[Effect of peripheral blood inflammatory indicators on the efficacy of immunotherapy in patients with advanced non-small cell lung cancer and chronic obstructive pulmonary disease].

Objective: To investigate the impact of peripheral blood inflammatory indicators on the efficacy of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) complicated with chronic obstructive pulmonary disease (COPD). Methods: A retrospective cohort study was performed to include 178 patients with Ⅲ-Ⅳ NSCLC complicated with COPD who received at least 2 times of immunotherapy in Xinqiao Hospital of the Army Medical University from January 2019 to August 2021. Baseline peripheral blood inflammatory indicators such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) were collected within 2 weeks before the first treatment, with the last one being on or before February 7, 2022. X-tile software was used to determine the optimal cut-off value of peripheral blood inflammatory indicators. The Cox multivariate regression models were used to analyze the factors affecting progression free survival (PFS) and overall survival (OS). Results: Among the 178 patients, there were 174 males (97.8%) and 4 females (2.2%); the age ranged from 42 to 86 (64.3±8.3) years old.There were 30 cases (16.9%) of immunotherapy monotherapy, 114 cases (64.0%) of immunotherapy combined with chemotherapy, 21 cases (11.8%) of immunotherapy combined with antivascular therapy, and 13 cases (7.3%) of immunotherapy combined with radiotherapy. The median follow-up period was 14.5 months (95%CI: 13.6-15.3 months). The objective response rate (ORR) and disease control rate (DCR) were 44.9% (80/178) and 90.4% (161/178) for the whole group, the median PFS was 14.6 months (95%CI: 11.6-17.6 months), and the median OS was 25.7 months (95%CI: 18.0-33.4 months). The results of Cox multivariate analysis showed that IL-6>9.9 ng/L (HR=5.885, 95%CI: 2.558-13.543, P<0.01), TNF-α>8.8 ng/L (HR=3.213, 95%CI: 1.468-7.032, P=0.003), IL-8>202 ng/L (HR=2.614, 95%CI: 1.054-6.482, P=0.038), systemic immune inflammatory index (SII)>2 003.95 (HR=2.976, 95%CI: 1.647-5.379, P<0.001) were risk factors for PFS, and advanced lung cancer inflammation index (ALI)>171.15 was protective factor for PFS (HR=0.545, 95%CI: 0.344-0.863, P=0.010). IL-6>9.9 ng/L(HR=6.124, 95%CI: 1.950-19.228, P<0.002), lactate dehydrogenase (LDH)>190.7 U/L (HR=2.776, 95%CI: 1.020-7.556, P=0.046), SII>2 003.95 (HR=4.521, 95%CI: 2.241-9.120, P<0.001) were risk factors for OS, and ALI>171.15 was a protective factor for OS (HR=0.434, 95%CI: 0.243-0.778, P=0.005). Conclusion: Baseline high levels of IL-6, TNF-α, IL-8, SII, LDH, and low levels of ALI are risk factors for poor prognosis in patients with advanced NSCLC-COPD receiving immunotherapy.

[Clinical analysis of sirolimus as an alternative GVHD prophylaxis for patients with kidney injury undergoing allo-HSCT].

Objective: To explore the feasibility of sirolimus as an alternative graft versus host disease (GVHD) prophylaxis in patients with kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Retrospective case series study. Medical records of 11 patients in Peking University People's Hospital from 1 August 2008 to 31 October 2022, who received sirolimus instead of cyclosporine to prevent GVHD, due to renal insufficiency after allo-HSCT, were analyzed retrospectively. Incidence of GVHD, infection, and transplant-associated thrombotic microangiopathy (TA-TMA), as well as renal function, were evaluated. Results: Among the 11 patients who received sirolimus, 6 were treated with haploidentical donor HSCT, and 5 were treated using matched sibling donor HSCT. The median (range) time of sirolimus administration was 30 (7-167) days after allo-HSCT, and the median (range) sirolimus course duration was 52 (9-120) days. During sirolimus treatment, 1 case did not undergo combined treatment with other prophylactic drugs, 3 cases received combined mycophenolate mofetil (MMF), and 1 case underwent combined CD25 monoclonal antibody treatment, while 6 cases had combined therapy with both MMF and CD25 monoclonal antibody. Of the 11 patients, 2 developed Grade Ⅲ acute GVHD, 1 developed severe pneumonia and died, and 1 developed TA-TMA, while nine patients had normal or improved renal function. Median (range) follow-up time was 130 (54-819) days. Non-relapse mortality was observed in 1 patient. Relapse mortality was also observed in 1 patient. Conclusion: Sirolimus-based alternative GVHD prophylaxis is a potentially viable option for patients undergoing allo-HSCT who cannot tolerate cyclosporine, but its efficacy and safety require further optimization and verification in prospective studies.

[Pelvic coronal inclination change in adolescent flexible flatfoot surgically treated with arthroereisis].

