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The study evaluated the efficacy of thalidomide in prevention of camrelizumab-induced reactive cutaneous capillary endothelial proliferation (RCCEP).In this study, patients treated with camrelizumab plus thalidomide or camrelizumab alone were included. The occurrences, onset time, severity of RCCEP and the adverse effect of thalidomide were analysed.A total of 19 patients were enrolled. The incidence of RCCEP in thalidomide group (2/9, 22.2%) was significantly lower than that in camrelizumab group (8/10, 80%). The median onset time of RCCEP was 5 weeks and 4 weeks respectively. The adverse events of thalidomide were mild, and no treatment-associated interruption was observed.Thalidomide showed a promising in prevention of the RCCEP in patients receiving camrelizumab therapy with an acceptable safety profile.

We identified proteins significant for rheumatoid arthritis (RA) in peripheral blood mononuclear cells (PBMCs), and to clarify mechanisms mediated by underlying proteins that may involve in the pathogenesis of RA.Proteome-wide protein expressions were profiled by employing label-free quantitative proteomics methodology (Easy-nLC1000 and Q-exactive). The t-test was applied to identify differentially expressed proteins (DEP, p ≤ 0.05) between RA case and control samples. Gene Ontology enrichment analyses and Protein-Protein Interaction analyses were performed to annotate functions of DEPs. The selected DEP was validated in independent samples using Simple Western assay. Plasma protein level of α2 component of integrin (ITGA2) was measured by using ELISA. The DEP, ITGA2, was assessed for its effects on T cell proliferation, cell cycle, apoptosis, and inflammatory cytokine expression.Sixty-four DEPs (p 0.05) were identified in PBMCs. The selected ITGA2 (Fold Change, FC = 2.20, p = 1.49E-02) was validated to be up-regulated (FC = 12.33, p = 4.90E-2) with RA, and plasma ITGA2 protein level significantly elevated in RA patients vs. controls. Over-expression of ITGA2 could promote proliferation and inhibit apoptosis of Jurkat T cell, and induce IL-8, IFN-γ and TNF-α expression in Jurkat T cells.ITGA2 protein was significantly over-expressed in PBMCs in RA patients, and affects T cell growth and pro-inflammatory cytokine expression in T cells.

Sepsis-associated encephalopathy(SAE) caused by infections outside the central nervous system always presents extensive brain damage.It is common in clinical practice and associated with a poor prognosis.There are problems in the assessing and diagnosing of SAE.Many factors,such as sedation and mechanical ventilation,make it difficult to assess SAE,while electrophysiological examination may play a role in the assessment.We reviewed the studies of electrophysiological techniques such as electroencephalography and somatosensory evoked potentials for monitoring SAE,hoping to provide certain evidence for the clinical evaluation and diagnosis of SAE.

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.

Objective: To verify if AngII/NOX/ROS/MAPK signaling pathway is involved in Doxorubicin (DOX)-induced myocardial injury and if mesenchymal stem cells (MSCs) could enhance the protective effects of valsartan (Val) on attenuating DOX-induced injury in vitro. Methods: Reactive oxygen species (ROS) formation and the protein expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling were assessed in H9c2 cardiomyocytes exposed to DOX for 24 h in the absence or presence of Val, NADPH oxidase inhibitor DPI or knockdown and overexpression of NADPH oxidase subunit: NOX2 and NOX4, co-culture with MSCs, respectively. Finally, MTT assay was used to determine the cell viability of H9c2 cells, MDA-MB-231 breast cancer cells and A549 pulmonary cancer cells under Val, DOX and Val+ DOX treatments. Results: DOX increased ROS formation and upregulated proteins expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling including p-p38, p-JNK, p-ERK in H9c2 cells. These effects could be attenuated by Val, DPI, NOX2 siRNA and NOX4 siRNA. Meanwhile, overexpression of NOX2 and NOX4 could significantly increase DOX-induced ROS formation and further upregulate apoptotic protein expressions and protein expressions of MAPK signaling. MSCs on top of Val further enhanced the protective effects of Val on reducing the DOX-induced ROS formation and downregulating the expression of apoptotic proteins and MAPK signaling as compared with Val alone in DOX-treated H9c2 cells. Simultaneous Val and DOX treatment did not affect cell viability of DOX-treated MDA-MB-231 breast cancer cells or A549 pulmonary cancer cells but significantly improved cell viability of DOX-treated H9c2 cardiomyocytes. Conclusions: AT1R/NOX/ROS/MAPK signaling pathway is involved in DOX-induced cardiotoxicity. Val treatment significantly attenuated DOX-induced cardiotoxicity, without affecting the anti-tumor effect of DOX. MSCs enhance the protective effects of Val on reducing the DOX-induced toxicity in H9c2 cells.

To investigate the clinical effect of Kinesio Taping combined with electroacupuncture in the treatment of Bigliani typeⅠsubacromial impingement syndrome.From January 2019 to June 2021, 82 cases with Bigliani typeⅠsubacromial impingement syndrome were selected and divided into treatment group and control group. Treatment group included 41 cases, 23 males and 18 females, aged from 20 to 52 years old, with an average of (39.31±5.80)years old. There were 12 cases on left shoulder and 29 cases on right shoulder. The course of disease was from 3.2 to 35.4 months. The treatment group was treated with Kinesio Taping and electroacupuncture. In control group, there were 41 cases, including 22 males and 19 females, aged from 19 to 53 years old with an average of (40.67±6.13) years old, 30 cases on right shoulder, 11 cases on left shoulder. The courses of disease was from 3.0 to 36.0 months. The control group was treated with simple shoulder electroacupuncture. Patients in both groups were treated with electroacupuncture 3 times a week for 3 weeks. After each electroacupuncture treatment in the treatment group, the Kinesio Taping was applied immediately and kept for 2 days. Before treatment, immediately after treatment, and after 1, 3, 8 weeks, the shoulder joint Constant-Murley score, pain visual analogue scale (VAS), and shoulder joint range of motion were used to evaluate the treatment effect.After 1 week of treatment, there was 1 patient in treatment group refused treatment due to hypersensitivity to Kinesio Taping, 1 patient in control group was allergic to the metal needle and refused treatment. And the other 80 patients completed all treatment. Immediately after treatment, and 1, 3, and 8 weeks after treatment, VAS of treatment group were (2.06±1.03), (2.74±1.66), (3.28±1.04), and (3.90±0.12) points, respectively. The Constant-Murley scores of shoulder joint were(86.41±3.52), (82.44±3.14), (80.46±2.54), (76.97±2.01) points. VAS of control group were(3.35±0.41), (3.08±0.92), (3.77±0.67), (3.96±1.04) points, and the Constant-Murley scores of the shoulder joint were(75.82±2.73), (74.72±1.53), (73.66±1.53), (70.68±1.95) points respectively. Immediately after treatment, VAS, Constant-Murley score, and shoulder range of motion between two groups were better than those of before treatment (The treatment for bigliani typeⅠsubacromial impingement syndrome with Kinesio Taping combined with electroacupuncture can reduce pain, effectively improve the function of shoulder joint. In addition, with Kinesio Taping protection when motion, the patients sports ability can be improved obviously, with good immediate effect, and no trauma. If the patients are willing to accept it, it would be an immediate and effective treatment.

