Reversal of C9orf72 mutation-induced transcriptional dysregulation and pathology in cultured human neurons by allele-specific excision.

Efforts to genetically reverse C9orf72 pathology have been hampered by our incomplete understanding of the regulation of this complex locus. We generated five different genomic excisions at the C9orf72 locus in a patient-derived induced pluripotent stem cell (iPSC) line and a non-diseased wild-type (WT) line (11 total isogenic lines), and examined gene expression and pathological hallmarks of C9 frontotemporal dementia/amyotrophic lateral sclerosis in motor neurons differentiated from these lines. Comparing the excisions in these isogenic series removed the confounding effects of different genomic backgrounds and allowed us to probe the effects of specific genomic changes. A coding single nucleotide polymorphism in the patient cell line allowed us to distinguish transcripts from the normal vs. mutant allele. Using digital droplet PCR (ddPCR), we determined that transcription from the mutant allele is upregulated at least 10-fold, and that sense transcription is independently regulated from each allele. Surprisingly, excision of the WT allele increased pathologic dipeptide repeat poly-GP expression from the mutant allele. Importantly, a single allele was sufficient to supply a normal amount of protein, suggesting that the C9orf72 gene is haplo-sufficient in induced motor neurons. Excision of the mutant repeat expansion reverted all pathology (RNA abnormalities, dipeptide repeat production, and TDP-43 pathology) and improved electrophysiological function, whereas silencing sense expression did not eliminate all dipeptide repeat proteins, presumably because of the antisense expression. These data increase our understanding of C9orf72 gene regulation and inform gene therapy approaches, including antisense oligonucleotides (ASOs) and CRISPR gene editing

A Rare Finding of a BRAF Mutation in Renal Cell Carcinoma with Response to BRAF-Directed Targeted Therapy

Whole exome sequencing can identify somatic mutations in malignant tumors and allow for personalized and novel treatment of common malignancies. Mutations in the BRAF gene are rare in renal cell carcinoma, and thus, BRAF inhibitors are not considered standard in the treatment of these cancers. Here, we report a case of a patient with a rare BRAF-mutated metastatic renal cell carcinoma who obtained a good clinical response to BRAF inhibition. This case underscores the value of precision medicine in an era of rapidly evolving therapeutics for malignancies

Clinical development of reovirus for cancer therapy: An oncolytic virus with immune-mediated antitumor activity

Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirus-mediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus (Reolysin(®)) across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed

Myelodysplastic syndromes: Where do we stand?

Myelodysplastic syndromes (MDS) are fairly common hematological disorder of elderly. They are a group of clonal malignant hematopoietic stem cell disorders characterized by dysplastic morphology, variable cytopenia and a variable threat of transformation to AML. These dysplastic changes are a result of chromosomal abnormalities and somatic mutations. MDS is the most common myeloid neoplasm of the older adults with median age at diagnosis being 72 years and an average incidence rate of 0.2 per 100,000 people per year. MDS is diagnosed and classified according to the WHO 2008 classification system, which utilizes peripheral blood and bone marrow findings. Other essential investigations include flow cytometry, genetic profile and chromosomal analysis. Various prognostic scoring system have been developed which help guide the treatment. Treatment of complications associated with MDS also forms an essential component of the management of this disease

Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy (TTC) is an acute, stress-induced cardiomyopathy with an increased prevalence in post-menopausal women. The syndrome is most frequently precipitated by an acute emotional or physical stressor and mimics acute myocardial infarction with symptoms, electrocardiogram (ECG) changes and cardiac troponin elevation that are indistinguishable from those caused by plaque rupture or coronary thrombosis. Diagnosis of TTC is made when coronary angiography reveals no obstructive coronary artery disease and the left ventricle demonstrates apical ballooning and basal hypercontractility. Other ventricular patterns have also been described. An abnormal myocardial response to the catecholamine surge from an emotional or a physical stressor is implicated in the pathophysiology, but the reasons for the high prevalence of TTC presentations in post-menopausal women are unknown. Several mechanisms including multi-vessel coronary vasospasm, endothelial and coronary microvascular dysfunction and direct catecholamine toxicity have been proposed. No specific guidelines for treatment of TTC have been established, but treatment is based on the American Heart Association/ American College of Cardiology guidelines for acute coronary syndrome/acute myocardial infarction and heart failure guidelines. In this review article, we discuss the characteristic clinical presentation of TTC and the commonly proposed mechanisms.</jats:p

Statins and pancreatic cancer

Pancreatic cancer remains among the most lethal cancers, despite ongoing advances in treatment for all stages of the disease. Disease prevention represents another opportunity to improve patient outcome, with metabolic syndrome and its components, such as diabetes, obesity and dyslipidemia, having been recognized as modifiable risk factors for pancreatic cancer. In addition, statins have been shown to potentially reduce pancreatic cancer risk and to improve survival in patients with a combination of metabolic syndrome and pancreatic cancer. Furthermore, preclinical studies have demonstrated that statins exhibit antitumor effects in pancreatic cancer cell lines in vitro and animal models in vivo, in addition to delaying the progression of pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma (PDAC) and inhibiting PDAC formation in conditional K-Ras mutant mice. The mechanisms by which statins produce anticancer effects remain poorly understood, although appear to involve inhibition of the mevalonate/cholesterol synthesis pathway, thus blocking the synthesis of intermediates important for prenylation and activation of the Ras/mitogen-activated protein kinase 1 signaling pathway. Furthermore, statins have been identified to modulate the phosphoinositide 3-kinase/Akt serine/threonine kinase 1 and inflammation signaling pathways, and to alter the expression of genes involved in lipid metabolism, which are important for PDAC growth and proliferation. In addition, statins have been demonstrated to exhibit further antitumor mechanisms in a number of other cancer types, which are beyond the scope of the present review. In the present review, current evidence highlighting the potential of statins as chemopreventive agents in pancreatic cancer is presented, and the antitumor mechanisms of statins elucidated thus far in this disease are discussed