RNA and TCR sequencing of six-paired tumors and adjacent normal tissues to map the CC immune landscape. T and NK cells were highly enriched in the tumor area and transitioned from cytotoxic to exhaustion phenotypes. Our analyses suggest that cytotoxic large-clone T cells are critical effectors in the antitumor response. This study also revealed tumor-specific germinal center B cells associated with tertiary lymphoid structures. A high-germinal center B cell proportion in patients with CC is predictive of improved clinical outcomes and is associated with elevated hormonal immune responses. We depicted an immune-excluded stromal landscape and established a joint model of tumor and stromal cells to predict CC patients' prognosis. The study revealed tumor ecosystem subsets linked to antitumor response or prognosis in the TME and provides information for future combinational immunotherapy.

Development and validation of a prognostic model incorporating tumor thrombus grading for nonmetastatic clear cell renal cell carcinoma with tumor thrombus: A multicohort study.

There is significant variability with respect to the prognosis of nonmetastatic clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT). By applying multiregion whole-exome sequencing on normal-tumor-thrombus-metastasis quadruples from 33 ccRCC patients, we showed that metastases were mainly seeded by VTT (81.8%) rather than primary tumors (PTs). A total of 706 nonmetastatic ccRCC patients with VTT from three independent cohorts were included in this study. C-index analysis revealed that pathological grading of VTT outperformed other indicators in risk assessment (OS: 0.663 versus 0.501-0.610, 0.667 versus 0.544-0.651, and 0.719 versus 0.511-0.700 for Training, China-Validation, and Poland-Validation cohorts, respectively). We constructed a risk predicting model, TT-GPS score, based on four independent variables: VTT height, VTT grading, perinephric fat invasion, and sarcomatoid differentiation in PT. The TT-GPS score displayed better discriminatory ability (OS, c-index: 0.706-0.840, AUC: 0.788-0.874; DFS, c-index: 0.691-0.717, AUC: 0.771-0.789) than previously reported models in risk assessment. In conclusion, we identified for the first-time pathological grading of VTT as an unheeded prognostic factor. By incorporating VTT grading, the TT-GPS score is a promising prognostic tool in predicting the survival of nonmetastatic ccRCC patients with VTT.

Responses of soil microbes and enzymes to long-term warming incubation in different depths of permafrost peatland soil.

Soil microbes and enzymes mediate soil carbon-climate feedback, and their responses to increasing temperature partly affect soil carbon stability subjected to the effects of climate change. We performed a 50-month incubation experiment to determine the effect of long-term warming on soil microbes and enzymes involved in carbon cycling along permafrost peatland profile (0-150 cm) and investigated their response to water flooding in the active soil layer. Soil bacteria, fungi, and most enzymes were observed to be sensitive to changes in temperature and water in the permafrost peatland. Bacterial and fungal abundance decreased in the active layer soil but increased in the deepest permafrost layer under warming. The highest decrease in the ratio of soil bacteria to fungi was observed in the deepest permafrost layer under warming. These results indicated that long-term warming promotes recalcitrant carbon loss in permafrost because fungi are more efficient in decomposing high-molecular-weight compounds. Soil microbial catabolic activity measured using Biolog Ecoplates indicated a greater degree of average well color development at 15 °C than at 5 °C. The highest levels of microbial catabolic activity, functional diversity, and carbon substrate utilization were found in the permafrost boundary layer (60-80 cm). Soil polyphenol oxidase that degrades recalcitrant carbon was more sensitive to increases in temperature than ß-glucosidase, N-acetyl-ß-glucosaminidase, and acid phosphatase, which degrade labile carbon. Increasing temperature and water flooding exerted a synergistic effect on the bacterial and fungal abundance and ß-glucosidase, acid phosphatase, and RubisCO activity in the topsoil. Structural equation modeling analysis indicated that soil enzyme activity significantly correlated with ratio of soil bacteria to fungi and microbial catabolic activity. Our results provide valuable insights into the linkage response of soil microorganisms, enzymes to climate change and their feedback to permafrost carbon loss.

Perineal nerve block versus periprostatic block for patients undergoing transperineal prostate biopsy (APROPOS): a prospective, multicentre, randomised controlled study.