Galectin-3 (Gal-3), a member of the β-galactoside-binding protein family, is implicated in a wide variety of human diseases. Identification of Gal-3 inhibitors with the right combination of potency (against both human and mouse Gal-3) and pharmacokinetic properties to fully evaluate the potential of Gal-3 for therapeutic intervention has been a major challenge due to the characteristics of its binding pocket: high hydrophilicity and key structural differences between human Gal-3 and the mouse ortholog. We report the discovery of a novel series of monosaccharide-based, highly potent, and orally bioavailable inhibitors of human and mouse Gal-3. The novel monosaccharide derivatives proved to be selective for Gal-3, the only member of the chimeric type of galectins, over Gal-1 and Gal-9, representative of the prototype and tandem-repeat type of galectins, respectively. The proposed binding mode for the newly identified ligands was confirmed by an X-ray cocrystal structure of a representative analogue bound to Gal-3 protein.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various biological processes, including proliferation, metastasis, angiogenesis, immune response, and chemoresistance. In normal cells, STAT3 is tightly regulated to maintain a transiently active state, while persistent STAT3 activation occurs frequently in cancers, associating with a poor prognosis and tumor progression. Targeting the STAT3 protein is a potentially promising therapeutic strategy for tumors. Although none of the STAT3 inhibitors has been marketed yet, a few of them have succeeded in entering clinical trials. This Review aims to systematically summarize the progress of the last 5 years in the discovery of directive STAT3 small-molecule inhibitors and degraders, focusing primarily on their structural features, design strategies, and bioactivities. We hope this Review will shed light on future drug design and inhibitor optimization to accelerate the discovery process of STAT3 inhibitors or degraders.

BACKGROUND: Cervical cancer is a common gynecological cancer among women worldwide. OBJECTIVE: To determine the effects of 6 MV and 10 MV volumetric-modulated arc therapy (VMAT) photon beams on the target volume (TV) planning and critical organs in cases of cervical cancer. METHODS: Fifty patients with carcinoma of the cervix who underwent radiotherapy were selected. The transverse diameter (T) of the cross section of the upper edge of the sacroiliac joint on computerized tomography (CT) images of the patients was measured, and the mean value was calculated as 34 cm. All patients were divided into two groups: Group A (T < 34 cm) and Group B (T > 34 cm). The VMAT plans were generated using 6 MV and 10 MV plans separately. The prescription dose was 47.5 Gy, and the daily dose was 1.9 Gy. RESULTS: In Group A, the planning target volume (PTV) dose assessment parameters of 6 MV and 10 MV plans and their homogeneity and conformity indices were not statistically significantly different. A significant difference was observed between the 6 MV and 10 MV plans for the PTV dose assessment parameters and the homogeneity index of the plans for Group B. The monitor units (MUs) of the 10 MV plans were lower than in the 6 MV plans in both Groups A and B, and the difference was statistically significant. The assessment parameter V40 Gy of both the rectum and bladder in the 6 MV plans was smaller than the corresponding parameter in the 10 MV plans in Group A; in Group B, the assessment parameter V50 Gy of the rectum in the 10 MV plans was smaller than in the 6 MV plans. CONCLUSION: When T < 34 cm, 6 MV energy is more suitable for the external irradiation of cervical cancer. When T > 34 cm, 10 MV energy is more suitable for cervical cancer radiotherapy. Therefore, 10 MV should be considered for patients with a large abdominal size.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease often caused by sarcomeric gene mutations. MYBPC3 is one of the most common genes associated with HCM. In this study, we generated a human induced pluripotent stem cell line ZZUNEUi028-A from a 19-year-old male HCM patient with c. 1504C → T in MYBPC3 gene using non-integrative Sendai viral reprogramming technology. This cell line expresses pluripotency markers, exhibits a normal male karyotype (46, XY) and can differentiate into all three germ layers in vitro. ZZUNEUi028-A can serve as a cell disease model in the understanding of HCM pathogenesis.

To evaluate the predictors for efficacy and safety of patients with acute ischemic stroke (AIS) and Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) ＜6 undergoing endovascular therapy (EVT).This study retrospectively analyzed consecutive patients presented between December 2020 and December 2021 with large vessel occlusions (LVO) within the anterior circulation and an ASPECTS ＜6, followed by EVT. The efficacy outcome was 90-day functional independence, defined as modified Rankin Scale (mRS) score 0-3. The primary safety outcome was symptomatic intracranial hemorrhage (sICH). Secondary safety outcomes included 90-day all-cause mortality and 24-hour any ICH.A total of 22 patients were included. The percentage of patients with mRS 0-3 at 90 days was 36.4% (8/22). The occurrence of sICH was 22.7% (5/22). The occurrence of any ICH was 45.5% (10/22). The 90-day all-cause mortality was 36.4% (8/22). Median (interquartile range, IQR) cerebral blood volume (CBV) index was 0.5 (0.4-0.7). CBV index in mRS 0-3 group (n = 8) was higher than mRS 4-5 group (n = 14) (P＜0.05). There was no significant difference of age, gender, comorbidities, baseline National Institutes of Health Stroke Scale (NIHSS) score, mismatch ratio, CBV index, interval between stroke onset and re-perfusion, good re-perfusion rate between sICH group (n = 5) and non-sICH group (n = 17).AIS patients with low ASPECTS can still benefit from EVT and gain good functional outcome, especial those had higher CBV index on pre-EVT computed tomography perfusion (CTP). Further studies with larger sample size are needed to validate our findings.

We previously reported the neuroprotective effects of (+)-balasubramide derived compound 3C, but its action on atherosclerosis in vivo remains unknown. The study was designed to investigate the potential effects of 3C on atherogenesis and explore the possible underlying mechanisms. 3C ameliorated high-fat diet-induced body weight gain, hyperlipidemia, and atherosclerotic plaque burden in apolipoprotein E-deficient (ApoE-/-) mice after 10 weeks of treatment. 3C suppressed the expression of genes involved in triglyceride synthesis in liver. 3C prevented aortic inflammation as evidenced by reduction of adhesive molecule levels and macrophage infiltration. Mechanistic studies revealed that activation of AMP-activated protein kinase (AMPK) is central to the athero-protective effects of 3C. Increased AMPK activity by 3C resulted in suppressing interferon-γ (IFN-γ) induced activation of signal transducer and activator of transcription-1 (STAT1) and stimulator of interferon genes (STING) signaling pathways and downstream pro-inflammatory markers. Moreover, 3C inhibited ox-LDL triggered lipid accumulation and IFN-γ induced phenotypic switch toward M1 macrophage in RAW 264.7 cells. Our present data suggest that 3C prevents atherosclerosis via pleiotropic effects, including amelioration of lipid profiles, vascular inflammation and macrophage pro-inflammatory phenotype. 3C has the potential to be developed as a promising drug for atherosclerosis and related cardiovascular disease.

TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-chain TRAIL receptor binding domain monomers. This hexavalent agonistic fusion protein binds to the death-inducing DR4 and DR5 receptors with nanomolar affinity to drive on-target biological activity with enhanced caspase-8 aggregation and death-inducing signaling complex formation independent of FcγR-mediated cross-linking, and without clinical signs or pathologic evidence of toxicity in nonrodent species. ABBV-621 induced cell death in approximately 36% (45/126) of solid cancer cell lines in vitro at subnanomolar concentrations. An in vivo patient-derived xenograft (PDX) screen of ABBV-621 activity across 15 different tumor indications resulted in an overall response (OR) of 29% (47/162). Although DR4 (TNFSFR10A) and/or DR5 (TNFSFR10B) expression levels did not predict the level of response to ABBV-621 activity in vivo, KRAS mutations were associated with elevated TNFSFR10A and TNFSFR10B and were enriched in ABBV-621–responsive colorectal carcinoma PDX models. To build upon the OR of ABBV-621 monotherapy in colorectal cancer (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-XL. In summary, these data provide a preclinical rationale for the ongoing phase 1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in patients with cancer. Significance: This study describes the activity of a hexavalent TRAIL-receptor agonistic fusion protein in preclinical models of solid tumors that mechanistically distinguishes this molecular entity from other TRAIL-based therapeutics.

