We report on the highest energy photons from the Crab Nebula observed by the Tibet air shower array with the underground water-Cherenkov-type muon detector array. Based on the criterion of a muon ...number measured in an air shower, we successfully suppress 99.92% of the cosmic-ray background events with energies E>100 TeV. As a result, we observed 24 photonlike events with E>100 TeV against 5.5 background events, which corresponds to a 5.6σ statistical significance. This is the first detection of photons with E>100 TeV from an astrophysical source.
Extra-intestinal clostridial infection (EICI) is rare but can be fatal. Traditional phenotypic methods can only assign many of the Clostridium species to the genus level.
A total of 376 ...non-repetitive Clostridium isolates from sterile sites were collected and subjected to matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) Biotyper analysis and 16S rRNA sequencing. Antimicrobial susceptibility was determined, and clinical characteristics of the patients were assessed. Clostridium innocuum isolates were characterized by genome sequencing and genotyping. We used molecular and cellular methods to explore the virulence and resistance mechanisms of C.innocuum.
Clostridium innocuum was the second most common species to cause EICI, only next to Clostridium perfringens. All Clostridium isolates showed susceptibility to clindamycin, metronidazole, penicillin, piperacillin and ampicillin-sulbatam, while C. innocuum isolates were invariably resistant to vancomycin. Among 24 patients with EICI caused by C. innocuum, two (8.3%) had diarrhoea, three (12.5%) had soft-tissue infection, six (25%) had appendicitis and four (16.7%) each had shock and gastrointestinal perforation. The 30-day mortality was 16.7%. The C. innocuum isolated from different sites could not be separated from one another by genotyping. No known toxin genes were identified in the genome of C. innocuum but the species expressed cytotoxicity to epithelial cells. d-Alanine-d-alanine ligase, alanine racemase and d-alanyl-d-alanine carboxypeptidase are three main genes responsible for vancomycin resistance in C. innocuum.
Vancomycin-resistant C. innocuum is a previously unrecognized, yet prominent, cause for EICI. Genome analysis showed that the species could carry a lipopolysaccharide-like structure that is associated with cytotoxicity to cells in vitro.
Increasing evidence indicates that the risk of cryptococcal infections is increased in patients with rheumatoid arthritis (RA). However, the association between cryptococcosis and immunosuppressive ...medications in RA patients is still uncertain and little is known about risk factors for cryptococcal disease among RA patients. We conducted a retrospective case–control study to investigate the epidemiology of RA patients with cryptococcosis in a medical centre during the period 2001–14. We estimated ORs with 95% CI for cryptococcosis according to co-morbidities and immunosuppressive medications by using backward stepwise logistic regression. Among 9132 newly diagnosed RA patients, 20 (0.22%) were newly diagnosed with cryptococcal infection after RA identification. All cryptococcosis cases had been receiving corticosteroid treatment for some time (3.9±3.3 years) before infection. After full adjustment, chronic kidney disease (adjusted OR (aOR) 2.72, 95% CI 1.04–7.08, p 0.041) was a significant risk factor for cryptococcosis in RA patients. Exposure to adalimumab (monoclonal anti-tumour necrosis factor (TNF) antibodies) (aOR 4.50, 95% CI 1.03–19.66, p 0.046) were significantly associated with increased risks of cryptococcosis. Time to cryptococcosis diagnosis among RA patients receiving anti-TNF biologicals was shorter than in patients not receiving anti-TNF biologicals (1.5±1.2 years versus 8.4±5.5 years, p<0.001). Among RA patients, the risk for development of cryptococcosis was higher among those who had chronic kidney disease and were receiving the monoclonal anti-TNF antibody adalimumab. Therefore, we suggest that cryptococcal infection should be suspected in RA patients with risk factors.
Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this ...study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation. Knock down of GP78 significantly increased the expression of HSPA5 and enhanced migration/invasive ability of breast cancer cells. Knock down of histone deacetylase-6 (HDAC6) increased the acetylation of HSPA5 at lysine residues 353 (K353) and reduced GP78-mediated ubiquitination of HSPA5 at K447 and then increased cell migration/invasion. In addition, we demonstrate that E3 ubiquitin ligase GP78 preferentially binds to deacetylated HSPA5. Notably, the expression levels of GP78 inversely correlated with HSPA5 levels in breast cancer patients. Patients with low GP78 expression significantly correlated with invasiveness of breast cancer, advanced tumor stages and poor clinical outcome. Taken together, our results provide new mechanistic insights into the understanding that deacetylation of HSPA5 by HDAC6 facilitates GP78-mediated HSPA5 ubiquitination and suggest that post-translational regulation of HSPA5 protein is critical for HSPA5-mediated metastatic properties of breast cancer.