Background: We aimed to investigate perineal nerve block versus periprostatic block in pain control for men undergoing a transperineal prostate biopsy. Methods: In this prospective, randomised, blinded and parallel-group trial, men in six Chinese hospitals with suspected prostate cancer were randomly assigned (1:1) at the point of local anaesthesia to receive a perineal nerve block or periprostatic block and followed by a transperineal prostate biopsy. Centres used their usual biopsy procedure. Operators who performed anaesthesia were trained in both techniques before the trial and were masked to the randomised allocation until the time of anaesthesia and were not involved in the subsequent biopsy procedure and any assessment or analysis. Other investigators and the patients were masked until trial completion. The primary outcome was the level of the worst pain experienced during the prostate biopsy procedure. Secondary outcomes included pain (post-biopsy at 1, 6 and 24 h), changes in blood pressure, heart rate and breathing rate during the biopsy procedure, external manifestations of pain during biopsy, anaesthesia satisfaction, the detection rate of PCa and clinically significant PCa. This trial is registered on ClinicalTrials.gov, NCT04501055. Findings: Between August 13, 2020, and July 20, 2022, 192 men were randomly assigned to perineal nerve block or periprostatic block, 96 per study group. Perineal nerve block was superior for the relief of pain during the biopsy procedure (mean 2.80 for perineal nerve block and 3.98 for periprostatic block; adjusted difference in means -1.17, P < 0.001). Although the perineal nerve block had a lower mean pain score at 1 h post-biopsy compared with the periprostatic block (0.23 vs 0.43, P = 0.042), they were equivalent at 6 h (0.16 vs 0.25, P = 0.389) and 24 h (0.10 vs 0.26, P = 0.184) respectively. For the change in vital signs during biopsy procedure, perineal nerve block was significantly superior to periprostatic block in terms of maximum value of systolic blood pressure, maximum value of mean arterial pressure and maximum value of heart rate. There are no statistical differences in average value of systolic blood pressure, average value of mean, average value of heart rate, diastolic blood pressure and breathing rate. Perineal nerve block was also superior to periprostatic block in external manifestations of pain (1.88 vs 3.00, P < 0.001) and anaesthesia satisfaction (8.93 vs 11.90, P < 0.001). Equivalence was shown for the detection rate of PCa (31.25% for perineal nerve block and 29.17% for periprostatic block, P = 0.753) or csPCa (23.96% for perineal nerve block and 20.83% for periprostatic block, P = 0.604). 33 (34.8%) of 96 patients in the perineal nerve block group and 40 (41.67%) of 96 patients in the periprostatic block group had at least one complication. Interpretation: Perineal nerve block was superior to periprostatic block in pain control for men undergoing a transperineal prostate biopsy. Funding: Grant 2019YFC0119100 from the National Key Research and Development Program of China.

Microendoscopy in vivo for the pathological diagnosis of cervical precancerous lesions and early cervical cancer.

BACKGROUND: Cervical cancer is an important public health problem. Conventional colposcopy is inefficient in the diagnosis of cervical lesions and massive biopsies result in trauma. There is an urgent need for a new clinical strategy to triage women with abnormal cervical screening results immediately and effectively. In this study, the high-resolution microendoscopy combined with methylene blue cell staining technology was used to perform real-time in vivo imaging of the cervix for the first time. METHODS: A total of 41 patients were enrolled in the study. All patients underwent routine colposcopy and cervical biopsy, and high-resolution images of methylene blue-stained cervical lesions were obtained in vivo using microendoscopy. The cell morphological features of benign and neoplastic cervical lesions stained with methylene blue under microendoscopy were analyzed and summarized. The microendoscopy and histopathology findings of the high-grade squamous intraepithelial lesion (HSIL) and more severe lesions were compared. RESULTS: The overall consistency of microendoscopy diagnosis with pathological diagnosis was 95.12% (39/41). Diagnostic cell morphological features of cervicitis, low-grade squamous intraepithelial lesion (LSIL), HSIL, adenocarcinoma in situ, and invasive cancer were clearly demonstrated in methylene blue stained microendoscopic images. In HSIL and more severe lesions, microendoscopic methylene blue cell staining technology can show the microscopic diagnostic features consistent with histopathology. CONCLUSIONS: This study was an initial exercise in the application of the microendoscopy imaging system combined with methylene blue cell staining technology to cervical precancerous lesions and cervical cancer screening. The results provided the basis for a novel clinical strategy for triage of women with abnormal cervical screening results using in vivo non-invasive optical diagnosis technology.

Screening of prognosis-related Immune cells and prognostic predictors in Colorectal Cancer Patients.

