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To evaluate the safety and efficacy of transepithelial accelerated corneal crosslinking (CXL) for advanced keratoconus eyes with maximum keratometry (Kmax) values58 diopters (D).Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China.Prospective parallel control study.41 keratoconus eyes from 41 patients (mean age, 21.93 ± 5.48 years) who underwent transepithelial accelerated CXL were included prospectively. The enrolled eyes were divided into 2 groups according to their Kmax values (Group A, Kmax ≥58.0 D; Group B, Kmax58.0 D). The examinations including assessment of uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), corneal topography, and corneal endothelial cell density count were conducted preoperatively, at 1 day, 1 month, 3 months, 6 months, and 1 year postoperatively.All 41 eyes finished 1 year follow-up. No statistical difference was noted between the mean UDVA and CDVA in both groups throughout the follow-up duration. At 1-year postoperative follow-up, the CDVA increased by ≥2 lines in 45% (9/20) and 28.6% (6/21) eyes in Groups A and B, respectively. The mean preoperative Kmax in Groups A and B were 62.51 ± 3.34 D and 49.98 ± 4.32 D, respectively, and that at postoperative 1-year follow-up were 61.94 ± 4.11 D and 50.24 ± 4.72 D, respectively. The Kmax values of 30% (6/20) eyes in Group A and 4.8% (1/21) eyes in Group B decreased by more than 1 D. Deduction of flat K, steep K, mean K, and Kmax showed no significant difference between the 2 groups at 1-year postoperative follow-up. Moreover, 20% (4/20) and 23.8% (5/21) of eyes in Groups A and B, respectively, showed progress at postoperative 1-year follow-up.Transepithelial accelerated CXL can safely treat advanced keratoconus eyes with Kmax values ≥58.0 D with some extent of efficacy and has similar progressive rate as Kmax values58.0 D.

Background Hip fracture is common in older adults, and can cause severe post-fracture pain. Fascia iliaca nerve block has consequently been used for preoperative analgesia. Methods We performed a randomized, controlled, double-blind clinical trial and recruited older patients with hip fractures. These patients were randomized into two groups and received ultrasound-guided fascia iliaca compartment block using either the supra-inguinal approach (group F) or the classical approach (group C). Heart rate, blood pressure, and resting and exercising visual analog scales were recorded before the procedure and at 30 min, and 6, 12, and 24 h after completion of the procedure. We recorded the duration of the procedure—as well as complications such as bleeding, hypotension, and intractable vomiting; the sleep duration in a 24 h period was also documented. Results A total of 38 patients completed the trial, and we observed no differences in the baseline characteristics or pre-procedural measurements between the two groups. Compared with the patients in group C, patients in group F exhibited significantly lower exercising VAS scores at 6 and 12 h after the procedure, faster heart rates at 6 and 24 h after the procedure, a longer procedural duration, and a longer sleep duration. There were no differences in the frequencies of complications between the two groups. The percentages of patients who took oral analgesics and the numbers of medications consumed were also not different between the two groups. Conclusions The supra-inguinal FICB provided effective analgesia and improved exercise tolerance compared with the classical approach. Trial registration The trial was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2100045644, registration date: 2021 April 20).

Hydrogen sulfide (H2S), emerging as an important gaseous signal, has attracted more and more attention for its key role in chronic fatty liver diseases. However, lacking tools for H2S-specific in situ detection, the changes of endogenous hepatic H2S levels in the pathological progression of chronic liver diseases are still unclear. To this end, we adopted a strategy of combining molecular probe design and nanofunctionalization to develop a highly selective near-infrared (NIR) fluorescent probe, which allows in vivo real-time monitoring of hepatic H2S levels in the process of nonalcoholic fatty liver disease (NAFLD). As a proof of strategy demonstration, we first designed NIR molecular probes for H2S sensing through chemical design and probe screening and then loaded molecular probes into mesoporous silicon nanomaterials (MSNs) with surface encapsulation using poly(ethylene glycol) to construct a highly selective probe MSN@CSN@PEG, with significantly improved selectivity and photostability. Moreover, MSN@CSN@PEG exhibited high selectivity and sensitivity for endogenous H2S in cells and tumors in vivo, eliminating the interference of a high concentration of biothiols and sulfhydryl proteins. Furthermore, the probe was applied to in situ intravital imaging and systematic assessment of hepatic H2S levels in different stages of NAFLD for the first time, which may offer a promising tool for the future study of fatty liver diseases and other chronic liver diseases.

CD8+CD103+ tissue-resident memory T cells (TRMs) are involved in tumor immune response and linked to favorable clinical outcome in human cancer. However, the distribution, phenotype, functional properties and clinical relevance of these cells in gastric cancer (GC) remain elusive. Here, our data show that, in comparison to non-tumor tissues, the percentages of CD8+CD103+ TRMs in tumors are significantly decreased. Most tumor-infiltrating CD8+CD103+ TRMs are CD45RA−CCR7− effector-memory cells with higher PD-1 and 4-1BB expression than those from non-tumor tissues. Further, tumor-infiltrating CD8+CD103+ TRMs show impaired cytolytic capacity due to decreased granzyme B and perforin expression. Moreover, ex vivo PD-1 blockade could restore the cytolytic capacity of tumor-infiltrating CD8+CD103+ TRMs, and such anti-PD-1-mediated reinvigoration of CD8+CD103+ TRMs could be further enhanced by 4-1BB co-stimulation. Finally, lower levels of Tumor-infiltrating CD8+CD103+ TRMs are positively correlated with GC progression and poor patients’ survival. Our data suggest that restoring CD8+CD103+ TRM function by combining PD-1 blockade and 4-1BB co-stimulation may be a promising strategy for treating GC.

Background: We described the demographics, cancer subtypes, comorbidities, and outcomes of patients with a history of cancer and coronavirus disease 2019 (COVID-19). Second, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza. Methods: We conducted a cohort study using eight routinely collected health care databases from Spain and the United States, standardized to the Observational Medical Outcome Partnership common data model. Three cohorts of patients with a history of cancer were included: (i) diagnosed with COVID-19, (ii) hospitalized with COVID-19, and (iii) hospitalized with influenza in 2017 to 2018. Patients were followed from index date to 30 days or death. We reported demographics, cancer subtypes, comorbidities, and 30-day outcomes. Results: We included 366,050 and 119,597 patients diagnosed and hospitalized with COVID-19, respectively. Prostate and breast cancers were the most frequent cancers (range: 5%–18% and 1%–14% in the diagnosed cohort, respectively). Hematologic malignancies were also frequent, with non-Hodgkin's lymphoma being among the five most common cancer subtypes in the diagnosed cohort. Overall, patients were aged above 65 years and had multiple comorbidities. Occurrence of death ranged from 2% to 14% and from 6% to 26% in the diagnosed and hospitalized COVID-19 cohorts, respectively. Patients hospitalized with influenza (n = 67,743) had a similar distribution of cancer subtypes, sex, age, and comorbidities but lower occurrence of adverse events. Conclusions: Patients with a history of cancer and COVID-19 had multiple comorbidities and a high occurrence of COVID-19-related events. Hematologic malignancies were frequent. Impact: This study provides epidemiologic characteristics that can inform clinical care and etiologic studies.