Objective: To evaluate adolescent pelvic coronal inclination angle change after flatfoot treated with arthroereisis. Method: A case-series study. From June 2018 to September 2020, 25 children with flexible flat foot and pelvic obliquity were included in this retrospective study in Peking University Shenzhen Hospital. There were 17 males and 8 females with a mean age of (11.2±2.2) years (9-15 years). There were 5 cases of unilateral flatfoot and 20 cases of bilateral flatfoot. All of the patients were surgically treated with arthroereisis. Regular follow-up was done in 3 months, 1 and 2 years postoperatively. Weightbearing fluoroscopy of entire lower limb and foot were investigated to measure Meary's angle, calcaneal pitch angle, height difference at ankle and pelvic plane, pelvic inclination and sacrum-iliac distance (F value) on coronal plane. Results: The mean Mearys' angle at 3 month postoperatively was improved when compared with that before the operation (3.1°±1.5° vs 25.9°±4.3°, P<0.001), and it remained at the same level 2 years after the operation (compared with that at 1 year after the operation, P=0.748). The calcaneal pitch angle improved significantly at 3-month follow-up when compared with that before the operation (16.6°±2.4° vs 9.9°±1.5°, P<0.001), and there was no significant change between 1 year and 2 years after operation (P=0.542). The height difference at mortise plane were also reduced at the 3-month follow-up(P<0.001), and it remained at the same level at 1 year and 2 years after the operation (P=0.159). Pelvic height difference decreased dramatically from (12.4±1.7) mm (before operation) to (7.1±1.2) mm(3 month after the operation) (P<0.001), it decreased to (3.6±1.8) mm 1 year after the operation (compared with that at 3 months after the operation, P<0.001), and no further reduction was observed 2 years after the surgery (P=0.483). The pelvic inclination angle and sacrum-iliac distance were also improved at 3-month follow-up when compared with those before the operation (both P<0.001), and they declined further 1 year after the operation(both P<0.05), but the decreasing trend disappeared at the 2-year follow-up (both P>0.05). Conclusion: For adolescent flexible flat foot patients with pelvic obliquity, the coronal inclination and pelvic height discrepancy would partially recovered with correction of flatfoot deformity, but it could not be completely corrected in the mean follow-up period of 2 years after the operation.

[Clinical analysis of the usefulness of letermovir for prevention of cytomegalovirus infection after haploidentical hematopoietic stem cell transplantation].

Objective: To analyze the efficacy and safety of letermovir in primary prophylaxis of cytomegalovirus (CMV) reactivation in patients receiving haploidentical hematopoietic stem cell transplantation. Methods: This retrospective, cohort study was conducted using data of patients who underwent haploidentical transplantation at Peking University Institute of Hematology and received letermovir for primary prophylaxis between May 1, 2022 and August 30, 2022. The inclusion criteria of the letermovir group were as follows: letermovir initiation within 30 days after transplantation and continuation for≥90 days after transplantation. Patients who underwent haploidentical transplantation within the same time period but did not receive letermovir prophylaxis were selected in a 1∶4 ratio as controls. The main outcomes were the incidence of CMV infection and CMV disease after transplantation as well as the possible effects of letermovir on acute graft versus host disease (aGVHD), non-relapse mortality (NRM), and bone marrow suppression. Categorical variables were analyzed by chi-square test, and continuous variables were analyzed by Mann-Whitney U test. The Kaplan-Meier method was used for evaluating incidence differences. Results: Seventeen patients were included in the letermovir prophylaxis group. The median patient age in the letermovir group was significantly greater than that in the control group (43 yr vs. 15 yr; Z=-4.28, P<0.001). The two groups showed no significant difference in sex distribution and primary diseases, etc. (all P>0.05). The proportion of CMV-seronegative donors was significantly higher in the letermovir prophylaxis group in comparison with the control group (8/17 vs. 0/68, χ2=35.32, P<0.001). Three out of the 17 patients in the letermovir group experienced CMV reactivation, which was significantly lower than the incidence of CMV reactivation in the control group (3/17 vs. 40/68, χ2=9.23, P=0.002), and no CMV disease development observed in the letermovir group. Letermovir showed no significant effects on platelet engraftment (P=0.105), aGVHD (P=0.348), and 100-day NRM (P=0.474). Conclusions: Preliminary data suggest that letermovir may effectively reduce the incidence of CMV infection after haploidentical transplantation without influencing aGVHD, NRM, and bone marrow suppression. Prospective randomized controlled studies are required to further verify these findings.

[Effect of Friday surgery on clinical outcome of elderly patients with hip fracture under multidisciplinary treatment].

