[Spatiotemporal Trends and Driving Factors of PM2.5-related Health Burden in Gansu Province, China from 2013 to 2020].

To evaluate the spatiotemporal trends and drivers of PM2.5-related health effects in Gansu Province since the implementation of the Air Pollution Prevention and Control Action Plan, the latest global exposure mortality model （GEMM） was adopted to estimate the health burden attributable to PM2.5 in Gansu Province from 2013 to 2020. The factor decomposition method was used to further quantify the main causes of the long-term changes in deaths attributable to PM2.5 pollution. The results showed that from 2013 to 2020, the population-weighted PM2.5 concentration in Gansu Province decreased by 34.57%, and the proportion of people exposed to areas with an annual average PM2.5 concentration exceeding 35 µg·m-3 decreased significantly from 72.89% to 11.61%. Moreover, the number of attributable deaths in Gansu Province declined from 12 826 （95%CI： 7 840-17 408） in 2 013 to 9 814 （95%CI： 6 407-13 036） in 2020, indicating a decrease of 23.48%. Attributable deaths from stroke, chronic obstructive pulmonary disease, lung cancer, and lower respiratory infection declined, whereas deaths from ischemic heart disease increased by 12.11%. Notably, individuals aged 60 years and older accounted for more than 80% of all age-related deaths. The number of deaths attributable to PM2.5 in central and eastern Gansu Province was significantly higher than that in the Hexi region, and most regions showed a downward trend. The contribution of the total population, age structure, baseline mortality rate, and PM2.5 concentration to the change in PM2.5-related deaths was -1.26%, 16.16%, -9.84%, and -28.55%, respectively. Overall, population aging and a decrease in PM2.5 concentration were the main factors contributing to the increase and decrease in PM2.5-related deaths, respectively. The active clean air policies in Gansu Province have reduced the health burden caused by PM2.5 pollution, but with the trend of population aging, a significant reduction in PM2.5 concentration will be needed in the future to avoid more attributable deaths.

Preoperative parent education and postoperative nurse-led care for boys versus routine hospital care for urethroplasty for hypospadias in Western China: a retrospective study.

Background/aim: Urethroplasty is the preferred treatment for hypospadias but is affected by the severity of anomalies, making it a complex procedure with potential postoperative complications. Following surgery, parents receive instructions and recommendations, whether from nurses or physicians, regardless of complication rates. However, nurses play a crucial role in educating caregivers before surgery and providing postoperative care during follow-up. The study aims to assess parents' knowledge and practices, as well as the frequency of complications in boys who underwent urethroplasty for hypospadias and received postoperative nurse-led care and whose parents received preoperative education against those of boys who underwent urethroplasty under routine hospital care. Materials and methods: In this retrospective study, Han Chinese boys aged 21-41 months in Western China who underwent urethroplasty for hypospadias were divided into two groups: the NI cohort (n = 103), where they received postoperative nurse-led care and their parents received preoperative education, and the RH cohort (n = 142), where boys underwent routine hospital care. Results: After urethroplasty, higher numbers of caregivers with satisfactory knowledge (96 (93%) vs. 80 (56%), p < 0.0001) and practice (102 (99%) vs. 132 (93%), p = 0.0276) were reported in the NI cohort compared to the RH cohort. Additionally, a higher number of boys in the RH cohort experienced adverse effects such as moderate bleeding (13 (9%) vs. 1 (1%), p = 0.0052), wound infection (17 (12%) vs. 4 (4%), p = 0.0356), urinary obstruction (35 (25%) vs. 10 (10%), p = 0.0049), burning sensation (47 (33%) vs. 15 (15%), p = 0.0019), and urinary stent fall (32 (23%) vs. 6 (6%), p = 0.0008) compared to those in the NI cohort. Conclusion: Preoperative instructions enhance caregivers' knowledge and practices following urethroplasty, while postoperative nurse-led care reduces immediate postoperative complications associated with hypospadias in boys.

VDR restores the expression of PINK1 and BNIP3 in TECs of streptozotocin-induced diabetic mice.

