Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a critical role in maintaining the intracellular calcium homeostasis during cardiac contraction and relaxation. It has been well documented over the years that altered expression and activity of SERCA2a can lead to systolic and diastolic dysfunction. The activity of SERCA2a is regulated by two structurally similar proteins, phospholamban (PLB) and sarcolipin (SLN). Although, the relevance of PLB has been extensively studied over the years, the role SLN in cardiac physiology is an emerging field of study. This review focuses on the advances in the understanding of the regulation of SERCA2a by SLN and PLB. In particular, it highlights the similarities and differences between the two proteins and their roles in cardiac patho-physiology.     

阿托伐他汀联合非诺贝特治疗混合性高脂血症的疗效及对肝功能的影响

目的探讨阿托伐他汀与非诺贝特联合应用治疗混合性高脂血症的较佳给药剂量及方法,以及对肝功能和高敏C反应蛋白的影响。方法60只Wistar大鼠随机分为正常对照组、高脂对照组、阿托伐他汀组[1.8mg/(kg·d)]、顿服组[阿托伐他汀0.9mg/(kg·d) 非诺贝特18mg/(kg·d),顿服]及分服组[阿托伐他汀0.9mg/(kg·d) 非诺贝特18mg/(kg·d),早晚分开服用],实验过程共8周,复制高脂血症模型4周,用药4周。分别检测血脂、丙氨酸氨基转移酶、天门冬氨酸氨基转移酶和高敏C反应蛋白。结果8周末时,与高脂对照组比较,正常对照组及各用药组总胆固醇、低密度脂蛋白胆固醇及甘油三酯降低(P<0.01),与高脂对照组及阿托伐他汀组比较,联合用药组高密度脂蛋白胆固醇水平升高(P<0.01),甘油三酯水平降低(P<0.01)。8周末时,与正常对照组比较,高脂组及各用药组C反应蛋白水平升高(P<0.05);与阿托伐他汀组比较,高脂组C反应蛋白水平明显升高(P<0.01),联合用药组降低(P<0.05)。8周末时,与正常组比较,高脂组及各用药组丙氨酸氨基转移酶及天门冬氨酸氨基转移酶升高(P<0.01);与高脂组比较,各用药组丙氨酸氨基转移酶及天门冬氨酸氨基转移酶降低(P<0.05);与阿托伐他汀组和分服组比较,顿服组丙氨酸氨基转移酶及天门冬氨酸氨基转移酶水平升高(P<0.05)。结论阿托伐他汀与非诺贝特联合应用可增强调脂疗效及控制C反应蛋白的水平,较加倍剂量的阿托伐他汀效果更佳;二者联合应用时应适当减少各自剂量,早晚分开服用,在保护高脂血症对肝功能损害的同时减少药物性肝损害。     

Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival

Background:

Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.

Methods:

The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)–BRCA pathway, ATM–ATR pathway and enzymatic activation of MMC. Functionality of the FA–BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).

Results:

High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA–BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).

Conclusions:

Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.     

Impact of hepatitis C virus eradication on hepatocellular carcinogenesis

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death in the world. Infection with hepatitis C virus (HCV) represents one of the most common risk factors for HCC development, and cases of HCV‐related complications have been rising over the last 2 decades. Although the standard for HCV therapy has been interferon (IFN)‐based for many years, the therapeutic revolution spurred by the development of direct‐acting antivirals (DAAs) promises to usher in a new era in which chronic HCV becomes a rare disease. On the basis of long‐term follow‐up of patients experiencing IFN‐based sustained virological responses (SVRs), it can be expected that rates of HCV‐associated HCC will decrease significantly after the widespread adoption of DAAs, but there remains a persistent risk for HCC even among some patients with advanced fibrosis who have achieved SVR. As such, individuals treated for HCV with advanced fibrosis should continue to be screened regularly for HCC after SVR. Furthermore, as the population of SVR patients grows, it will become imperative to accurately identify those individuals at high risk for developing HCC, appropriately allocate resources for screening, and consider cost‐effective chemopreventive strategies. Risk factors include preexisting advanced fibrosis/cirrhosis, older age, diabetes mellitus, and ethanol use. In addition, laboratory biomarkers and genetic signatures are currently being identified that not only predict the likelihood of HCC development in SVR patients but also may serve as dynamic indicators of therapeutic response. Cancer 2015;121:2874–2882. © 2015 American Cancer Society.     