Objective: To assess the impact of Friday surgery on clinical outcomes in elderly patients with hip fracture under multidisciplinary treatment. Methods: A retrospective cohort study. The clinical data of 414 geriatric patients with hip fractures admitted to Zhongda Hospital Affiliated with Southeast University from January 2018 to March 2021 were analyzed retrospectively, including 126 males and 288 females with a mean age of (81.3±7.6) years. The patients were divided into two groups based on whether they underwent surgery on Friday or not. The Friday group(n=69) and the non-Friday group(n=345) were compared in terms of general information, American Society of Anesthesiologists(ASA) classification, fracture type, injury to admission time, preoperative waiting time, surgical method, anesthesia type and use of intensive care unit (ICU) fast track. Propensity score matching (PSM) was performed based on age, ASA grade, time from injury to admission, preoperative waiting time, hemoglobin and albumin levels at admission. Clinical outcomes were collected and compared between the two groups, including length of hospital stay, total hospitalization cost and 30-day, 90-day and 1-year mortality rates, and postoperative complications. Multivariate logistic regression analyses were conducted to identify influencing factors for 1-year mortality in geriatric patients with hip fracture. Results: Baseline data showed statistically significant differences in hemoglobin, albumin and preoperative waiting time between the two groups (all P<0.05). After PSM matching, 69 patients were included in each group, and no significant differences were observed in baseline data between the two groups (all P>0.05). There was no significant differences in 30-day mortality rate (4.3% vs 0, P=0.080), 90-day mortality rate (7.2% vs 1.4%, P=0.095), length of hospital stay [(10.85±4.45)d vs (10.92±3.68)d, P=0.919], total hospitalization cost [(60.9±15.4) thousands yuan vs (59.1±15.4) thousands yuan, P=0.489], postoperative complications [pneumonia (11.6% vs 13.0%, P=0.796), cardio-cerebrovascular complications (11.6% vs 8.7%, P=0.573) and delirium (5.7% vs 2.9%, P=0.245)] between the Friday group and the non-Friday group (all P>0.05). However, the 1-year mortality rate was higher in the Friday group than that in the non-Friday group(18.8% vs 4.3%, P=0.008). Multivariate analysis revealed that surgery on Friday (OR=11.222, 95%CI: 2.198-57.291, P=0.004), low hemoglobin levels at admission (OR=0.920, 95%CI: 0.875-0.967, P=0.001), hemiarthroplasty treatment (OR=5.127, 95%CI: 1.308-20.095, P=0.019) and longer surgery duration (OR=0.958, 95%CI: 0.927-0.989, P=0.009) were influencing factors for 1-year mortality in geriatric patients with hip fracture. Conclusions: In the context of multidisciplinary treatment, Friday surgery does not increase short-term mortality, length of hospital stay, total hospitalization cost or incidence of complications in geriatric patients with hip fracture. However, it remains a influencing factor for 1-year mortality in those patients.

MicroRNA-137 inhibits pituitary prolactinoma proliferation by targeting AKT2.

PURPOSE: Prolactinoma is the most common type of pituitary adenoma. Most prolactinoma need medical treatment, but some of them are aggressive and require surgery. In previous decades, some miRNAs have been manifested as oncogenes or tumor suppressors. Consequently, miRNAs' abnormal expression involves tumorigenesis, invasion, and metastasis of different types of tumors, including pituitary tumors. The current study aim to explore the aggressiveness-associated miRNAs in prolactinoma and underlying molecular mechanisms based on the bioinformatic analysis and fundamental experiment studies. METHODS: GSE46294 miRNA expression profile from the Gene Expression Omnibus (GEO) database was downloaded. Differentially expressed miRNAs (DEMs) were filtered from this data. Subsequently, the target genes of downregulated miRNAs were analyzed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RT-qPCR, western blot, and CCK-8 assays were used to validate the effect of miR-137 on the proliferation of MMQ cells through AKT2. Finally, the binding site of rat miR-137 to AKT2 were predicted by Targetscan and Bibiserv database, and verified by double luciferase reporter assay. RESULTS: Twenty-four changed DEMs (fourteen upregulated and ten downregulated) were identified. Target genes of downregulated DEMs were classified into three groups by GO terms. KEGG pathway enrichment analysis revealed these target genes enriched in the PI3K-Akt pathway. We also confirmed that miR-137 can target AKT2 and inhibit the proliferation of MMQ cells induced by AKT2. CONCLUSION: MiR-137 suppressed prolactinomas' aggressive behavior by targeting AKT2.

Hydrogen sulfide alleviates lipopolysaccharide-induced myocardial injury through TLR4-NLRP3 pathway.

To investigate the effect of hydrogen sulfide (H2S) on myocardial injury in sepsis-induced myocardial dysfunction (SIMD), male C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg, i.p.) to induce cardiac dysfunction without or with the H2S donor sodium hydrosulfide (NaHS) (50 µmol/kg, i.p.) administration 3 h after LPS injection. Six hours after the LPS injection, echocardiography, cardiac hematoxylin and eosin (HE) staining, myocardial damage and inflammatory biomarkers and Western blot results were analyzed. In mice, the administration of LPS decreased left ventricular ejection fraction (LVEF) by 30 % along with lowered H2S levels (35 % reduction). It was observed that cardiac troponin I (cTnI), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) levels were all increased (by 0.22-fold, 2000-fold and 0.66-fold respectively). HE staining revealed structural damage and inflammatory cell infiltration in the myocardial tissue after LPS administration. Moreover, after 6 h of LPS treatment, toll-like receptor 4 (TLR4) and nod-like receptor protein 3 (NLRP3) expressions were up-regulated 2.7-fold and 1.6-fold respectively. When compared to the septic mice, NaHS enhanced ventricular function (by 0.19-fold), decreased cTnI, TNF-alpha, and IL-1beta levels (by 11 %, 33 %, and 16 % respectively) and downregulated TLR4 and NLRP3 expressions (by 64 % and 31 % respectively). Furthermore, NaHS did not further improve cardiac function and inflammation in TLR4-/- mice or mice in which NLRP3 activation was inhibited by MCC950, after LPS injection. In conclusion, these findings imply that decreased endogenous H2S promotes the progression of SIMD, whereas exogenous H2S alleviates SIMD by inhibiting inflammation via the TLR4-NLRP3 pathway suppression.

