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Background: Glioma is the most aggressive and lethal tumor of the central nervous system. Due to the cellular heterogeneity, the invasiveness, and blood-brain barrier (BBB), current therapeutic approaches, such as chemotherapy and radiotherapy, are poorly to obtain great anti-tumor efficacy. However, peptides, a novel type of therapeutic agent, displayed excellent ability in the tumor, which becomes a new molecule for glioma treatment. Method: We review the current knowledge on peptides for the treatment of glioma through a PubMed-based literature search. Results: In the treatment of glioma, peptides can be used as (i) decoration on the surface of the delivery system, facilitating the distribution and accumulation of the anti-tumor drug in target site;(ii) anti-tumor active molecules, inhibiting the growth of glioma and reducing solid tumor volume; (iii) immune-stimulating factor, and it activating immune cells in the tumor microenvironment or recruiting immune cells to the tumor for breaking out the immunosuppression by glioma cells. Conclusion: The application of peptides has revolutionized the treatment of glioma, which based on targeting, penetrating, anti-tumor activities and immunostimulatory. Moreover, better outcomes have been discovered in combining different kinds of peptides rather than a single one. Until now, more and more preclinical studies have been developed with multifarious peptides, which shows promising results in vitro or vivo with the model of glioma.

Background Microwave ablation (MWA) and radiofrequency ablation (RFA) have recently attracted interest as minimally invasive treatment modalities for papillary thyroid carcinoma (PTC). However, the ablation outcomes of T1N0M0 PTC are not well characterized. Purpose To evaluate the efficacy and safety of thermal ablation (MWA or RFA) of solitary T1N0M0 PTC in patients who were ineligible for (due to presence of comorbid cardiovascular disease, renal failure, other malignancy, etc) or who refused surgery. Materials and Methods This was a retrospective multicenter study of 847 patients (660 women) who underwent thermal ablation for PTC (673 T1a, 174 T1b) between March 2015 and March 2020; of these patients, 645 underwent MWA and 202 underwent RFA. The mean age of patients was 46 years ± 11 (standard deviation) (age range, 18-81 years); the mean follow-up time was 22 months ± 13 (range, 6-60 months). Changes in tumor size and volume and the rates of technical success, tumor disappearance, disease progression, and complications were assessed. Results The technical success rate was 100%. Relative to preablation measurements, the maximum diameter and volume of the ablation zone increased during the 1st month after ablation (P < .001), whereas there was no difference by the 3rd month; subsequently, the tumors showed reduction in size at 6, 9, and 12 months (all P < .001). Complete disappearance of tumors occurred in 68% of patients (577 of 847; 69% [466 of 673] in the T1a group vs 64% [111 of 174] in the T1b group; P < .001). The postablation disease progression rate was 1.1% (nine of 847 patients; 0.9% [six of 673 patients] in the T1a group vs 1.7% [three of 174 patients] in the T1b group; P = .54). The overall complication rate was 3.4% (29 of 847 patients; 2.7% [18 of 673 patients] in the T1a group vs 6.3% [11 of 174 patients] in the T1b group; P = .02). Conclusion This multicenter study provided evidence that thermal ablation is an effective and safe treatment option in selected -patients with solitary T1N0M0 papillary thyroid carcinoma. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Baek and Cho in this issue.

Triazole resistance in Aspergillus fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed, with novel targets, that are effective in triazole-resistant infection., Triazole resistance in Aspergillus fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed, with novel targets, that are effective in triazole-resistant infection. In this study, we retrospectively evaluated the potency of the novel drug olorofim compared to contemporary antifungal agents against 111 clinical A. fumigatus isolates collected from Huashan Hospital, Shanghai, China, using EUCAST methodology, and we reviewed the literature on triazole-resistant A. fumigatus (TRAF) published between 1966 and 2020 in China. Olorofim was active in vitro against all tested A. fumigatus isolates, with a MIC90 of 0.031 mg/liter (range, 0.008 to 0.062 mg/liter). For 4 triazole-resistant A. fumigatus isolates, the olorofim MIC ranged between 0.016 and 0.062 mg/liter. The reported rates of TRAF in China are 2.5 to 5.56% for clinical isolates and 0 to 1.4% for environmental isolates. TR34/L98H/S297T/F495I is the predominant resistance mechanism, followed by TR34/L98H. Non-TR-mediated TRAF isolates, mostly harboring a cyp51A single point mutation, showed greater genetic diversity than TR-mediated resistant isolates. Resistance due to TR34/L98H and TR34/L98H/S297T/F495I mutations among TRAF isolates might have evolved from separate local isolates in China. Continuous isolation of TRAF in China underscores the need for systematic resistance surveillance as well as the need for novel drug targets, such as olorofim.

Epigenetics, including histone modifications, play a significant role in central nervous system diseases, but the underlying mechanism remains to be elucidated. The aim of this study was to evaluate the role of H3K27me3 in regulating transcriptomic and pathogenic mechanisms following global ischemic stroke. Here, we found that in vivo ischemic/reperfusion (I/R) injury induced marked upregulation of H3K27me3 in the hippocampus. The administration of GSK-126 to rat brains decreased the levels of H3K27me3 in the hippocampus and reduced neuronal apoptosis after experimental stroke. Furthermore, ChIP-seq data demonstrated that the primary role of GSK-126 in the ischemic brain is to reduce H3K27me3 enrichment, mediating negative regulation of the execution phase of apoptosis and the MAPK signaling pathway. Further study suggested that the protective role of GSK-126 in ischemic rats was antagonized by U0126, an inhibitor of ERK1/2. Collectively, we demonstrated the potential of H3K27me3 as a novel stroke therapeutic target, and GSK-126 exerted a neuroprotective function in ischemic brain injury, which might be associated with activation of the MAPK/ERK pathway. Graphical Abstract

Epilepsy (EP) is a common neurological disorder which is characterized by excessive abnormal synchronization of neuronal discharges in the brain due to chronic recurrent seizures of multiple etiologies. Variety of microRNAs have been associated with the occurrence and development of EP. This study aimed to determine the aberrant expression of miR-378 and miR-575 in EP patients to validate their potential to distinguish EP from healthy patients.RT-qPCR was used to determine the expressions of miR-378 and miR-575 from serum specimens of 106 EP and 103 control individuals. Clinical indicators between EP patients and controls were assessed. Based on surgical outcome, EP patients were further divided into Engel I-IV EP. The potentials of miR-378 and miR-575 in discriminating EP from healthy participants and predicting surgical prognosis were calculated by receiver operating characteristic (ROC) analysis.We found the miR-378 and miR-575 were significantly declined (P0.001) in Engel I-II and III-IV EP patients with no difference in clinical parameters compared. Moreover, miR-378 and miR-575 displayed high sensitivity, specificity, and accuracy in distinguishing EP patients and predicting surgical outcomes. Moreover, after surgical treatment, miR-378 and miR-575 levels were increased compared with those at admission, suggesting their potentials in treatment response.miR-378 and miR-575 could be utilized as novel and non-invasive serum biomarkers in discriminating EP from healthy controls and predicting surgical outcome, shedding new insights on epileptogenesis and EP treatment.Epilepsija (EP) je uobičajen neurološki poremećaj koji se karakteriše prekomernom sinhronizacijom pražnjenja neurona u mozgu usled hroničnih ponovljenih napada različitih etiologija. Različite mikro RNK su povezane sa pojavom i razvojem EP. Ova studija je imala za cilj da odredi aberantnu ekspresiju miR-378 i miR-575 kod pacijenata sa EP kako bi potvrdila njihov potencijal da se ustanovi razlika izme|u pacijenata sa EP i zdravih pacijenata.RT-qPCR je korišćen da bi se odredila ekspresija miR-378 i miR-575 iz serumskih uzoraka 106 pacijenata sa EP i 103 kontrolna ispitanika. Izvršena je procena kliničkih pokazatelja kod pacijenata sa EP i kontrolnih ispitanika. Na osnovu ishoda hirurškog lečenja, pacijenti sa EP su dalje podeljeni na Engel I-IV EP. Analizom krive operativnih karakteristika (ROC) izračunat je potencijal koji imaju miR-378 i miR-575 i koji karakteriše pacijente sa EP u odnosu na zdrave učesnike istraživanja kako bi se predvideo tok lečenja.Utvrdili smo da su miR-378 i miR-575 značajno smanjeni (P0,001) kod pacijenata sa Engel I-II i III-IV EP bez razlika u upore|enim kliničkim parametrima. Štaviše, miR-378 i miR-575 su pokazali visoku osetljivost, specifičnost i tačnost u razlikovanju EP pacijenata i predvi |anju ishoda. Dalje, nakon hirurškog lečenja, nivoi miR-378 i miR-575 su povećani u pore|enju sa onima pri prijemu, što ukazuje na njihov potencijal u rekaciji na lečenje.miR-378 i miR-575 se mogu koristiti kao novi i neinvazivni biomarkeri u serumu za diferencijaciju pacijenata sa EP od zdravih kontrolnih ispitanika i predvi|anje hirurškog ishoda, otkrivajući nove uvide u epileptogenezu i lečenje EP.