Introduction Gastric cancer (GC) has a high incidence and mortality rate, especially in East Asians, and about 90% of GCs are adenocarcinomas. Histological and etiological heterogeneity and ethnic diversity make molecular subtyping of GC complicated, thus making it difficult to determine molecular division systems and standard treatment modalities. Limited cohorts from South Korea, Singapore, Australia, and Japan have been studied; however, the mutational landscape of gastric adenocarcinomas in Chinese patients is still unknown. Methods We performed a targeted sequencing panel focusing on cancer‐related genes and tumor‐associated microorganisms of 529 gastric adenocarcinoma samples with matched blood controls. We identified 449 clinically relevant gene mutations. Results Approximately 47.1% of Chinese patients with GC harbored at least one actionable mutation. The top somatic mutations were TP53, ARID1A, LRP1B, PIK3CA, ERBB2, CDH1, KRAS, FAT4, CCNE1, and KMT2D. Truncation mutations of ARID1A, KMT2D, RNF43, TGFBR2, and CIC occurred in patients with high tumor mutational burden. Gene amplifications of ERBB2, CCNE1, CDK12, and CCND1 were detected in patients with low tumor mutational burden. Pathway analysis revealed common gene alterations in the Wnt and PI3K/Akt signaling pathways. The ratio of patients with high microsatellite instability was significantly lower than other cohorts, and high microsatellite instability and Epstein‐Barr virus (EBV)–positive features seemed mutually inclusive in Chinese patients with GC. In 44 (8.3%) patients, 45 germline mutations were identified, among which SPINK1 mutations, all SPINK1 c.194 + 2T > C, were present in 15.9% (7/44) of patients. Microorganisms found in Chinese patients with GC included Helicobacter pylori, EBV, hepatitis B virus, and human papillomavirus types 16 and 18. Conclusion Identification of varied molecular features by targeted next‐generation sequencing provides more insight into patient stratification and offers more possibilities for both targeted therapies and immunotherapies of Chinese patients with GC. Implications for Practice This study investigated the genomic alteration profile of 529 Chinese patients with gastric adenocarcinoma by deep targeting sequencing, which might be the largest Chinese cohort on the genomic research of gastric adenocarcinoma up to now., Novel molecular targeted therapies for gastric cancer are urgently needed. This article explores the mutational landscape covering somatic, germline, and microorganisms among a cohort of Chinese patients with gastric cancer. Findings provide insight on patient stratification and potential molecular targets, and for developing new treatment strategies for patients in China and worldwide.

Background The detection rate of methylated Septin9 (mSEPT9) in colorectal cancer (CRC) is varied greatly across the studies. This study aimed to evaluate the diagnostic ability of mSEPT9 in CRC, and compare the diagnostic efficacy with fecal immunochemical test (FIT). Methods 326 subjects from four centers were prospectively recruited, including 179 CRC and 147 non-CRC subjects. The plasma was collected for mSEPT9 and CEA, AFP, CA125, CA153 and CA199 test, and fecal samples for FIT tests. Sensitivity, specificity and area under the curve (AUC) of receiver operating characteristic curve were calculated to evaluate the diagnostic value of each biomarker. Results The positive rate in mSEPT9 and FIT, and the level of CEA, CA125 and CA199 were significantly higher in CRC compared with non-CRC subjects. The mSEPT9 positive rate was not associated with TNM stage and tumor stage. The sensitivity, specificity and AUC of mSEPT9 in diagnostic CRC were 0.77, 0.88 and 0.82, respectively, while the value in FIT was 0.88, 0.80 and 0.83, respectively. mSEPT9 and FIT have higher AUC value than that of CEA, CA125 and CA199. Combination of both mSEPT9 and FIT positive increased sensitivity and AUC to 0.98 and 0.83, respectively, but the specificity was declined. mSEPT9 has a slightly low sensitivity in diagnosis of colon cancer (0.87) compared with rectal cancer (0.93). Conclusion mSEPT9 demonstrated moderate diagnostic value in CRC detection, which was similar to the FIT but superior to the CEA, CA125 and CA199. Combination of mSEPT9 and FIT further improved diagnostic sensitivity in CRC. Trial registration: ChiCTR2000038319.

Most of complete hydatidiform moles (CHMs) showcase an androgenetic nature of the nuclear genome. In the normal female embryo, one of the 2 X chromosomes is inactive. However, the status of X chromosome inactivation (XCI) in androgenetic CHMs remains unknown. Seventy-one androgenetic CHM tissues with the 46, XX karyotype were collected. Seventy-four normal female villi and 74 normal male villi were collected as controls. The expression of XCI markers (XIST, TSIX, and XACT) and an X-linked gene (CDX4) was detected by real-time polymerase chain reaction. Other XCI-associated genes were also examined, including the methylation status of the human androgen receptor gene (HUMARA) by methylation-specific polymerase chain reaction), and the expression of H3K27me3, USP21, and Nanog by Western blot and immunofluorescence, respectively. In addition, 126 CHMs and 63 normal female villous samples were collected for CDX4 immunohistochemical staining. The expression of XIST RNA was significantly lower, and TSIX RNA expression was significantly higher in androgenetic CHMs than that in normal female villi (both P

BACKGROUND Subjective cognitive decline (SCD) has been called the prodromal stage of amnestic mild cognitive impairment (aMCI); however, further investigation is needed to confirm this observation. OBJECTIVE To define the relationship between SCD and aMCI. METHOD In this case-control study, we used the feeling-of-knowing in episodic memory (FOK-EM) test to measure the memory-monitoring function of 40 adults with aMCI, 60 with SCD, and 55 healthy controls. RESULTS The recognition rates of FOK-EM (53.53% ± 7.82%; 55.12% ± 6.08%) and judgment accuracy of the aMCI and SCD groups (γ values 0.21 ± 0.11; 0.30 ± 0.16) were significantly lower than those of the control group (72.32% ± 5.14%; 0.57 ± 0.16) (F = 116.24, P < 0.01; F = 128.57, P < 0.01; F = 73.33, P < 0.01). The scores for correct decision/correct recognition (RR; 27.2 ± 6.43; 29.36 ± 5.16) and correct decision/false recognition (RF; 30.41 ± 5.06; 27.26 ± 4.37) of the aMCI and SCD groups were also significantly lower than those of the control group (49.35 ± 7.13; 11.16 ± 4.35) (FRR = 132.67, P < 0.01; FRF = 131.8, P < 0.01). CONCLUSION Mild clinical impairments in memory-monitoring function may precede clinically confirmed objective memory impairment in individuals with SCD.

MicroRNAs (miRNAs) are reported to be involved in renal hypoxia/reoxygenation (H/R) damage. To investigate this further, human kidney (HK‑2) cells were cultured, subjected to H/R and the function of miR‑30a‑5p and glutamate dehydrogenase 1 (GLUD1) was evaluated. The results showed that, miR‑30‑5p was downregulated and GLUD1 was upregulated in HK‑2 cells exposed to H/R. The relationship between miR‑30a‑5p and GLUD1 was determined using dual luciferase assays. Primary HK‑2 cells were cultured in H/R and transfected with negative control 1 (NC1), negative control 2 (NC2), mimic, inhibitor or GLUD1 siRNA plasmids. Reactive oxygen species (ROS) generation, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and the rate of apoptosis in HK‑2 cells were assessed. The results showed that, miR‑30a‑5p mimic reduced the production of ROS in HK‑2 cells treated with H/R, but increased the activity of SOD, CAT and GPx. In addition, miR‑30a‑5p mimic significantly decreased H/R‑mediated apoptosis, decreased the expression of bax and activity of caspase‑3 and enhanced the expression of bcl‑2. However, miR‑30a‑5p inhibitor showed the opposite effect with regard to the degree of oxidative damage and apoptosis in H/R‑induced HK‑2 cells. Silencing GLUD1 rescued the influence of miR‑30a‑5p inhibitor on oxidative injury and apoptosis in HK‑2 cells stimulated with H/R. These results demonstrated that under H/R conditions, miR‑30a‑5p can reduce oxidative stress in vitro by targeting GLUD1, which may be a novel therapeutic target for liver failure and worth further study.