Defective mitophagy in renal tubular epithelial cells is one of the main drivers of renal fibrosis in diabetic kidney disease. Our gene sequencing data showed the expression of PINK1 and BNIP3, two key molecules of mitophagy, was decreased in renal tissues of VDR-knockout mice. Herein, streptozotocin (STZ) was used to induce renal interstitial fibrosis in mice. VDR deficiency exacerbated STZ-induced renal impairment and defective mitophagy. Paricalcitol (pari, a VDR agonist) and the tubular epithelial cell-specific overexpression of VDR restored the expression of PINK1 and BNIP3 in the renal cortex and attenuated STZ-induced kidney fibrosis and mitochondrial dysfunction. In HK-2 cells under high glucose conditions, an increased level of α-SMA, COL1, and FN and a decreased expression of PINK1 and BNIP3 with severe mitochondrial damage were observed, and these alterations could be largely reversed by pari treatment. ChIP-qPCR and luciferase reporter assays showed VDR could positively regulate the transcription of Pink1 and Bnip3 genes. These findings reveal that VDR could restore mitophagy defects and attenuate STZ-induced fibrosis in diabetic mice through regulation of PINK1 and BNIP3.

Hypomethylation-Mediated Upregulation of NFE2L3 Promotes Malignant Phenotypes of Clear Cell Renal Cell Carcinoma Cells.

This work aimed to study the effect of NFE2 like bZIP transcription factor 3 (NFE2L3) on clear cell renal cell carcinoma (ccRCC) cells and whether NFE2L3 expression was mediated by DNA methylation. Twenty-one ccRCC patients were collected. The gene methylation and expression data of TCGA-KIRC were accessed from TCGA. Candidate methylation driver genes were identified by "MethylMix" package, and finally, NFE2L3 was selected as the target gene. The methylation of NFE2L3 was assayed by Ms PCR and QMSP. mRNA level of NFE2L3 was analyzed by qRT-PCR. Protein level of NFE2L3 was measured by Western blot. Demethylation was performed with methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR). Proliferative, migratory, and invasive abilities of ccRCC cells were assayed via cell colony formation assay, scratch healing assay, and transwell assay, respectively. Analysis of TCGA database presented that DNA hypomethylation occurred in the NFE2L3 promoter region in ccRCC tissues. NFE2L3 was significantly upregulated in ccRCC tissues and cells. Its expression in cells treated with 5-Aza-CdR was proportional to the concentration of methylation inhibitor. In cell function experiments, overexpressing NFE2L3 or demethylation could stimulate proliferation, migration, and invasion abilities of ccRCC and normal cells. 5-Aza-CdR treatment rescued repressive impact of knockdown NFE2L3 on malignant phenotypes of ccRCC and normal cells. DNA hypomethylation could induce high expression of NFE2L3 and facilitate malignant phenotypes of ccRCC cells. These results may generate insights into ccRCC therapy.

A framework to validate fluorescently labeled DNA-binding proteins for single-molecule experiments.

Due to the enhanced labeling capability of maleimide-based fluorescent probes, lysine-cysteine-lysine (KCK) tags are frequently added to proteins for visualization. In this study, we employed an in vitro single-molecule DNA flow-stretching assay as a sensitive way to assess the impact of the KCK tag on the property of DNA-binding proteins. Using Bacillus subtilis ParB as an example, we show that, although no noticeable changes were detected by in vivo fluorescence imaging and chromatin immunoprecipitation (ChIP) assays, the KCK tag substantially altered ParB's DNA compaction rates and its response to nucleotide binding and to the presence of the specific sequence (parS) on the DNA. While it is typically assumed that short peptide tags minimally perturb protein function, our results urge researchers to carefully validate the use of tags for protein labeling. Our comprehensive analysis can be expanded and used as a guide to assess the impacts of other tags on DNA-binding proteins in single-molecule assays.

The optimal dose of oxycodone in PCIA after laparoscopic surgery for gastrointestinal cancer in elderly patients: A randomized controlled trial.