OBJECTIVE: To accurately screen potential immune cells that can predict the survival of colorectal cancer (CRC) patients and identify related prognostic predictors. METHODS: The sample data of CRC patients were downloaded from the GEO database as a training set to establish a prognosis-scoring model and screen prognosis-related immune cells. The sample data of CRC patients from the TCGA database were used as the validation set. Simultaneously, cancer tissue samples from 116 patients with CRC diagnosed pathologically in Shanghai Dongfang Hospital were collected to analyze the relationship of prognosis-related immune cells with patients' survival, and clinical and pathological parameters, and to screen prognostic predictors. RESULTS: Prognosis-related immune cells screened from GEO and TCGA databases mainly included Follicular Helper T cells (Tfh), Monocytes and M2 Macrophages. In the training set, the 2,000- and 4,000-day survival rates were 48.3% and 10.7% in the low-risk group (N = 234), and 42.1% and 7.5% in the high-risk group (N = 214), respectively. In the validation set, the 2,000- and 4,000-day survival rates were 34.8% and 8.6% in the low-risk group (N = 187), and 28.9% and 6.1% in the high-risk group (N = 246), respectively. The prognosis of patients in the high-risk group was worse than that in the low-risk group (P < 0.05). Furthermore, the screened primary prognostic predictors were CD163 and CD4 + CXCR5. CD163 protein expression was distributed in Monocytes and M2 Macrophages. The 1,000- and 2,000-day survival rates were 56.1% and 7.0% in the CD163 low-expression group, and 40.7% and 1.7% in the high-expression group (N = 214), respectively, showing a worse prognosis in the high-expression group than that in the low-expression group. Meanwhile, the immune marker CD4 + CXCR5 could identify Tfh. The 1,000- and 2,000-day survival rates were 63.9% and 5.6% in the CD4 + CXCR5 high-expression group, and 33.3% and 2.8% in the low-expression group (N = 214), respectively, with a better prognosis in the high-expression group than that in the low-expression group. CONCLUSION: Prognostic-related immune cells of CRC mainly include Tfh cells, Monocytes and M2 Macrophages. Monocytes and M2 Macrophages correlate negatively, while Tfh cells correlate positively with the prognosis of CRC patients. Immune markers CD163 and CD4 + CXCR5 can be considered as the prognostic predictors of CRC with clinical value of the application.

Development of a bridging ELISA for detection of antibodies against ZV0203 in cynomolgus monkey serum.

Immunogenicity has been a major concern in the safety evaluation of therapeutic proteins. The assessment of the unwanted immunogenicity of the therapeutic proteins performed in animals prior to clinical trials has been a regulatory requirement. In preclinical studies of therapeutic proteins, cynomolgus monkeys are usually the most relevant animal species. ZV0203, a recombinant humanized anti-human epidermal growth factor receptor 2 monoclonal antibody covalently bound to a cytotoxic drug (Duo-5), possesses a novel format of antibody drug conjugates. In this study, we reported the development, validation, and application of a bridging enzyme-linked immunosorbent assay for the detection of antibodies against ZV0203 in cynomolgus monkey serum. Drug interference at low positive control (18.0 ng/mL) and high positive control (130 ng/mL) of anti-ZV0203 antibodies was not observed when ZV0203 concentration is below 1.74 µg/mL and 1.49 µg/mL, respectively. In addition, no interference was found from mouse IgG1, but interference was observed with human IgG1. No effect of hemolysis was found on the analysis results of the testing samples present in 100% pooled rabbit serum containing 2% (V/V) erythrocyte hemolysates. Besides, spiked anti-ZV0203 antibody in rabbit serum was stable after 5 freeze/thaw cycles. The results showed that the method is suitable for the detection of anti-ZV0203 antibodies in cynomolgus monkey serum. The assay was also successfully applied in the repeated dose study of ZV0203.

Soil CO2 and N2O emissions and microbial abundances altered by temperature rise and nitrogen addition in active-layer soils of permafrost peatland.