BACKGROUND Enteric anastomotic (EA) bleeding is a potentially life-threatening surgical complication associated with enteric anastomosis during simultaneous pancreas and kidney transplantation (SPKT). AIM To investigate whether suture ligation (SL) for submucosal hemostasis during hand-sewn enteric anastomosis could decrease the morbidity of early EA bleeding in SPKT. METHODS We compared the outcomes of 134 patients classified into SL (n = 44) and no SL (NSL) groups (n = 90). This study adheres to the declarations of Istanbul and Helsinki and all donors were neither paid nor coerced. RESULTS During the first postoperative week, the EA bleeding rate in the SL group was lower than that in the NSL group (2.27% vs 15.56%; P = 0.021); no relationship was found between EA bleeding and donor age, mean pancreatic cold ischemia time, platelet count, prothrombin time international normalized rate, activated partial thromboplastin time, and thrombin time. Anastomotic leakage was observed in one case in the SL group at postoperative day (POD) 14 and in one case at POD 16 in the NSL group (P = 0.754). No significant difference was found between the two groups in the patient survival, pancreas graft survival, or kidney graft survival. CONCLUSION SL for submucosal hemostasis during hand-sewn enteric anastomosis in SPKT can decrease the morbidity of early EA bleeding without increasing the anastomotic leakage rate.

The aim of this study was to explore the optimal method of small-incision lenticule extraction (SMILE)-derived lenticules, subjected to long-term preservation using glycerol, under a range of temperatures, and using an array of dehydration agents.In total, 108 myopic lenticules were collected from patients undergoing the SMILE procedure. Fresh lenticules served as a control group for this study, whereas all other lenticules were separated into 8 groups, which were preserved at 4 different temperatures (room temperature [RT], 4, -20, and -80°C) with or without silica gel in anhydrous glycerol. Evaluated parameters included thickness, transmittance, hematoxylin and eosin staining, transmission electron microscopy, and immunohistochemistry analyses.After a 3-month preservation period, lenticular thickness in these different groups was significantly increased, particularly for samples stored at RT. The mean percentage transmittance of lenticules stored at -80°C with or without silica gel was closest to that of fresh lenticules. Hematoxylin and eosin staining revealed sparsely arranged collagen fibers that were more scattered in preserved lenticules relative to fresh lenticules, particularly in RT samples. Transmission electron microscopy revealed that the fibril bundles densities in lenticules stored at RT were significantly less than those stored at other temperatures. Immunohistochemistry analyses revealed reductions in or loss of CD45 and human leukocyte antigens in all preserved lenticules relative to control samples.Of the tested approaches, the preservation of SMILE-derived lenticules over a 3-month period was optimal at -80°C with or without silica gel in anhydrous glycerol.

Osteoporosis, a noteworthy age-related disease induced by imbalanced osteogenesis and osteoclastogenesis, is a serious economic burden on both individuals and society. Small molecule drugs with dual effects on both bone resorption and mineralization are pressingly needed. Secreted frizzled-related protein 1 (SFRP1), a well-known extracellular repressor of canonical Wnt signaling, has been reported to regulate osteogenesis. Global SFRP1 knockout mice show significantly elevated bone mass. Although osteoclasts (OCs) express and secrete SFRP1, the role of SFRP1 produced by OCs in osteoclastogenesis and osteoporosis remains unclear. In this work, the levels of SFRP1 were found to be increased in patients with osteoporosis compared with healthy controls. Pharmacological inhibition of SFRP1 by WAY-316606 (WAY)- attenuated osteoclastogenesis and bone resorption in vitro. The expressions of OC-specific genes were suppressed by the SFRP1 inhibitor, WAY. Mechanistically, both extracellular and intracellular SFRP1 could block activation of the canonical Wnt signaling pathway, and WAY reverse the silent status of canonical Wnt through dual effects, leading to osteoclastogenesis inhibition and osteogenesis promotion. Severe osteopenia was observed in the ovariectomized (OVX) mouse model, and WAY treatment effectively improved the OVX-induced osteoporosis. In summary, this work found that SFRP1 supports OC differentiation and function, which could be attenuated by WAY through dual modulation of canonical Wnt signaling, suggesting its therapeutic potential. © 2021 American Society for Bone and Mineral Research (ASBMR).

Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC., Circulating tumor cell (CTC) clusters are more efficient at mediating metastasis as compared to single cells and are associated with poor prognosis in breast cancer. Here, the authors show that ICAM1 is enriched in CTC clusters and its loss suppresses cell-cell interaction and CTC cluster formation, and propose ICAM1 as a therapeutic target for treating breast cancer metastasis.

Perioperative neurocognitive disorders (PNDs) refer to cognitive decline identified in the preoperative or postoperative period. It has been reported that the incidence of postoperative neurocognitive impairment after noncardiac surgery in patients older than 65 at 1 week was 25.8∼41.4%, and at 3 months 9.9∼12.7%. PNDs will last months or even develop to permanent dementia, leading to prolonged hospital stays, reduced quality of life, and increased mortality within 1 year. Despite the high incidence and poor prognosis of PNDs in the aged population, no effective clinical prediction model has been established to predict postoperative cognitive decline preoperatively. To develop a clinical prediction model for postoperative neurocognitive dysfunction, a prospective observational study (Clinical trial registration number: ChiCTR2000036304) will be performed in the Shanghai General Hospital during January 2021 to October 2022. A sample size of 675 patients aged >65 years old, male or female, and scheduled for elective major noncardiac surgery will be recruited. A battery of neuropsychological tests will be used to test the cognitive function of patients at 1 week, 1 month, and 3 months postoperatively. We will evaluate the associations of PNDs with a bunch of candidate predictors including general characteristics of patients, blood biomarkers, indices associated with anesthesia and surgery, retinal nerve-fiber layer thickness, and frailty index to develop the clinical prediction model by using multiple logistic regression analysis and least absolute shrinkage and the selection operator (LASSO) method. The k-fold cross-validation method will be utilized to validate the clinical prediction model. In conclusion, this study was aimed to develop a clinical prediction model for postoperative cognitive dysfunction of old patients. It is anticipated that the knowledge gained from this study will facilitate clinical decision-making for anesthetists and surgeons managing the aged patients undergoing noncardiac surgery.

BACKGROUND AND AIMS Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma. APPROACH AND RESULTS Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P

While morphine has long been widely used in treating acute heart failure (AHF) due to its vasodilatory properties and anticipated anxiolysis, it remains unclear whether the application of morphine to those patients is reasonable. We aim to conduct a systematic review and meta‐analysis to assess the safety of morphine in patients with AHF. We searched PubMed, Cochrane Library, and Embase electronic databases from inception through March 2020. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the outcomes. Seven studies with 172, 226 patients were included. The results showed that morphine usage was not associated with increased in‐hospital mortality (OR: 1.94; 95% CI 0.93 to 4.03; p = 0.08). However, the use of morphine significantly increased the risk of invasive ventilation (OR: 2.72; 95% CI 1.09 to 6.80; p = 0.03). Furthermore, the subgroup analysis indicated that the application of morphine was not associated with increased 7‐day all‐cause mortality in patients with AHF (OR: 1.69; 95% CI 0.80 to 3.22; p = 0.11) but significantly increased the risk of 30‐day all‐cause mortality (OR: 1.59; 95% CI 1.16 to 2.17; p = 0.004). Based on current evidence, our results suggested that although morphine therapy did not significantly increase the risk of short‐term death (in the hospital or within 7 days) in patients with AHF, the risk of long‐term death and invasive ventilation were significantly increased. This result needs to be further confirmed by an ongoing randomized control trial.

Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We identified ubiquitin-activating enzyme 1 (UBA1) inhibitor TAK-243 that can strongly induce UPR in GBM cells. In this study, we evaluated the functional activity and mechanism of TAK-243 in preclinical models of GBM. TAK-243 significantly inhibited the survival, proliferation, and colony formation of GBM cell lines and primary GBM cells. It also revealed a significant anti-tumor effect on a GBM PDX animal model and prolonged the survival time of tumor-bearing mice. Notably, TAK-243 more effectively inhibited the survival and self-renewal ability of glioblastoma stem cells (GSCs) than GBM cells. Importantly, we found that the expression level of GRP78 is a key factor in determining the sensitivity of differentiated GBM cells or GSCs to TAK-243. Mechanistically, UBA1 inhibition disrupts global protein ubiquitination in GBM cells, thereby inducing ER stress and UPR. UPR activates the PERK/ATF4 and IRE1α/XBP signaling axes. These findings indicate that UBA1 inhibition could be an attractive strategy that may be potentially used in the treatment of patients with GBM, and GRP78 can be used as a molecular marker for personalized treatment by targeting UBA1.

Hepatocellular carcinoma is a highly fatal disease and threatens human health seriously. Fluid shear stress (FSS), which is caused by the leakage of plasma from abnormally permeable tumor blood vessels and insufficient lymphatic drainage, has been identified as contributing pathologically to cancer metastasis. Autophagy and epithelial-mesenchymal transition (EMT) are both reported to be involved in cancer cell migration and invasion, but little has been revealed about the interaction between autophagy and EMT under a tumor mechanical microenvironment. Here, we identified that exposure to 1.4 dyne/cm2 FSS could promote the formation of autophagosomes and significantly increase the expressions of autophagy-related markers of beclin1 and ATG7, and the ratio of LC3Ⅱ/Ⅰ in both of HepG2 and QGY-7703 cells. The FSS loading also elevated the levels of mesenchymal markers N-cadherin, Vimentin, Twist, Snail, and β-catenin, while the epithelial markers E-cadherin showed a decrease. Once the autophagy was blocked by 3-methyladenine (3-MA) or knocking ATG5 down, the occurrence of FSS-induced EMT was inhibited dramatically according to the expression and translocation of E-cadherin, N-cadherin, and β-catenin. Given the effect of EMT on cell migration, we observed that inhibition of autophagy could impede FSS-induced cell migration. Collectively, this study demonstrated that autophagy played a crucial role in FSS-induced EMT and cell migration in hepatocellular carcinoma.

Purpose: The current stratification system for acute promyelocytic leukemia (APL) is based on the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. However, the borderlines among different risk groups are sometimes ambiguous, and for some patients, early death and relapse remained challenges. Besides, with the evolving of the treatment strategy from all-trans-retinoic acid (ATRA) and chemotherapy to ATRA–arsenic trioxide-based synergistic targeted therapy, the precise risk stratification with molecular markers is needed. Experimental Design: This study performed a systematic analysis of APL genomics and transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial (NCT01987297) to illustrate the potential molecular background of Sanz score and further optimize it. The least absolute shrinkage and selection operator algorithm was used to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score). Results: Through combining NRAS mutations, APL9 score, and WBC, 321 cases can be stratified into two groups with significantly different outcomes. The estimated 5-year overall (P = 0.00031), event-free (P < 0.0001), and disease-free (P = 0.001) survival rates in the revised standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be validated using The Cancer Genome Atlas dataset. Conclusions: We have proposed a two-category system for improving prognosis in patients with APL. Molecular markers identified in this study may also provide genomic insights into the disease mechanism for improved therapy.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Background: Bioinformatics showed that long non-coding RNA (lncRNA) pgm5-as1 was regulated in patients with colorectal cancer (CRC), and miR-484 was also regulated in CRC. We aimed at determining t...

Background The most effective treatment for advanced cirrhosis and portal hypertension is liver transplantation (LT). However, splenomegaly and hypersplenism can persist even after LT in patients with massive splenomegaly. Aim To examine the feasibility of performing partial splenectomy during LT in patients with advanced cirrhosis combined with severe splenomegaly and hypersplenism. Methods Between October 2015 and February 2019, 762 orthotopic LTs were performed for patients with end-stage liver diseases in Tianjin First Center Hospital. Eighty-four cases had advanced cirrhosis combined with severe splenomegaly and hypersplenism. Among these patients, 41 received partial splenectomy during LT (PSLT group), and 43 received only LT (LT group). Patient characteristics, intraoperative parameters, and postoperative outcomes were retrospectively analyzed and compared between the two groups. Results The incidence of postoperative hypersplenism (2/41, 4.8%) and recurrent ascites (1/41, 2.4%) in the PSLT group was significantly lower than that in the LT group (22/43, 51.2%; 8/43, 18.6%, respectively). Seventeen patients (17/43, 39.5%) in the LT group required two-stage splenic embolization, and further splenectomy was required in 6 of them. The operation time and intraoperative blood loss in the PSLT group (8.6 ± 1.3 h; 640.8 ± 347.3 mL) were relatively increased compared with the LT group (6.8 ± 0.9 h; 349.4 ± 116.1 mL). The incidence of postoperative bleeding, pulmonary infection, thrombosis and splenic arterial steal syndrome in the PSLT group was not different to that in the LT group, respectively. Conclusion Simultaneous PSLT is an effective treatment and should be performed in patients with advanced cirrhosis combined with severe splenomegaly and hypersplenism to prevent postoperative persistent hypersplenism.

The purpose of this study was to analyze the acute effect of ambient temperature on hospitalization due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD), stroke, and myocardial infarction (MI) in Shenyang, China. We used the distributed delayed nonlinear model to evaluate the impact of ambient temperature on respiratory and cardiovascular diseases. The study population was divided into four groups: < 65 group and ≥ 65 age groups, female and male groups. The < 65 age group of AECOPD patients was more likely to be affected by high ambient temperature, while the ≥ 65 age group of AECOPD patients was more sensitive to low ambient temperature. The hospitalization risk of MI admission increased in the ≥ 65 age group at 1–8 days delay under low ambient temperature conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s11356-020-11934-2.