Objective: To explore the optimal bolus dose of oxycodone for patient controlled intravenous analgesia (PCIA) without background dose in elderly patients after laparoscopic surgery for gastrointestinal cancer. Methods: In this prospective, randomized, double-blind, parallel-controlled study, we recruited patients aged 65 years or older. They underwent laparoscopic resection for gastrointestinal cancer and received PCIA after surgery. Eligible patients were randomly divided into 0.01, 0.02, or 0.03 mg/kg group according to the bolus dose of oxycodone in PCIA. The primary outcome was VAS scores of pain on mobilization at 48 h after surgery. Secondary endpoints included the VAS scores of rest pain, the total and effective numbers of press in PCIA, cumulative dose of oxycodone used in PCIA, the incidence of nausea, vomiting and dizziness, as well as patients' satisfaction at 48 h after surgery. Results: A total of 166 patients were recruited and randomly assigned to receive a bolus dose of 0.01 mg/kg (n = 55), 0.02 mg/kg (n = 56) or 0.03 mg/kg (n = 55) of oxycodone in PCIA. The VAS scores of pain on mobilization, the total and effective numbers of press in PCIA in 0.02 mg/kg group and 0.03 mg/kg group were lower than those in 0.01 mg/kg group (P < 0.05). Cumulative dose of oxycodone used in PCIA and patients' satisfaction in 0.02 and 0.03 mg/kg groups were more than those in 0.01 mg/kg group (P < 0.01). The incidence of dizziness in 0.01 and 0.02 mg/kg groups was lower than that in 0.03 mg/kg group (P < 0.01). There were no significant differences in VAS scores of rest pain, the incidence of nausea and vomiting among three groups (P > 0.05). Conclusion: For elderly patients undergoing laparoscopic surgery for gastrointestinal cancer, 0.02 mg/kg bolus dose of oxycodone in PCIA without background infusion may be a better choice.

A novel near-infrared fluorescent probe for the imaging of viscosity in cells and tumor-bearing mice.

A near-infrared fluorescent probe (IC-V) for detecting viscosity is constructed. The probe has a large Stokes shift (170 nm) and an about 180-fold increase in fluorescence intensity at 700 nm. In addition, IC-V can not only distinguish cancer cells from normal cells, but also monitor viscosity in normal mice and tumor-bearing mice.

Preoperative ultrasound can accurately predict the diameter of double-stranded peroneus longus tendon autografts.

PURPOSE: This study aimed to determine the correlation between the intraoperative diameter of double-stranded peroneus longus tendon (2PLT) and length of the PLT autograft and preoperative ultrasound (US) measurements, as well as radiographic and anthropometric measurements. The hypothesis was that US can accurately predict the diameter of 2PLT autografts during operation. METHODS: Twenty-six patients underwent ligament reconstruction with 2PLT autografts were included. Preoperative US was used to calculate the in situ PLT cross-sectional area (CSA) at seven levels (0, 1, 2, 3, 4, 5, 10 cm proximal to the harvest start point). Femoral width, notch width, notch height, maximum patellar length, and patellar tendon length were determined on preoperative radiographs. Intraoperative measurements of PLT were made, including all fiber lengths of PLT and diameters of 2PLT using sizing tubes calibrated to 0.5 mm. RESULTS: CSA at 1 cm proximal to the harvest site had the highest correlation with the diameter of 2PLT (r = 0.84, P < 0.001). Calf length had the highest correlation with PLT length (r = 0.65, P < 0.001). The diameter of the 2PLT autografts could be predicted by the following formula: 4.6 + 0.2 × [sonographic CSA of PLT at 1 cm level]; the length of PLT could be predicted by the following formula: 5.6 + 0.5 × Calf length. CONCLUSION: The diameter of 2PLT and length of PLT autografts can be accurately predicted by preoperative US and calf length measurements, respectively. Accurate preoperative prediction of the diameter and length of autologous grafts can provide the most suitable and individualized graft for patients. LEVEL OF EVIDENCE: IV.

Clinical characteristics and prognostic characterization of endometrial carcinoma: a comparative analysis of molecular typing protocols.