Glioblastoma (GBM) patients have extremely poor prognoses, and currently no effective treatment available including surgery, radiation, and chemotherapy. MAPK-interacting kinases (MNK1/2) as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells. Research has shown that targeting MNKs may be an effective strategy to treat GBM. In this study we investigated the antitumor activity of osimertinib, an FDA-approved epidermal growth factor receptor (EGFR) inhibitor, against patient-derived primary GBM cells. Using high-throughput screening approach, we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients, found that osimertinib (3 μM) suppressed the proliferation of a subset (10/22) of EGFR-negative GBM cells (>50% growth inhibition). We detected the gene expression difference between osimertinib-sensitive and -resistant cells, found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway. We further showed that osimertinib potently inhibited the MNK kinase activities with IC(50) values of 324 nM and 48.6 nM, respectively, against MNK1 and MNK2 kinases; osimertinib (0.3–3 μM) dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). In GBM patient-derived xenografts mice, oral administration of osimertinib (40 mg· kg(−1) ·d(−1), for 18 days) significantly suppressed the tumor growth (TGI = 74.5%) and inhibited eIF4E phosphorylation in tumor cells. Given the fact that osimertinib could cross the blood–brain barrier and its toxicity was well tolerated in patients, our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.

Previous investigations showed inconsistent results for associations between vitamin D and knee osteoarthritis (OA). The present study aimed to make a systematic review and meta-analysis for the association between vitamin D and knee OA.We systematically searched for articles published in the databases PubMed, Web of Science, EMBASE, Medline, and Google Scholar through July 2019. All statistical analyses were made using STATA 12.0 software. The Q test and IThe study indicated that there were no significant associations between serum levels of 25-hydroxy (OH) vitamin D and prevalence, incidence or progression of knee radiographic OA (ROA), and joint space narrowing (JSN). However, a subgroup study showed significant associations of low vitamin D levels with the progression of knee OA. Additionally, the present study showed no significant effect of vitamin D supplementation on knee OA.The results do not support that serum levels of 25(OH) vitamin D are associated with the risks of knee OA, except perhaps with progression of knee OA. In addition, vitamin D supplementation may not have a clinically significant effect on pain control or structure (tibial cartilage volume and JSW) progression in patients with knee OA. Longer-term clinical trials are essential to explore the effect of vitamin D supplementation on knee OA.Frühere Untersuchungen ergaben inkonsistente Ergebnisse für Assoziationen zwischen Vitamin D und Knie-Osteoarthritis (Knie-OA). Die vorliegende Studie zielte auf eine systematische Überprüfung und Metaanalyse des Zusammenhangs zwischen Vitamin D und Knie-OA ab.Wir haben systematisch nach Artikeln gesucht, die in folgenden Datenbanken (PubMed, Web of Science, EMBASE, Medline und Google Scholar) bis Juli 2019 veröffentlicht wurden. Alle statistischen Analysen wurden mit der Software STATA 12.0 durchgeführt. Der Q-Test und IDie Studie ergab, dass keine signifikanten Zusammenhänge zwischen dem Serumspiegel von 25-Hydroxy-Vitamin D (25-OH-Vitamin D) und der Prävalenz, Inzidenz oder Progression von radiografischem OA (ROA) und Gelenkspaltverengung (JSN) im Knie bestehen. Eine Subgruppenstudie zeigte jedoch signifikante Assoziationen niedriger Vitamin-D-Spiegel mit dem Fortschreiten der Knie-OA. Zusätzlich zeigte die vorliegende Studie keinen signifikanten Effekt der Vitamin-D-Supplementierung auf die Knie-OA.Die Ergebnisse belegen nicht, dass Serumspiegel von 25-OH-Vitamin D mit dem Risiko einer Knie-OA assoziiert waren, außer vielleicht mit dem Fortschreiten der Knie-OA. Darüber hinaus hat eine Vitamin-D-Supplementierung möglicherweise keinen klinisch signifikanten Einfluss auf die Schmerzkontrolle oder den Strukturverlauf (Tibiaknorpelvolumen und JSW) bei Patienten mit Knie-OA. Langfristige klinische Studien sind unerlässlich, um die Wirkung der Vitamin-D-Supplementierung auf die Knie-OA zu untersuchen.

Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, chemo-resistance is the main cause for treatment failure. Our previous studies have found that SKOV3 could promote immune escape and tumor progression via Notch1 pathway. Therefore, Notch1 is suspected to be involved in chemo-resistance. The current study is to investigate the possible mechanisms of platinum-resistance in epithelial ovarian cancer mediated by Notch1. Methods: The expressions of Notch1, Snail, MMP-2, N-cadherin, Vimentin and E-cadherin were detected by Western-blot. A stable high expression or low expression of Notch1 in ovarian cancer cells was established by using lentiviral gene engineering. The cell migration and invasion ability were observed by scratch test and transwell test. Cell apoptosis rate and cell cycle were analyzed by flow cytometry. Results: The expression levels of Notch1, Snail, MMP-2, N-cadherin and Vimentin in ovarian cancer were high, while the expression levels of E-cadherin were low.Notch1 promoted the expression of Snail, vimentin, N-cadherin and MMP2 protein, but inhibiting the expression of E-cadherin, promoting cell migration and invasion. Notch1 affected apoptosis of cells through Epithelial-Mesenchymal Transition (EMT), increasing the proportion of cells in S phase and G2 phase, thus affecting drug resistance. Conclusion: Notch1 affects EOC cells chemo-resistance by regulating EMT. This may provide a new target for the treatment of ovarian cancer.

Monoacylglycerol acyltransferase 2 (MGAT2) is an important enzyme highly expressed in the human small intestine and liver for the regulation of triglyceride absorption and homeostasis. We report that treatment with BMS-963272, a potent and selective MGAT2 inhibitor, decreased inflammation and fibrosis in CDAHFD and STAM, two murine nonalcoholic steatohepatitis (NASH) models. In high-fat-diet-treated cynomolgus monkeys, in contrast to a selective diacylglycerol acyltransferase 1 (DGAT1) inhibitor, BMS-963272 did not cause diarrhea. In a Phase 1 multiple-dose trial of healthy human adults with obesity (NCT04116632), BMS-963272 was safe and well tolerated with no treatment discontinuations due to adverse events. Consistent with the findings in rodent models, BMS-963272 elevated plasma long-chain dicarboxylic acid, indicating robust pharmacodynamic biomarker modulation; increased gut hormones GLP-1 and PYY; and decreased body weight in human subjects. These data suggest MGAT2 inhibition is a promising therapeutic opportunity for NASH, a disease with high unmet medical needs.

Background Pancreatic cancer is one of the most lethal cancers worldwide. The IAPs function as E3 ubiquitin ligases and contribute to pancreatic cancer initiation, progression, and metastasis. Although IAP-targeted therapies have been developed and shown anticancer efficacy in preclinical settings, none of them has been approved yet. Methods Transcriptome data from public datasets were used to analyze the correlation of IAPs and E2s, and the biological function of E2 UbcH5c in pancreatic cancer. A structure-based virtual screen was used to identify UbcH5c inhibitor, and surface plasmon resonance analysis and cellular thermal shift assays were employed to evaluate the binding affinity. The anticancer activities were demonstrated through in vitro and in vivo assays, while the related mechanisms were explored through transcriptomic and proteomic analyses and confirmed by western blot, immunofluorescence, and qRT-PCR. Results UbcH5c is positively correlated with the expression of IAPs in pancreatic cancer. We further found that UbcH5c is overexpressed and associated with a poor prognosis in pancreatic cancer. We identified a small-molecule UbcH5c inhibitor, termed DHPO, which directly bound to UbcH5c protein. DHPO inhibited cell viability and colony formation, induced apoptosis, and suppressed migration and invasion of pancreatic cancer cells in vitro. The compound inhibited UbcH5c-mediated IκBα degradation and NF-κB activation, which is critical for its anticancer activity. Furthermore, DHPO suppressed the tumor growth and metastasis in two orthotopic pancreatic tumor mouse models. Conclusions These results indicated that inhibiting UbcH5c is a novel and effective strategy for treating pancreatic cancer and DHPO represents a new class of UbcH5c inhibitor and may be further developed as an anti-pancreatic cancer therapeutic agent.