Objectives Microwave ablation (MWA) is used for the treatment of severe secondary hyperparathyroidism (SHPT), but its efficacy and safety still remained unclear. This study aimed to investigate the efficacy and safety of ultrasound (US)-guided MWA in patients with SHPT. Methods The PubMed, Cochrane library, Embase, China national knowledge infrastructure (CNKI) and Wanfang databases were searched to identify published studies that evaluated the efficacy and safety of US-guided MWA in patients with SHPT. The primary outcomes were parathyroid hormone (PTH), serum calcium and phosphorus levels. Results A total of 26 studies with 932 patients were identified. The PTH levels showed significant reduction at 1 month [weighted mean difference (WMD) = 945.33, 95% CI: 797.15∼1093.52] and 6 months (WMD = 1,151.91, 95% CI: 990.93∼1312.89) after MWA of SHPT patients. The serum calcium (WMD = 0.39, 95% CI: 0.30 ∼ 0.48) and phosphorus levels (WMD = 0.64, 95% CI: 0.43 ∼ 0.85) showed significant reduction at 6 months after MWA of SHPT patients. The most common complications observed were hypocalcemia (35.2%) and transient hoarseness (9.2%). No other major complications or death occurred in our study patients. Conclusion These findings suggest MWA as a safe and effective minimally invasive technique for the management of SHPT. PTH, calcium, and phosphorus levels were significantly reduced at 1 and 6 months after MWA.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye., Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.

Purpose. To compare the corneal biomechanical properties between post-LASIK ectasia and primary keratoconus. Methods. A total of 42 eyes of 42 patients with matching age and central corneal thickness (CCT) were divided into two groups according to diagnosis of post-LASIK ectasia (PLE group; n = 21; age range: 22–47 years) and primary keratoconus (KC group; n = 21; age range: 21–47 years). The corneal biomechanical properties were assessed using Scheimpflug-based technology (Corvis ST; Oculus Optikgeräte, Wetzlar, Germany). The paired t-test and linear regression analysis were performed. Results. The PLE group had significantly higher mean stiffness parameter at the first applanation (SP-A1; 76.65 ± 21.66 vs 52.72 ± 13.65, p ≤ 0.001 ) and mean stress-strain index (SSI) (SSI: 0.78 ± 0.16 versus 0.64 ± 0.12, p = 0.001 ) than the KC group. SP-A1 was positively correlated with CCT in the PLE group (Pearson’s r = 0.816, p ≤ 0.001 ), but not in the KC group (Pearson’s r = −0.014, p = 0.952 ). No statistical correlation was observed between SSI and CCT in either group (Pearson’s r = 0.292, p = 0.199 , and Pearson’s r = 0.004, p = 0.985 , respectively). Conclusions. In our case series, KC manifested more severe than PLE in biomechanical properties. Since SSI measurements were independent of corneal thickness, it can be used for corneal biomechanical assessment.

Background Hereditary multiple exostoses (HME), a rare genetic pediatric disorder, has a peculiar pathogenic mechanism. The results of previous studies have shown that HME is associated with mutations of the EXT1 and EXT2 genes at a molecular genetics level. In our study, two families who received therapy in the Department of Orthopedics of Shanghai Children's Hospital between June, 2017 and November, 2018 were recruited, and a mutational analysis of the EXT1 genes was conducted to further elucidating the relationship between HME and EXT1. Methods Venous blood samples were collected from individuals with HME and their families. Exon sequencing and RT-PCR were performed to comprehensively analyze 11 exons of the EXT1 gene. Results The deletion of exon 7 and the 2397 G>T mutation in exon 7 caused deletion mutation and nonsense mutation only in the HME patients. The mutations in exon 7 were tested and verified by Sanger sequencing. RT-PCR showed that the mRNA expression of EXT1 was significantly decreased in the mutation samples compared with the normal samples, which exerted a great influence on the function of EXT1. Conclusions This study identified new mutation sites for the pathogenesis of HME and further clarified the relationship between HME and EXT1.

The ‘publish or perish’ system has been widespread in the global higher education sector to incentivize academic performance. How the system affects academics in non-western countries has received ...

Objective The objective of this study was to evaluate the outcomes of open surgery (OS) and endovascular surgery (ES) for extracranial carotid aneurysm (ECCA) in the authors' centre. Methods Fifty-seven consecutive patients who were diagnosed with ECCA and underwent intervention from January 2005 to July 2019 at Zhongshan Hospital, Fudan University, were reviewed retrospectively. Patient characteristics and surgical outcomes for OS and ES were analysed. ECCAs were divided into three morphological subgroups: subgroup Ⅰ, no severe tortuosity of the internal carotid artery (ICA) or common carotid artery (CCA) proximal to the aneurysm, tortuosity of the aneurysm and 1 cm of peri-aneurysmal carotid artery ≤ 90°; subgroup Ⅱ, severe ICA or CCA tortuosity proximal to the aneurysm, tortuosity of the aneurysm and 1 cm of peri-aneurysmal carotid artery ≤ 90°; subgroup Ⅲ, aneurysm tortuosity and 1 cm peri-aneurysmal carotid artery > 90°. Results 35 patients underwent OS, 20 patients underwent ES and 2 patients underwent OS after the failure of ES. Thirty-six cases were classified in subgroup Ⅰ, 11 cases in subgroup Ⅱ, and 10 cases in subgroup Ⅲ. ES was achieved successfully in all 18 cases of subgroup I, but failed in three of four cases in subgroups Ⅱ and Ⅲ. With a mean duration of 62.9 ± 44.5 months of follow up, five deaths were recorded in the OS group, two of which were caused by ipsilateral stroke and three were not neurologically related. There was no stroke or death in the ES group during follow up. One case of stroke and two cases of death occurred in symptomatic patients, while one case of stroke and three cases of death occurred in asymptomatic patients. Conclusion This series demonstrates that ES may be a safe and durable option for ECCA in subgroup Ⅰ, while in subgroups Ⅱ and Ⅲ, ES alone may be difficult to apply. A 30 day stroke rate around 5% existed in ECCAs with interventions, which should be considered before the intervention.

Background and aims The proinflammatory cytokine IL-1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1β promotes liver injury in these diseases is unclear, as no IL-1β receptor-linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy's function in hepatotoxicity from proinflammatory cytokines. Approach and results AML12 cells with decreased autophagy from a lentiviral autophagy-related 5 (Atg5) knockdown were resistant to toxicity from TNF, but sensitized to death from IL-1β, which was markedly amplified by TNF co-treatment. IL-1β/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin-1s to prevent death. IL-1β/TNF depleted autophagy-deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL-1β/TNF-induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy-deficient cells. Mice with a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were similarly sensitized to cathepsin-dependent hepatocellular injury and death from IL-1β/TNF in combination, but neither IL-1β nor TNF alone. Knockout mice had increased hepatic inflammation, and IL-1β/TNF-treated, autophagy-deficient AML12 cells secreted exosomes with proinflammatory damage-associated molecular patterns. Conclusions The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL-1β/TNF-induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage-associated molecular patterns.

After half a century of development, auxiliary liver transplantation (ALT) technology gradually matured and major indications of ALT have been gradually expanded. This review summarized the history of ALT and introduced indications for ALT which including metabolic liver disease, fulminant hepatic failure, highly sensitized kidney transplantation, prevention of hepatic resection of small hepatic syndrome, etc.; at the same time, the hot issues related to ALT were discussed, including the regulation of hepatic portal blood flow of transplanted liver and residual liver, how to treat the graft liver and remaining liver on second stage. Additionally, the expansion of indications for ALT which included the implementation of ALT for patients with liver cancer and ALT for patients with liver cirrhosis was discussed. It was believed that ALT can greatly alleviate the contradiction of insufficient source of graft liver.