BACKGROUND: Endometrial carcinoma (EC) is one of the most common gynecological malignancies in China and globally, accounting for the fourth-prevalent cancer in women. Although numerous studies have confirmed prognostic value of The Cancer Genome Atlas (TCGA) molecular subgroups, it is unclear how they are combined with histological features. The main objective of this study was to compare ProMisE and TCGA classification for the rapid and accurate prediction of prognosis within EC patients, together with the provision of a revised strategy for individualized diagnosis and treatment of patients. METHODS: Within this study, 70 patients with EC from Beijing Tsinghua Changgeng Hospital (affiliated to Tsinghua University) were retrospectively examined between July 2015 and December 2021. Samples were processed for determination of clinical markers, together with ProMisE and TCGA classification. RESULTS: Comparative analysis across four TCGA types (POLE, Low-CN, High-CN, and MSI-H) and age, was statistically significant (χ²= 7.000, p = 0.029). There was no significant difference observed among the four TCGA types and FIGO stage, vascular invasion and depth of invasion, or lymph node metastasis and tumor area. There was no significant association between the expression of Vimentin, Ki-67, PTEN, MSH2, PAX-8, ß-catenin, CD10, ER, PR, P16, MLH1, and PMS2 with the four TCGA types. In addition, p63 expression (χ²= 11.09, p = 0.029) and p53 expression (χ²= 11.585, p = 0.005) were statistically significant. Numerous models demonstrated that patients with POLE mutations and low-CN had higher progression free survival (PFS) and overall survival (OS), whereas those with high-CN had lowest values. The log-rank test revealed that the survival rate of PR-positive and ER-positive patients was significantly higher (p < 0.001). CONCLUSION: Overall, these results can be of additional benefit for clinical applications, in comparison to the ProMisE classification method. In addition, PR, ER, vascular infiltration, hyperlipidemia and atherosclerosis were found to be the key factors affecting EC prognosis.

Intraoperative dexmedetomidine use is associated with lower incidence of acute kidney injury after non-cardiac surgery.

BACKGROUND: Previous studies have shown that perioperative dexmedetomidine could reduce the incidence of postoperative AKI in cardiovascular surgery, however, its effectiveness in the non-cardiovascular surgery patient population has not been reported. The aim of this study was to investigate the effect of intraoperative dexmedetomidine on the incidence of postoperative AKI and postoperative ICU admissions in patients undergoing non-cardiovascular surgery. DESIGN AND SETTING: A single-center retrospective cohort study obtained from the database of the Center for Anesthesia and Surgery, the Third Xiangya Hospital. PATIENTS: Inpatients between 18 and 75 years of age who were admitted to our hospital for non-cardiovascular surgery from 2012 to 2019. RESULTS: Overall 2391 patients who used dexmedetomidine intraoperatively were analyzed in comparison to 4552 patients who did not use dexmedetomidine after one-to-two matching. The two cohorts had similar baseline values and demographic characteristics. The incidence of AKI was lower in patients with intraoperative dexmedetomidine use than in the nonuse group (OR 0.60, p < .001). The rate of severe renal failure needing dialysis was also lower than in the nonuse group (ß = -0.02, p < .05). After adjusting for confounding factors, the rate of AKI was still lower in the dexmedetomidine group. The rate of postoperative ICU admissions and in-hospital deaths were similar in the two groups (p > .05). CONCLUSION: For non-cardiovascular surgery patient population, intraoperative use of dexmedetomidine was associated with a lower incidence and less severity of postoperative AKI. However, there was no significant correlation with postoperative ICU occupancy or in-hospital mortality. Further prospective RCTs are needed in the future.

Using DNA flow-stretching assay as a tool to validate the tagging of DNA-binding proteins for single-molecule experiments.