The limb-bud and heart (LBH) gene was reported to suppress nasopharyngeal carcinoma (NPC) progression in our previous study. Distant metastasis predominantly accounts for the unsatisfactory prognosis of NPC treatment, in which epithelial-mesenchymal transition (EMT) and tumor angiogenesis are of great significance. The roles of exosomes in mediating NPC progression have been highlighted in recent researches, and attempts have been made to explore the clinical application of NPC exosomes. Here we investigated the function of the LBH gene in NPC exosomes, and its potential mechanism. NPC xenografts were constructed, showing that vascular endothelial growth factor A (VEGFA) expression and neovascularity were attenuated by LBH overexpression, together with diminished EMT progression. NPC-derived exosomes were isolated, identified and applied for in vitro/in vivo experiments, and the exosomal distribution of LBH was elevated in exosomes derived from LBH-upregulated cells. Ectopic LBH, αB-crystallin (CRYAB) and VEGFA expression was induced by lentiviral infection or plasmid transfection to explore their functions in modulating EMT and angiogenesis in NPC. The addition of LBH+ NPC exosomes during a Matrigel plug assay in mice suppressed in vivo angiogenesis, and the treatment of human umbilical vein endothelial cells (HUVECs) with LBH+ NPC exosomes inhibited cellular proliferation, migration and tube formation. The interactions among LBH, CRYAB and VEGFA were confirmed by colocalization and fluorescence resonance energy transfer (FRET) assays, and extracellular VEGFA secretion from both HUVECs and NPC cells under the treatment with LBH+ NPC exosomes was diminished according to ELISA results. We concluded that exosomal LBH inhibits EMT progression and angiogenesis in the NPC microenvironment, and that its effects are partially implemented by modulation of VEGFA expression, secretion and related signaling. Thus, LBH could serve as a promising therapeutic target in VEGFA-focused NPC treatment.

Engineered liver organogenesis is not yet a viable therapeutic option, but ectopic liver histogenesis may be possible. Accumulating evidence has suggested that cell-cell interactions and cell-matrix interactions play an important role in determining the properties of engineered hepatic tissue in vitro and in vivo. In the current study, we utilized heparinized decellularized liver scaffolds and bone marrow mesenchymal stromal cell spheroids to fabricate engineered hepatic tissue, which was subsequently implanted into the omentum of Sprague-Dawley rats with or without liver injury. The survival, liver-specific functions, differentiation level and regenerative potential of the implanted hepatocyte-like cells in this ectopic liver system were evaluated, together with the vascularization status and therapeutic potential of the engineered hepatic tissue. We demonstrated that these hepatic grafts could survive and possess hepatocyte specific function in this ectopic liver system but could also efficiently anastomose with host vascular networks. Furthermore, we found that hepatocyte-like cells within grafts expanded more than 9-fold over the course of 4 weeks in immunocompetent rats with injured livers. Immunostaining revealed that these hepatocyte-like cells could self-organize into cord-like structures in vivo. In addition, these hepatic grafts exhibited therapeutic potential in liver injury induced by CCl4. To our knowledge, this is the first report demonstrating the generation of long-term vascularized hepatic parenchyma at ectopic sites based on decellularized liver scaffolds and stem cells. These results provide an economic and feasible method for engineering hepatic tissue from construction to transplantation. This methodology may be applicable in clinical medicine, especially metabolic liver diseases. Statement of significance In this manuscript, we presented an optimized method for the hepatic engineered tissue (HET) from construction to transplantation. The core of this method is utilizing the combination of heparinized decellularized liver scaffolds and stem cell spheroids, which could provide necessary cell-cell and cell-extracellular matrix interactions for HET in vitro and in vivo. We proved that these hepatic grafts could possess hepatocyte specific function and exhibit strong proliferative activity in ectopic liver system, but also able to anastomose with the host vascular networks efficiently and be compatible with the host immune system. This methodology may be possible one day to apply in clinical medicine, especially metabolic liver diseases.

Our aim is to investigate the association of cerebral deep medullary veins (DMVs) with white matter microstructural integrity and regional brain atrophy in MRI. In a community-based cohort of 979 participants (mean age 55.4 years), DMVs were identified on susceptibility-weighted imaging. Brain structural measurements including gray matter and hippocampus volumes, as well as diffusion tensor metrics, were evaluated. The mean (SD)number of DMVs was 19.0 (1.7). A fewer number of DMVs was related to lower fractional anisotropy and higher mean diffusivity in multiple voxels on the white matter skeleton (threshold-free cluster enhancement corrected p

Subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are represented in the majority of cutaneous lupus subtypes, each of which has variable implications for systemic manifestations such as lupus nephritis. On dermatologic examination, subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are distinct. However, it is often difficult to diagnose the subtype from histology alone. Our study utilized whole-genome microarray expression analysis on human skin samples of subacute cutaneous lupus erythematosus, on human skin samples of chronic cutaneous lupus erythematosus, and on healthy controls, along with analysis on human samples of lupus nephritis and normal kidney tissue to compare cutaneous lupus subtypes with each other as well as with lupus nephritis. The data revealed that cutaneous lupus subtypes were distinct from healthy control skin, with gene expression predominantly characterized by upregulation of IFN-1 and T-cell chemotactic genes. However, the cutaneous lupus subtypes were very similar to one another; comparative analyses revealed few statistically significant differences in gene expression. There were also distinct differences between the gene signatures of cutaneous lupus and lupus nephritis. Cutaneous lupus samples revealed gene signatures demonstrating a prominent inflammatory component that may suggest the skin as an early site of initiation of lupus pathogenesis, whereas lupus nephritis reflected the recruitment and activation of M2 macrophages and a wound healing signature.

Breast cancer, with high morbidity worldwide, is a threat to the life of women. MiR-543 was identified as playing an active part in the development of breast cancer involving multiple molecules. The goal of this study was to explore the molecular mechanisms of the involvement of miR-543 in the development of breast cancer. Quantitative real-time PCR (qRT-PCR) or Western blotting was used to detect mRNA or protein expression. Cell counting kit-8 (CCK-8), and the 5-bromo-2ʹ-deoxyuridine (BrdU), wound healing, and Transwell assays were the main experimental procedures. Furthermore, subcutaneous tumor formation experiments were conducted to detect the function of miR-543 in breast cancer development in vivo. The match of miR-543 and ubiquitin-conjugating enzyme E2T (UBE2T) was detected through a dual-luciferase reporter experiment and RNA pull-down assay. Based on these results, miR-543 exhibited reduced expression in breast cancer tissues and cell lines, whereas UBE2T exhibited high levels. Furthermore, miR-543 directly targeted UBE2T, and a negative correlation between miR-543 and UBE2T was also observed in breast cancer tissues. Moreover, miR-543 overexpression led to inhibition of viability, proliferation, migration, and invasion of breast cancer. Furthermore, miR-543 overexpression undermined the UBE2T promotional effect by inhibiting ERK/MAPK pathway activity in breast cancer cells. Our study revealed that miR-543 impaired breast cancer progression by targeting UBE2T and downregulating UBE2T expression through the ERK/MAPK pathway, which suggested that miR-543 and UBE2T might serve as promising therapeutic gene targets for breast cancer in clinical application.