Changes in soil CO2 and N2O emissions due to climate change and nitrogen input will result in increased levels of atmospheric CO2 and N2O, thereby feeding back into Earth's climate. Understanding the responses of soil carbon and nitrogen emissions mediated by microbe from permafrost peatland to temperature rising is important for modeling the regional carbon and nitrogen balance. This study conducted a laboratory incubation experiment at 15 and 20°C to observe the impact of increasing temperature on soil CO2 and N2O emissions and soil microbial abundances in permafrost peatland. An NH4NO3 solution was added to soil at a concentration of 50 mg N kg-1 to investigate the effect of nitrogen addition. The results indicated that elevated temperature, available nitrogen, and their combined effects significantly increased CO2 and N2O emissions in permafrost peatland. However, the temperature sensitivities of soil CO2 and N2O emissions were not affected by nitrogen addition. Warming significantly increased the abundances of methanogens, methanotrophs, and nirK-type denitrifiers, and the contents of soil dissolved organic carbon (DOC) and ammonia nitrogen, whereas nirS-type denitrifiers, ß-1,4-glucosidase (ßG), cellobiohydrolase (CBH), and acid phosphatase (AP) activities significantly decreased. Nitrogen addition significantly increased soil nirS-type denitrifiers abundances, ß-1,4-N- acetylglucosaminidase (NAG) activities, and ammonia nitrogen and nitrate nitrogen contents, but significantly reduced bacterial, methanogen abundances, CBH, and AP activities. A rising temperature and nitrogen addition had synergistic effects on soil fungal and methanotroph abundances, NAG activities, and DOC and DON contents. Soil CO2 emissions showed a significantly positive correlation with soil fungal abundances, NAG activities, and ammonia nitrogen and nitrate nitrogen contents. Soil N2O emissions showed positive correlations with soil fungal, methanotroph, and nirK-type denitrifiers abundances, and DOC, ammonia nitrogen, and nitrate contents. These results demonstrate the importance of soil microbes, labile carbon, and nitrogen for regulating soil carbon and nitrogen emissions. The results of this study can assist simulating the effects of global climate change on carbon and nitrogen cycling in permafrost peatlands.

MIR4435-2HG in exosomes promotes gastric carcinogenesis by inducing M2 polarization in macrophages.

Gastric cancer (GC) is a cancer with a high mortality rate. lncRNAs play a role in regulating GC tumorigenesis. In this paper, we analyzed differentially expressed lncRNAs between GC and adjacent normal tissues using multiple bioinformatics tools to identify new potential targets in GC. Cell viability and migration ability were detected using the Cell Counting Kit-8 (CCK-8) and transwell assays, MIR4435-2HG was negatively correlated with the survival rate of GC patients, and by inhibiting the activity of MIR4435-2HG, the viability and migration ability of GC cells could be reduced. In addition, RT- qPCR and western blot to detect gene and protein level expression, transmission electron microscopy and nanoparticle tracking analysis (NTA) to study the efficiency of exosome isolation, and flow cytometry to observe cell differentiation were employed, delivery of MIR4435-2HG shRNA via MKN45 cell-derived exosomes significantly reversed the MKN45 exosome-induced M2 polarization in macrophages. Furthermore, the low expression of MIR4435-2HG in MKN45 cell-derived exosomes inhibited the Jagged1/Notch and JAK1/STAT3 pathways in macrophages; MIR4435-2HG downregulated exosomes were found to significantly inhibit GC tumor growth in vivo by establishing a mouse model. In short, MKN45 cell-derived exosomes deliver lncRNA MIR4435-2HG, which promotes gastric carcinogenesis by inducing macrophage M2 polarization.

[Change in nitrogen availability of northern peatlands and its effect on carbon sink function]. / åŒ—æ–¹æ³¥ç‚­åœ°æ°®ç´ æœ‰æ•ˆæ€§çš„å˜åŒ–åŠå ¶å¯¹ç¢³æ±‡åŠŸèƒ½çš„å½±å“.

Northern peatlands are typical nitrogen-limited ecosystems, which are sensitive to global climate change and human activities. The increases of endogenous available nitrogen caused by climate warming and exogenous nitrogen input caused by human activities changed the nitrogen availability of northern peatlands, and would affect carbon and nitrogen cycling and carbon sink function of peatland. Here, we review the influence factors of carbon accumulation rate and carbon sink function in northern peatlands. The effects of nitrogen deposition, freezing and thawing, fire and other factors on nitrogen availability of northern peatlands were reviewed. The responses of plants and soil microorganisms to changes in nitrogen availability were elaborated from carbon fixation and carbon emission processes, respectively. The research related to carbon sink function of peat ecosystems under the influence of glo-bal change was prospected, aiming to help the implementation of the 'double carbon' goal.

Survival outcomes analysis according to mismatch repair status in locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy.

