Exosomal long noncoding RNA MLETA1 promotes tumor progression and metastasis by regulating the miR-186-5p/EGFR and miR-497-5p/IGF1R axes in non-small cell lung cancer.

BACKGROUND: Lung cancer is the most common and deadliest cancer worldwide, and approximately 90% of all lung cancer deaths are caused by tumor metastasis. Tumor-derived exosomes could potentially promote tumor metastasis through the delivery of metastasis-related molecules. However, the function and underlying mechanism of exosomal long noncoding RNA (lncRNA) in lung cancer metastasis remain largely unclear. METHODS: Cell exosomes were purified from conditioned media by differential ultracentrifugation and observed using transmission electron microscopy, and the size distributions were determined by nanoparticle tracking analysis. Exosomal lncRNA sequencing (lncRNA-seq) was used to identify long noncoding RNAs. Cell migration and invasion were determined by wound-healing assays, two-chamber transwell invasion assays and cell mobility tracking. Mice orthotopically and subcutaneously xenografted with human cancer cells were used to evaluate tumor metastasis in vivo. Western blot, qRT‒PCR, RNA-seq, and dual-luciferase reporter assays were performed to investigate the potential mechanism. The level of exosomal lncRNA in plasma was examined by qRT‒PCR. MS2-tagged RNA affinity purification (MS2-TRAP) assays were performed to verify lncRNA-bound miRNAs. RESULTS: Exosomes derived from highly metastatic lung cancer cells promoted the migration and invasion of lung cancer cells with low metastatic potential. Using lncRNA-seq, we found that a novel lncRNA, lnc-MLETA1, was upregulated in highly metastatic cells and their secreted exosomes. Overexpression of lnc-MLETA1 augmented cell migration and invasion of lung cancer. Conversely, knockdown of lnc-MLETA1 attenuated the motility and metastasis of lung cancer cells. Interestingly, exosome-transmitted lnc-MLETA1 promoted cell motility and metastasis of lung cancer. Reciprocally, targeting lnc-MLETA1 with an LNA suppressed exosome-induced lung cancer cell motility. Mechanistically, lnc-MLETA1 regulated the expression of EGFR and IGF1R by sponging miR-186-5p and miR-497-5p to facilitate cell motility. The clinical datasets revealed that lnc-MLETA1 is upregulated in tumor tissues and predicts survival in lung cancer patients. Importantly, the levels of exosomal lnc-MLETA1 in plasma were positively correlated with metastasis in lung cancer patients. CONCLUSIONS: This study identifies lnc-MLETA1 as a critical exosomal lncRNA that mediates crosstalk in lung cancer cells to promote cancer metastasis and may serve as a prognostic biomarker and potential therapeutic target for lung cancer diagnosis and treatment.

Reduced Expression of Metallothionein-I/II in Renal Proximal Tubules Is Associated with Advanced Chronic Kidney Disease.

Chronic kidney disease (CKD) is a commonly occurring complex renal syndrome that causes overall mortality in many diseases. The clinical manifestations of CKD include renal tubulointerstitial fibrosis and loss of renal function. Metallothionein-I/II (MT-I/II) is potentially expressed in the liver and kidney, and possesses antioxidant and metal detoxification properties. However, whether MT-I/II expression is associated with the prognosis of nephropathy remains unknown. In this study, we investigated the MT-I/II level in human CKD, using immunohistochemistry. MT-I/II is located on the proximal tubules and is notably reduced in patients with CKD. MT-I/II expression was significantly correlated with the functional and histological grades of CKD. In an aristolochic acid (AAI)-induced nephropathy mouse model, MT-I/II was abundantly increased after AAI injection for 7 days, but decreased subsequently compared to that induced in the acute phase when injected with AAI for 28 days. Furthermore, we found that ammonium pyrrolidinedithiocarbamate (PDTC) restored AAI-induced MT-I/II reduction in HK2 cells. The injection of PDTC ameliorated AAI-induced renal tubulointerstitial fibrosis and reduced the concentrations of blood urea nitrogen and creatinine in mouse sera. Taken together, our results indicate that MT-I/II reduction is associated with advanced CKD, and the retention of renal MT-I/II is a potential therapeutic strategy for CKD.

Updates on the diagnosis and management of multicentric Castleman disease.

Multicentric Castleman disease (MCD) is an uncommon systemic lymphoproliferative disease. The diagnosis of this disease is typically challenging and requires collaboration between clinicians and pathologists. Moreover, it is important to exclude other diseases (such as malignancies, autoimmune diseases, and infectious diseases) that have similar clinical manifestations and pathological findings. Patients with untreated severe MCD have high mortality due to devastating cytokine storms. Thus, early diagnosis and prompt treatment is a key imperative. The diagnosis of MCD is based on the clinical signs of systemic inflammation, serological tests, and typical pathological features. In this review article, we provide an overview of MCD with a focus on the emerging evidence pertaining to its diagnosis and treatment.