As a result of the limited therapeutic options, advanced cervical cancer is difficult to treat, making the prognosis poor. Therefore, new therapeutic modalities or combinations need to be explored. We herein reported a case of stage IVB cervical cancer which was irresponsive to chemotherapy alone. Based on previous studies and after patient's consent was obtained, we made a therapeutic plan: chemotherapy (albumin-bound paclitaxel and carboplatin) combined with immunotherapy (PD-1 inhibitor pembrolizumab). After 6 cycles of combined treatment, the patient got almost complete resolution with slight advent event. The treatment was further supported by local radiotherapy combined with immunotherapy. During the treatment period, disease was relatively stable, but the patient suffered severe grade 4 myelosuppression. We were therefore left with no other choice than to interrupt both chemotheraphy and radiotherapy. Before long, the tumor grew explosively again. These guided us to conclude that the combination use of albumin-bound paclitaxel (nab-paclitaxel) and carboplatin and pembrolizumab is effective and well tolerated in the treatment of advanced cervical cancer. The combined use of radiotherapy and pembrolizumab may also be effective. However, the combination use of chemotherapy, radiotherapy and immunotherapy in advanced cancer has not been well studied, and there are still many unsolved queries.

Cervical cancer (CC) is a malignant tumor that could seriously endanger women's life and health, of which cervical squamous cell carcinoma (CESC) accounts for more than 80%. High-risk human papillomavirus (HR-HPV) infection is the primary cause of CC. The 5-year survival rate is low due to poor prognosis. We need to explore the pathogenesis of CC and seek effective biomarkers to improve prognosis. The purpose of this research is to construct an HR-HPV-related long non-coding RNA (lncRNA) signature for predicting the survival and finding the biomarkers related to CC prognosis. First, we downloaded the CESC data from The Cancer Genome Atlas (TCGA) database to find HR-HPV-related lncRNAs in CC. Then, the differentially expressed lncRNAs were analyzed by univariate and multivariate Cox regression. Six lncRNAs were found to be associated with the prognosis and can be used as independent prognostic factors. Next, based on these prognostic genes, we established a risk score model, which showed that patients with higher score had poorer prognosis and higher mortality. Moreover, the Kaplan-Meier curve of the model indicated that the model was statistically significant (

Dengue fever has been attracting more attention in recent years. Dengue fever is mainly transmitted to humans by the Aedes albopictus mosquito and disease patterns are influenced by its wide distribution and high density during the summer season in China. Dengue epidemics in central China previously occurred exclusively in rural areas, while these recent outbreaks mostly occurred in urban areas in southern China. Until now, the presence of Aedes Albopictus in central China has been scarcely acknowledged. This study is a survey of Aedes and attempts to clarify this new distribution pattern using the Breteau Index (BI) method and a polylactic-glycolic acid (PLGA) copolymer mosquito trap simultaneously in urban and rural areas. The BI can provide a direct value on Aedes density compared to CI. Rural areas are at a higher risk for dengue compared to urban areas in central China. Our findings provide a basis for the prevention and control of dengue vectors, as well as providing information for control strategies for other infectious diseases transmitted by Aedes mosquitoes. Vector control strategy related to the management of diseases transmitted by Aedes should be based on the distribution patterns of different vector species, particularly in the rural environments in central China.

AIM: To evaluate the anatomic and visual outcomes of 25-gauge vitrectomy combined with air tamponade for the treatment of idiopathic macular hole (IMH). METHODS: Thirty eyes of 27 patients with IMH were included in this prospective interventional study. All patients underwent 25-gauge pars plana vitrectomy (PPV) combined with phacoemulsification and air tamponade. Best corrected visual acuity [BCVA; logarithm of the minimum angle of resolution (logMAR)], perimetry and multifocal electroretinography (mfERG) were conducted before and after the operation. Anatomical changes were evaluated with optical coherence tomography (OCT). RESULTS: The macular holes closed successfully in 28 eyes after the primary vitrectomy. The mean BCVA improved from 0.72±0.22 logMAR preoperatively to 0.29±0.18 logMAR postoperatively (P

BACKGROUND: Loss of graft function after liver transplantation (LT) inevitably requires liver retransplant. Retransplantation of the liver (ReLT) remains controversial because of inferior outcomes compared with the primary orthotopic LT (OLT). Meanwhile, if accompanied by vascular complications such as arterial and portal vein (PV) stenosis or thrombosis, it will increase difficulties of surgery. We hereby introduce our center's experience in ReLT through a complicated case of ReLT. CASE SUMMARY: We report a patient who suffered from hepatitis B-associated cirrhosis and underwent LT in December 2012. Early postoperative recovery was uneventful. Four months after LT, the patient’s bilirubin increased significantly and he was diagnosed with an ischemic-type biliary lesion caused by hepatic artery occlusion. The patient underwent percutaneous transhepatic cholangial drainage and repeatedly replaced intrahepatic biliary drainage tube regularly for 5 years. The patient developed progressive deterioration of liver function and underwent liver re-transplant in January 2019. The operation was performed in a classic OLT manner without venous bypass. Both the hepatic artery and PV were occluded and could not be used for anastomosis. The donor PV was anastomosed with the recipient’s left renal vein. The donor hepatic artery was connected to the recipient’s abdominal aorta. The bile duct reconstruction was performed in an end-to-end manner. The postoperative process was very uneventful and the patient was discharged 1 mo after retransplantation. CONCLUSION: With the development of surgical techniques, portal thrombosis and arterial occlusion are no longer contraindications for ReLT.

Endometrial cancer (EC) is one of the three major malignant tumors of the female reproductive system in developed countries. In recent years, the incidence of EC ranks first in gynecological malignancy and the mainstay of treatment is Surgery. Although EC has a high prevalence, its several features associated with management are still unclear. Endometrial cancer lymph node status is the most important predictor of survival and also guides postoperative treatment planning but in gynecologic oncology, lymphadenectomy, as a part of initial surgical management remains controversial. The current introduction of sentinel lymph node mapping in EC patients represents a midway between the execution and omission of node dissection. Sentinel lymph node (SLN) mapping has emerged as an alternative staging strategy hence, the role of SLN mapping is currently being evaluated prospectively in several centers. The objective of this review is to provide an update of the emerging role of sentinel node mapping in EC. In this review, we discussed how several different techniques, type of tracers utilized and injection sites has been described and used for lymphatic mapping in EC impacting on sentinel lymph node detection rates. In addition, we also discussed another evolving field in EC staging i.e. interpretation of pathologic ultra staging of SLN, which can identify low volume metastasis for which the clinical significance and ideal management remain uncertain. Future perspective regarding EC management is also discussed in this review.