Background: The predictive role of mismatch repair (MMR) status for survival outcomes and sensitivity in neoadjuvant chemoradiotherapy settings for patients with locally advanced rectal cancer (LARC) has been inconclusive. Methods: A retrospective cohort of patients with LARC treated with neoadjuvant chemoradiotherapy (nCRT) was recruited. After adjusting for baseline characteristics, we used propensity score matching to reduce the effect of potential confounding factors on MMR status. The primary analysis was based on overall survival as the more important endpoint. Results: This study included 269 patients. Patients with defective MMR (dMMR) were younger (58.5% vs. 60.0%, p=0.0274) and had lower body mass indices (p=0.0091), higher differentiation grades (p=0.0889), and more advanced rectal cancers (clinical T4 or T4b, p=0.0851; M1, p=0.0055) than those with proficient MMR (pMMR). However, propensity score-matched patients with dMMR (p=0.0013) exhibited superior overall survival, even in the M1 subgroup. More importantly, patients with proficient MMR who undergo early pathological downstaging, especially lymph node pathological downstaging, can achieve a prognosis similar to that of patients with dMMR. Conclusion: The clinical significance of this retrospective study mainly includes two points: (1) Data from our study confirmed that LARC patients with dMMR status had better overall survival rates after nCRT, even in the M1 subgroup. (2) Similar survival outcomes were observed in older and female patients with early lymph node pathological downstaging, regardless of dMMR or pMMR.

Long-term nitrogen addition alters peatland plant community structure and nutrient resorption efficiency.

As an elemental carbon (C) and nitrogen (N) pool in the world, peatlands are very sensitive to environmental changes. Under global warming, the increase in available N affects the dynamic changes of plant community structure and nutrients in a permafrost peatland. This study was based on a long-term in situ N addition experiment that had been conducted for 9 years. It utilized the peatland in the permafrost area of Great Hing'an Mountain as the research object to analyze the effects of N addition on the growth characteristics, community structure, and nutrient dynamics of peatland plants. The N inputs were N1: 6 g N m-2·year-1, N2: 12 g N m-2·year-1 and N3: 24 g N m-2·year-1, respectively. Our results showed that the adding N can affect the plant community structure of peatland by affecting the plant growth characteristics. The diversity and richness of plant species in the peatland decreased as the concentration of added N increased. The long-term N addition can reduce the N limitation of plants to some extent. Still, it could further aggravate their phosphorus (P) limitation, resulting in the joint limitation of N and P or the complete limitation by P. The N resorption efficiency decreased with the increase of N addition level. The P resorption efficiency of different plants had varied responses to the changes in the N nutrient environment. Our study clarified the impact of long-term N addition on the plant community structure and nutrient dynamics of peatland in a permafrost area and provided an important theoretical basis to accurately evaluate the carbon and nitrogen balance of peatland in a permafrost area owing to future climate change.

Impact of visit-to-visit fasting plasma glucose variability on the development of diabetes: The mediation by insulin resistance.

BACKGROUND: Little is known about the risk of diabetes due to higher glycemic variability and the underlying mechanisms. We aimed to examine the association of visit-to-visit variability (VVV) in fasting plasma glucose (FPG) with incident diabetes in Chinese adults and whether the association was mediated by changes in insulin resistance (IR). METHODS: We included 1856 community residents without a history of diabetes and having attended 3 examinations in 2008, 2009, and 2013 respectively. The SD, the average successive variability (ASV), the coefficient of variation (CV), and the variability independent of the mean (VIM) of three recorded FPG measurements were calculated for each participant, and SD, ASV, CV, and VIM were used as a measure of VVV in FPG. Incident diabetes was defined according to the 1999 World Health Organization criteria. IR was evaluated using the homeostatic model assessment (HOMA). RESULTS: A total of 153 (8.2%) participants developed incident diabetes at the third visit. Compared with the lowest tertile (0-5.83 mg/dl) of FPG-SD, the highest tertile (9.55-74.17 mg/dl) was associated with a 148% increased risk of diabetes (odds ratio [OR], 2.48; 95% confidence interval [CI], 1.36-4.49), after adjustment for covariates including mean FPG at 3 visits. Mediation analyses suggested that changes in IR (ΔHOMA-IR) might mediate 17.3% of the association between increased FPG-SD and elevated diabetes risk. Similar results were found for FPG-CV, FPG-ASV, and FPG-VIM. CONCLUSIONS: The VVV in FPG was significantly associated with risks of diabetes in Chinese adults, which was partially mediated by changes in IR.