Doxorubicin (Dox) is an anthracycline drug widely applied in various malignancies. However, the fatal cardiotoxicity induced by Dox limits its clinical application. Post-transcriptional protein modification via ubiquitination/deubiquitination in cardiomyocytes mediates the pathophysiological process in Dox-induced cardiotoxicity (DIC). In this study, we aimed to clarify the regulatory role and mechanism of a deubiquitinating enzyme, ubiquitin-specific peptidase 13 (USP13), in DIC. RNA-seq analysis and experimental examinations identified that cardiomyocyte-derived USP13 positively correlated with DIC. Mice with cardiac-specific deletion of USP13 were subjected to Dox modeling. Adeno-associated virus serotype 9 (AAV9) carrying cTNT promoter was constructed to overexpress USP13 in mouse heart tissues. Cardiomyocyte-specific knockout of USP13 exacerbated DIC, while its overexpression mitigated DIC in mice. Mechanistically, USP13 deubiquitinates the stimulator of interferon genes (STING) and promotes the autolysosome-related degradation of STING, subsequently alleviating cardiomyocyte inflammation and death. Our study suggests that USP13 serves a cardioprotective role in DIC and indicates USP13 as a potential therapeutic target for DIC treatment.

Clinical practice guidelines (CPGs) have become ubiquitous in every field of medicine today but there has been limited success in implementation and improvement in health outcomes. Guidelines are largely based on the results of traditional randomised controlled trials (RCTs) which adopt a highly selective process to maximise the intervention's chance of demonstrating efficacy thus having high internal validity but lacking external validity. Therefore, guidelines based on these RCTs often suffer from a gap between trial efficacy and real world effectiveness and is one of the common reasons contributing to poor guideline adherence by physicians. "Real World Evidence" (RWE) can complement RCTs in CPG development. RWE-in the form of data from integrated electronic health records-represents the vast and varied collective experience of frontline doctors and patients. RWE has the potential to fill the gap in current guidelines by balancing information about whether a test or treatment works (efficacy) with data on how it works in real world practice (effectiveness). RWE can also advance the agenda of precision medicine in everyday practice by engaging frontline stakeholders in pragmatic biomarker studies. This will enable guideline developers to more precisely determine not only whether a clinical test or treatment is recommended, but for whom and when. Singapore is well positioned to ride the big data and RWE wave as we have the advantages of high digital interconnectivity, an integrated National Electronic Health Record (NEHR), and governmental support in the form of the Smart Nation initiative.
Big Data ; Electronic Health Records ; Evidence-Based Medicine ; Guideline Adherence ; Humans ; Practice Guidelines as Topic ; Practice Patterns, Physicians' ; Pragmatic Clinical Trials as Topic ; Precision Medicine ; Singapore

Objective To investigate the association of silent information regulator 1 (SIRT1) polymorphisms with intracerebral hemorrhage (ICH) susceptibility.Methods From September 1,2013 to May 30,2017,Han ethnic 201 ICH patients and 203 controls from South China were enrolled in this study.Genotyping and sequencing ofSIRT1 polymorphisms (rs7069102,rs2273773 and rs7895833) were performed by PCR-restriction fragment length polymorphism (PCR-RFLP).The correlation of SIRT1 polymorphisms with ICH was analyzed.Results (1) The rs7895833 A allele frequency distribution was significantly higher and the rs7895833 GG+AG gene frequency distribution was significantly lower in the ICH group than those in the control group (P＜0.05);the rs7069102 C allele frequency distribution was lower and the GG+CG gene frequency distribution was higher in the ICH group than those in the control group,without significant differences (P＞0.05).(2) Logistic regression analysis indicated rs7895833 AA genotype carriers had increased risk for ICH (OR:1.57,95％CI:1.14-2.18,P=0.006).(3) As compared with patients with rs2273773 TT genotype,patients with CC and CT genotypes had significantly higher high-density lipoprotein cholesterol level (P＜0.05);there were no associations between rs2273773/rs7069102 and ICH.Conclusion SIRT1 rs7895833 is significantly associated with ICH susceptibility;rs2273773 genotypes affect plasma high-density lipoprotein cholesterol level in the Chinese Han ethnic population.

Metastasis of hepatocellular carcinoma (HCC) to the ovary is notably rare. We present a case of HCC metastasis to the ovary with a review of the literature, which includes only 7 reported cases. A 43-year-old hepatitis B virus carrier was admitted with a right ovarian cystic mass. She had been diagnosed with HCC 2 years prior, for which she underwent transarterial chemoembolization followed by right posterior sectionectomy. Eight months after the hepatectomy, the first intrahepatic recurrence was detected and treated with transarterial chemoembolization. An additional intrahepatic recurrence occurred 12 months after transarterial chemoembolization and was managed with left medial sectionectomy and intra-operative radiofrequency ablation. Over the following 3 months, the patient developed elevated alpha-fetoprotein, and positron emission tomography showed a cystic mass in the right side of the pelvic cavity with focal hypermetabolic activity, which suggested a site of recurrent HCC. An exploratory laparotomy was performed, and a soft, ovoid cystic mass was identified in the right ovary. There was no evidence of metastases in the liver, left ovary, or peritoneum. Because of the absence of tumor on the surface of the ovary and the lack of peritoneal seeding, the mode of metastasis was thought to be hematogenous. Therefore, a right salphingo-oophorectomy was performed. The pathological features showed metastatic HCC with clear resection margins. Although metastasis of HCC to the ovary is very rare, it should be suspected in a female patient with a lower abdominal mass and an elevated serum AFP level in the absence of other demonstrable metastases.
Adult ; alpha-Fetoproteins ; Carcinoma, Hepatocellular ; Female ; Hepatectomy ; Hepatitis B virus ; Humans ; Laparotomy ; Liver ; Neoplasm Metastasis ; Ovarian Cysts ; Ovary ; Peritoneum ; Positron-Emission Tomography ; Recurrence ; Seeds