[Clinical characteristics and prognosis of patients with anti-glutamic acid decarboxylase antibody-related cerebellar ataxia].

The clinical data, diagnosis, treatment, and prognosis of 10 patients with anti-glutamic acid decarboxylase (GAD) antibody-related cerebellar ataxia in Department of Neurology, Peking Union Medical College Hospital, from May 2015 to November 2021 were retrospectively analyzed. There were 8 female patients with a median age of 55 years old. Patients mainly presented with gait ataxia (10/10), dizziness (8/10), diplopia (6/10), and dysarthria (5/10). Four of them were complicated with other autoimmune disease, including vitiligo (3/4), Hashimoto thyroiditis (1/4), thrombocytopenia (1/4), and small cell lung cancer (1/4). All patients received immunotherapy, 6 out of 10 exhibited a good response, and half of them had satisfied functional prognosis. Patients of anti-GAD antibody-related cerebellar ataxia may be complicated with other autoimmune diseases, but underlying tumor is rare. More than half of patients have a good response to immunotherapy and satisfied prognosis.

Dynamic transcriptome profiling reveals essential roles of the receptor tyrosine kinases (RTK) family in feather development of duck.

1. The following study examined the expression profiles of the receptor tyrosine kinases (RTK) family in the developing feather follicles of Pekin ducks and Nonghua ducks at 6-9 weeks of age. The RTK subfamilies related to feather development were summarised, and other candidate genes related to feather development were enriched.2. To reveal the potential role of all RTK members in feather development, the feather follicles of two duck breeds (Pekin and Nonghua ducks) at 6-9 weeks were isolated and chosen for RNA-Seq determination.3. A total of 53 RTK members were confirmed in the duck genome, and 42 were expressed in duck feather follicles. Among RTK subfamilies, the VEGFR, PDGFR, FGFR, EGFR, and InsR subfamilies, along with and Met and KIT genes, were the main ones regulating feather growth.4. Genes with a similar expression pattern to the RTK were identified, and KEGG and PPI analyses were performed to explore the new potential feather development genes associated with RTK genes. Results showed that BCAR1, PXN, LAMA2, LAMC1 and LAMC3 are essential candidate genes for regulating feather growth.

[Effect of hypochloric acid on Escherichia coli biofilm and the clinical efficacy of hypochloric acid for wounds with Escherichia coli infection].