MicroRNAs (miRNAs) are small RNAs that suppress gene expression by their interaction with 3'untranslated region of specific target mRNAs. Although the dysregulation of miRNAs has been identified in ...human cancer, only a few of these miRNAs have been functionally documented in breast cancer. Thus, defining the important miRNA and functional target involved in chemoresistance is an urgent need for human breast cancer treatment. In this study, we, for the first time, identified a key role of miRNA 520h (miR-520h) in drug resistance. Through protecting cells from paclitaxel-induced apoptosis, expression of miR-520h promoted the drug resistance of human breast cancer cells. Bioinformatics prediction, compensatory mutation and functional validation further confirmed the essential role of miR-520h-suppressed Death-associated protein kinase 2 (DAPK2) expression, as restoring DAPK2 abolished miR-520h-promoted drug resistance, and knockdown of DAPK2 mitigated cell death caused by the depletion of miR-520h. Furthermore, we observed that higher level of miR-520h is associated with poor prognosis and lymph node metastasis in human breast cancer patients. These results show that miR-520h is not only an independent prognostic factor, but is also a potential functional target for future applications in cancer therapeutics.
Background Kidney biopsy provides important information for nephrologists, but the risk of complications has not been systematically described. Study Design Meta-analysis of randomized controlled ...trials and prospective or retrospective observational studies. Setting & Population Adults undergoing native kidney biopsy in an inpatient or outpatient setting. Selection Criteria for Studies MEDLINE indexed studies from January 1980 through June 2011; sample size of 50 or more. Intervention Native kidney biopsy with automated biopsy device and real-time ultrasonographic guidance. Outcomes Macroscopic hematuria and erythrocyte transfusion rates and factors associated with these outcomes. Results 34 studies of 9,474 biopsies met inclusion criteria. The rate of macroscopic hematuria was 3.5% (95% CI, 2.2%-5.1%), and erythrocyte transfusion was 0.9% (95% CI, 0.4%-1.5%). Significantly higher rates of transfusion were seen with the following: 14-gauge compared with smaller needles (2.1% vs 0.5%; P = 0.009), studies with mean serum creatinine level ≥2.0 mg/dL (2.1% vs 0.4%; P = 0.02), ≥50% women (1.9% vs 0.6%; P = 0.03), and ≥10% of biopsies for acute kidney injury (1.1% vs 0.04%; P < 0.001). Higher transfusion rates also were observed in studies with a mean age of 40 years or older (1.0% vs 0.2%; P = 0.2) and mean systolic blood pressure ≥130 mm Hg (1.4% vs 0.1%; P = 0.09). Similar relationships were noted for the macroscopic hematuria rate with the same predictors, but none was statistically significant. Limitations Publication bias, few randomized controlled trials, and missing data. Conclusions Native kidney biopsy using automated biopsy devices and real-time ultrasonography is associated with a relatively small risk of macroscopic hematuria and erythrocyte transfusion requirement. Using smaller gauge needles may lower complication rates. Patient selection may affect outcome because studies with higher serum creatinine levels, more women, and higher rates of acute kidney injury had higher complication rates. Future studies should further evaluate risk factors for complications.
Chronic kidney disease (CKD) affects >10% of the adult population. Each year, approximately 120,000 Americans develop end-stage kidney disease and initiate dialysis, which is costly and associated ...with functional impairments, worse health-related quality of life, and high early-mortality rates, exceeding 20% in the first year. Recent declarations by the World Kidney Day and the U.S. Government Executive Order seek to implement strategies that reduce the burden of kidney failure by slowing CKD progression and controlling uremia without dialysis. Pragmatic dietary interventions may have a role in improving CKD outcomes and preventing or delaying dialysis initiation. Evidence suggests that a patient-centered plant-dominant low-protein diet (PLADO) of 0.6–0.8 g/kg/day composed of >50% plant-based sources, administered by dietitians trained in non-dialysis CKD care, is promising and consistent with the precision nutrition. The scientific premise of the PLADO stems from the observations that high protein diets with high meat intake not only result in higher cardiovascular disease risk but also higher CKD incidence and faster CKD progression due to increased intraglomerular pressure and glomerular hyperfiltration. Meat intake increases production of nitrogenous end-products, worsens uremia, and may increase the risk of constipation with resulting hyperkalemia from the typical low fiber intake. A plant-dominant, fiber-rich, low-protein diet may lead to favorable alterations in the gut microbiome, which can modulate uremic toxin generation and slow CKD progression, along with reducing cardiovascular risk. PLADO is a heart-healthy, safe, flexible, and feasible diet that could be the centerpiece of a conservative and preservative CKD-management strategy that challenges the prevailing dialysis-centered paradigm.
HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), ...Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0-340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2-125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6-192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4-20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4-11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and ...covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
The rich phenomena in the FeSe and related compounds have attracted great interests as it provides fertile material to gain further insight into the mechanism of high temperature superconductivity. A ...natural follow-up work was to look into the possibility of superconductivity in MnSe. We demonstrated in this work that high pressure can effectively suppress the complex magnetic characters of MnSe, and induce superconductivity with T
~ 5 K at pressure ~12 GPa confirmed by both magnetic and resistive measurements. The highest T
is ~ 9 K (magnetic result) at ~35 GPa. Our observations suggest the observed superconductivity may closely relate to the pressure-induced structural change. However, the interface between the metallic and insulating boundaries may also play an important role to the pressure induced superconductivity in MnSe.
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