Due to the enhanced labeling capability of maleimide-based fluorescent probes, lysine-cysteine-lysine (KCK) tags are frequently added to proteins for visualization. In this study, we employed in vitro single-molecule DNA flow-stretching assay as a sensitive way to assess the impact of the KCK-tag on the property of DNA-binding proteins. Using Bacillus subtilis ParB as an example, we show that, although no noticeable changes were detected by in vivo fluorescence imaging and chromatin immunoprecipitation (ChIP) assays, the KCK-tag substantially altered ParB's DNA compaction rates, its response to nucleotide binding and to the presence of the specific sequence (parS) on the DNA. While it is typically assumed that short peptide tags minimally perturb protein function, our results urge researchers to carefully validate the use of tags for protein labeling. Our comprehensive analysis can be expanded and used as a guide to assess the impacts of other tags on DNA-binding proteins in single-molecule assays.

Case report: A case of complete clinical response in a patient experiencing high microsatellite instability unresectable colon cancer being treated with a PD-L1 inhibitor after interstitial pneumonia.

Immune checkpoint inhibitors (ICI) have dramatically transformed the treatment landscape for metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) or high microsatellite instability (MSI-H). Envafolimab, a novel programmed death-1 ligand 1 (PD-L1) inhibitor, has been reported to be efficient and safe for the management of advanced MSI-H/dMMR solid tumors. Here, we report the case of a 35-year-old female patient with MSI-H/dMMR mCRC who was treated with envafolimab following mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) plus bevacizumab. While suffering from interstitial pneumonia after chemotherapy, the patient achieved a complete clinical response with the use of envafolimab without additional adverse events. Thus, PD-L1 inhibitors may be potential candidates for treating patients with MSI-H/dMMR mCRC.

Remimazolam Tosylate Combined with Low-Dose Propofol Improves Sedation and Safety in Hysteroscopy.

Background: Propofol is widely used for sedation of hysteroscopy. It can cause injection pain, respiratory depression, and hypotension. Remimazolam is a novel ultra-short-acting benzodiazepine. Clinical practice has found that the use of remimazolam alone often leads to body movement during hysteroscopy, which decreases the safety and comfort. Here this study is to investigate whether remimazolam combined with low-dose propofol can improve the sedation effect and safety of hysteroscopy. Patients and Methods: In this prospective, randomized, parallel-controlled trial, women (18 to 60 years) undergoing hysteroscopy were randomly assigned to receive propofol (Group P), remimazolam tosylate (Group R), or remimazolam tosylate plus propofol (Group RP). Intraoperative sedation depth was kept at the bispectral index (BIS) value of 40-60. 6 µg/kg alfentanil was used for analgesic before sedation. Intraoperative low pulse oxygen saturation (SpO2), body movement, injection pain, mean arterial pressure (MAP), heart rate (HR), and postoperative recovery time, dizziness, nausea and vomiting were recorded and compared. Results: From February to July 2022, 193 patients were recruited and randomly assigned to group P (n=64), group R (n=64), or group RP (n=65). There was no significant inter-group difference of the intraoperative BIS values. The incidence of low SpO2, injection pain, hypotension, and postoperative dizziness in group RP were less than that in group P, and had no significant difference from group R. The incidence of body movement in group RP was less than that in group R, and had no significant difference from group P. Postoperative recovery time of group RP was shorter than that of the other two groups. No significant inter-group difference in bradycardia, nausea and vomiting was observed. Conclusion: Remimazolam tosylate combined with low dose of propofol improved sedation and safety in hysteroscopy, and may be a more ideal sedative method for hysteroscopy.

Mining Potential Drug Targets and Constructing Diagnostic Models for Heart Failure Based on miRNA-mRNA Networks.