Objective: To investigate the effect of hypochloric acid on Escherichia coli biofilm and the clinical efficacy of hypochloric acid for wounds with Escherichia coli infection. Methods: One strain of Escherichia coli with the strongest bacterial biofilm forming ability among the strains isolated from specimens in 25 patients (16 males and 9 females, aged 32-67 years) from five clinical departments of the 940th Hospital of the Joint Logistic Support Force was collected for the experimental study from September to December 2019. The Escherichia coli was cultured with hypochloric acid at 162.96, 81.48, 40.74, 20.37, 10.18, 5.09, 2.55, 1.27, 0.64, and 0.32 µg/mL respectively to screen the minimum bactericidal concentration (MBC) of hypochloric acid. The Escherichia coli was cultured with hypochloric acid at the screened MBC for 2, 5, 10, 20, 30, and 60 min respectively to screen the shortest bactericidal time of hypochloric acid. The biofilm formation of Escherichia coli was observed by scanning electron microscopy at 6, 12, 24, 48, 72, and 96 h of incubation, respectively. After 72 h of culture, hypochloric acid at 1, 2, 4, 8, and 16 times of MBC was respectively added to Escherichia coli to screen the minimum biofilm eradicate concentration (MBEC) of hypochloric acid against Escherichia coli. After hypochloric acid at 1, 2, 4, and 8 times of MBEC and sterile saline were respectively added to Escherichia coli for 10 min, the live/dead bacterial staining kit was used to detect the number of live and dead cells, with the rate of dead bacteria calculated (the number of samples was 5). From January to December 2020, 41 patients with infectious wounds meeting the inclusion criteria and admitted to the Department of Burns and Plastic Surgery of the 940th Hospital of Joint Logistic Support Force of PLA were included into the prospective randomized controlled trial. The patients were divided into hypochloric acid group with 21 patients (13 males and 8 females, aged (46±14) years) and povidone iodine group with 20 patients (14 males and 6 females, aged (45±19) years) according to the random number table. Patients in the 2 groups were respectively dressed with sterile gauze soaked with hypochloric acid of 100 µg/mL and povidone iodine solution of 50 mg/mL with the dressings changed daily. Before the first dressing change and on the 10th day of dressing change, tissue was taken from the wound and margin of the wound for culturing bacteria by agar culture method and quantifying the number of bacteria. The amount of wound exudate and granulation tissue growth were observed visually and scored before the first dressing change and on the 3rd, 7th, and 10th days of dressing change. Data were statistically analyzed with one-way analysis of variance, Dunnett-t test, independent sample t test, Mann-Whitney U test, Wilcoxon signed-rank test, chi-square test, or Fisher's exact probability test. Results: The MBC of hypochloric acid against Escherichia coli was 10.18 µg/mL, and the shortest bactericidal time of hypochloric acid with MBC against Escherichia coli was 2 min. Escherichia coli was in a completely free state after 6 and 12 h of culture and gradually aggregated and adhered with the extension of culture time, forming a mature biofilm at 72 h of culture. The MBEC of hypochloric acid against Escherichia coli was 20.36 µg/mL. The Escherichia coli mortality rates after incubation with hypochloric acid at 1, 2, 4, and 8 times of MBEC for 10 min were significantly higher than that after incubation with sterile saline (with t values of 6.11, 25.04, 28.90, and 40.74, respectively, P<0.01). The amount of bacteria in the wound tissue of patients in hypochloric acid group on the 10th day of dressing change was 2.61 (2.20, 3.30)×104 colony forming unit (CFU)/g, significantly less than 4.77 (2.18, 12.48)×104 CFU/g in povidone iodine group (Z=2.06, P<0.05). The amounts of bacteria in the wound tissue of patients in hypochloric acid group and povidone iodine group on the 10th day of dressing change were significantly less than 2.97 (2.90, 3.04)×106 and 2.97 (1.90, 7.95)×106 CFU/g before the first dressing change (with Z values of 4.02 and 3.92, respectively, P<0.01). The score of wound exudate amount of patients in hypochloric acid group on the 10th day of dressing change was significantly lower than that in povidone iodine group (Z=2.07, P<0.05). Compared with those before the first dressing change, the scores of wound exudate amount of patients in hypochloric acid group on the 7th and 10th days of dressing change were significantly decreased (with Z values of -3.99 and -4.12, respectively, P<0.01), and the scores of wound exudate amount of patients in povidone iodine group on the 7th and 10th days of dressing change were significantly decreased (with Z values of -3.54 and -3.93, respectively, P<0.01). The score of wound granulation tissue growth of patients in hypochloric acid group on the 10th day of dressing change was significantly higher than that in povidone iodine group (Z=2.02, P<0.05). Compared with those before the first dressing change, the scores of wound granulation tissue growth of patients in hypochloric acid group on the 7th and 10th days of dressing change were significantly increased (with Z values of -3.13 and -3.67, respectively, P<0.01), and the scores of wound granulation tissue growth of patients in povidone iodine group on the 7th and 10th days of dressing change were significantly increased (with Z values of -3.12 and -3.50, respectively, P<0.01). Conclusions: Hypochloric acid can kill Escherichia coli both in free and biofilm status. Hypochloric acid at a low concentration shows a rapid bactericidal effect on mature Escherichia coli biofilm, and the higher the concentration of hypochloric acid, the better the bactericidal effect. The hypochloric acid of 100 µg/mL is effective in reducing the bacterial load on wounds with Escherichia coli infection in patients, as evidenced by a reduction in wound exudate and indirect promotion of granulation tissue growth, which is more effective than povidone iodine, the traditional topical antimicrobial agent.

Dietary Protein Intake in Relation to the Risk of Osteoporosis in Middle-Aged and Older Individuals: A Cross-Sectional Study.

OBJECTIVES: Dietary protein intake is of great significance for the bone health of middle-aged and elderly people. This study is aimed to explore the relationships between dietary protein intake and the risk of osteoporosis in middle-aged and older individuals among US population. METHODS: Based on the National Health and Nutrition Examination Survey (NHANES), this study includes a total of 20497 participants during 2005-2008, and identify 4707 middle-aged and older people aged 45 years or above. Demographic data and relevant dietary intake information are acquired through in-home management questionnaires. The logistic regression models are established to identify the odds ratio (OR) and 95% confidence interval (CI) of OP in each quartile category of energy-adjusted dietary protein intake. The receiver operating characteristic (ROC) curve is applied to explore the optimal cut-off value of daily dietary protein intake for predicting risk of OP. RESULTS: 442 participants with OP are identified among 4707 middle-aged and older people, and the dietary protein intake of OP group is significantly lower than that of non-OP group (P<0.001). The logistic regression analysis shows that with the increase of daily dietary protein intake, the prevalence of OP in each quartile category decreases gradually (P<0.001). This trend is not altered in univariate model (P<0.001), as well as the adjustments for the covariates of age and BMI (Model 1, P<0.001), the covariates of sex (Model 2, P=0.036), the covariates of smoking, drinking alcohol, education, ratio of family income to poverty, hypertension and diabetes (Model 3, P<0.001), and the covariates of dietary intake (Model 4, P=0.008). Moreover, we also identify that the daily dietary protein intake of 61.2g is the optimal cut-off value for predicting risk of OP. CONCLUSION: In general, among US population, the lower daily dietary protein intake is positively related to the ascending risk of OP in middle-aged and older individuals.

Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia.

BACKGROUND: In the randomized phase III KEYNOTE-181 study, pembrolizumab prolonged overall survival (OS) compared with chemotherapy as second-line therapy in patients with advanced esophageal cancer and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10. We report a post hoc subgroup analysis of patients with esophageal squamous cell carcinoma (ESCC) enrolled in KEYNOTE-181 in Asia, including patients from the KEYNOTE-181 China extension study. PATIENTS AND METHODS: Three hundred and forty Asian patients with advanced/metastatic ESCC were enrolled in KEYNOTE-181, including the China cohort. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200 mg every 3 weeks for ≤2 years or investigator's choice of paclitaxel, docetaxel, or irinotecan. OS, progression-free survival, response, and safety were analyzed without formal comparisons. OS was evaluated based on PD-L1 CPS expression level. RESULTS: In Asian patients with ESCC, median OS was 10.0 months with pembrolizumab and 6.5 months with chemotherapy [hazard ratio (HR), 0.63; 95% CI 0.50-0.80; nominal P < 0.0001]. Median progression-free survival was 2.3 months with pembrolizumab and 3.1 months with chemotherapy (HR, 0.79; 95% CI 0.63-0.99; nominal P = 0.020). Objective response rate was 17.1% with pembrolizumab and 7.1% with chemotherapy; median duration of response was 10.5 months and 7.7 months, respectively. In patients with PD-L1 CPS <1 tumors (pembrolizumab versus chemotherapy), the HR was 0.99 (95% CI 0.56-1.72); the HR (95% CI) for death was better for patients with PD-L1 CPS cut-offs >1 [CPS ≥1, 0.57 (0.44-0.75); CPS ≥5, 0.56 (0.41-0.76); CPS ≥10, 0.53 (0.37-0.75)]. Treatment-related adverse events were reported in 71.8% of patients in the pembrolizumab group and 89.8% in the chemotherapy group; grade 3-5 events were reported in 20.0% and 44.6%, respectively. CONCLUSIONS: Pembrolizumab monotherapy demonstrated promising efficacy in Asian patients with ESCC, with fewer treatment-related adverse events than chemotherapy. PD-L1 CPS ≥1 is an appropriate cut-off and a predictive marker of pembrolizumab efficacy in Asian patients with ESCC.

First-line Cemiplimab versus Standard Chemotherapy in Advanced Non-small Cell Lung Cancer Patients with at Least 50% Programmed Cell Death Receptor Ligand-1 Positivity: Analysis of Cost-effectiveness.

AIMS: The EMPOWER-Lung 1 trial showed that cemiplimab significantly prolongs the duration of progression-free survival and overall survival in advanced non-small cell lung cancer (NSCLC) patients with at least 50% programmed cell death receptor ligand-1 (PD-L1) positivity, yet the financial burden may limit its use. The aim of the present study was to evaluate the cost-effectiveness of cemiplimab versus chemotherapy in a US setting. MATERIALS AND METHODS: A Markov model, with three mutually exclusive health states, was used to compare the expected health outcomes and cost of cemiplimab with chemotherapy. Survival data and transition probabilities were collected from the EMPOWER-Lung 1 trial. Utility values and costs are publicly available from open sources. One-way and probabilistic sensitivity analyses were conducted in both the whole population and subgroups to test the robustness of the parameters and structure. RESULTS: Treatment of NSCLC with cemiplimab yielded an extra 1.07 quality-adjusted life years (QALYs) at an additional cost of $98 211 compared with chemotherapy, associated with an incremental cost-effectiveness ratio of $91 891/QALY and an incremental net health benefit of 0.087 QALYs at a willingness to pay threshold of $100 000/QALY. The probabilistic sensitivity analysis indicated that cemiplimab provided an 83.2% probability of being cost-effective. One-way sensitivity analysis suggested that the price of cemiplimab was the chief driver in this model. A subgroup analysis showed that cemiplimab was the preferred incremental net health benefit in more than half of the subgroups, including patients with squamous type disease and metastases. CONCLUSIONS: Cemiplimab is a cost-effective option in the first-line treatment of NSCLC in patients who are at least 50% PD-L1 positive from an American perspective.

[Parathyroid hormone-related protein aggravates nonalcoholic fatty liver disease induced by methionine choline-deficient diet in mice].