Yi Lin,1 Kaushik Chattopadhyay,2 Xi Yang,3 Jia-Lin Li,4 Yan-Shu Chen,4 Ye Zhou,4 Li Li4 1Center for Health Economics, Faculty of Humanities and Social Sciences, University of Nottingham, Ningbo, Zhejiang Province, People’s Republic of China; 2Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK; 3Department of Nutrition, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 4Department of Endocrinology and Metabolism, Ningbo First Hospital, Ningbo, Zhejiang Province, People’s Republic of ChinaCorrespondence: Li LiDepartment of Endocrinology and Metabolism, Ningbo First Hospital, 59, Liuting Street, Ningbo, 315010, Zhejiang Province, People’s Republic of ChinaTel +86 13757426626Email lilyningbo@163.comYi LinCenter for Health Economics, Faculty of Humanities and Social Sciences, University of Nottingham, 199, Taikang East Road, University Park, Ningbo, 315100, People’s Republic of ChinaTel +86-13916608572Email Lily.Lin@nottingham.edu.cnPurpose: Type 2 diabetes (T2D) is one of the major public health concerns in China. Studies on the association between dietary salt intake and the glycemic response of T2D are lacking in China. The aim was to investigate the association between the levels of dietary salt intake and the plasma glucose, insulin and hemoglobin A1c (HbA1c) levels in T2D patients.Methods: Patients with T2D, who accepted management and treatment by the National Standardized Metabolic Disease Management Center at Ningbo First Hospital from March 2018 to January 2020, were included in this study. Dietary salt intake was assessed through a standardized food frequency questionnaire. Anthropometry, blood pressure and biomarkers were measured by well-trained endocrinology nurses. Generalized linear models (GLMs) were used to examine the associations.Results: A total of 1145 eligible T2D patients with a mean age of 51.4 years were included in the study. Fasting plasma glucose (FPG), 2-hour postprandial plasma glucose and 2-hour postprandial insulin were significantly increased across dietary salt categories. The GLMs further showed that dietary salt intake > 8 g/day was positively associated with FPG and HbA1c.Conclusion: Higher daily salt intake was found to be associated with FPG and HbA1c in T2D patients. Lifestyle education and promotion of salt reduction should be provided to T2D patients.Keywords: dietary salt, type 2 diabetes, blood glucose, insulin, glycated hemoglobin A1c, China

Obesity is closely related to dyslipidaemia, diabetes and other metabolic syndromes. Long-term consumption of a high-fat diet (HFD) is an important risk factor that can lead to obesity. In the current research, three Lactobacillus strains, namely, Loigolactobacillus coryniformis subsp. torquens T3 (T3), Lacticasebacillus paracasei subsp. paracasei M5 (M5), and Lacticaseibacillus paracasei subsp. paracasei X12 (X12), were tested to determine their inhibitory effects on HFD-induced obesity. The results showed that M5, T3, and X12 significantly decreased the body weight gain, Lee's index and adipose index. T3 showed significant effects on reducing serum TG levels to 0.92 mmol/ml and increasing HDL-C levels to 2.18 mmol/ml. The M5 treatment significantly reduced the serum TG level and leptin content to 1.11 mmol/ml and 3.7 ng/ml, respectively, and it increased the HDL-C level and adiponectin content to 2.35 mmol/ml and 7 ng/ml, respectively. M5 and T3 dramatically ameliorated hepatic steatosis in HFD-treated mice by reducing the liver index, lipid droplet number in the liver and TC levels in the liver. Gene expression of PPAR-γ and TNF-α was notably downregulated and FAS was upregulated by T3 and M5 treatment. Additionally, administration of M5 and T3 modified the diversity of the gut microbiota with increased OTU number, ACE index, and Chao1, and decreased the Shannon index and the Bacteroidetes /Firmicutes ratio. Overall, our results indicate that Lactobacillus may be used to prevent obesity and gut dysbiosis. PRACTICAL APPLICATION: Lactobacillus from traditional Chinese foods showed strong anti-obesity effects on high-fat diet-fed mice through the regulation of adipocytokines. Additionally, administration of certain Lactobacilli modified the diversity of the gut microbiota. The results indicate that Lactobacillus may be promising functional materials in healthy foods.

Background and aims Porokeratosis (PK) is a heterogeneous group of cutaneous keratinization disorders and has five clinical subtypes. DSAP is the most common clinical subtype and is characterized by multiple small, annular, anhidrotic, keratotic lesions predominantly on sun-exposed areas of the skin. It is an autosomal dominantly inherited epidermal keratinization disorder. However, studies on its molecular basis is limited. Materials and methods We performed mutation analysis of genes in four pedigrees and three sporadic cases of DSAP in the Chinese population. Genomic DNA was extracted from blood samples obtained from patients, unaffected family members, and 100 unrelated individuals. All exons and flanking intron sequences of the mevalonate kinase (MVK) and farnesyl diphosphate synthase (FDPS) genes were amplified. Results One missense mutation in exon 7 (C.G677A) of the MVK gene was identified in pedigree 3, and one missense mutation in exon 5 (C.C535T) of the FDPS gene was identified in sporadic case 3. No mutation was detected in the MVK and FDPS genes in the remaining three pedigrees and two sporadic cases with DSAP. Conclusion Our results may be useful for genetic counseling and prenatal diagnosis of affected families and for expanding the repertoire of MVK and FDPS mutations underlying DSAP.

Background Human papillomavirus (HPV) E6/E7 mRNA in situ hybridization (HPV E6/E7 RNAscope) appears to be a sensitive and specific technique in detecting transcriptionally active HPV. We aimed to examine the diagnostic utility of this technique in endocervical adenocarcinoma (ECA), to explore the prognostic factors for ECA patients and develop a clinically useful nomogram based on clinicopathological parameters to predict it. Methods We retrospectively analyzed 200 patients with ECA who had undergone surgery at Sun Yat-sen University Cancer Center from 2010 and 2014. The diagnostic performance of HPV E6/E7 RNAscope were evaluated by receiver operating characteristic (ROC) curve. A prognostic nomogram model including HPV E6/E7 RNAscope was generated based on multivariate Cox regression analysis, then we compared the predictive accuracy of the prognostic model with FIGO staging and treatment using concordance index (C-index), time-dependent ROC (tdROC), and decision curve analysis (DCA). Results The sensitivity and specificity of HPV E6/E7 RNAscope for distinguishing HPV-associated adenocarcinoma (HPVA) from non-HPV-associated adenocarcinoma (NHPVA) in the whole cohort were 75.8% and 80%, respectively. According the univariate analysis and multivariate logistic regression analysis, age, lymphovascular invasion (LVI), lymph node involvement (LNI), and HPV E6/E7 RNAscope were valuable predictive factors for OS. These parameters were incorporated into the nomogram model (nomogram A) compared with FIGO stage and treatment. The C-index of nomogram A for predicting OS was 0.825, which was significantly higher than FIGO stage (C-index = 0.653, p = 0.002) and treatment (C-index = 0.578, p Conclusions HPV E6/E7 RNAscope is highly specific for ECA, and the 4-variable nomogram showed more accurate prognostic outcomes in patients with ECA.

Background Early detection of lung cancer in asymptomatic patients remains challenging, especially for stage I. Considering the substantial interaction with tumor immunogenicity, we hypothesized that lung cancer-associated TCR (LC-aTCR) may serve as potential biomarker in early detection of stage I lung cancer. Methods Individuals who received low-dose computed tomography (LDCT) screening were enrolled in the study. Surgical tissues and peripheral blood specimens were collected and performed with DNA-based T cell repertoire (TCR) sequencing. The motif-based algorithm was used to deconstruct specific lung cancer-associated TCRs (LC-aTCRs). Results A total of 146 individuals participating in the real-world LDCT screening project were enrolled in this study, including 52 patients with pathologically-confirmed stage I lung cancer and 94 non-cancer controls. We developed a motif-based algorithm to define 80 LC-aTCRs in the training cohort. Moreover, in the validation cohort, high sensitivity and specificity was showed in stage I lung cancer with 72% and 91% respectively, and the AUC of the ROC curve was 0.91 (95% CI: 0.85 ∼ 0.96). Conclusion This work provides inspiration for stage I lung cancer detection by using blood TCR profiling data. The combination of TCR-based assay and routine screening deserves further testing in larger cohorts.

