Glycotherapy: A New Paradigm in Breast Cancer Research

Breast cancer is an ancient disease recognized first by the Egyptians as early as 1600 BC. The first cancer-causing gene in a chicken tumor virus was found in 1970. The United States signed the National Cancer Act in 1971, authorizing federal funding for cancer research. Irrespective of multi-disciplinary approaches, diverting a great deal of public and private resources, breast cancer remains at the forefront of human diseases, affecting as many as one in eight women during their lifetime. Because of overarching challenges and changes in the breast cancer landscape, five-year disease-free survival is no longer considered adequate. The absence of a cure, and the presence of drug resistance, severe side effects, and destruction of the patient’s quality of life, as well as the fact that therapy is often expensive, making it unaffordable to many, have created anxiety among patients, families, and friends. One of the reasons for the failure of cancer therapeutics is that the approaches do not consider cancer holistically. Characteristically, all breast cancer cells and their microenvironmental capillary endothelial cells express asparagine-linked (N-linked) glycoproteins with diverse structures. We tested a small biological molecule, Tunicamycin, that blocks a specific step of the protein N-glycosylation pathway in the endoplasmic reticulum (ER), i.e., the catalytic activity of N-acetylglusosaminyl 1-phosphate transferase (GPT). The outcome was overwhelmingly exciting. Tunicamycin quantitatively inhibits angiogenesis in vitro and in vivo, and inhibits the breast tumor progression of multiple subtypes in pre-clinical mouse models with “zero” toxicity. Mechanistic details support ER stress-induced unfolded protein response (upr) signaling as the cause for the apoptotic death of both cancer and the microvascular endothelial cells. Additionally, it interferes with Wnt signaling. We therefore conclude that Tunicamycin can be expected to supersede the current therapeutics to become a glycotherapy for treating breast cancer of all subtypes

Pentoxifylline versus prednisolone for severe alcoholic hepatitis: A randomized controlled trial

AIM: To compare the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis, and to evaluate the role of different liver function scores in predicting prognosis. METHODS: Sixty-eight patients with severe alcoholic hepatitis (Maddrey score ≥ 32) received pentoxifylline (n = 34, group I) or prednisolone (n = 34, group II) for 28 d in a randomized double-blind controlled study, and subsequently in an open study (with a tapering dose of prednisolone) for a total of 3 mo, and were followed up over a period of 12 mo. RESULTS: Twelve patients in group II died at the end of 3 mo in contrast to five patients in group I. The probability of dying at the end of 3 mo was higher in group II as compared to group I (35.29% vs 14.71%, P = 0.04; log rank test). Six patients in group II developed hepatorenal syndrome as compared to none in group I. Pentoxifylline was associated with a significantly lower model for end-stage liver disease (MELD) score at the end of 28 d of therapy (15.53 ± 3.63 vs 17.78 ± 4.56, P = 0.04). Higher baseline Maddrey score was associated with increased mortality. CONCLUSION:Reduced mortality, improved risk-benefit profile and renoprotective effects of pentoxifylline compared with prednisolone suggest that pentoxifylline is superior to prednisolone for treatment of severe alcoholic hepatitis

Geology and regional significance of the Sarnoo Hills, eastern rift margin of the Barmer Basin, NW India

The Barmer Basin is a poorly understood rift basin in Rajasthan, northwest India. Exposures in the Sarnoo Hills, situated along the central eastern rift margin of the Barmer Basin, reveal a sedimentary succession that accumulated prior to the main Barmer Basin rift event, and a rift-oblique fault network that displays unusual geometries and characteristics. Here, we present a comprehensive study of Lower Cretaceous sedimentology on the basin margin, along with a detailed investigation of rift-oblique faults that are exposed nowhere else in the region and provide critical insights into Barmer Basin evolution. Lower Cretaceous sediments were deposited within a rapidly subsiding alluvial plain fluvial system. Subsequent to deposition, the evolving Sarnoo Hills fault network was affected by structural inheritance during an early, previously unrecognised, rift-oblique extensional event attributed to transtension between India and Madagascar, and formed a juvenile fault network within the immediate rift-margin footwall. Ghaggar-Hakra Formation deposition may have been triggered by early rifting which tectonically destabilised the Marwar Craton prior to the main northeast-southwest Barmer Basin rift event. The identification of early rifting in the Barmer Basin demonstrates that regional extension and the associated rift systems were established throughout northwest India prior to the main phase of Deccan eruptions. Inheritance of early oblique fault systems within the evolving Barmer Basin provides a robust explanation for poorly understood structural complications interpreted in the subsurface throughout the rift. Critically, the presence of syn-rift sedimentary successions within older oblique rift systems obscured beneath the present-day Barmer Basin has significant implications for hydrocarbon exploration