OBJECTIVE: To study the effect of parathyroid hormone-related protein (PTHrP) on nonalcoholic fatty liver disease (NAFLD) induced by methionine choline-deficient diet (MCD) in mice. METHODS: Twelve male C57BL/6J mice were randomized into blank control group, vehicle group and PTHrP group (n=4). The mice in vehicle group and PTHrP group received injections of a control adeno-associated virus (AAV) vector and an AVV vector carrying PTHrP (AAV-PTHrP) gene, respectively, followed one week later by MCD feeding for 3 weeks; the mice in the blank control were fed a normal diet for 4 weeks. Body weight changes of the mice were monitored during the experiment. At the end of the experiment, liver tissues were harvested from the mice for histological analysis using HE staining, oil red O staining, and Sirius red staining. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride, and free fatty acids (FFAs) in the liver and serum were detected to assess hepatic impairment and lipid metabolism of the mice. Cell models of NAFLD were established in mouse and human normal liver cells by treatment with 250 µmol/L FFAs for 24 h, and the effect of AAV-PTHrP on lipid deposition and viability of the cells were tested using Oil Red O and Nile red staining and CCK8 assay. RESULTS: Treatment with AAV-PTHrP, as compared with the control AVV vector, caused more rapid reduction of body weight in mice with MCD feeding and significantly increased the levels of AST (P < 0.05), ALT (P < 0.05), triglyceride (P < 0.01) and FFA (P < 0.05) in the liver and the scores of NAS (P < 0.01) and SAF (P < 0.05). HE and Oil red O staining of the liver tissue revealed obvious lipid deposition after MCD feeding, which was more serious in PTHrP group. In the cell experiment, FFAs induced steatosis in both mouse and human hepatocytes, and treatment with PTHrP increased the accumulation of lipid droplets and lowered the viability of the cell model of NAFLD (P < 0.01 or 0.05). CONCLUSION: PTHrP may aggravate MCD-induced NAFLD in mice by promoting the deposition of lipid droplets in the hepatocytes.

Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy.

PURPOSE: To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). METHODS: Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). RESULTS: Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. CONCLUSION: Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.

[Research progress in gene therapy for Wilson's disease].

Wilson's disease (WD) is a kind of inherited single-gene autosomal recessive disorder in which mutations in the ATP7B gene cause copper excretion disorders. Drug therapy is currently the main treatment method for WD. Liver transplantation should be considered for poor drug response or acute liver failure. However, it faces problems such as medication adherence, adverse reactions and shortage of liver source. Gene therapy in WD may permanently correct abnormal copper metabolism, which is why it is the focus of current research. This article summarizes the research progress of WD around gene therapy vectors and CRISPR/Cas9 gene editing system.

[Combined effect of noise and hand-transmitted vibration on noise-induced hearing loss in the automobile manufacturing industry].

Objective: To investigate the combined effect of noise and hand-transmitted vibration on noise-induced hearing loss (NIHL) in the automobile manufacturing industry. Methods: From September 2018 to January 2019, cluster sampling was used to select 998 workers in an automobile factory as study subjects, among whom 352 workers exposed to noise alone were enrolled as noise group, 342 workers exposed to noise and hand-transmitted vibration were enrolled as combined effect group, and 304 workers without exposure to occupational hazardous factors were enrolled as control group. A questionnaire survey and pure tone audiometry were performed for all study subjects. An analysis of variance was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data between groups; a ordinal polytomous logistic regression analysis was used to investigate the influencing factors for NIHL (with 0.05 as the inclusion criteria and 0.10 as the exclusion criteria for independent variables) . Results: There was a significant difference in L(Aeq, 8 h) between groups (P<0.05) ; the noise group and the combined effect group had a significantly higher L(Aeq, 8 h) than the control group (P<0.05) , while there was no significant difference in L(Aeq, 8 h) between the noise group and the combined effect group (P>0.05) . The control group had a significantly lower detection rate of hearing loss than the noise group and the combined effect group (P<0.0125) , and the combined effect group had a significantly higher detection rate of hearing loss than the noise group (P<0.0125) . The ordinal polytomous logistic regression analysis showed that after adjustment for confounding factors such as age, working years, sex, smoking, and drinking, both noise exposure and exposure to both noise and hand-transmitted vibration had an influence on workers' hearing (P<0.05) , and the workers exposed to both noise and hand-transmitted vibration had a higher risk of hearing loss than those exposed to noise alone. Conclusion: There may be a combined effect of noise and hand-transmitted vibration in the automobile manufacturing industry, which can increase the risk of NIHL in workers.

Histological changes, lipid metabolism, and oxidative and endoplasmic reticulum stress in the liver of laying hens exposed to cadmium concentrations.