Fatty acid synthase is a metabolic oncogene targetable in malignant peripheral nerve sheath tumors

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas with minimal therapeutic opportunities. We observed that lipid droplets (LDs) accumulate in human MPNST cell lines and in primary human tumor samples. The goal of this study was to investigate the relevance of lipid metabolism to MPNST survival and as a possible therapeutic target.MethodsBased on preliminary findings that MPNSTs accumulate LDs, we hypothesized that a deregulated lipid metabolism supports MPNST cell survival/proliferation rate. To test this, we examined respiration, role of fatty acid oxidation (FAO), and the enzyme fatty acid synthase involved in de novo fatty acid synthesis in MPNSTs using both genetic and pharmacological tools.ResultsWe demonstrate that LDs accumulate in MPNST cell lines, primary human and mouse MPNST tumors, and neural crest cells. LDs from MPNST cells disappear on lipid deprivation, indicating that LDs can be oxidized as a source of energy. Inhibition of FAO decreased oxygen consumption and reduced MPNST survival, indicating that MPNST cells likely metabolize LDs through active FAO. FAO inhibition reduced oxygen consumption and survival even in the absence of exogenous lipids, indicating that lipids synthesized de novo can also be oxidized. Consequently, inhibition of de novo fatty acid synthesis, which is overexpressed in human MPNST cell lines, effectively reduced MPNST survival and delayed induction of tumor growth in vivo.ConclusionOur results show that MPNSTs depend on lipid metabolic pathways and suggest that disrupting lipid metabolism could be a potential new strategy for the development of MPNST therapeutics.     

非小细胞肺癌二线治疗的进展

晚期非小细胞肺癌（NSCLC）二线标准治疗药物包括细胞毒药物培美曲塞和多西他赛,表皮生长因子酪氨酸激酶抑制剂厄洛替尼和吉非替尼。对于表皮生长因子受体基因野生型患者,研究提示化疗优于靶向治疗。在标准治疗药物基础上联合其他靶向治疗结果乏善可陈。克唑替尼针对间变性淋巴瘤激酶阳性的 NSCLC 患者二线治疗疗效显著。     

塞来昔布联合吉非替尼对HCC827细胞凋亡影响机制探讨

目的探讨Cox-2抑制剂塞来昔布联合吉非替尼对肺癌EGFR 19号外显子E746-A750缺失细胞株HCC827细胞凋亡的影响及其可能机制。方法 RPMI1640培养HCC827细胞,分为正常对照组、塞来昔布组、吉非替尼组、塞来昔布加吉非替尼组。塞来昔布与吉非替尼药物浓度均为5、10、20、40、80μmol/L。药物干预细胞48h后,MTT法检测细胞增殖,流式细胞术检测细胞凋亡,蛋白质印迹法检测细胞中Cox-2和p-EGFR蛋白表达。结果 MTT结果显示,塞来昔布和吉非替尼单独用药时HCC827细胞的增殖受到明显的抑制,且随着药物浓度的增加,抑制作用逐步增强,药物剂量与细胞增殖抑制率呈正相关;塞来昔布与吉非替尼联合用药时对HCC827细胞呈现出更强的抑制作用,与单独用药相比差异有统计学意义,P<0.001;对照组细胞凋亡率为(0.26±0.09)%,塞来昔布组为(4.86±0.37)%,吉非替尼组为(8.53±0.78)%,塞来昔布+吉非替尼组为(23.28±1.63)%,组间比较差异有统计学意义,F=111.291,P<0.001,且两药联合时具有交互效应,F=90.440,P<0.001;蛋白质印记法结果显示,用药组较对照组Cox-2(F=185.351,P<0.001)和p-EGFR(F=61.328,P<0.001)蛋白水平均有不同程度的下调,其中两药联合组下调最为明显。结论塞来昔布与吉非替尼具有良好的协同作用,其机制可能与诱导凋亡、抑制EGFR的活化和下调Cox-2蛋白的表达有关,在治疗非小细胞肺癌中联合用药可能会具有较大的应用潜力。     

The Role of CDK4/6 Inhibition in Breast Cancer

Imbalance of the cyclin D and cyclin‐dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D‐dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan‐CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor‐positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2‐positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double‐strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.