Objective:. Blocking mechanistic target of rapamycin (mTOR) activation with mTOR inhibitors has promising therapeutic potential for keloids. However, the precise mechanism of mTOR inhibitors remains unclear. This study was aimed to investigate the role of autophagy machinery in the anti-keloid effects of mTOR inhibitors. Methods:. We first validated the biological effects induced by the mTOR inhibitors rapamycin (100 nmol/L) and KU-0063794 (5 μmol/L) on the proliferation, apoptosis, migration, and collagen synthesis of keloid fibroblasts (KFs) derived from Han Chinese persons through a Cell Counting Kit-8 assay, 5-Bromo-2’-deoxyuridine incorporation, Annexin V/propidium iodide staining, migration, and western blotting. To explore whether autophagy machinery is involved in the anti-keloid effects of mTOR inhibitors, we first blocked the autophagy activation induced by rapamycin and KU-0063794 with a pharmacological autophagy inhibitor (wortmannin) or by silencing the key autophagy gene (ATG5), and we then re-evaluated these biological effects on KFs. Results:. Blocking mTOR activation with either rapamycin or KU-0063794 completely inhibited proliferation, migration, and collagen synthesis of primary KFs but did not affect apoptosis. Incubating KFs with the autophagy inhibitor wortmannin or performing ATG5 silencing abrogated the subsequent activation of autophagic activity induced by rapamycin (rapamycin + E-64d + pepstatin vs. rapamycin + wortmannin + E-64d + pepstatin: 1.88 ± 0.38 vs. 1.02 ± 0.35, F = 6.86, P = 0.013), (non-sense control + rapamycin vs. ATG5 small interfering RNA + rapamycin: 1.46 ± 0.18 vs. 0.75 ± 0.20, respectively; F = 7.68, P = 0.01) or KU-0063794 (KU-0063794 + E-64d + pepstatin vs. KU-0063794 + wortmannin + E-64d + pepstatin: 1.65 ± 0.35 vs. 0.76 ± 0.17, F = 10.01, P = 0.004), (NC + KU-0063794 vs. ATG5 small interfering RNA + KU-0063794: 1.59 ± 0.50 vs. 0.77 ± 0.09, F = 5.93, P = 0.02) as evidenced by decreased accumulation of LC3-II. However, blockage of autophagy induction in mTOR inhibitor-treated KFs with both methods did not disturb their anti-keloid effects, such as inhibition of cell viability, cell migration, and collagen synthesis (P > 0.05 each). Conclusion:. Blocking mTOR activation with the mTOR inhibitors rapamycin and KU-0063794 showed anti-keloid effects in KFs. Restoration of autophagy inhibition by mTOR inhibitors does not contribute to their anti-keloid effects.

The problems of anterior teeth include dental plaque, dental caries, and fracture, which are usually treated with common composite resin clinically. Although good repair effect can be achieved, patients are prone to anterior tooth sensitivity after surgery. Therefore, the purpose of this study is to analyze the cosmetic effect of nanocomposite resin on anterior teeth. Up to 176 patients (176 teeth) undergoing anterior dental cosmetic restoration in our hospital were selected and assigned to the LR group ( n = 88 ) and the NR group ( n = 88 ) according to patients’ voluntary choice of prosthetic materials. The LR group was cured with light-cured composite resin, while the NR group was cured with nanocomposite resin. By comparing the related indexes of patients in the two groups, it was discovered that in the NR group, the excellent and good rate and patients’ evaluation of the repair effect were higher, while the periodontal attachment, gingival index, dental plaque index, VAS score, and the incidence of tooth sensitivity were lower, all P < 0.05 . The results indicated that the nanocomposite resin had significant cosmetic effect on anterior teeth and had application value.

Purpose: Phase I results of this phase I/II study showed that pamiparib 60 mg twice a day had antitumor activity and an acceptable safety profile in Chinese patients with advanced cancer, including epithelial ovarian cancer. Patients and Methods: This open-label phase II study was conducted in China and enrolled adult (≥18 years) patients with platinum-sensitive ovarian cancer (PSOC; disease progression occurring ≥6 months after last platinum treatment) or platinum-resistant ovarian cancer (PROC; disease progression occurring Results: In the total patient population (N = 113; PSOC, n = 90; PROC, n = 23), median age was 54 years (range, 34–79) and 25.6% of patients received ≥4 prior systemic chemotherapy lines. Median study follow-up was 12.2 months (range, 0.2–21.5). Eighty-two patients with PSOC and 19 patients with PROC were evaluable for efficacy. In patients with PSOC, 8 achieved a complete response (CR) and 45 achieved a partial response (PR); ORR was 64.6% [95% confidence interval (CI), 53.3–74.9]. In patients with PROC, 6 achieved a PR; ORR was 31.6% (95% CI, 12.6–56.6). Frequently reported grade ≥3 adverse events were hematologic toxicities, including anemia and decreased neutrophil count. Conclusions: Pamiparib 60 mg twice a day showed antitumor activity with durable responses in patients with PSOC or PROC with gBRCAmut, and had a manageable safety profile.

In the last few decades, hyperuricemia has drawn increasing attention owing to its global prevalence. Observational surveys have manifested that there is a relation between hyperuricemia and increased risks of hypertension, chronic kidney disease, cardiovascular events, metabolic disorders, end stage renal disease, and mortality. As alternatives, Traditional Chinese medicinal herbs have demonstrated concrete effects in mitigating hyperuricemia in different experiments. Researchers have made efforts to investigate the role of herbal medicine in attenuating hyperuricemia. This review focuses on traditional Chinese herbal medicines that have been reported to ameliorate hyperuricemia in experimental studies.

Aims Few studies have examined the secular trend of the energy intake distribution, and its effect on future risk of hyperglycemia. This study aims to describe trajectories of energy intake distribution over 12 years and relate them to subsequent risk of hyperglycemia over 9 years of follow-up. Methods Our study used ten waves of data from the CHNS survey, a population-based longitudinal survey in China, ongoing since 1989. We examined a cohort of adult participants who were free from diabetes but had at least three waves of dietary data from 1997 to 2009. We assessed energy intake using three consecutive 24 h recalls. We used these data to identify trajectory groups of energy intake distribution by multi-trajectory model based on energy intake proportions of breakfast, lunch, and dinner. We followed up participants for hyperglycemia, diabetes, and impaired fasting glucose for 9 years from 2009 to 2018. Outcomes were ascertained with fasting glucose, serum HbA1c, and self-report of diabetes and/or glucose-lowering medication. We estimated relative risk (RR) for hyperglycemia, diabetes, and impaired fasting glucose by identified trajectory groups using multilevel mixed-effects modified Poisson regression with robust (sandwich) estimation of variance. Gender difference was additionally examined. Results A total of 4417 participants were included. Four trajectory groups were identified, characterized and labeled by “Energy evenly distributed with steady trend group” (Group 1), “Dinner and lunch energy dominant with relatively steady trend group” (Group 2), “Dinner energy dominant with increasing trend and breakfast energy with declining trend group” (Group 3), and “breakfast and dinner energy dominant with increasing trend group” (Group 4). During 48,091 person-years, 1053 cases of incident hyperglycemia occurred, 537 cases of incident diabetes occurred, and 516 cases of impaired fasting glucose occurred. Compared with Group 1, Group 3 was associated with higher subsequent risk of incident hyperglycemia in 9 years of follow-up (RR = 1.28, 95% CI = 1.02, 1.61). No association was found for incident diabetes and impaired fasting glucose. Among males, Group 3 was associated with higher risk of incident hyperglycemia in 9 years of follow-up (RR = 1.44, 95% CI = 1.07, 1.94). No relationship was found in females. Conclusions Energy intake distribution characterized by over 40% of energy intake from dinner with a rising trend over years was associated with higher long-term risk of hyperglycemia in Chinese adults.

We aimed to analyze the expression of Cyclin D1 (CCND1) gene in ovarian cancer and the influence of silencing its expression on ovarian cancer cells based on the Oncomine database. The expression of CCND1 gene in ovarian cancer was analyzed by utilizing the relevant information in different tumors and Oncomine database. The correlation between CCDN1 expression level and prognosis of ovarian cancer was analyzed by the online database Kaplan-Meier (kmplot.com). The expression of CCND1 gene in ovarian cancer and the effect of silencing its expression on cancer cells were analyzed by cell experiments. After mining and comprehensively analyzing 7 studies on the differential expression of CCND1 gene in ovarian cancer tissue and normal ovarian tissue included in the Oncomine database, it was found that the median value of CCND1 gene ranked 218.0 (P = 8.03 × 10−6) among all differentially expressed genes, suggesting that CCND1 gene expression in ovarian cancer tissue was higher than that in normal ovarian tissue. Adib Ovarian, Bonome Ovarian and Hendrix Ovarian microarrays revealed that the expression of CCND1 gene in ovarian cancer tissue was significantly higher than that in normal ovarian tissue (P

Antitumor immunotherapy can enable promising and durable responses following their clinical application. However, heterogeneity in the tumor immune microenvironment leads to differences in the individual response rates. In this study, we identified novel immune-related molecular subclasses of breast cancer using a non-negative matrix factorization analysis. We enrolled 4184 patients with breast cancer, including 1104 patients from The Cancer Genome Atlas as a training cohort and 3080 patients from another four independent datasets as validation cohorts. In the training cohort, 36.9% of patients who exhibited significantly higher immunocyte infiltration and enrichment of immune response-associated signatures were categorized into an immune class, which was confirmed by probing the expression of immunocyte markers (CD3, CD19, and CD163). Within the immune class, 53.3% of patients belonged to an immune-suppressed subclass, characterized by the activation of stroma-related signatures and immune-suppressive cells. The remaining patients in the immune class were allocated to an immune-activated subclass. The interferon-γ and granzyme B levels were higher in the immune-activated subclass, whereas the transforming growth factor-β1 and programmed cell death-1 (PD-1) levels were higher in the immune-suppressed subclass. The established molecular classification system was recapitulated in validation cohorts. The immune-activated subclass was predicted to have a better response to anti-PD-1 immunotherapy. The immune-related subclasses were associated with differences in copy number alterations, tumor mutation burden, neoantigens, tumor-infiltrating lymphocyte enrichment, PD-1/programmed death-ligand 1 expression, mutation landscape, and various infiltration immunocytes. Overall, we established a novel immune-related molecular classification of breast cancer, which may be used to select candidate patients for immunotherapy.