Gliosarcoma (GSM), a histologic variant of glioblastoma (GBM), carries a poor prognosis with less than one year of median survival. Though GSM is similar with GBM in most clinical and pathological symptoms, GBM has unique molecular and histological features. However, as the rarity of GSM samples, the genetic information of this tumor is still lacking. Here, we take a comprehensive analysis of DNA copy number variations (CNV) in GBM and GSM. Whole genome sequencing was performed on 21 cases of GBM and 15 cases of GSM. CNVKIT is used for CNV calling. Our data showed that chromosomes 7, 8, 9, and 10 were the regions where CNV frequently happened in both GBM and GSM. There was a distinct CNV signal in chromosome 2 especially in GSM. The pathway enrichment of genes with CNV was suggested that the GBM and GSM shared the similar mechanism of tumor development. However, the CNV of some screened genes displayed a disparate form between GBM and GSM, such as AMP, BEND2, HDAC6, FOXP3, ZBTB33, TFE3, and VEGFD. It meant that GSM was a distinct subgroup possessing typical biomarkers. The pathways and copy number alterations detected in this study may represent key drivers in gliosarcoma oncogenesis and may provide a starting point toward targeted oncologic analysis with therapeutic potential.

Gastric cancer remains a significant health burden worldwide. In continuation of our previous study and development of effective small molecules against gastric cancer, a series of benzochalcone analogues involving heterocyclic molecules were synthesised and biologically evaluated in vitro and in vivo. Among them, the quinolin-6-yl substituted derivative KL-6 inhibited the growth of gastric cancer cells (HGC27, MKN28, AZ521, AGS, and MKN1) with a submicromolar to micromolar range of IC50, being the most potent one in this series. Additionally, KL-6 significantly inhibited the colony formation, migration and invasion, and effectively induced apoptosis of MKN1 cells in a concentration-dependent manner. The mechanistic study revealed that KL-6 could concentration-dependently suppress STAT3 phosphorylation, which may partly contribute to its anticancer activity. Furthermore, in vivo antitumour study on the MKN1 orthotopic tumour model showed that KL-6 effectively inhibited tumour growth (TGI of 78%) and metastasis without obvious toxicity. Collectively, compound KL-6 may support the further development of candidates for gastric cancer treatment.

Gastric cancer (GC) is a common malignancy with low 5‐year overall survival (OS). Recently, immune therapy has been used to treat cancer. B7H5 and CD28H are novel immune checkpoint molecules. However, the prognostic value of B7H5/CD28H expression in patients with GC remains unclear. In this study, seventy‐one patients diagnosed with GC were included in this study. Patients' GC tissues and matched adjacent tissue constructed a tissue microarray. The expression levels of B7H5 and CD28H were examined using immunohistochemistry. Correlations between the expression of B7H5 and CD28H and the clinical data were evaluated. We found that the expression of B7H5 and CD28H (both P = .001) were higher in GC tumour tissues than in adjacent noncancerous tissues. B7H5/CD28H expression acted as an independent predictive factor in the OS of patients with GC. High expression of B7H5 and CD28H predicted poor outcome. Patients in the B7H5+CD28H+ group had a lower 5‐year OS compared with patients in the B7H5−CD28− group (4.5% vs 55.6%, P = .001). A significant difference was found in the 5‐year OS between patients in the B7H5+CD28H− and B7H5+CD28H+ groups (33.5% vs 4.5%, P = .006). However, there was no correlation between B7H5 and CD28H expression (P = .844). Therefore, B7H5 and CD28H expression are up‐regulated in GC and are independent prognostic factors for overall survival in patients with GC. Although there was no correlation between B7H5 and CD28H expression, high expression of B7H5 and CD28H predicts poor prognosis, especially when both are highly expressed.

BackgroundNot all lung adenocarcinoma (LUAD) patients with activating epidermal growth factor receptor (EGFR) mutations respond to tyrosine kinase inhibitors (TKIs) as intended. Thus, biomarkers are needed to identify patients who benefit most from EGFR-targeted therapy. Our previous in vitro data has shown that the co-signal molecule B7-H3 determines EGFR-TKI gefitinib susceptibility ofEGFR-mutated LUAD cell lines, based on the potential crosslinking between B7-H3-induced signaling and EGFR signaling.MethodsWe detected tumoral B7-H3 expression in the original biopsy from 56 treatment-naïve LUAD patients and analyzed the association between high/low B7-H3 expression with the clinical outcomes of first-line anti-EGFR therapy. The main criteria for the analysis of response were overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS), and the secondary criterion was overall survival (OS).ResultsIn the subgroups of B7-H3 high and low expression, the ORR were 16.0% (4/25) and 74.2% (23/31) (ppp=0.001]. The median OS was 15.9 (95% CI 10.0–21.8) months in the B7-H3 high cohort and 25.7 (95% CI 9.0–42.4) months in the B7-H3 low subjects [HR 2.08 (95% CI 1.07–4.02),p=0.03], respectively. Both the univariate and multivariate analyses identified B7-H3 as an independent factor associated with poor PFS (p=0.001,p=0.000) and OS (p=0.03,p=0.015).ConclusionB7-H3 may serve as a potential biomarker to predict clinical outcomes inEGFR-mutated LUAD patients treated with first-line EGFR-TKIs.

ObjectivesThe administration of nursing assistants is closely associated with patient outcomes, but the current situation needs improvement. Studies evaluating intrahospital administration of nursing assistants are limited, and there is a lack of available evidence-based reviews in this field. This study aimed to identify existing literature on intrahospital nursing assistants’ administration approaches.DesignScoping review.Search strategyWe searched fifteen electronic databases for English and Chinese articles published between January 2011 and March 2022. Publications on administration approaches, models and appraisal tools of intrahospital nursing assistants were included.ResultsThirty-six studies were eligible for the review with acceptable quality. We identified one administration model, nine administration methods, fifteen educational programs, and seven appraisal tools from the included studies. The frequency effect size analysis yielded 15 topics of the main focus at four levels, suggesting that included articles were mainly (33%) focused on the competency of nursing assistants, and the lectures were the most (80%) used strategy in quality improvement projects. Evidence from the studies was of low-to-moderate quality, indicating huge gaps between evidence-based research and management practice.ConclusionsA series of practical intrahospital administration approaches was revealed, and fifteen primarily focused topics were identified. We should explore this area more thoroughly using structured frameworks and standardized methodology. This scoping review will help managers find more effective ways to improve the quality of care. Researchers may focus more on evidence-based practice in nursing assistant administration using the 15 topics as a breakthrough.Strengths and limitationsFirst scoping review of practical administration approaches for nursing assistants in hospitals.Presenting the main topics and focus of related articles.Development of the nursing assistant administration was widely varied among countries.Most of the included studies were of moderate-to-low methodological quality, and a huge gap exists between evidence-based research and management practice.

