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 The melanoma field has seen an unprecedented set of clinical advances over the past decade. Therapeutic efficacy for advanced or metastatic melanoma went from being one of the most poorly responsive to one of the more responsive. Perhaps most strikingly, the advances which transformed management of the disease are based upon modern mechanism-based therapeutic strategies. The targeted approaches which primarily suppress the BRAF oncoprotein pathway, have high predictability of efficacy although less optimal depth or durability of response. Immunotherapy is primarily based upon blockade of one or two immune checkpoints, and has lower predictability of response, but higher fractions of durable remissions. This article reviews the clinical progress in management of advanced melanoma and also discusses impact of the same therapies on earlier stage disease, where the agents have shown significant promise in treating resectable but high-risk clinical scenarios. Collectively, the progress in melanoma therapeutics has transformed the standard of care for patients, informed new approaches that are increasingly utilized for treatment of other malignancies, and suggest novel strategies to further boost efficacy for the many patients not yet receiving optimal benefit from these approaches. Vascular calcification is a pathological process closely related to atherosclerosis, diabetic vascular diseases, vascular injury, hypertension, chronic kidney disease and aging. Lethal giant larvae 1 (LGL1) is known as a key regulator of cell polarity and plays an important role in tumorigenesis. However, whether LGL1 regulates vascular calcification remains unclear. In this study, we generated smooth muscle-specific LGL1 knockout (LGL1SMKO) mice by cross-breeding LGL1flox/flox mice with α-SMA-Cre mice. LGL1 level was significantly decreased during calcifying conditions. Overexpression of LGL1 restrained high phosphate-induced calcification in vascular smooth muscle cells (VSMCs). Mechanically, LGL1 could bind with high mobility group box 1 (HMGB1) and promote its degradation via the lysosomal pathway, thereby inhibiting calcification. Smooth muscle-specific deletion of LGL1 increased HMGB1 level and aggravated vitamin D3-induced vascular calcification, which was attenuated by an HMGB1 inhibitor. LGL1 may inhibit vascular calcification by preventing osteogenic differentiation via promoting HMGB1 degradation. BACKGROUND Coronary artery calcium is a guideline recommended cardiovascular disease risk stratification tool that increases with age and is also associated with non-cardiovascular disease outcomes including cancer.  https://www.selleckchem.com/products/abt-199.html  We sought to define the age-specific change in the association between coronary artery calcium and cause-specific mortality. METHODS The Coronary Artery Calcium Consortium includes 59,502 asymptomatic patients age 40-75 without known cardiovascular disease. Age-stratified mortality rates and parametric survival regression modeling was performed to estimate the age-specific coronary artery calcium score at which cardiovascular disease and cancer mortality risk were equal. RESULTS The mean age was 54±8 years (67% men) and there were 2,423 deaths over a mean 12±3 years follow-up. Among individuals with coronary artery calcium = 0, cancer was the leading cause of death, with low cardiovascular disease mortality rates for both younger (40-54 years) 0.2/1,000 person-years and older participants (65-75 years) 1.3/1,000 person-years. When coronary artery calcium ≥400, cardiovascular disease was consistently the leading cause of death among younger (71% of deaths) and older participants (56% of deaths). The coronary artery calcium score at which cardiovascular disease overtook cancer as the leading cause of death increased exponentially with age and was approximately 115 at age 50 and 380 at age 65. CONCLUSIONS Regardless of age, when coronary artery calcium = 0 cancer was the leading cause of death and the cardiovascular disease mortality rate was low.  https://www.selleckchem.com/products/abt-199.html  Our age-specific estimate for the coronary artery calcium score at which cardiovascular disease overtakes cancer mortality allows for a more precise approach to synergistic prediction and prevention strategies for cardiovascular disease and cancer. BACKGROUND Transcatheter pulmonary valve replacement (TPVR) has emerged as an alternative to surgery in patients with pulmonary valve dysfunction. METHODS We searched the MEDLINE and Cochrane databases since their inception to January 2019, as well as references from articles, for all publications comparing TPVR with surgical pulmonary valve replacement (SPVR). Studies were considered for inclusion if they reported comparative data regarding any of the study endpoints. The primary endpoint was early mortality after pulmonary valve replacement. Secondary endpoints included procedure-related complications, length of hospital stay, mortality during follow-up, infective endocarditis (IE), need for re-intervention, post-PVR transpulmonary peak systolic gradient and significant pulmonary regurgitation (PR). RESULTS There were no differences in peri-operative mortality between groups (0.2% vs 1.2%; pooled OR 0.56, 95% CI 0.19-1.59, P=0.27, I2=0%). However, TPVR conferred a significant reduction in procedure-related complications and length of hospital stay compared to SPVR. Mid-term mortality and the need for repeat intervention were similar with both techniques, but pooled IE was significantly more frequent in the TPVR group (5.8 vs 2.7%, pooled OR 3.06, 95% CI 1.89-5.06, P less then 0.001, I2 =0%). Significant PR during follow-up was less frequent after TPVR, and there were no differences in the transpulmonary peak systolic gradient. CONCLUSIONS TPVR is a safe alternative to SPVR in selected patients, and is associated with a shorter length of hospital stay and fewer procedure-related complications. At mid-term follow-up, TPVR was comparable to SPVR in terms of mortality and repeat intervention but was associated with an increased risk of IE. BACKGROUND Pulmonary sarcomatoid carcinoma (PSC) is a rare lung cancer. This study aimed to explore the appropriate treatment for PSC. METHODS Two cohorts were used patients from the SEER database (1988-2014) and shanghai resident patients at Shanghai Pulmonary Hospital (2009-2019). Cox regression analysis was applied to identify prognostic factors for progression-free survival and overall survival (OS). Interaction assessments were performed using likelihood ratio tests to examine relationships between adjuvant chemotherapy and other baseline characteristics. RESULTS In the SEER cohort, 1,640 patients with PSCs were identified, with a median survival and a 5-year OS rate of 7 (95%CI 6-8) months and 19.5%, respectively. Multivariable Cox analysis, among surgically-treated patients, revealed that adjuvant chemotherapy was significantly associated with better survival (HR 0.78, 95%CI 0.62-0.98), and the benefit was more pronounced in T3-T4 stage (p=0.04) and N positive patients (p25kg/m2, p less then 0.01) by interaction assessments.