Heart failure (HF) is a globally prevalent cardiovascular disease, but effective drug targets and diagnostic models are still lacking. This study was designed to investigate effective drug targets and diagnostic models for HF in terms of miRNA targets, hoping to contribute to the understanding and treatment of HF. Using HF miRNA and gene expression profile data from the GEO database, we analyzed differentially expressed miRNAs/gene identification in HF using Limma and predicted miRNA targets by the online TargetScan database. Subsequently, gene set enrichment analysis and annotation were performed using WebGestaltR package. Protein-protein interactions were identified using the STRING database. The proximity of drugs to treat HF was also calculated and predicted for potential target therapeutic drug. In addition, further drug identification was performed by molecular docking. Finally, diagnostic models were constructed based on differential miRNAs. The GEO dataset was used to screen 66 differentially expressed miRNAs, incorporating 56 downregulated miRNAs and 10 upregulated miRNAs. The JAK-STAT signaling pathway, MAPK signaling pathway, p53 signaling pathway, Prolactin signaling pathway, and TGF-beta signaling pathway were enriched, as shown by KEGG enrichment analysis on the target genes. In addition, we found that 83 genes were upregulated and 92 genes were downregulated in HF patients vs. healthy individuals. Based on the inflammation-related score, hypoxia-related score, and energy metabolism-related score, we identified key miRNA-mRNA pairs and constructed an interaction network. Following that, TAP1, which had the highest expression and network connectivity in acute HF with crystal and molecular docking studies, was selected as a key candidate gene in the network. And the compound DB04847 was selected to produce a large number of favorable interactions with TAP1 protein. Finally, we constructed two diagnostic models based on the differential miRNAs hsa-miR-6785-5p and hsa-miR-4443. In conclusion, we identified TAP1, a key candidate gene in the diagnosis and treatment of HF, and determined that compound DB04847 is highly likely to be a potential inhibitor of TAP1. The TAP1 gene was also found to be regulated by hsa-miR-6785-5p and hsa-miR-4443, and a diagnostic model was constructed. This provides a new promising direction to improve the diagnosis, prognosis, and treatment outcome and guide more effective immunotherapy strategies of HF.

MicroRNA-204-5p Hampers the Malignant Progression of Clear Cell Renal Cell Carcinoma through GXYLT2 Downregulation.

INTRODUCTION: At present, the mortality rate of clear cell renal cell carcinoma (ccRCC) remains high. The development of biomarkers is conducive to the early diagnosis and treatment of cancer. This research aimed to explore the role of microRNA-204-5p and the downstream gene in ccRCC. METHODS: We used bioinformatics analysis and qRT-PCR for measurement of microRNA-204-5p, qRT-PCR, and Western blot for GXYLT2 mRNA and protein levels, respectively. We conducted in vitro experiments like CCK-8, colony formation, Transwell, wound healing, and cell cycle assays to assess the role of microRNA-204-5p and GXYLT2 in ccRCC. Besides, the target relationship of microRNA-204-5p and GXYLT2 was confirmed through dual-luciferase assay. RESULTS: This study disclosed that microRNA-204-5p was underexpressed in ccRCC cells and tissues, which was closely associated with prognosis of patients with ccRCC. Stable forced expression of microRNA-204-5p hindered malignant phenotypes of ccRCC cells. Further detection unfolded that micro-RNA-204-5p bound the 3'-UTR of GXYLT2 to repress its expression. Besides, forced expression of microRNA-204-5p restored the promoting impact of overexpression of GXYLT2 on malignant progression of ccRCC cells. CONCLUSION: These findings revealed the vital role of microRNA-204-5p and GXYLT2 in ccRCC progression, as well as the possibility of microRNA-204-5p in improving ccRCC prognosis and treatment.

Tribbles homolog 3 contributes to high glucose-induced injury in retinal pigment epithelial cells via binding to growth factor receptor-bound 2.

Diabetic retinopathy (DR) is the most typical complication of diabetes, which severely threatens sight. Tribbles homolog 3 (TRB3), a kind of pseudokinase, is discovered to be highly expressed in diabetes and retinas after retinal detachment. TRB3 expression in human retinal pigment epithelial (hRPE) cells exposed to different concentrations of glucose was tested by RT-qPCR and western blot. Then, cells were induced with 30 mM high glucose (HG) to establish a DR cell model. Following TRB3 knockdown, cell viability estimation employed CCK-8 assay. The mRNA levels of inflammatory factors were detected by RT-qPCR. Reactive oxygen species (ROS) level was measured by DCFH-DA assay, and levels of oxidative stress markers were evaluated applying corresponding kits. Cell apoptosis was assayed by TUNEL assay and western blot. Following, the growth factor receptor-bound 2 (GRB2) expression was also examined by RT-qPCR and western blot. The interaction between TRB3 and GRB2 was verified by Co-IP assay. After GRB2 was overexpressed in HG-induced hRPE cells transfected with shRNA-TRB3, functional experiments were conducted again. The results manifested that TRB3 expression was elevated under HG conditions. Deficiency of TRB3 enhanced the viability while alleviated inflammation, oxidative stress, and apoptosis in HG-induced hRPE cells. GRB2 was also increased in HG-exposed hRPE cells. Moreover, GRB2 had a strong affinity with TRB3 and positively regulated by TRB3. After GRB2 overexpression, the effects of TRB3 knockdown on HG-stimulated hRPE cells were all reversed. Briefly, this study confirmed the promoting role of TRB3/GRB2 axis in the progression of DR.