Background In previous studies, the growth rate and diameter of infrarenal aorta was paucity of Chinese data. This study aim to evaluate the normal inside diameter and growth rate of the infrarenal aorta and common iliac artery in Chinese adult population and to explore the relationship between related factors and the arterial diameter. Methods A retrospective study was performed among 1,340 hospitalized adult patients undergoing contrast-enhanced abdominopelvic computed tomography from April 2017 to March 2018 in our hospital. The inside diameter of infrarenal aorta and common iliac artery was measured. Linear regression was used to analyze the relationship between various factors and arterial diameter. Kruskal-Wallis H test was used to analyze the relationship between the arterial diameter and age. Mann-Whitney U test was used to analyze the relationship between arterial diameter and sex. Results The inside diameter of the infrarenal aorta was 16.49 ± 2.12 mm in male patients and 14.50 ± 1.73 mm in female patients. In male patients, the right common iliac artery was 9.77 ± 1.75 mm, and the left was 9.65 ± 1.76 mm. In female patients, the right common iliac artery was 8.59 ± 1.31 mm and the left was 8.45 ± 1.28 mm. Comparing the oldest group with the youngest, the infrarenal aortic diameter increased 27.32% in male patients and 30.11% in female patients. Right common iliac artery increased 25.13% in male patients and 30.30% in female patients. Left common iliac artery increased 25.19% in male patients and 34.26% in female patients. The growth rate increased at the beginning, reached its peak at the age of 50–60 years, and then decreased. Multiple linear regression analysis results showed that sex, age, body surface area (BSA), hypertension, and cancer were significantly correlated with the diameter of infrarenal aorta. Sex, age, BSA, and hypertension were correlated with the diameter of right common iliac artery. Sex, age, BSA, and cancer were correlated with the diameter of left common iliac artery. Conclusions The diameter of the infrarenal abdominal aorta and common iliac artery of Chinese people is smaller than that of other countries. The abdominal aortic aneurysm (AAA) guideline might be developed based on the basic diameter to suit patients with AAA and a different basic abdominal aortic diameter. Artery diameter was increased by the age, and female patients have smaller diameter and larger arterial growth rate than male patients. Female and young patients with AAA may choose more oversize grafts for endovascular AAA repair.

Aim To explore the effects of protein phosphatase 2 regulatory subunit B''Alpha (PPP2R3A) on the proliferation and migration of liver cancer cells. Methods Expression of PPP2R3A in tumor tissues of hepatocellular carcinoma (HCC) patients was detected by immunohistochemistry and western blotting. In two liver cancer cell lines (HepG2 and HuH7), PPP2R3A expression was silenced and then overexpression with PPP2R3A lentiviral vectors, and the effects of PPP2R3A knockdown or overexpression on the proliferation, cell cycle, migration, and invasion of HCC cells were determined in vitro. In a xenograft cancer model in nude mice, the in vivo effects of PPP2R3A knockdown on tumor growth and cancer cell proliferation were evaluated. Results PPP2R3A expression was found in tumor foci in six of eight HCC samples, at a level higher than that in the adjacent para‐tumor tissues. PPP2R3A expression was observed primarily in the cytoplasm of the cancer cells. Knockdown of PPP2R3A resulted in significant inhibition of hepatoma cell proliferation (P, The PPP2R3A may play a pro‐tumor function in HCC by regulating the proliferation and invasion of HCC cells.

(3β,5α,16α,20S)-4,4,14-trimethyl-3,20-bis(methylamino)-9,19-cyclopregnan-16-ol-dihydrochloride (JLX-001), a structural analogue of cyclovirobuxine D (CVB-D), is a novel compound from synthesis. This study aims to confirm the therapeutic effects of JLX001 on ischemic stroke (IS) and research its induction of autophagy function via 5'-AMP-activated protein kinase (AMPK)-Human Serine/threonine-protein kinase (ULK1) signaling pathway activation. The therapeutic effects of JLX001 were evaluated by infarct sizes, brain edema, neurological scores and proportion of apoptotic neurons in Sprague-Dawley (SD) rats with middle cerebral artery occlusion/reperfusion (MCAO/R). The number of autophagosomes was obtained by transmission electron microscopy. The expression of LC3-II was measured by immunofluorescence. p-AMPK and activated ULK1 were detected by western blots. Results showed that JLX001 treatment markedly alleviated cerebral infarcts, edema, neurological scores and proportion of apoptotic neurons in MCAO/R rats. The number of autophagosomes was increased, accompanying with the increased expressions of LC3-II, p-AMPK and ULK1. In summary, JLX001 attenuates cerebral ischemia injury and the underlying mechanisms may relate to inducing autophagy via AMPK-ULK1 signaling pathway activation.

JLX001, a novel compound with similar structure with cyclovirobuxine D (CVB-D), has been proved to exert therapeutical effects on permanent focal cerebral ischemia. However, the protective effects of JLX001 on cerebral ischemia/reperfusion (I/R) injury and its anti-apoptotic effects have not been reported. We investigated the efficacy of JLX001 in two pharmacodynamic tests (pre-treatment test and post-treatment) with rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). The pharmacodynamic tests demonstrated that JLX001 ameliorated I/R injury by reducing infarct sizes and brain edema. The results of Morris water maze, neurological scores, cylinder test and posture reflex test implied that JLX001 improved the learning, memory and motor ability after MCAO/R in the long term. Anti-apoptotic effects of JLX001 and its regulation of cytosolic c-Jun N-terminal Kinases (JNKs) signal pathway were confirmed in vivo by co-immunofluorescence staining and western immunoblotting. Furthermore, primary cortical neuron cultures were prepared and exposed to oxygen glucose deprivation/reoxygenation (OGD/R) for in vitro studies. Cytotoxicity test and mitochondrial membrane potential (MMP) test showed that JLX001 enhanced cell survival rate and maintained MMP. Flow cytometry and TdT-mediated dUTP-X nick end labeling (TUNEL) staining demonstrated the anti-apoptotic effects of JLX001 in vitro. Likewise, JLX001 regulated JNK signal pathway in vivo, which was also confirmed by western immunoblotting. Collectively, this study presents the first evidence that JLX001 exerted protective effects against I/R injury by reducing neuronal apoptosis via down-regulating JNK signaling pathway.

Baicalin is a plant-derived flavonoid from Scutellaria baicalensis Georgi with multiple bioactivities and has a protective effect against avian pathogenic Escherichia coli (APEC) infection. However, the underlying mechanism of baicalin against APEC infection is still unknown. Therefore, we aimed to explore whether the protective effects and mechanisms of baicalin on APEC-induced lung inflammation were related to the regulation of gut microbiota. The results showed that baicalin significantly reduced APEC colonization and pro-inflammatory cytokines production, and additionally recovered air-blood barrier integrity in the lungs after APEC challenge. However, depletion of gut microbiota significantly weakened the protective effects of baicalin against APEC infection as mentioned above. Furthermore, baicalin markedly restored the dysbiosis of gut microbiota induced by APEC as well as increased the abundance of short chain fatty acid (SCFA)-producing bacteria and the production of SCFAs including acetic acid, propionic acid and butyric acid, especially acetic acid. In addition, the concentrations of acetic acid and its receptor free fatty acid receptor 2 (FFAR2) were significantly upregulated in the lung tissues after baicalin treatment. In conclusion, gut microbiota played a key role in the pharmacological action of baicalin against APEC-induced lung inflammation. Baicalin remodeled the dysbiosis of gut microbiota caused by APEC and increased the production of SCFAs, especially acetic acid in the gut, and then the increased acetate may circulate to the lungs to activate FFAR2 to defend APEC infection. Together, our study suggested that baicalin inhibited APEC infection through remodeling the gut microbiota dysbiosis and increasing the SCFA production. Furthermore, baicalin may serve as an alternative antibiotic and a novel therapeutic drug to prevent or treat APEC infection.