Objective To develop a rapid, sensitive and specific assay based on multiplex real-time PCR for detecting and identifying Escherichia coli O157: H7. Methods The lipopolysaccharide gene (rJbE) and H7 flagellar antigen gene(fliC) of Escherichia coli O157:H7 was chosen as targets, and then the primers and TaqMan-MGB probe were designed. The 5'end of probes was labeled with FAM and HEX fluo-resceins respectively; the 3'end of probes was labeled with MGB. The PCR reaction was optimized systemati-cally. Then the specificity, sensitivity and reproducibility of multiplex real-time PCR were estimated. Final-ly, multiplex real-time PCR was applied to detected clinical specimens. Results Escherichia coil O157:H7 were detected by multiplex real-time PCR accurately and quickly, which could distinguish Escherichia coli O157:H7 from O157: non-H7. Meanwhile, none of other bacteria could be identified. The sensitivity was 10 CFU/ml in pure culture. The coefficient of variation of intra-assay and inter-assay was less than 5%. When this assay was applied directly to identify 66 clinical specimens, the results showed that t5 were positive to Escherichia coil O157:H7 and 2 were positive to Escherichia coil O157: non-H7, in which 16 was the same to the results obtained from the conventional assays. The coincidence was 98.49%. Conclusion It is showed that multiplex real-time PCR is a reliable, accurate and feasible assay for detecting and identifying Escherich-ia coli Oi57: H7, The assay reported here provided a tool for analysis and diagnosis in the field of detecting clinical pathogens, epidemiologic survey and food safety monitoring.

Non-surgical treatment is usually performed for the cases of hepatocellular carcinoma (HCC) that are not suitable for curative treatment, such as those cases with a large tumor size with an insufficient hepatic remnant after resection, those cases with extensive and multifocal bilobar tumors or those cases with extrahepatic metastases of the disease. However, in this case report we present a case of palliative hepatectomy for treating advanced HCC with multiple metastases and the patient has had an excellent 1-year follow-up outcome. A 71-year-old man was referred to our hospital and the imaging studies showed a 10 cm mass in the right liver, with multiple variable sized masses in both lungs and a 1 cm nodule in the left adrenal gland. A lung biopsy revealed HCC; therefore, the working diagnosis was HCC with multiple lung metastases and a left adrenal gland adenoma or metastasis. We expected the cause of death would be deterioration of the hepatic function as the liver mass increased in size. Therefore, we performed a palliative right trisectionectomy for the primary liver mass. After recovery from the hepatectomy, the patient was managed with sorafenib. During the 1-year follow-up period after palliative hepatectomy, the patient is still alive with a good general performance status and no evidence of intrahepatic recurrence, even though there has been an aggravation of the lung metastases in size and number, and a slight increase in the size of the left adrenal gland. We suggest that in highly selected patients with advanced HCC and multiple extrahepatic metastases, and especially in the cases involving a large HCC with mild liver cirrhosis and a good general performance status, an aggressive treatment strategy with palliative hepatectomy can be an optional treatment modality to improve the overall survival.
Adenoma ; Adrenal Glands ; Aged ; Benzeneacetamides ; Biopsy ; Carcinoma, Hepatocellular ; Cause of Death ; Follow-Up Studies ; Hepatectomy ; Humans ; Liver ; Liver Cirrhosis ; Lung ; Neoplasm Metastasis ; Niacinamide ; Palliative Care ; Phenylurea Compounds ; Piperidones ; Recurrence

Non-surgical treatment is usually performed for the cases of hepatocellular carcinoma (HCC) that are not suitable for curative treatment, such as those cases with a large tumor size with an insufficient hepatic remnant after resection, those cases with extensive and multifocal bilobar tumors or those cases with extrahepatic metastases of the disease. However, in this case report we present a case of palliative hepatectomy for treating advanced HCC with multiple metastases and the patient has had an excellent 1-year follow-up outcome. A 71-year-old man was referred to our hospital and the imaging studies showed a 10 cm mass in the right liver, with multiple variable sized masses in both lungs and a 1 cm nodule in the left adrenal gland. A lung biopsy revealed HCC; therefore, the working diagnosis was HCC with multiple lung metastases and a left adrenal gland adenoma or metastasis. We expected the cause of death would be deterioration of the hepatic function as the liver mass increased in size. Therefore, we performed a palliative right trisectionectomy for the primary liver mass. After recovery from the hepatectomy, the patient was managed with sorafenib. During the 1-year follow-up period after palliative hepatectomy, the patient is still alive with a good general performance status and no evidence of intrahepatic recurrence, even though there has been an aggravation of the lung metastases in size and number, and a slight increase in the size of the left adrenal gland. We suggest that in highly selected patients with advanced HCC and multiple extrahepatic metastases, and especially in the cases involving a large HCC with mild liver cirrhosis and a good general performance status, an aggressive treatment strategy with palliative hepatectomy can be an optional treatment modality to improve the overall survival.
Adenoma ; Adrenal Glands ; Aged ; Benzeneacetamides ; Biopsy ; Carcinoma, Hepatocellular ; Cause of Death ; Follow-Up Studies ; Hepatectomy ; Humans ; Liver ; Liver Cirrhosis ; Lung ; Neoplasm Metastasis ; Niacinamide ; Palliative Care ; Phenylurea Compounds ; Piperidones ; Recurrence