Cordycepin Suppresses Endothelial Cell Proliferation, Migration, Angiogenesis, and Tumor Growth by Regulating Focal Adhesion Kinase and p53.

Focal adhesion kinase (FAK) plays an important role in vascular development, including the regulation of endothelial cell (EC) adhesion, migration, proliferation, and survival. 3'-deoxyadenosine (cordycepin) is known to suppress FAK expression, cell migration, and the epithelial⁻mesenchymal transition in hepatocellular carcinoma (HCC). However, whether cordycepin affects FAK expression and cellular functions in ECs and the specific molecular mechanism remain unclear. In this study, we found that cordycepin suppressed FAK expression and the phosphorylation of FAK (p-FAK) at Tyr397 in ECs. Cordycepin inhibited the proliferation, wound healing, transwell migration, and tube formation of ECs. Confocal microscopy revealed that cordycepin significantly reduced FAK expression and decreased focal adhesion number of ECs. The suppressed expression of FAK was accompanied by induced p53 and p21 expression in ECs. Finally, we demonstrated that cordycepin suppressed angiogenesis in an in vivo angiogenesis assay and reduced HCC tumor growth in a xenograft nude mice model. Our study indicated that cordycepin could attenuate cell proliferation and migration and may result in the impairment of the angiogenesis process and tumor growth via downregulation of FAK and induction of p53 and p21 in ECs. Therefore, cordycepin may be used as a potential adjuvant for cancer therapy.

Prognostic Significance of 14-3-3ε, Aldo-keto Reductase Family 1 B10 and Metallothionein-1 in Hepatocellular Carcinoma.

BACKGROUND/AIM: Expression of 14-3-3ε is associated with prognostic outcomes of hepatocellular carcinoma (HCC) patients. Metallothionein-1 (MT-1) proteins and aldo-keto-reductase family 1 B10 (AKR1B10) are considered potential tumor regulators of HCC. The aim of this study, was to examine the prognostic value of 14-3-3ε, MT-1 and AKR1B10 expression in HCC. MATERIALS AND METHODS: The expression levels of 14-3-3ε, MT-1 and AKR1B10 in HCC cell lines and paraffin-embedded tissues were examined by western blotting and immunohistochemical analysis. RESULTS: 14-3-3ε positivity was significantly associated with decreased MT-1 expression in HCC. Patients with decreased MT-1 expression had worse survival rates and a higher risk of metastasis than 14-3-3ε-positive HCC patients with unchanged MT-1 expression. Distinct expression patterns of 14-3-3ε/MT-1/AKR1B10 were significantly associated with the metastatic incidence and survival rates of HCC patients. Patients with negative 14-3-3ε staining in primary tumors had better prognostic outcomes. In contrast, patients with positive 14-3-3ε staining, decreased MT-1 expression and no increase in AKR1B10 expression in primary tumors had the worst overall and disease-free survival rates and the highest metastatic risk. CONCLUSION: 14-3-3ε, AKR1B10, and MT-1 act as potential prognostic biomarkers of HCC.

Medical Comorbidity in Alzheimer's Disease: A Nested Case-Control Study.

BACKGROUND: Little is known about the distribution of medical comorbidities in Alzheimer's disease (AD). OBJECTIVE: We aimed to describe the comorbidity pattern of AD in a nested case-control study. METHODS: Incident AD cases were identified by International Classification of Diseases codes in a random sample of 2 million individuals in Taiwan National Health Insurance program during 2001-2011. We further restricted cases to those treated with AD drugs of approved reimbursement. We sampled a set of age- and sex-matched control subjects (2:1 ratio) and employed conditional logistic regression to estimate the associations between pre-specified 14 comorbidities and AD. The clusters of multiple chronic diseases were then identified by exploratory factor analysis. RESULTS: A total of 2,618 AD cases were identified during 2001-2011 with a mean age of 76.1 years and female preponderance (59%). The most common 5 comorbidities in AD were hypertension (55.1%), osteoarthritis (38.2%), depression (32.3%), diabetes mellitus (DM) (25.7%), and cerebrovascular disease (CVD) (22.7%). After adjusting for age and sex, DM, osteoporosis, depression, and CVD were significantly associated with AD. The number of comorbidity was 3-fold greater in the AD group. The cluster of hypertension, DM, and hyperlipidemia was the most common combination in old age, whereas the cluster osteoarthritis and osteoporosis was the only multimorbidity pattern significantly associated with AD. CONCLUSION: Multimorbidity is common in AD. Depression, CVD, osteoporosis, and DM are associated with incident AD, supporting that their co-existence is a typical feature of AD at old age. Comorbidity care should be integrated into current management for patients with AD.

Insulinoma in a young female patient with systemic lupus erythematosus: a case report.