Background Survival benefit of adjuvant radiotherapy for locally advanced gastric cancer following gastrectomy plus D2 lymphadenectomy has always been controversial. Esophagogastric junction (EGJ) adenocarcinoma, which is usually classified as gastric cancer in East Asia, often has a higher locoregional recurrence rate after operation because of its special anatomical characteristics. The aim of this study is to determine whether adjuvant radiotherapy can improve survival of locally advanced EGJ adenocarcinoma after D2 radical resection. Methods In this phase III, randomized, open label, controlled trial, we plan to recruit 378 patients with Siewert type II and III adenocarcinoma of EGJ, who had undergone transabdominal radical surgery and D2 lymphadenectomy, and were divided into pathological stage IIB to IIIC. All patients will be randomized 1:1 to receive either adjuvant chemotherapy alone (control group) or adjuvant chemotherapy plus chemoradiotherapy (experimental group). Patients allocated to control group will receive eight cycles of S-1 plus oxaliplatin (SOX), while the experimental group will receive two cycles of SOX followed by 45-Gy RT combined with S-1 and four additional cycles of SOX. The primary endpoint is 3-year disease-free survival rate (DFS). The secondary endpoints are 3-year overall survival rate (OS), 3-year locoregional recurrence-free survival rate (LRFS), 3-year distant metastasis-free survival rate (DMFS), and quality of life (QoL). Discussion In the past, the adjuvant treatment of EGJ adenocarcinoma needs to draw on the experience of esophageal adenocarcinoma or gastric adenocarcinoma. In this study, EGJ adenocarcinoma is considered as an independent disease, and the conclusion will provide evidence for optimal adjuvant therapy of locally advanced EGJ adenocarcinoma after D2 radical resection. Trial registration ClinicalTrials.govNCT03973008. Registered on 1 June 2019 (retrospectively registered), URL: https://clinicaltrials.gov/ct2/show/NCT03973008?term=NCT03973008&draw=2&rank=1

To analyze the clinical characteristics of patients with POEMS syndrome and explore its effective treatment strategies.The clinical data of 75 patients with POEMS syndrome treated in The First Affiliated Hospital of Zhengzhou University from June 2012 to June 2018 were collected and retrospectively analyzed. The clinical characteristics, treatment regimes and outcomes of the patients were summarized.The median age of 75 diagnosed patients was 50 (30-81) years old and 100% (75/75) of the patients were accompanied with peripheral neuropathy, 77.3% (58/75) with organ enlargement, 82.7% (62/75) with endocrine abnormality, 93.3% (70/75) with monoclonal plasma cell diseases and 64.0% (48/75) with skin changes. Among the 75 patients, 5 cases gave up treatment, while the others showed varying degrees of improvement after treatment. The hematological complete remission (CRThe clinical manifestations of POEMS syndrome are complex and diverse, the clinicians therefore should be vigilant to reduce the misdiagnosis and missed diagnosis. Bortezomib or Lenalidomide can be recommended as the first-line medicines and autologous HSCT should be considered for appropriate patients.POEMS综合征患者的临床特征及疗效分析.分析POEMS综合征患者的临床特征，并探讨有效的治疗策略。.对2012年6月至2018年6月本院收治的75例POEMS综合征患者的病历资料进行收集并回顾性分析，总结患者的临床特点、治疗方法及疗效。.75例POEMS患者诊断时中位年龄50（30-81）岁，100%（75/75）见周围神经病变，77.3%（58/75）合并器官肿大，82.7%（62/75）伴有内分泌功能异常，93.3%（70/75）存在单克隆性浆细胞疾病，64.0%（48/75）伴有皮肤改变。75例患者中，5例放弃治疗，剩余70例患者经治疗后症状得到不同程度的改善，血液学完全缓解（CRPOEMS综合征临床表现复杂多样，临床医师应提高警惕，减少误诊、漏诊。硼替佐米或来那度胺等药物可用于一线治疗，有条件者建议行自体造血干细胞移植。.

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.

Background Establishing a normal L3–5 model and using finite element analysis to explore the biomechanical characteristics of extreme lateral interbody fusion (XLIF) with different internal fixation methods. Method The L3–5 CT image data of a healthy adult male volunteer were selected to establish a normal lumbar finite element model (M0). The range of motion (ROM) of L3–4 and L4–5, under flexion, extension, left bending, right bending, left rotation, and right rotation, together with L3–4 disc pressure was analyzed. Then the L4–5 intervertebral disc was excised and implanted with a cage, supplemented by different types of internal fixation, including lateral two-hole plate model (M1), lateral four-hole plate model (M2), VerteBRIDGE plating model (M3), lateral pedicle model (M4), posterior unilateral pedicle screw model (M5) and posterior bilateral pedicle screw model (M6). The ROM,the maximum stress value of the cage, and the maximum stress value of the intervertebral disc of L3–4 were analyzed and studied . Results The ROM of L3–4 and L4-L5 segments in the validation model under various motion states was basically consistent with previous reports. The lumbar finite element model was validated effectively. After XLIF-assisted internal fixation, the range of activity in L3–4 segments of each internal fixation model was greater than that of the normal model under various working conditions, among which the M5、M6 model had the larger range of activity in flexion and extension. After the internal fixation of L4–5 segments, the mobility in M1-M6 was significantly reduced under various motion patterns. In terms of flexion and extension, the posterior pedicle fixation model (M5、M6) showed a significant reduction,followed by M2. The maximal von mises cage stress of M1 was obviously greater than that of other models (except the left bending). Compared with M0, the intervertebral disc stress of M1-M6 at L3–4 segments was increased. Conclusions It is recommended that the posterior bilateral pedicle screw model is the first choice, followed by the lateral four-hole plate model for fixation during XLIF surgery. However, it is still necessary to be aware of the occurrence of adjacent segment degeneration (ASD) in the later stage.

Targeting pathogenic proteins with small-molecule inhibitors (SMIs) has become a widely used strategy for treating malignant tumors. However, most intracellular proteins have been proven to be undruggable due to a lack of active sites, leading to a significant challenge in the design and development of SMIs. In recent years, the proteolysis-targeting chimeric technology and related emerging degradation technologies have provided additional approaches for targeting these undruggable proteins. These degradation technologies show a tendency of superiority over SMIs, including the rapid and continuous target consumption as well as the stronger pharmacological effects, being a hot topic in current research. This review mainly focuses on summarizing the development of protein degradation technologies in recent years. Their advantages, potential applications, and limitations are also discussed. We hope this review would shed light on the design, discovery, and clinical application of drugs associated with these degradation technologies.

To observe the clinical efficacy of Kinesio Taping combined with electroacupuncture in the treatment of patellofemoral disorder in middle-aged and elderly exercise enthusiasts.From April 2018 to April 2020, 62 middle-aged and elderly exercisers with patellofemoral disorder were selected and divided into observation group and control group. In the observation group, there were 30 cases:12 males and 18 females, aged from 35 to 66 years old, with an average age of (48.32±6.80) years old. The observation group was treated with Kinesio Taping and electroacupuncture . In the control group, there were 32 cases:12 males and 20 females, aged from 35 to 67 years old, with an averageage of (48.67±8.13) years old. The patients in the control group was treated with knee electroacupuncture. All the patients in both groups were treated once every other day, 3 times a week, for a total of 4 weeks. The VAS pain score and knee Lysholm score before and after treatment were compared between the two groups before and after treatment, and statistical analysis was conducted.In the control group, 2 patients were not satisfied with the curative effect after 2 weeks of treatment and gave up treatment, while the remaining 60 patients completed all the treatments. After 4 weeks of treatment, the VAS and Lyshlom scores of the control group were 2.73±1.46 and 75.63±8.62 respectively;the VAS and Lyshlom scores of the observation group were 2.02±1.85 and 83.31±5.53 respectively;the VAS and Lyshlom scores of the observation group and the control group were better than those before treatment, and the Lyshlom scores of the observation group were better than those of the control group.Kinesio Taping combined with electroacupuncture is aimed at patellofemoral disorderof middle-aged and elderly sports enthusiasts. It has little trauma, can relieve pain and has a fast onset speed, which is readily accepted by patients, and promotes the rehabilitation of knee joint function of patients, thus providing a favorable reference for the promotion in clinical application.

OBJECTIVES Diabetes mellitus (DM), osteoporosis (OP), and obesity (OB) are three complex diseases. OB is associated with both DM and OP, but it is unclear whether OB mediates association between DM and OP. The study aimed to investigate the potential mediation effects of OB on association between DM and bone mineral density (BMD) by the causal inference tests (CIT). METHODS A total of 5682 Chinese aged over 65 years were enrolled in an ongoing cohort: Osteoporosis Preventive Project (OPP). Obesity-related indexes, including body mass index (BMI), waist circumference, and waist circumference-hip circumference-ratio (WHR), and BMD at total hip (TH) and femur neck (FN) were measured. RESULTS Subjects with DM had significant greater values of age, weight, BMI, waist circumference, WHR, and BMD than non-DM subjects. BMD at TH and FN was significantly associated with DM (p

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury.