Second primary malignancies after ovarian cancer: A SEER-based analysis (1975-2016).

OBJECTIVE: To investigate the risk of occurrence of second primary malignancies (SPMs) in survivors of ovarian cancer (OC) using large data from the Surveillance, Epidemiology, and End Results (SEER) database. MATERIALS AND METHODS: Multiple primaries standardized incidence ratios (MP-SIRs) to calculate the risk of developing second primary malignancies after a diagnosis of ovarian cancer. RESULTS: Of our included 59,880 women with OC, 3972 cases (6.6%) developed 4495 s primary malignancies over an average follow-up period of 114.39 (±102.66) months. Overall, the risk of occurrence of second primary malignancies after a diagnosis of OC was greater than what would be expected for a reference US population (SIR = 1.05, 95%CI = 1.02-1.08, p-value < 0.05). The occurrence of second myeloid malignancies and second thyroid cancer were most notable across our latency periods. Among the most significant second primary malignancies by latency were malignancies of the appendix (SIR = 14.04, 95%CI = 5.65-28.93, p-value <0.05) at 2-11 months, the small intestine (SIR = 3.15, 95%CI = 1.76-5.2, p-value <0.05) at 12-59 months, and the urinary bladder (SIR = 1.63, 95%CI = 1.3-2.02, p-value <0.05) after 10 years of an OC diagnosis. CONCLUSION: Women with OC are at significant risk for the development of second primary malignancies across all sites, as compared to a reference US population, and may benefit from second primary malignancies site-specific screening post-diagnosis.

Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial.

BACKGROUND: Chemotherapy-related cognitive impairment (CRCI) is highly prevalent in patients with cancer and is associated with poor outcomes and quality of life. To date, the management of CRCI remains a clinical challenge. Herein, we aim to determine the preventive effects of probiotics on CRCI development and underlying mechanisms. METHODS: We conducted a randomised, double-blind and placebo-controlled trial (ChiCTR-INQ-17014181) of 159 patients with breast cancer and further investigated the underlying mechanism in a pre-clinical setting. From 2018 to 2019, patients with breast cancer (Stage I-III) who needed adjuvant chemotherapy were screened, enrolled and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) during chemotherapy. Their cognition, anxiety and depression were assessed with well-established assays; their plasma biomarkers, metabolites and faecal microbiota compositions were measured. In addition, the systemic effects of the metabolites found in the clinical trial on long-term potentiation, synapse injury, oxidative stress and glial activation were assessed in rats. RESULTS: Probiotics supplement significantly decreased the incidence of CRCI, improved the allover cognitive functions, changed the gut microbial composition and modulated nine plasma metabolite changes. Among these metabolites, p-Mentha-1,8-dien-7-ol, Linoelaidyl carnitine and 1-aminocyclopropane-1-carboxylic acid were negatively correlated with the occurrence of CRCI. Furthermore, probiotics supplement increased plasma p-Mentha-1,8-dien-7-ol in rats. Administration of exogenous p-Mentha-1,8-dien-7-ol significantly alleviated chemotherapy-induced long-term potentiation impairment, synapse injury, oxidative stress and glial activation in the hippocampus of rats. CONCLUSION: Our data indicated that probiotics supplement prevents the occurrence of CRCI in patients with breast cancer via modulating plasma metabolites, including p-Mentha-1,8-dien-7-ol. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-INQ-17014181) [http://www.chictr.org.cn/showproj.aspx?proj=24294].