Purpose Ovarian cancer (OC) is the most common malignancy in women with high mortality. Increasing studies have revealed that long non-coding RNA (lncRNA) MNX1-AS1 has a promoting effect on various cancers. However, the mechanisms of MNX1-AS1 in OC are still unclear. Therefore, this study focused on exploring the mechanisms of MNX1-AS1 in OC. Materials and methods The expression of SOX12 at the protein level was detected by western blot. Cell proliferation was detected by CCK8 assay and colony formation assay. Cell cycle and cell apoptosis were detected by flow cytometry. Wound-healing assay, transwell assay and western blot were used to detect the ability of cell migration and invasion. The target binding was confirmed through the luciferase reporter assay. Results The expression of MNX1-AS1 was increased in OC tumor tissues and cells. Elevated MNX1-AS1 expression is associated with advanced stage and lower overall survival rate. Knockdown of MNX1-AS1 inhibited cell proliferation, migration and invasion, blocked cell cycle, and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. MNX1-AS1 was competitively binding with miR-744-5p, and its downstream target gene was SOX12. miR-544-5p expression was decreased, while SOX12 expression was increased in OC tumor tissues and cells. Overexpression of miR-744-5p inhibited cell proliferation, migration, invasion and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. Conclusion MNX1-AS1 promoted the development of OC through miR-744-5p/SOX12 axis. This study revealed a novel mechanism of MNX1-AS1 in OC, which may provide a new treatment or scanning target for OC.

Aim: The prognosis of patients with ovarian cancer (OC) is highly heterogeneous which hinders to make an appropriate clinical decision. The study aimed to stratify patients’ prognoses by establishing a risk assessment model in the context of mRNA levels of immune-related genes (IRGs). Methods: Comprehensive bioinformatics analyses were done using datasets from The UCSC Xena platform, ICGC Data Portal, The Cancer Genome Atlas (TCGA), and the Genotype‐Tissue Expression (GTEx) project. LASSO regression was done to determine the independence of associations of specific factors with overall survival (OS). Nomogram that combined the independent prognostic factors was constructed to predict the OS of OC patients. The tumor microenvironment and immune response were estimated by cell type identification via estimating the relative subset of known RNA transcripts (CIBERSORT) and immunophenoscore (IPS). Results: Overall ten IRGs were significantly associated with the OS probability and were used for the prognostic model construction of OC patients. According to the prognostic model, ovarian cancer samples were identified as high- or low-risk group. A nomogram containing risk score, stage, histological grade and age could significantly predict 1-year, 3-years, and 5-years OS probability of OC patients, as well as a higher IPS score and a higher immunoreactivity phenotype, which were probably correlated with better immunotherapy response and good prognosis. Conclusions: We established a reliable IRGs-based risk model with potential prognostic value for patients with ovarian cancer. Further studies are needed to confirm these prognosis-associated biomarkers.

Purpose To investigate the morphologic and histopathologic changes in allogeneic endokeratophakia using hyperopic lenticules derived from small-incision lenticule extraction (SMILE). Methods Six New Zealand rabbits (12 eyes) were included in this experiment and randomly and evenly divided into donor and recipient groups. The donor group underwent bilateral hyperopic SMILE surgery, and the concave lenticules were implanted into eyes in the recipient group. Corneal topography and anterior segment optical coherence tomography (OCT) examinations were performed at 1 day, 1 week, 1 month, and 5 months after surgery. All eyes were enucleated 5 months after surgery. Hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM) were used to observe the corneal morphology in the recipient group. Results No complications were observed, and the corneas remained transparent in the follow-up period. There was mild corneal edema within 1 week after surgery. Slit-lamp microscopy and OCT showed that the lenticules were gradually integrated with the surrounding corneal stroma. HE staining showed that the arrangement of corneal collagen was regular. The boundary between the lenticules and surrounding tissue could be identified with HE staining and TEM, and no inflammatory cells were found under TEM. The corneal Km values were significantly lower at 5 months postoperatively compared to preoperatively (P < 0.05). Conclusions This pilot study showed that allogeneic hyperopic SMILE lenticule endokeratophakia seems to be safe and feasible. Translational Relevance Allogeneic hyperopic SMILE lenticule endokeratophakia may be applicable for the correction of corneal regression, ectasia, ultra-high myopia, or keratoconus.

Background: We report the application of transuterine suspension sutures (TUSSs) for manipulation and vaginal closure before colpotomy in laparoscopic radical hysterectomy for early-stage cervical cancer. Methodology: Eight patients with clinical stage IB1 cervical squamous cell cancer were treated with laparoscopic radical hysterectomy between October 2019 and May 2020. The procedure was performed without a traditional uterine manipulator, and the vaginal cuff was closed with a stapler before colpotomy to prevent tumour spillage. Results: All patients successfully underwent the surgery, with a median hospitalisation of 8 days (range 6–14). All drains and urethral catheters were removed after a median of 7 days (range 5–11) and 16 days (range 12–21), respectively. A median of 26 (range 20–32) pelvic lymph nodes were resected and no lymph-related complications were encountered post-operatively. With an enclosed colpotomy, no visible tumour tissues were exposed to the pelvic cavity, and all vaginal stumps healed well without complications. All pathological examinations of the vaginal margin were negative, and there were no residual lesions. At a median follow-up of 6 months, all patients were alive with no recurrence of disease. Conclusion: We found that laparoscopic radical hysterectomy with TUSS and vaginal closure before colpotomy is a useful and effective procedure to prevent tumour spillage for the treatment of cervical cancer.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. In adults with NAFLD, fibrosis can develop and progress to liver cirrhosis and liver failure. However, the underlying molecular mechanisms of fibrosis progression are not fully understood. Using total RNA-Seq, we investigated the molecular mechanisms of NAFLD and fibrosis. We sequenced liver tissue from 143 adults across the full spectrum of fibrosis stage including those with stage 4 fibrosis (cirrhosis). We identified gene expression clusters that strongly correlate with fibrosis stage including four genes that have been found consistently across previously published transcriptomic studies on NASH i.e. COL1A2, EFEMP2, FBLN5 and THBS2. Using cell type deconvolution, we estimated the loss of hepatocytes versus gain of hepatic stellate cells, macrophages and cholangiocytes with advancing fibrosis stage. Hepatocyte-specific functional analysis indicated increase of pro-apoptotic pathways and markers of bipotent hepatocyte/cholangiocyte precursors. Regression modelling was used to derive predictors of fibrosis stage. This study elucidated molecular and cell composition changes associated with increasing fibrosis stage in NAFLD and defined informative gene signatures for the disease.

