Citations

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. These malignancies have limited treatment options, resulting in poor patient outcomes. Metabolism reprogramming, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty acid synthase (FASN) catalyzes the de novo synthesis of long‐chain fatty acids from acetyl‐coenzyme A and malonyl‐coenzyme A. Increased FASN expression has been reported in multiple tumor types, and inhibition of FASN expression has been shown to have tumor‐suppressing activity. Intriguingly, we found that while FASN is up‐regulated in human HCC samples, its expression is frequently low in human ICC specimens. Similar results were observed in mouse ICC models induced by different oncogenes. Ablating FASN in the mouse liver did not affect activated AKT and Notch (AKT/Notch intracellular domain 1) induced ICC formation in vivo. Furthermore, while both HCC and ICC lesions develop in mice following hydrodynamic injection of AKT and neuroblastoma Ras viral oncogene homolog oncogenes (AKT/Ras), deletion of FASN in AKT/Ras mice triggered the development almost exclusively of ICCs. In the absence of FASN, ICC cells might receive lipids for membrane synthesis through exogenous fatty acid uptake. In accordance with the latter hypothesis, ICC cells displayed high expression of fatty acid uptake‐related proteins and robust long‐chain fatty acid uptake. Conclusion: Our data demonstrate that FASN dependence is not a universal feature of liver tumors: while HCC development is highly dependent of FASN and its mediated lipogenesis, ICC tumorigenesis can be insensitive to FASN deprivation; our study supports novel therapeutic approaches to treat this pernicious tumor type with the inhibition of exogenous fatty acid uptake. (Hepatology 2016;63:1900‐1913)

Key Clinical MessageTyrosine kinase inhibitor treated chronic myelogenous leukemia patients with monosomy 7 arising in Philadelphia chromosome negative (Ph−) cells tend to evolve into MDS/AML. However, monosomy 7 in Ph− cells can be a transient finding, and it is not an absolute indication of the emergence of a new myeloid malignancy.

Abstract Peterson, BJ, Fitzgerald, JS, Dietz, CC, Ziegler, KS, Baker, SE, and Snyder, EM. Off-ice anaerobic power does not predict on-ice repeated shift performance in hockey. J Strength Cond Res 30(9): 2375–2381, 2016—Anaerobic power is a significant predictor of acceleration and top speed in team sport athletes. Historically, these findings have been applied to ice hockey although recent research has brought their validity for this sport into question. As ice hockey emphasizes the ability to repeatedly produce power, single bout anaerobic power tests should be examined to determine their ability to predict on-ice performance. We tested whether conventional off-ice anaerobic power tests could predict on-ice acceleration, top speed, and repeated shift performance. Forty-five hockey players, aged 18–24 years, completed anthropometric, off-ice, and on-ice tests. Anthropometric and off-ice testing included height, weight, body composition, vertical jump, and Wingate tests. On-ice testing consisted of acceleration, top speed, and repeated shift fatigue tests. Vertical jump (VJ) ( r = −0.42; r = −0.58), Wingate relative peak power (WRPP) ( r = −0.32; r = −0.43), and relative mean power (WRMP) ( r = −0.34; r = −0.48) were significantly correlated ( p ≤ 0.05) to on-ice acceleration and top speed, respectively. Conversely, none of the off-ice tests correlated with on-ice repeated shift performance, as measured by first gate, second gate, or total course fatigue; VJ ( r = 0.06; r = 0.13; r = 0.09), WRPP ( r = 0.06; r = 0.14; r = 0.10), or WRMP ( r = −0.10; r = −0.01; r = −0.01). Although conventional off-ice anaerobic power tests predict single bout on-ice acceleration and top speed, they neither predict the repeated shift ability of the player, nor are good markers for performance in ice hockey.

Abstract Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). Genome-wide association studies have suggested the less studied gene HEAT repeat-containing protein 1 (HEATR1) as a possible determinant of cellular sensitivity to different chemotherapeutic drugs. In this study, we assessed this hypothesized link in PDAC, where HEATR1 expression is downregulated significantly. HEATR1 silencing in PDAC cells increased resistance to gemcitabine and other chemotherapeutics, where this effect was associated with increased AKT kinase phosphorylation at the Thr308 regulatory site. Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as a scaffold to facilitate interactions between AKT and the protein phosphatase PP2A, thereby promoting Thr308 dephosphorylation. Consistent with these findings, treatment with the AKT inhibitor triciribine sensitized HEATR1-depleted PDAC cells to gemcitabine, suggesting that this therapeutic combination may overcome gemcitabine resistance in patients with low HEATR1 expression. Clinically, we found that HEATR1 downregulation in PDAC patients was associated with increased AKT phosphorylation, poor response to tumor resection plus gemcitabine standard-of-care treatment, and shorter overall survival. Collectively, our findings establish HEATR1 as a novel regulator of AKT and a candidate predictive and prognostic indicator of drug responsiveness and outcome in PDAC patients. Cancer Res; 76(3); 572–81. ©2015 AACR.

Background— Integrins are heterodimeric (α/β) membrane proteins that play fundamental roles in many biological processes, for example, cell adhesion and spreading, which are important for platelet function and hemostasis. The molecular mechanism that regulates integrin activation is not completely understood. Methods and Results— Here, we show that VPS33B, a member of the Sec1/Munc18 family, binds directly to the integrin β subunit. Overexpression of VPS33B in Chinese hamster ovary cells potentiated αIIbβ3 outside-in signaling but not inside-out signaling. Platelets, from megakaryocyte- and platelet-specific VPS33B conditional knockout mice, had normal morphology, yet their spreading on fibrinogen was impaired and they failed to support clot retraction. Platelet aggregation and ATP secretion in response to low-dose agonists were reduced in the VPS33B knockout mice. αIIbβ3-mediated endocytosis of fibrinogen was also defective. Tail bleeding times and times to occlusion in an FeCl 3 -induced thrombosis model were prolonged in the VPS33B knockout mice. Furthermore, VPS33B acted upstream of the RhoA-ROCK-MLC and Rac1-dependent pathways that lead to clot retraction and cell spreading, respectively. Conclusions— Our work demonstrates that vesicular trafficking complexes, containing VPS33B, are a novel class of modifiers of integrin function. Our data also provide insights into the molecular mechanism and treatment of arthrogryposis, renal dysfunction, and cholestasis syndrome.

Nanoparticles emerged as carriers of promising diagnostic and therapeutic molecules due to their unique size, injectability, and potential to sustainably release molecular cargos.

Key Clinical MessageDistinguishing chronic lymphoproliferative disorder of NK‐cells from aggressive NK‐cell leukemia is critical because they have distinct clinical course and management. Immunophenotyping plays a key role in distinguishing these two entities, however, it could not be used as sole criteria and clinical/laboratory findings are equally important.