Case report: Long-term clinical benefit of pyrotinib therapy following trastuzumab resistance in HER2-amplification recurrent mucinous ovarian carcinoma.

Advanced or recurrent mucinous carcinoma of the ovary minimally responds to current cytotoxic treatments and has a poor prognosis. Despite multimodal treatment with chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. Anti-HER2 therapy has been demonstrated to be an effective strategy for the treatment of HER2-positive breast cancer. However, the role of anti-HER2 therapy in ovarian cancer remains largely unknown. Here, we report the case of a young woman with FIGO Stage IIIc recurrent mucinous ovarian carcinoma (MOC) who developed trastuzumab resistance and disease progression following cross-treatment with trastuzumab combined with pertuzumab. HER2 amplification was discovered using next-generation sequencing (NGS). The patient then received bevacizumab, and pyrotinib (an irreversible HER2 antagonist) plus capecitabine treatment, and achieved a long-term clinical benefit for 22 months. Pyrotinib combined with bevacizumab is a potential treatment for MOC patients who are heavily pretreated and harbor a HER2 amplification. Our case may provide valuable treatment information for patients with advanced or recurrent MOC.

Vitamin D-VDR (vitamin D receptor) regulates defective autophagy in renal tubular epithelial cell in streptozotocin-induced diabetic mice via the AMPK pathway.

Diabetic nephropathy (DN) has become a major cause of end-stage renal disease, and autophagy disorder is implicated in the pathogenesis of DN. Our previous studies found that vitamin D (VD) and VDR (vitamin D receptor) played a renoprotective role by inhibiting inflammation and fibrosis. However, whether VD-VDR regulates autophagy disorders in DN remains unclear. In this study, we established a streptozotocin (STZ)-induced diabetic model in vdr knockout (vdr-KO) mice and VDR specifically overexpressed in renal proximal tubular epithelial cells (Vdr-OE) mice. Our results showed that paricalcitol (an activated vitamin D analog) or Vdr-OE could alleviate STZ-induced ALB (albumin) excretion, renal tubule injury and inflammation, while these were worsened in vdr-KO mice. Defective autophagy was observed in the kidneys of STZ mice, which was more pronounced in vdr-KO mice and could be partially restored by paricalcitol or Vdr-OE. In high glucose-induced HK-2 cells, defective autophagy and decreased PRKAA1/AMPK phosphorylation was observed, which could be partially restored by paricalcitol in a VDR-dependent manner. AMPK inhibitor abolished paricalcitol-induced autophagy activation, and AMPK activator restored the defective autophagy in high glucose-induced HK-2 cells. Furthermore, paricalcitol-mediated AMPK activation was abrogated by CAMKK2/CaMKKß inhibition, but not by STK11/LKB1 knockout. Meanwhile, paricalcitol rescued the decreased Ca2+ concentration induced by high glucose. In conclusion, VD-VDR can restore defective autophagy in the kidney of STZ-induced diabetic mice, which could be attributed to the activation of the Ca2+-CAMKK2-AMPK pathway in renal tubular epithelial cells.Abbreviations: ACTB/ß-actin: actin beta;AGE: advanced glycation end-products;AMPK: AMP-activated protein kinase;CAMKK2/CaMKKß: calcium-calmodulin dependent protein kinase kinase 2;CQ: chloroquine;DN: diabetic nephropathy;HG: high levels of glucose;KO: knockout;LG: low levels of glucose;MAP1LC3/LC3: microtubule associated protein 1 light chain 3;NOD2: nucleotide binding oligomerization domain containing 2;OE: overexpression;PAS: periodic acid Schiff; Pari: paricalcitol;PTECs: proximal renal tubule epithelial cells;RT: room temperature;SQSTM1/p62: sequestosome 1;STK11/LKB1: serine/threonine kinase 11;STZ: streptozotocin;TEM: transmission electron microscopy;VD: vitamin D;VDR: vitamin D receptor;WT: wild-type.