PurposeThis study aimed to investigate the effect of essential ingredients of licorice on the chronic obstructive pulmonary disease (COPD).MethodThe ingredients information were obtained fromPubChem(https://pubchem.ncbi.nlm.nih.gov/), related genes about COPD was collected fromgeneCards(http://www.genecards.org/).Networkpharmacology was utilized in this study.ResultThe intersection data set contains 20 molecular targets between COPD and liquorice. Protein-protein interaction network showed that there are a total of 58 nodes and 137 edges involved. The link number of AKT1 in PPI network was 39, which is the highest level of interaction. MAPK1 is an important target of Licorice on COPD.ConclusionMAPK signaling pathway could be the important key target of main ingredients of licorice on COPD.

Background: Dexamethasone (DEX) is widely adopted to reduce tumor-associated edema in glioblastoma (GBM) patients despite its side effects. However, the benefits of using DEX in GBM patients remains elusive.Methods: In this study, we performed a comprehensive meta-analysis to address this concern. We searched the relevant studies from PubMed, Web of Science, and EMBASE databases, and then applied random or fixed-effects models to generate estimated summary hazard radios (HRs) and the 95% confidence intervals (CIs). Moreover, subgroup and sensitivity analysis were conducted and publication bias were further evaluated.Results: Ten articles with a total of 2,230 GBM patients were eligible according to the inclusion criteria. In the assessment of overall survival (OS), meta-analysis data revealed that DEX was significantly associated with the poor prognosis of GBM patients (HR=1.44, 95% CI=1.32−1.57). In the progression-free survival (PFS), the pooled results indicated that the use of DEX can increase 48% death risk for GBM patients (HR=1.48, 95% CI=1.11−1.98). Subgroup analyses revealed that DEX was associated with poorer outcome of GBM in subgroup of newly diagnosed patients and GBM patients treated with ≥ 2mg/day. Sensitivity analyses showed that no study changed the pooled results materially for both OS and PFS analyses. The funnel plot had no obvious asymmetry.Conclusion: Our findings partly confirmed that use of DEX was associated with poor treatment outcome in GBM patients. To reach a definitive conclusion, large samples from multi-centers are urgent to address this concern.

BackgroundAlzheimer’s disease (AD) is the most common type of dementia. However, no curative therapy has been found effective to slow down the process of AD. It is reported that anesthesia and surgery will induce neurocognitive deterioration in AD, but the mechanism is not quite clear. In this study, we aim to compare the cognitive impairment between 5XFAD transgenic (Tg) mice and its littermate (LM) after isoflurane anesthesia and surgery to clarify the specific impacts of anesthesia and surgery on individuals with AD and to explore the mechanisms.MethodsWe performed abdominal surgery in cognitively impaired, 4-month-old female 5XFAD mice and LM control mice. Isoflurane anesthesia (1.4%) was induced and maintained over 2 h. Open field and fear conditioning tests were conducted on 1, 3 and 7 days after anesthesia and surgery. The total distance, velocity and freezing time were the major outcomes. P-tau (AT8), tau oligomers (T22), stress granules (SGs), the SYK tyrosine kinase and p-SYK in the hippocampus at postoperative day 1 were evaluated by Western Blot assays. The colocalization of SGs, SYK, p-SYK, and neurons in the hippocampus section was assessed using qualitative immunofluorescence.ResultsIn the open field test, no difference between the distance moved and the velocity of LM mice and 5XFAD Tg mice were found on day 1 after anesthesia and surgery. 5XFAD Tg mice exhibited reduced freezing time of fear conditioning context test on postoperative day 3, but not on day 7; the LM mice showed no changes in FCTs. Furthermore, p-tau, tau oligomers, SGs, SYK and p-SYK were evident in the hippocampus region of 5XFAD Tg mice on a postoperative day 1. In addition, SGs, SYK, p-SYK were colocalized with hippocampus neurons, as shown by immunofluorescence.ConclusionThis study demonstrates that anesthesia and surgery may induce tau-associated neurocognitive deterioration in individuals with AD. The mechanism under it may be associated with SGs and the tyrosine kinase, SYK. After anesthesia and surgery, in 5XFAD Tg mice, SGs were formed and SYK was phosphorylated, which may contribute to the phosphorylation of tau protein. This study provided hints that individuals with AD may be more vulnerable to anesthesia and surgery.

Background The aim of this study was to analyze the risk factors, causes, and management of intestinal obstruction after pediatric liver transplantation. Methods Retrospective analysis was performed on pediatric liver transplantation recipients from January 1st 2013 to December 31st 2019 at Organ Transplant Center, Tianjin First Central Hospital. The cases of intestinal obstruction were analyzed. Results A total of 1034 pediatric liver transplantations were performed during the study period, 66 intestinal obstructions were diagnosed in 61 recipients. Three recipients suffered intestinal obstructions twice, and one recipient suffered three times. Forty of the 66 cases were treated with non-surgical treatment, including fasting, gastrointestinal decompression, purgation, enema, and parenteral nutrition. Surgical intervention was performed in 26 cases. Diaphragmatic hernia, intestinal inflammatory stenosis, PTLD, and intestine perforation are essential causes of intestinal obstruction in pediatric liver transplant recipients. Diaphragmatic hernia was independent risk factors for intestinal obstruction. The 1-, 2- and 3-year survival rate of the recipients with or without intestinal obstruction were 98.4%, 96.5%, 96.5% and 95.3%, 94.4%, 94.0%, respectively, without significant difference. Conclusions Most cases of intestinal obstruction after liver transplantation in children can be remitted by non-surgical treatment, but there are still some cases need to be treated by surgery. Both measures are related to ideal outcomes, intestinal obstruction does not increase the mortality rate in pediatric liver transplantation.

IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.

Critical limb ischemia (CLI) is the most advanced clinical stage of peripheral vascular disease with high mobility and mortality. CLI patients suffer from lower extremity rest pain, ulceration, and gangrene caused by insufficient blood and oxygen supply. Seeking for effective biomarkers and therapeutic targets is of great significance for improving the life quality of CLI patients. The circadian clock has been reported to be involved in the progression of kinds of cardiovascular diseases. Whether and how circadian genes play a role in CLI remains unknown. In this study, by collecting femoral artery and muscle specimens of CLI patients who underwent amputation, we confirmed that the circadian gene Bmal1 is downregulated in the CLI femoral artery and ischemic distal lower limb muscle. Furthermore, we verified that Bmal1 affects CLI by regulating lipid metabolism, inflammation, and angiogenesis. A hindlimb ischemia model performed in wild-type and Bmal1−/− mice confirmed that Bmal1 disruption would lead to impaired angiogenesis. In vitro experiments indicated that the decreased expression of Bmal1 would increase ox-LDL uptake and impair endothelial cell functions, including proliferation, migration, and tube formation. As for mechanisms, Bmal1 represses inflammation by inhibiting lipid uptake and by activating IL-10 transcription and promotes angiogenesis by transcriptionally regulating VEGF expression. In conclusion, we provide evidence that the circadian gene Bmal1 plays an important role in CLI by inhibiting inflammation and promoting angiogenesis. Thus, Bmal1 may be an effective biomarker and a potential therapeutic target in CLI.