OBJECTIVE: Fasting hypoglycemia may occur in subjects with systemic lupus erythematosus (SLE) when accompanied with insulin-binding antibodies or insulin-receptor antibodies. However, insulinoma has not been reported in SLE subjects with hypoglycemia. METHODS: We present a case report and review the relevant literature. RESULTS: A 26-year-old female with underlying SLE experienced several episodes of neuropsychiatric symptoms in a fasting state. The steroid dosage was titrated up, but in vain. Timely imaging studies showed a pancreatic tumor, and insulinoma was proven by pathology. Hypoglycemia did not recur after surgery. CONCLUSION: Physicians should distinguish insulinoma from autoimmunity-mediated hypoglycemia in SLE patients with fasting hypoglycemia.

Long-term outcomes of dialysis patients after coronary revascularization: a population-based cohort study in Taiwan.

BACKGROUND AND AIMS: The outcomes of Chinese patients undergoing dialysis after coronary revascularization are unknown. We examined the outcomes of Taiwanese dialysis patients after coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), or coronary stenting. METHODS: Using data from the National Health Research Institute database, we determined the outcomes of 1,287 dialysis patients who underwent initial coronary revascularization between 1997 and 2008. RESULTS: The 7-year overall survival rates were 69 ± 4%, 68 ± 3%, and 57 ± 2% for the CABG, stent, and PTCA patients (p = 0.001), respectively. After demographic and comorbidity adjustment, hazard ratios (HRs) for all-cause death in the CABG (vs. PTCA) and stent (vs. PTCA) patients were 0.695 (p = 0.015) and 0.721 (p = 0.009). Additionally, no significant difference in all-cause death was found between the CABG and stent patients. Moreover, the ≥65-year-old CABG group patients and the <65-year-old coronary stent group patients showed better survival than the PTCA group patients. Compared with the PTCA and CABG groups, the coronary stent group was significantly associated with a higher risk for recurrent acute myocardial infarction (AMI). Based on age stratification, the ≥65-year-old stent group had a higher risk for recurrent AMI than the PTCA group (HR, 1.562; p = 0.026). CONCLUSIONS: Chinese patients undergoing dialysis who underwent CABG or coronary stenting had better survival than those who underwent PTCA. Moreover, being ≥65 years old, CABG shows better survival compared with PTCA; being <65 years old, coronary stenting show better survival compared with PTCA.

Faculty development program for general medicine in Taiwan: Past, present, and future.

General medical training programs are aimed at promoting competency in general practice skills with a holistic perspective of patient-centered medicine for the new generation of physicians. The faculty development program was implemented to promote learning and application of the six core competencies established by the Accreditation Council for Graduate Medical Education. This article describes the implementation and outcome of the current faculty development program. Additional assessment tools of the faculty development program are recommended to evaluate different perspectives of outcome. Our experience suggests that OSTEs are a realistic and well-received approach for faculty development that merits further investigation. According to the clinical instructors' response, our faculty development program effectively increased familiarity with various teaching and assessment skills needed to teach PGY 1 residents and ACGME competencies, and these clinical instructors also then subsequently applied these skills.

A 12-year ecological study of hip fracture rates among older Taiwanese adults.

Hip fracture rates in Taiwan are among the highest in the world. The aim of this study was to describe the trends of hip fracture hospitalizations among Taiwanese elderly (aged ≥ 65 years) and the trends of antiosteoporosis medication expenditure from 1999 to 2010. We conducted an ecological study using inpatient health care-utilization data from the Department of Health, and medication expenditure data from the IMS Health, Taiwan. The International Classification of Disease, Clinical Modification, 9th version, code 820 was used to identify hip fracture hospitalizations. Medications included alendronate, calcitonin, ibandronate, raloxifene, strontium ranelate, teriparatide, and zoledronic acid. Year 2010 was assigned as the reference point for age-standardized rates, currency exchange (to the US dollar), and discount rates. Over the 12-year study period, age-standardized hip fracture hospitalizations decreased by 2.7 % annually (p for trend < 0.001) for Taiwanese elders. The decline was more obvious among those aged ≥75 years (6.1 %). However, the number of hip fracture hospitalizations increased from 14,342 to 18,023. Total hospitalization costs increased by US$0.6 ± 0.2 million annually (p for trend = 0.002); however, the per capita costs decreased by US$23.0 ± 8.0 (p for trend = 0.017). The total medication expenditure increased 7.2-fold, from US$8.1 million to US$58.9 million, accounting for an increase in the overall pharmaceutical market by fivefold, from 3.4 to 15.9 ‰ (both p for trend < 0.001). From 1999 to 2010, there was a decline in hip fracture rates among elderly Taiwanese adults with a concomitant increase in antiosteoporosis medication expenditure.

Methemoglobinemia induced by indoxacarb intoxication.

Indoxacarb is a recently introduced insecticide whose mode of action is blockage of voltage-gated sodium channels. There are limited data on human ingestion. A case of 68-year-old healthy male who presented with general cyanosis because of methemoglobinemia following the ingestion of indoxacarb is presented. After receiving a methylene blue injection, the patient recovered without sequelae.