Female ovaries degenerate about 20 years earlier than testes leading to reduced primordial follicle reserve and a reduction in oocyte quality. Here we found that bridge integrator 2 (BIN2) is enriched in mouse ovaries and oocytes and that global knockout of this protein improves both female fertility and oocyte quality. Quantitative ovarian proteomics and phosphoproteomics showed that Bin2 knockout led to a decrease in phosphorylated ribosomal protein S6 (p-RPS6), a component of the mammalian target of rapamycin pathway and greatly increased nicotinamide nucleotide transhydrogenase (NNT), the free-radical detoxifier. Mechanistically, we find that phosphorylation of BIN2 at Thr423 and Ser424 leads to its translocation from the membrane to the cytoplasm, subsequent phosphorylation of RPS6 and inhibition of Nnt translation. We synthesized a BIN2-penetrating peptide (BPP) designed to inhibit BIN2 phosphorylation and found that a 3-week BPP treatment improved primordial follicle reserve and oocyte quality in aging and after chemotherapy-induced premature ovarian failure without discernible side effects. The authors found that deleting an ovary-rich gene called Bin2 improved fertility and oocyte quality in mice. Inhibiting BIN2 with a cell-penetrating peptide improved ovarian function in aging and in chemotherapy-treated mice.

Background Systemic corticosteroids for the treatment of COPD exacerbations decrease treatment failure and shorten the length of hospitalization. However, the optimal dose is unclear. Research Question Is personalized-dose corticosteroid administered according to a dosing scale more effective than fixed-dose corticosteroid administration in hospitalized patients with COPD with exacerbations? Study Design and Methods This was a prospective, randomized, open-label trial. In-hospital patients with COPD with exacerbations were randomly assigned at a 1:1 ratio to either the fixed-dose group (receiving the equivalent of 40 mg of prednisolone) or the personalized-dose group for 5 days. The primary end point was a composite measure of treatment failure that included in-hospital treatment failure and medium-term (postdischarge) failure. Secondary end points were length of stay and cost. Results A total of 248 patients were randomly assigned to the fixed-dose group (n = 124) or personalized-dose group (n = 124). One patient in each group was not included in the intention-to-treat population because of incorrect initial COPD diagnosis. Failure of therapy occurred in 27.6% in the personalized-dose group, compared with 48.8% in the fixed-dose group (relative risk, 0.40; 95% CI, 0.24-0.68; P = .001). The in-hospital failure of therapy was significantly lower in the personalized-dose group (10.6% vs 24.4%; P = .005), whereas the medium-term failure rate, adverse event rate, hospital length of stay, and costs were similar between the two groups. After treatment failure, a lower additional dose of corticosteroids and a shorter duration of treatment were needed in the personalized-dose group to achieve control of the exacerbation. In the personalized-dose cohort, those receiving 40 mg or less had an average failure rate of 44.4%, compared with 22.9% among those receiving more than 40 mg (P = .027). Interpretation Personalized dosing of corticosteroids reduces the risk of failure because more patients were provided with a higher initial dose, especially > 60 mg, whereas 40 mg or less was too low in either group. Clinical Trial Registration ClinicalTrials.gov ; No.: NCT02147015; URL: www.clinicaltrials.gov

Background Although renal insufficiency and dyslipidemia are known to be closely associated, the effect of kidney function on the size and clinical value of high-density lipoprotein (HDL) particles remains largely unknown, especially in patients with coronary heart disease. Methods A total of 419 coronary heart disease patients and 105 non-coronary heart disease patients were included. HDL particle size, represented by HDL-C/apoA-I, was compared between groups stratified by estimated glomerular filtration rate (eGFR) and Gensini scores using standard Student’s t test and one-way ANOVA. Pearson’s correlation test was performed to analyze the association between eGFR and HDL-C/apoA-I in patients with coronary heart disease. The relationship between HDL particle size and the occurrence of coronary heart disease was explored using Univariate logistic regression analysis. Results In patients with coronary heart disease, between-group analysis revealed that HDL-C/apoA-I increased as eGFR declined, and significance appeared as eGFR declined to under 60 ml/min·1.73 m2 (P 2), those with higher Gensini scores had smaller HDL-C/apoA-I. However, with or without kidney insufficiency, smaller HDL-C/apoA-I was associated with a higher occurrence of coronary heart disease (P Conclusion With the presence of renal insufficiency, HDL-C/apoA1 was higher in patients with coronary heart disease. Lower HDL-C/apoA1 was still associated with a higher occurrence of coronary heart disease, but the original association between lower HDL-C/apoA1 and more severe coronary artery stenosis was lost in patients with renal insufficiency.

Background To compare the dynamic corneal response (DCR) and tomographic parameters of thin normal cornea (TNC) with thinnest corneal thickness (TCT) (≤ 500 µm), forme fruste keratoconus (FFKC) and mild keratoconus (MKC) had their central corneal thickness (CCT) matched by Scheimpflug imaging (Pentacam) and corneal visualization Scheimpflug technology (Corvis ST). Methods CCT were matched in 50 eyes with FFKC, 50 eyes with MKC, and 53 TNC eyes with TCT ≤ 500 µm. The differences in DCR and tomographic parameters among the three groups were compared. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic significance of these parameters. Back propagation (BP) neural network was used to establish the keratoconus diagnosis model. Results Fifty CCT-matched FFKC eyes, 50 MKC eyes and 50 TNC eyes were included. The age and biomechanically corrected intraocular pressure (bIOP) did not differ significantly among the three groups (all P > 0.05). The index of height asymmetry (IHA) and height decentration (IHD) differed significantly among the three groups (all P 0.80) to differentiate FFKC and MKC from TNC eyes. Partial DCR parameters showed significant differences between the MKC and TNC groups, and the deflection amplitude of the first applanation (A1DA) showed a good potential to differentiate (AUC > 0.70) FFKC and MKC from TNC eyes. Diagnosis model by BP neural network showed an accurate diagnostic efficiency of about 91%. Conclusions The majority of the tomographic and DCR parameters differed among the three groups. The IHD and partial DCR parameters assessed by Corvis ST distinguished FFKC and MKC from TNC when controlled for CCT.

Background Circular RNAs (circRNAs) are implicated in the carcinogenesis of human cancers. However, the functional roles of circRFX3 in glioma are not elucidated. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) assay was performed for the levels of circRFX3, RFX3, miR-1179, miR-1229 and vasodilator stimulated phosphoprotein (VASP). Actinomycin D assay and RNase R assay were employed to analyze the characteristics of circRFX3. Cell Counting Kit-8 (CCK-8) assay and colony formation assay were conducted for cell proliferation. Transwell assay was used for cell migration and invasion. Flow cytometry analysis was adopted for cell apoptosis. RNA pull-down assay, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to analyze the interaction between miR-1179/miR-1229 and circRFX3 or VASP. Western blot assay was conducted for VASP protein level. Murine xenograft model assay was used to investigate the role of circRFX3 in vivo. Results CircRFX3 level was increased in glioma tissues and cells. Knockdown of circRFX3 suppressed glioma cell proliferation, migration and invasion and promoted apoptosis in vitro and repressed tumorigenesis of glioma in vivo. MiR-1179 and miR-1229 were identified to be the targets of circRFX3. MiR-1179 or miR-1229 inhibition reversed the impacts of circRFX3 knockdown on glioma cell malignant behaviors. Additionally, VASP was demonstrated to be the target gene of miR-1179 and miR-1229, and VASP overexpression abolished the effect of circRFX3 knockdown on glioma cell progression. Conclusion CircRFX3 served as a tumor promoter in glioma via modulating miR-1179/miR-1229-VASP axis, which might provide a novel target for glioma therapy.