The objective of this study was to determine the effects of cadmium (Cd) on histological changes, lipid metabolism, and oxidative and endoplasmic reticulum (ER) stress in the liver of layers. A total of 480 hens at 38 wk of age were randomly assigned in 5 groups that were fed a basal diet or basal diet supplemented with CdCl2 2.5H2O at 7.5, 15, 30, and 60 mg Cd/kg feed for 9 wk. The results showed that accumulation of Cd was the greatest in the kidney, followed by the liver, pancreas, and lung. Diet contaminated with 30 mg Cd/kg induced antioxidant defenses accompanied by the increase of the activities of antioxidant enzymes in the liver, while dietary supplementation with 60 mg Cd/kg decreased the antioxidant levels significantly (P < 0.05). Immunofluorescence assay showed Cd induced reactive oxygen species production and endoplasmic reticulum stress in hepatocytes. Exposure to 60 mg Cd/kg significantly upregulated the expression of cytochrome C, caspase 3, caspase 9, caspase 7, Grp78, and Chop (P < 0.05). Histopathology and quantitative real-time PCR results presented periportal fibrosis, bile duct hyperplasia, and periportal inflammatory cell infiltration in the liver accompanied by upregulating the expression of tumor necrosis factor-α, IL-6 and IL-10 in the 30- or 60-mg Cd/kg groups. Oil Red O staining and RT-qPCR results showed dietary supplementation with 7.5, 15, and 30 mg Cd/kg promoted the synthesis of lipid droplets and upregulated the expression of fatty acid synthase, while dietary supplementation with 60 mg Cd/kg attenuated the synthesis of lipid droplets and downregulated the expression of acyl-CoA oxidase 1, carnitine palmitoyltransferase-1, and perixisome proliferation-activated receptor α (P < 0.05). Besides, the expression of vitellogenin (VTG) II and microsomal triglyceride transfer protein were upregulated in the 7.5-mg Cd/kg group, and the expressions of apolipoprotein B, vitellogenin II, and apolipoprotein very-low-density lipoprotein-II were downregulated in the 30- and/or 60-mg Cd/kg groups (P < 0.05). Conclusively, although low-dose Cd exposure promoted the synthesis of lipids and lipoproteins in the liver, the increase of Cd exposure could trigger liver injury through inducing oxidative and endoplasmic reticulum stress and negatively affect lipid metabolism and yolk formation in laying hens.

Decreased expression of SorCS1 in colorectal cancer: An independent predictor of poor prognosis.

Previously, we identified that sortilin related VPS10 domain containing receptor 1 (SorCS1) was hypermethylated in colorectal cancer (CRC) tissues. Here, we aimed to investigate the association between CRC and SorCS1. DNA methylation was determined by methylation-specific polymerase chain reaction (MSP) or quantitative real-time methylation analysis (MethyLight). Colorectal cancer tissue specimens from 239 patients that had undergone surgical treatment were evaluated using immunohistochemistry (IHC) analysis for the expression of SorCS1 and correlated with clinicopathological variables and prognosis. We found that SorCS1 was hypermethylated in CRC cell lines and 67.5% (27/40) CRC tumor tissues. The loss of SorCS1 mRNA (p<0.001) and protein expression (p=0.033) were highly correlated with promoter methylation. In addition, SorCS1 expression was significantly increased in younger patients (p=0.006), low CEA level (p<0.001) and pT1-2 stage (p=0.005). Survival analysis revealed that decreased expression of SorCS1 was an independent factor for predicting the increased risk of recurrence (p=0.024) and poor overall survival (p=0.006). Subgroup analysis for CEA level, pT and pN classifications showed that SorCS1 retained its stratified significance only in patients with low CEA level, pT3-4 tumors and pN1-2 lymph node status. Our findings suggest that SorCS1 is epigenetically inactivated in a substantial fraction of CRC, and its expression may be a promising prognostic factor in CRC patients.

[Effects of periostin on hepatocellular carcinoma cells invasion, metastasis and prognosis].

Objective: To investigate the prognostic relationship between the expression levels of periostin (POSTN) in hepatocellular carcinoma (HCC) tissues as well as its effect in invasion and metastasis. Methods: The expression levels of POSTN in liver cancer tissues were detected with real-time quantitative PCR (QPCR) and immunohistochemistry (IHC). Kaplan-Meier method and Log-rank test were used to analyze the relationship between POSTN expression level and postoperative prognosis in patients with liver cancer. The expression of POSTN in hepatocellular carcinoma cells with different metastasis characteristics were detected in vitro and the overexpression of POSTN in low metastatic hepatocellular carcinoma cells was mediated through plasmid transfection techniques. The effects of POSTN on invasion and metastasis of hepatocellular carcinoma cells were determined by transwell migration and matrigel invasion assay. The comparative expression level of POSTN was analyzed by t-test. Results: The expression levels of POSTN in tissues from high to low was in the order of metastatic liver cancer tissues, non-metastatic liver cancer tissues and normal liver tissues (P = 0.006). The median survival time and 3-year survival rate in postoperative patients with hepatocellular carcinoma of high POSTN expression level were significantly lower than the low expression group (10.00 months, 44.44%; 59.00 months, 53.13%, P = 0.031 2). In in vitro testing, the expression of POSTN was highest in MHCC97H cells with high metastatic characteristics as compared with Huh7 and MHCC97L cells with low and medium metastatic characteristics. After overexpression of POSTN in MHCC97L cells, the migration and invasion capacity of MHCC97L cells was increased. Conclusion: POSTN is associated with pathological processes such as metastasis and invasion of liver cancer, which may promote the migration and invasion of liver cancer cells. It is expected to be an important prognostic biomarker of tumor recurrence and a therapeutic target for inhibiting the occurrence of metastasis in postoperative patients with hepatocellular carcinoma.