Purpose To compare the dosimetric differences between intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) in the treatment of male and female thymoma. Material and methods This single-institutional analysis included 20 patients with thymoma treated with RT between January 2017 and December 2020. Twenty patients were retrospectively planned for IMRT (IMRT1 with an average field angle of 216°, 288°, 0°, 72°,and 144°; IMRT2 with fan-shaped field angles of 280°, 320°, 0°, 40°, and 80°) and VMAT (VMAT1 with two arcs ranging form 280° to 80°,clockwise and then counterclockwise; VMAT2 with two 360° arcs). The plans for all investigated RT modalities were optimized for a prescriptional dose of 50 Gy and fractional dose of 2.0 Gy. Planning target volume (PTV) and organs-at-risk (OARs: heart, breasts, lungs, spinal cord, and esophagus) dosimetric parameters were compared. Results All plans met the preparation aims for all the included metrics. There was little difference in the median values of PTV parameters (D2%, D98%, Dmean, homogeneity index[HI], and conformity index [CI]). The CI of the VMAT2 plan was the closest to 1 in both therapy groups. The monitor unit (MU) of IMRT2 and the estimated total delivery time of VMAT1 were the lowest in both therapy groups and were statistically significant. In the male group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) for VMAT1 were the lowest and showed statistical significance. In the female group, the lung parameters (Dmean, V5Gy, V10Gy, and V20Gy) and bilateral breast parameters (Dmean, V5Gy, V10Gy, and V20Gy) of IMRT2 were the lowest and showed statistical significance. Conclusions In male thymoma patients undergoing postoperative RT (PORT) treatment, the choice of fan-shaped VMAT may be a better option for protecting the lungs. For female thymoma patients receiving PORT, fan-shaped IMRT can better protect the lungs and breasts. The fan-shaped field performed better than the average and the full arc fields in PORT for thymoma.

Galectin-3 is a member of a family of β-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.

Women who had delivered a macrosomic newborn will have a higher risk to deliver another macrosomia. We aimed to examine the recurrence risk of macrosomia in the subsequent pregnancy and the implications in long-term child health. Data from the Collaborative Perinatal Project, a longitudinal birth cohort with 54,371 singleton births, were used. 401 recurrent macrosomic infants (macro-macro) and 1327 normal weight babies with a macrosomia in the last pregnancy (macro-normal) were selected to explore risk factors for recurrent macrosomia. Furthermore, 768 newly onset macrosomia with normal birthweight infant in previous pregnancies (normal-macro) were identified to examine long-term health effects of recurrent macrosomia. The recurrent rate of macrosomia was 23.2% [95% confidence interval (CI) 21.2%, 25.2%]. White race, higher pre-pregnant body mass index (BMI), more gestational weight gain, male infant and more prior macrosomic infants were significant risk factors for recurrent macrosomia. At 4 years of age, recurrent macrosomic infants had a higher BMI (16.7 vs. 16.1 kg/m2, adjusted β: 0.36, 95% CI: 0.12, 0.60) and a higher risk of overweight and obesity (adjusted OR: 1.56, 95% CI: 1.10, 2.23) than infants with normal birthweight after a previous macrosomic sibling. There was no significant difference between recurrent macrosomia and newly onset macrosomia in child outcomes after adjustment for covariates. Fetal macrosomia has a high recurrence rate in the following pregnancy. Higher maternal pre-pregnant BMI and gestational weight gain are still important risk factors for recurrence of macrosomia, which in turn increases the risk for childhood obesity.

Background Low back pain has become a serious social and economic burden and the leading cause of disability worldwide. Among a variety of pathophysiological triggers, intervertebral disc (IVD) degeneration plays a primary underlying role in causing such pain. Specifically, multiple independent endplate changes have been implicated in the initiation and progression of IVD degeneration. Methods In this study, we built a signaling network comprising both well-characterized IVD pathology-associated proteins as well as some potentially correlated proteins that have been associated with one or more of the currently known pathology-associated proteins. We then screened for the potential IVD degeneration-associated proteins using patients’ normal and degenerative endplate specimens. Short hairpin RNAs for receptor interacting serine/threonine kinase 1 (RIPK1) were constructed to examine the effects of RIPK1 knockdown in primary chondrocyte cells and in animal models of caudal vertebra intervertebral disc degeneration in vivo. Results RIPK1 was identified as a potential IVD degeneration-associated protein based on IVD pathology-associated signaling networks and the patients’ degenerated endplate specimens. Construction of the short hairpin RNAs was successful, with short-term RIPK1 knockdown triggering inflammation in the primary chondrocytes, while long-term knockdown triggered apoptosis through cleavage of the caspase 3 pathway, down-regulated NF-κB and mitogen-activating protein kinase (MAPK)s cascades, and decreased cell survival and inflammation. Animal models of caudal vertebra intervertebral disc degeneration further demonstrated that apoptosis was induced by up-regulation of tumor necrosis factor (TNF) accompanied by down-regulation of NF-κB and MAPKs cascades that are dependent on caspase and RIPK1. Conclusions These results provide proof-of-concept for developing novel therapies to combat IVD degeneration through interfering with RIPK1-mediated apoptosis signaling pathways especially in patients with RIPK1 abnormality. Electronic supplementary material The online version of this article (10.1186/s12967-019-1886-3) contains supplementary material, which is available to authorized users.

Gliomas are the most common malignant primary brain tumors with poor prognosis. We attempted to explore the role of CYP17A1 in glioma progression. We demonstrated that the expression of CYP17A1 was significantly higher in the glioma tissues than the normal brain tissues, especially in malignant glioma. Moreover, the expression of CYP17A1 gene was positively correlative with glioma pathological grades. In vitro, CYP17A1 gene silence inhibited the proliferation and invasion of glioma cells and promoted the apoptosis in glioma cells. Also, the subcutaneously transplanted tumour in BALB/C-nu showed that CYP17A1 gene silence inhibited glioma growth. These results reveal that CYP17A1 plays a major role in the progress of glioma.

Acute myocardial infarction (AMI) is the most severe cardiovascular event in the world. However, the molecular mechanisms underlying AMI remained largely unclear. Recently, long non-coding RNAs (lncRNAs) were reported to play important roles in human diseases. In the present work, we analyzed a public dataset GSE48060 to confirm key lncRNAs and mRNAs in AMI. We observed 4835 mRNAs and 442 lncRNAs were significantly differently expressed in AMI. Then, we for the first time constructed PPI networks and lncRNA co-expression networks in AMI. The protein-protein interaction (PPI) networks revealed several mRNAs such as RHOA, GNB1, GNG, RAC1, FBXO32, DET1, MEX3C and HECTD1 functioned as key regulators in AMI. LncRNA co-expression network analysis showed 8 lncRNAs (CA5BP1, LOC101927608, BZRAP1-AS1, EBLN3, FGD5-AS1, HNRNPU-AS1, LINC00342, and LOC101927204) played key roles in AMI. Gene ontology (GO) analysis demonstrated these differently expressed lncRNAs were associated with more signaling pathways, such as regulating transcription, protein amino acid phosphorylation, signal transduction, development. Taken together, our research unveiled a series of key lncRNAs and mRNAs in AMI. Several lncRNAs, including CA5BP1, LOC101927608, BZRAP1-AS1, EBLN3, FGD5-AS1, HNRNPU-AS1, LINC00342, and LOC101927204 were identified as key lncRNAs. PPI networks were constructed to reveal key mRNAs in AMI. These results provided useful information for exploring novel molecular target therapy for AMI.