SummaryBackground. Anlotinib hydrochloride is an oral small molecule inhibitor of multiple tyrosine kinases, and it has been approved as a third-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) in China. This dose-exploration study was designed to investigate the feasibility of anlotinib in combination with other chemotherapy regimens in patients with nonsquamous NSCLC. Methods. This phase I study followed a 3 + 3 dose reduction design with three doses of anlotinib (12 mg, 10 mg, and 8 mg). Anlotinib was given at an initial dose of 12 mg with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC = 5) on 21-day cycles for 4 cycles. The primary goal of the study was to identify the maximum tolerated dose (MTD), and secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results. A total of eight participants were enrolled. Dose-limiting toxicities (DLTs) were observed in two patients (pts) at anlotinib 12 mg (grade 3 hand-foot syndrome and grade 3 appetite loss). No DLTs occurred with 10 mg anlotinib, and the MTD was 10 mg. Among seven evaluable pts, four achieved a confirmed partial response (PR), and three had stable disease (SD). With a median follow-up of 10.05 months, the median PFS was 7.00 months (95% CI: 2.76 to NE). Grade 3 treatment-related adverse events (TRAEs) included appetite loss (n = 2), hypertension (n = 2), thrombocytopenia (n = 1), diarrhea (n = 1) and hand-foot syndrome (n = 1). No grade 4 or grade 5 TRAEs were observed during the treatment. Conclusion. The feasible dose of anlotinib in combination with platinum/pemetrexed-based chemotherapy as a first-line regimen was 10 mg, which was well tolerated and showed promising antitumor activity in advanced nonsquamous NSCLC.

STEAP3 (Six-transmembrane epithelial antigen of the prostate 3, TSAP6, dudulin-2) has been reported to be involved in tumor progression in human malignancies. Nevertheless, how it participates in the progression of human cancers, especially HCC, is still unknown. In the present study, we found that STEAP3 was aberrantly overexpressed in the nuclei of HCC cells. In a large cohort of clinical HCC tissues, high expression level of nuclear STEAP3 was positively associated with tumor differentiation and poor prognosis (p

Kaidi Guo,1,2,&ast; Li Li1,2,&ast; 1Department of Gynecology and Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of China; 2Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li LiDepartment of Gynecology and Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, People’s Republic of ChinaTel +86 138 7811 3406Email lili@gxmu.edu.cnPurpose: Ovarian cancer is one of the common malignant tumors of female reproductive organs, which seriously threatens the life and health of women. Resistance to chemotherapeutic drugs for ovarian cancer is the root cause of recurrence in most patients. The purpose of this study is to determine the differentially expressed genes of platinum resistance in ovarian cancer, and to screen out molecular targets and diagnostic markers that could be used to treat ovarian cancer platinum resistance.Methods: We downloaded 5 gene microarray datasets GSE58470, GSE45553, GSE41499, GSE33482, and GSE15372 from the Gene Expression Omnibus database, all of which are associated with ovarian cancer platinum resistance. Subsequently, the intersection of the statistically significant differentially expressed genes in 5 gene chips was taken, and relevant bioinformatics and clinical parameters were performed on the screened differential genes. qRT-PCR was utilized to examine the mRNA expression levels in ovarian cancer sensitive and cisplatin-resistant cells.Results: Three differential genes, IFI27, JAG1, DNM3, may be closely related to platinum resistance of ovarian cancer, were screened by microarray datasets. According to the combined verification of bioinformatics, clinical case analyses and experiments, it was inferred that the increased expression of DNM3 was beneficial to patients with platinum resistance, but the high expression of IFI27 and JAG1 may lead to the risk of platinum resistance.Conclusion: IFI27, JAG1 and DNM3 screened by relevant gene chips may serve as new biomarkers of platinum resistance in ovarian cancer.Keywords: ovarian cancer, platinum resistance, bioinformatical analysis, differentially expressed genes

BACKGROUND Dizziness is a common symptom in adults and usually due to peripheral causes affecting semicircular canal function or central causes affecting the pons, medulla, or cerebellum. Arrhythmia is a recognized cause of dizziness in people with structural or ischemic heart disease. We report a case of exercise-induced transient ventricular tachycardia and dizziness in a man with no evidence of organic heart disease. CASE SUMMARY A 42-year-old man presented with a 6 mo history of transient exercise-induced dizziness and prodromal palpitations. The patient was otherwise asymptomatic. Physical examination, otoscopy, vestibular tests, cerebellar tests, laboratory investigations, and imaging investigations were all unremarkable. Twenty-four hour Holter monitoring revealed four episodes of transient ventricular tachycardia during exercise. The patient was started on metoprolol and subsequently underwent radiofrequency catheter ablation. The patient reported a full recovery and no dizziness during daily activities. These results were maintained at the 6 mo follow-up. CONCLUSION Ventricular tachycardia is an uncommon but potentially serious cause of dizziness. The outcome of this case illustrates the benefits of careful clinical examination and communication with specialized centers. High clinical suspicion of arrhythmia in a patient with dizziness merits consultation with a cardiologist and referral to a specialized center to ensure timely diagnosis and treatment.

AIM Bowel dysfunction after sphincter-preserving proctectomy, also known as low anterior resection syndrome (LARS), has significant impact on survivors of rectal cancer. This study aimed to assess the temporal change of LARS beyond 2 years after proctectomy, which has not been fully studied. METHODS We longitudinally enrolled consecutive patients who had received total mesorectal excision in a tertiary academic medical center, with preoperative neoadjuvant therapy if indicated. LARS score was longitudinally assessed by two serial follow-ups, with a fixed interval of 18 months. RESULTS Overall, 107 patients responded for the first follow-up after a median of q20 months, 96 of whom responded for the second follow-up after a median of 38 months. At the first follow-up, 48 patients (44.9%) reported major LARS, compared with 23 (24.0%) at the second follow-up (p

Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. The molecular mechanisms of DCM remain to be fully elucidated. The intronic long noncoding RNA of DACH1 (lncDACH1) has been demonstrated to be closely associated with heart failure and cardiac regeneration. In this study, we investigated the role of lncDACH1 in DCM and the underlying molecular mechanisms. The expression of lncDACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes. Knockout of lncDACH1 reduced mitochondrial oxidative stress, cell apoptosis, cardiac fibrosis and hypertrophy, and improved cardiac function in DCM mice. Overexpression of lncDACH1 exacerbated mitochondria-derived reactive oxygen species (ROS) level and apoptosis, decreased activity of manganese superoxide dismutase (Mn-SOD); while silencing of lncDACH1 attenuated ROS production, mitochondrial dysfunction, cell apoptosis, and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose. LncDACH1 directly bound to sirtuin3 (SIRT3) and facilitated its degradation by ubiquitination, therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts. In addition, SIRT3 silencing abrogated the protective effects of lncDACH1 deficiency in cardiomyocytes. In summary, lncDACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts. Inhibition of lncDACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy.

Background The wide spread of plasmid-mediated colistin resistance by mobile colistin resistance (MCR) in Enterobacteriaceae severely limits the clinical application of colistin as a last-line drug against bacterial infection. The identification of colistin potentiator from natural plants or their compound preparation as antibiotic adjuncts is a new promising strategy to meet this challenge. Methods Herein, the synergistic activity, as well as the potential mechanism, of Pingwei pill plus antibiotics against MCR-positive Gram-negative pathogens was examined using checkerboard assay, time-killing curves, combined disk test, western blot assay, and microscope analysis. Additionally, the Salmonella sp. HYM2 infection models of mouse and chick were employed to examine the in vivo efficacy of Pingwei pill in combination with colistin against bacteria infection. Finally, network pharmacology and molecular docking assay were used to predicate other actions of Pingwei pill for Salmonella infection. Results Our results revealed that Pingwei Pill synergistically potentiated the antibacterial activity of colistin against MCR-1-positive bacteria by accelerating the damage and permeability of the bacterial outer membrane with an FIC (Fractional Inhibitory Concentration) index less than 0.5. The treatment of Pingwei Pill neither inhibited bacterial growth nor affected MCR production. Notably, Pingwei Pill in combination with colistin significantly prolonged the median survival in mouse and chick models of infection using the Salmonella sp. strain HYM2, decreased bacteria burden and organ index of infected animal, alleviated pathological damage of cecum, which suggest that Pingwei Pill recovered the therapeutic performance of colistin for MCR-1- positive Salmonella infection in mice and the naturally infected host chick. Pharmacological network topological analysis, molecular docking, bacterial adhesion, and invasion pathway verification assays were performed to identify the other molecular mechanisms of Pingwei Pill as a colistin potentiator against Gram-negative bacteria infection. Conclusion Taken together, NMPA (National Medical Products Administration)-approved Pingwei Pill is a promising adjuvant with colistin for MCR-positive bacterial infection with a shortened R&D (research and development) cycle and affordable R&D cost and risk.

Ma-chao Li,1,&ast; Jie Lu,2,&ast; Yao Lu,1,3,&ast; Tong-yang Xiao,4,&ast; Hai-can Liu,1 Shi-qiang Lin,5 Da Xu,1 Gui-lian Li,1 Xiu-qin Zhao,1 Zhi-guang Liu,1 Li-li Zhao,1 Kang-lin Wan1 1State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China; 2Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 3School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Guangdong Key Laboratory for Diagnosis & Treatment of Emerging Infectious Diseases, Shenzhen Third People’s Hospital, Southern University of Science and Technology, Shenzhen, People’s Republic of China; 5Department of Bioinformatics, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-li Zhao; Kang-lin WanNational Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, P.O. Box 5, Changping, Beijing, 102206, People’s Republic of ChinaTel/Fax +86 10 58900779Email zhaolili@icdc.cn; wankanglin@icdc.cnObjective: To investigate the mutations within the whole rpoB gene of Mycobacterium tuberculosis and analyze their effects on rifampin (RIF) resistance based on crystal structure.Methods: We sequenced the entire rpoB gene in 175 tuberculosis isolates and quantified their minimum inhibitory concentrations using microplate-based assays. Additionally, the structural interactions between wild-type/mutant RpoB and RIF were also analyzed.Results: Results revealed that a total of 34 mutations distributed across 17 different sites within the whole rpoB gene were identified. Of the 34 mutations, 25 could alter the structural interaction between RpoB and RIF and contribute to RIF resistance. Statistical analysis showed that S450L, H445D, H445Y and H445R mutations were associated with high-level RIF resistance, while D435V was associated with moderate-level RIF resistance.Conclusion: Some mutations within the rpoB gene could affect the interaction between RpoB and RIF and thus are associated with RIF resistance. These findings could be helpful to design new antibiotics and develop novel diagnostic tools for drug resistance in TB.Keywords: Mycobacterium tuberculosis, rifampin resistance, structure, mutation

SCI (SCI) poses a challenge to nerve cell repair strategies. SCI injury can lead to the development of inflammation, which in turn can exacerbate nerve cell damage. The TLR4/NF-kappa B signaling pathway is a common inflammatory signaling pathway. Since BMSCs are involved in injury repair, whether they can promote the repair of SCI neuronal cells have not been reported. Spinal cord nerve cells were cultured in vitro and divided into mechanical injury group and BMSCs group followed by analysis of cell proliferation activity and detection of altered apoptotic activity. Changes in the concentrations of IL-6 and IL-1β were measured by ELISA and cellular mitochondrial alterations was assessed by JG-B staining along with analysis of NF-kappa B, TLR4, related neurodevelopmental factor BDNF, and NGF expression by western blot. Mechanical damage to neuronal cells resulted in decreased cell proliferation, increased apoptotic activity, decreased cellular mitochondrial activity, increased TLR4 and NF-kappa B expression, decreased BDNF and NGF expression, as well as increased secertions of IL-6 and IL-1β (P < 0.05). In contrast, co-culture with BMSCs resulted in increased proliferation and decreased apoptosis of mechanically injured neuronal cells, increased cellular mitochondrial activity, with observation of the inverse changes in other factors (P < 0.05). In conclusion, BMSCs can suppress inflammation and promote repair of injured neuronal cells by inhibiting TLR4/NF-kappa B signaling.

Background Alcohol consumption and smoking are the leading risk factors for laryngeal cancer (LC). Understanding the variations in disease burden of LC attributable to alcohol use and smoking is critical for LC prevention. Methods Disease burden data of LC were retrieved from the Global Burden of Disease Study 2019. We used estimated average percentage change (EAPC) to measure the temporal trends of the age-standardized mortality rate (ASMR) of LC. Results Globally, while the ASMR of LC decreased by 1.49% (95% CI, 1.41–1.57%) per year between 1990 and 2019, the number of deaths from LC has increased 41.0% to 123.4 thousand in 2019. In 2019, 19.4 and 63.5% of total LC-related deaths were attributable to alcohol use and smoking worldwide, respectively. The ASMR of alcohol- and smoking-related LC decreased by 1.78 and 1.93% per year, whereas the corresponding death number has increased 29.2 and 25.1% during this period, respectively. The decreasing trend was more pronounced in developed countries. In some developing countries, such as Guinea and Mongolia, the LC mortality has shown an unfavorable trend. Conclusion The ubiquitous decrease in LC mortality was largely attributed to the smoking control and highlighted the importance of smoking control policies. However, the disease burden of LC remained in increase and more effective strategies are needed to combat the global increase of alcohol consumption.

The Hedgehog (Hh) signalling pathway plays a critical role in the growth and patterning during embryonic development and maintenance of adult tissue homeostasis. Emerging data indicate that Hh signalling is implicated in the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic treatments for IBD require optimisation, and novel effective drugs are warranted. Targeting the Hh signalling pathway may pave the way for successful IBD treatment. In this review, we introduce the molecular mechanisms underlying the Hh signalling pathway and its role in maintaining intestinal homeostasis. Then, we present interactions between the Hh signalling and other pathways involved in IBD and colitis-associated colorectal cancer (CAC), such as the Wnt and nuclear factor-kappa B (NF-κB) pathways. Furthermore, we summarise the latest research on Hh signalling associated with the occurrence and progression of IBD and CAC. Finally, we discuss the future directions for research on the role of Hh signalling in IBD pathogenesis and provide viewpoints on novel treatment options for IBD by targeting Hh signalling. An in-depth understanding of the complex role of Hh signalling in IBD pathogenesis will contribute to the development of new effective therapies for IBD patients.

Background Multi-modal therapy has attracted increasing attention as it provides enhanced effectiveness and potential stimulation of the immune community. However, low accumulation at the tumor sites and quick immune clearance of the anti-tumor agents are still insurmountable challenges. Hypothetically, cancer cell membrane (CCM) can homologously target the tumor whereas multi-modal therapy can complement the disadvantages of singular therapies. Meanwhile, moderate hyperthermia induced by photothermal therapy can boost the cellular uptake of therapeutic agents by cancer cells. Results CCM-cloaked indocyanine green (ICG)-incorporated and abraxane (PTX-BSA)-loaded layered double hydroxide (LDH) nanosheets (LIPC NSs) were fabricated for target efficient photo-chemotherapy of colorectal carcinoma (CRC). The CCM-cloaked LDH delivery system showed efficient homologous targeting and cytotoxicity, which was further enhanced under laser irradiation to synergize CRC apoptosis. On the other hand, CCM-cloaking remarkably reduced the uptake of LDH NSs by HEK 293T cells and macrophages, implying mitigation of the side effects and the immune clearance, respectively. In vivo data further exhibited that LIPC NSs enhanced the drug accumulation in tumor tissues and significantly retarded tumor progression under laser irradiation at very low therapeutic doses (1.2 and 0.6 mg/kg of ICG and PTX-BSA), without observed side effects on other organs. Conclusions This research has demonstrated that targeting delivery efficiency and immune-escaping ability of LIPC NSs are tremendously enhanced by CCM cloaking for efficient tumor accumulation and in situ generated hyperthermia boosts the uptake of LIPC NSs by cancer cells, a potential effective way to improve the multi-modal cancer therapy. Graphical Abstract

Aim: To investigate the effect of aberrant expression of DHRS1 on hepatocellular carcinoma (HCC). Materials & methods: Kaplan–Meier and Cox regression analyses were performed to evaluate the correlation between DHRS1 and overall survival. Gene set enrichment analysis was performed to explore the potential function of DHRS1 in HCC. Results: Multiple data analysis revealed that DHRS1 mRNA and protein expression level were remarkably lower in HCC than that in normal tissues. In survival analysis, patients with low DHRS1 expression presented a poorer prognosis, and was an independent risk factor for HCC. Conclusion: Decreased DHRS1 expression may be a potential predictor of poor prognosis in HCC.