MicroRNAs (miRNAs) are endogenous noncoding RNAs of 19-24 nucleotides in length and are tightly related to tumorigenesis and progression. Recent studies have demonstrated that the tumor suppressor p53 and its negative controller MDMX are regulated by miRNAs in different ways. Some miRNAs directly target p53 and regulate its expression and function, whereas some miRNAs target MDMX and regulate p53's activity indirectly. The overexpression of several miRNAs can restore the activity of p53 by negatively regulating MDMX in cancer cells. Therefore, a better understanding of the miRNAs-MDMX-p53 network will put forward potential research directions for developing anticancer therapeutics. In the present review, we mainly focus on the regulatory effects of miRNAs on the MDMX-p53 interplay as well as the role of the miRNAs-MDMX-p53 network in human cancer.

The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide with poor prognosis and unclear pathogenesis. Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine has been used in the clinical treatment of a variety of solid tumors, including AEG. However, its anticancer components and molecular mechanisms are still unclear. In our previous studies, we have found that Huaier n-butanol extract (HBE) shows the most potent anticancer activity among different extracts. In the present study, we aimed to investigate the clinical relevance of p-MEK expression in AEG patients and the role of the MEK/ERK signaling pathway in the anti-AEG efficacy of HBE in vitro and in vivo. We herein demonstrate that p-MEK expression in AEG tissues was significantly higher than that in paracancerous tissues and correlated with a poor prognosis in AEG patients. We further found that HBE inhibited the colony formation, migration, and invasion in AEG cell lines in a concentration-dependent manner in vitro. HBE also suppressed the growth of AEG xenograft tumors without causing any host toxicity in vivo. Mechanistically, HBE caused the inactivation of the MEK/ERK signaling pathway by dephosphorylating MEK1 at S298, ERK1 at T202, and ERK2 at T185 and modulating the expression of EMT-related proteins. In summary, our results demonstrate that the high expression of p-MEK may be an independent factor of poor prognosis in patients with AEG. The clinically used anticancer drug Huaier may exert its anti-AEG efficacy by inhibiting the MEK/ERK signaling pathway.

Background Osteoporosis is a common phenomenon in HIV patients on tenofovir treatment, but its underlying mechanisms remain to be explored. Methods Quantitative real-time PCR was performed to analyze the expression of miR-302, miR-101, miR-145 and osteoclast-specific genes in the serum of HIV patients treated with tenofovir and ZOL. ELISA was used to evaluate the expression of RANKL, SMAD3 and PRKACB in the serum of these patients. Luciferase assay was carried out to explore the inhibitory effects of miR-302, miR-101 and miR-145 on the expression of PRKACB, RANKL and SMAD3, respectively. Western blot was used to examine the expression of genes involved in NF‑κB and JNK signaling pathways. Results ZOL treatment significantly suppressed the expression of CTx and osteocalcin in HIV patients treated with tenofovir. The BMD loss of HIV patients treated with tenofovir was effectively hindered by ZOL treatment. Mechanistically, the expression of miR-302, miR-101, miR-145, RANKL, SMAD3 and PRKACB in the serum was remarkably activated by ZOL treatment. Luciferase assays showed that miR-302, miR-101 and miR-145 effectively suppressed the expression of PRKACB, RANKL and SMAD3, respectively, through binding to their 3′ UTR. Furthermore, ZOL treatment notably restored the normal expression of osteoclast‑specific genes while activating NF‑κB and JNK signaling pathways. Conclusion The findings of this study demonstrated that administration of ZOL suppressed the expression of RANKL via modulating signaling pathways of miR-101-3p/RANKL, miR-302/PRKACB/RANKL and miR-145/SMAD3/RANKL. Furthermore, down-regulated expression of RANKL by ZOL treatment alleviated osteoporosis in HIV-positive subjects treated with tenofovir.

Hepatic stellate cells (HSCs) are thought to play key roles in the development of liver fibrosis. Extensive evidence has established the concept that αV integrins are involved in the activation of latent transforming growth factor β (TGF-β), a master regulator of the fibrotic signaling cascade. Based on mRNA and protein expression profiling data, we found that αVβ1 integrin is the most abundant member of the αV integrin family in either quiescent or TGF-β1-activated primary human HSCs. Unexpectedly, either a selective αVβ1 inhibitor, Compound 8 (C8), or a pan-αV integrin inhibitor, GSK3008348, decreased TGF-β1-activated procollagen I production in primary human HSCs, in which the role of β1 integrin was confirmed by ITGB1 siRNA. In contrast with an Activin receptor-like kinase 5 (Alk5) inhibitor, C8 and GSK3008348 failed to inhibit TGF-β1 induced SMAD3 and SMAD2 phosphorylation, but inhibited TGF-β-induced phosphorylation of ERK1/2 and STAT3, suggesting that αVβ1 integrin is involved in non-canonical TGF-β signaling pathways. Consistently, ITGB1 siRNA significantly decreased phosphorylation of ERK1/2. Furthermore, a selective inhibitor of MEK1/2 blocked TGF-β1 induced phosphorylation of ERK1/2 and decreased TGF-β1 induced procollagen I production, while a specific inhibitor of STAT3 had no effect on TGF-β1 induced procollagen I production. Taken together, current data indicate that αVβ1 integrin can regulate TGF-β signaling independent of its reported role in activating latent TGF-β. Our data further support that αVβ1 inhibition is a promising therapeutic target for the treatment of liver fibrosis.

To observe the clinical effects of zheng's massage combined with electroacupuncture in the treatment ofreflex sensory dystrophy syndrome of the wrist.From October 2016 to September 2018, 48 cases of reflex sensory dystrophy syndrome of the wrist were divided into the observation group and the control group. In the observation group, there were 24 cases, including 10 males and 14 females, ranging in age from 54 to 76 years old, with an average age of (61.41 ±7.90) years old. The patients in the observation group were treated withAfter 6 weeks of treatment, VAS in the control group was 4.9±1.8, and Cooney wrist score was 74.63±1.72; VAS in the observation group was 2.2±1.4, and Cooney wrist score was 86.31±2.53. The comprehensive scores of VAS and Cooney wrist joint between two groups were improved after treatment, and the observation group was better than control group(Zheng's massage combined with electroacupuncture has the following advantages in the treatment of reflex sympathetic dystrophy syndrome of the wrist, such as small trauma, patients' willingness promoting functional rehabilitation, which is worthy of clinical promotion.

Background Surgery is the only treatment option for operable gastric cancer. The CLASSIC and ACTS-GC studies showed that the 5-year overall survival (OS) of patients with stage III gastric cancer undergoing D2 gastrectomy is still very low. Whether adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) combined chemotherapy is more effective than the XELOX standard adjuvant chemotherapy in patients with stage III gastric cancer has not been confirmed. Methods This is a multicenter, open-label, phase III clinical study. In this trial, 616 patients with locally advanced stage III gastric cancer that underwent curative D2 radical surgery and achieved R0 are planned to be included. Patients will be randomized 1:1 to nab-paclitaxel combined with S-1 (AS) vs. oxaliplatin combined with capecitabine (XELOX). XELOX group: Patients assigned to the XELOX group received eight 3-week cycles of oral capecitabine (1000 mg/m2) twice daily on days 1–14 of each cycle plus intravenous oxaliplatin 130 mg/m2 on day 1 of each cycle. AS group: AS group received eight 3-week cycles of oral S-1 (80–120 mg) (2, 40 mg; 1.25 to 2, 50 mg; and > 1.5 m2, 60 mg) twice daily on days 1–14 plus intravenous nab-paclitaxel 120 mg/m2 on days 1 and 8 of each cycle. The primary endpoint was the 3-year disease-free survival (3-year-DFS) defined as the time from randomisation to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. The secondary endpoints were the overall survival, (defined as the time from the date of randomisation to date of death from any cause) and safety (any adverse event). Discussion Compared with previous studies, this study includes nab-paclitaxel based on S-1 adjuvant chemotherapy, which is expected to achieve better efficacy and lower toxicity than the standard treatment. This study is the first clinical study to evaluate the safety and efficacy of nab-paclitaxel combined with S-1 in patients with stage III gastric cancer after D2 radical resection. Trial registration This clinical trial has been registered with ClinicalTrials.gov, registration number: NCT04135781, on October 20th, 2019.

Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.