Background To evaluate the prognosis of acute cerebral infarction at 1-year follow-up in different circulation infarctions. Methods Clinical data of 858 consecutive patients with acute cerebral infarction were collected. Of the 858 cases, 21 (2.45%) were lost to follow-up and 837 completed follow-up and thus were enrolled in this study. At 1-year follow-up, death or moderate-to-severe dysfunction (modified Rankin Scale (mRS) ≥ 3 points) was regarded as the poor prognostic endpoint. Univariate analysis and multivariate logistic stepwise regression analysis were performed to assess the prognosis. The prediction probability of indicators was obtained for the multivariate model, and the receiver operating characteristic curve was delineated to calculate the area under the curve (AUC) to predict the fitness of the model. Results The older the age, the greater the probability of a poor prognosis. Patients with previous diabetes and cerebral infarction had a poor prognosis. The higher the National Institutes of Health Stroke Scale and mRS scores and the lower the Barthel index at admission, the worse the prognosis of the patients. The longer the hospital stay, the worse the prognosis of the patients. The prognosis of different circulation infarctions was different. The AUC of the multivariate model was AUC = 0.893, and the 95% confidence interval was 0.870–0.913, indicating a good fit. The prognosis of anterior circulation infarction (ACI) was worse than that of posterior circulation infarction (PCI) (P P > 0.05). Conclusions Diabetes, the Barthel index at admission and previous cerebral infarction are poor prognostic factors of acute cerebral infarction. The prognosis of ACI is worse than that of PCI. Different factors affect the prognosis of different circulatory system infarctions.

Background Colon adenocarcinoma (COAD) is one of the most common malignancies worldwide. Genomic instability is one of the hallmarks of colon cancer and is associated with prognosis. Nevertheless, the impact of genome instability-associated long non-coding RNAs (lncRNAs) along with their clinical significance in cancers has remained mostly unexplored. Methods In this study, a mutator hypothesis-derived computational frame integrating the somatic mutation profiles and lncRNA expression profiles in a tumor genome was developed, which enabled the identification of 137 novel genomic instability-associated lncRNAs in colon cancer. Subsequently, a genome instability-derived lncRNA signature (GILncSig) segregated the patients into low- and high-risk groups with prominent differences in outcomes. Results Combined with the overall survival data, we established 6 six lncRNA-based signature to predict prognosis, which were LINC00896, AC007996.1, NKILA, AP003555.2, MIRLET7BHG, and AC009237.14. We found that the expression level of PD-L1 (CD274) and somatic mutations in the high-risk group were higher than those in the low-risk group. This suggests that high-risk patients may be sensitive to immunotherapy. We further found that the prognosis of patients in the high-risk group was significantly lower than that of patients in the low-risk group, and that patients' prognosis was likely to be worse as the patient's risk score increased. Conclusions In conclusion, this study explores the role of lncRNAs in genomic instability and cancer prognosis and provides a new idea for the prognostic prediction of colon cancer.

Background Acute kidney injury is common in patients with COVID-19, however mechanisms of kidney injury remain unclear. Since cytokine storm is likely a cause of AKI and glomerular disease, we investigated the two major transcription factors, STAT3 and NF-kB, which are known to be activated by cytokines. Methods This is an observational study of the postmortem kidneys of 50 patients who died with COVID-19 in the Mount Sinai Hospital during the first pandemic surge. All samples were reviewed under light microscopy, electron microscopy, and immunofluorescence by trained renal pathologists. In situ hybridization evaluation for SARS-CoV-2 and immunostaining of transcription factors STAT3 and NF-kB were performed. Results Consistent with previous findings, acute tubular injury was the major pathological finding, together with global or focal glomerulosclerosis. We were not able to detect SARS-CoV-2 in kidney cells. ACE2 expression was reduced in the tubular cells of patients who died with COVID-19 and did not co-localize with TMPRSS2. SARS-CoV-2 was identified occasionally in the mononuclear cells in the peritubular capillary and interstitium. STAT3 phosphorylation at Tyr705 was increased in 2 cases in the glomeruli and in 3 cases in the tubulointerstitial compartments. Interestingly, STAT3 phosphorylation at Ser727 increased in 9 cases but only in the tubulointerstitial compartment. A significant increase in NF-kB phosphorylation at Ser276 was also found in the tubulointerstitium of the two patients with increased p-STAT3 (Tyr705). Conclusions Our findings suggest that, instead of tyrosine phosphorylation, serine phosphorylation of STAT3 is commonly activated in the kidney of patients with COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s40620-021-01173-0.

Background Synovial sarcoma (SS) is a highly malignant tumor of unknown histological origin. This tumor can occur in various parts of the body, including those without synovial structures, but mainly in and around the joints, mostly in the lower extremities. Primary intracranial SSs are remarkably rare. This paper aims to report a case of primary intracranial SS with hemorrhage. Case summary A 35-year-old male patient suffered a headache and slurred speech during manual labor and was sent to the emergency department. Through imaging examination, the patient was considered to have high-grade glioma complicated with hemorrhage and was treated with craniotomy. Postoperative pathology revealed SS. positron emission tomography/computed tomography was performed, which ruled out the possibility of metastasis to the intracranial from other parts of the body. Postoperative radiotherapy was given to the patient, during which radiation necrosis occurred. Sixteen months after craniotomy, cranial magnetic resonance imaging revealed recurrence of the tumor. Conclusion Primary intracranial SS is a rare malignant tumor. Primary intracranial SS with hemorrhage and radiation necrosis should be carefully monitored during postoperative radiotherapy. Surgical resection of the tumor combined with postoperative radiotherapy and chemotherapy is currently used, but the prognosis is poor.

Despite HER2-targeted cancer treatments have provided considerable clinical benefits, resistance to HER2-targeted agents will inevitably develop. Targeting non-oncogene vulnerabilities including endoplasmic reticulum (EnR) stress has emerged as an attractive alternative approach to improve the efficacy of existing targeted cancer therapies. In the current study, we find that Melatonin sensitizes HER2-positive breast cancer cells to the dual tyrosine kinase inhibitor Lapatinib in vitro. Mechanistically, Melatonin enhances the cytotoxic effects of Lapatinib through promoting excessive EnR stress-induced unfolded protein response (UPR) and ROS overaccumulation. Consistently, the antioxidant N-acetylcysteine remarkably reverses the effects of the drug combination on ROS production, DNA damage and cytotoxicity. Furthermore, Melatonin significantly enhances the anti-tumor effect of Lapatinib in an HCC1954 xenograft model. Meanwhile, Lapatinib resistant HER2-positive breast cancer cells (LapR) display lower basal expression levels of UPR genes and enhanced tolerance to EnR stress with attenuated response to Brefeldin A and Tunicamycin. Importantly, Melatonin also increases the sensitivity of HCC1954 LapR cells to Lapatinib. Together, our findings highlight the potential utility of Melatonin as an adjuvant in the treatment of primary or therapy resistant HER2-positive breast cancer via EnR stress-mediated mechanisms.

Due to advances in chip and sequencing technology, several types and numbers of long non-coding RNAs (lncRNAs) have been identified. LncRNAs are defined as non-protein-coding RNA molecules longer than 200 nucleotides, and are now thought as a new frontier in the study of human malignant diseases including NSCLC. Diagnosis of numerous malignant tumors has been closely linked to the differential expression of certain lncRNAs. LncRNAs are involved in gene expression regulation at multiple levels of epigenetics, transcriptional regulation, and post-transcriptional regulation. Mutations, deletions, or abnormal expression levels lead to physiological abnormalities, disease occurrence and are closely associated with human tumor diseases. LncRNAs play a crucial role in cancerous processes as either oncogenes or tumor suppressor genes. The expression of lncRNAs can regulate tumor cell in the proliferation, migration, apoptosis, cycle, invasion, and metastasis. As such, lncRNAs are potential diagnostic and treatment targets for cancer. And that, tumor biomarkers need to be detectable in easily accessible body samples, should be characterized by high specificity and sufficient sensitivity. Herein, it is significant clinical importance to screen and supplement new biomarkers for early diagnosis of lung cancer. This study aimed at systematically describing lncRNAs from five aspects based on recent studies: concepts, classification, structure, molecular mechanism, signal pathway, as well as review lncRNA implications in malignant tumor.