HGG-33. EXPLOITING METABOLIC DEFECTS WITH NAMPT INHIBITORS IN DIPG

Diffuse intrinsic pontine glioma (DIPG) are universally lethal pediatric brain tumors with limited treatment options. We recently performed synthetic lethal drug screen with a panel of DNA repair and metabolic inhibitors in vitro, in patient-derived DIPG cells and isogenic cell lines engineered to contain key DIPG-associated mutations. Nearly 80% of DIPGs harbor a recurrent H3K27M mutation in H3.3 (H3F3A) or H3.1 (HIST1H3B) histones. This has prompted us to consider H3K27M mutation-induced exploitable defects for a therapeutic gain. This screen identified synthetic lethal interactions between H3K27M mutations and the nicotinamide phosphoribosyl transferase (NAMPT) inhibitor, FK866. The association between H3K27M mutations and NAMPTi sensitivity was validated in follow-up studies using isogenic WT and H3K27M-mutant expressing pairs of human immortalized astrocytes and neural progenitor cells (NPCs). In addition, we tested the effects of FK866 in a panel of unique DIPG patient-derived tumor neurospheres in short-term viability assays. We found that FK866 induced depletion of NAD and exhibited toxicity towards H3K27M mutant DIPG cell lines with an IC50 of ~2.5 nM. These findings were consistent across three structurally unique NAMPT inhibitors. Finally, we found that inducible expression of mutant H3K27M results in a gradual, 50% decrease in cellular NAD levels over the course of five days, suggesting that H3K27M mutations may induce an inherent NAD metabolic defect that is exploited by NAMPTi’s. We now seek to understand the mechanistic basis for the observed metabolic defect and NAMPTi sensitivity associated with mutant H3K27M. In addition, we aim to identify specific NAMPTi and DNA damaging agent combinations which maximally exploit this H3K27M-associated NAD metabolic defects.

Atypical Presentation of Pseudoxanthoma Elasticum in Two Siblings from North India

Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder occurring due to metabolic defect in the liver and manifesting predominantly in the skin, eyes and arteries. It shows characteristic yellowish papules on the skin around the nape of neck along with looseness of skin over flexural surfaces. PXE shows marked phenotypic heterogeneity. Complications related to arterial wall and retinal Bruchs’ membrane calcification occur later in life; early diagnosis therefore helps keep patient on follow up for development of the same. In Indian patients, classic skin changes may be missed clinically making histopathology pivotal in diagnosis and patient management.

Indralupta (alopecia areata) Kshudraroga management in Sushruta Samhita and Alopathy

The history of cosmetics extents at least 6000 years and is present in almost every society all over the world. In today’s era people are suffering from stress and strain due to the hustle and bustle of urban lifestyle. This has succumbed them to various lifestyle disorder.. Due to which it’s effects are seen on the body and out of which hair is affected the most. Sushruta has mentioned about Khalitya. It is caused by vitiation of vata and pitta doshas. In Indralupta there will be vitiation of rakta with kapha which obstruct the hair follicle. sushruta had said that the drushti and the lomkupaa never grow throughtout lifetime but hairs and nail do. In chikitsasthana the treatment for Indralupta. The bald paer or seat should be anointed and fomented, and then bleeding (by venesection) should be resorted to, after which a plaster composed of Manahsila, Kasisa, Tuttha and Maricha, or of Kutannata and Devadaru pasted tighter, should be applied to it. Alopecia areata also known as spot baldness, is a state in which hair is lost from some or all areas of the body. Typical symptoms of alopecia areata are small bald patches, underlying skin is unscarred and looks superficially normal. Patients also tend to have a slightly higher incidence of condition related to the immune system, such as asthama, allergies atopic dermatitis, and hypothyroidism. It occurs at any age. Hair loss area may tingle or painful. Due to autoimmunity, colic disease, endogenous retinoids metabolic defect alopecia areata occur..

Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling

Diabetes is a risk factor for Alzheimer’s disease (AD) in humans. Branched-chain amino acids (BCAAs, namely valine, leucine, and isoleucine) metabolic defect is observed in human diabetes, which is associated with insulin resistance. But whether BCAAs connect diabetes and AD remains unknown. Here, we show that BCAA metabolic defect may be one of the drivers of AD. BCAA levels were increased in the blood in human patients and mice with diabetes or AD. BCAA-enriched diet promoted the development of AD in mice as evidenced by the behavior and pathological analysis. Branched-chain amino acid transaminase 1 and 2 (BCAT1 and BCAT2) are the two enzymes for the first step metabolism of BCAAs by catalyzing BCAAs to generate branched-chain ketoacids. The expression of Bcat1 but not Bcat2 was significantly down-regulated in the brain tissues of diabetic, aged, and AD mice. Leucine up-regulated the phosphorylation of Tau but not affected the accumulation of amyloid β in the brain tissues or isolated neurons. In addition, knockdown of the expression of Bcat1, which would result in the accumulation of BCAAs, led to the same phenotype as BCAAs supplement in neurons. Interestingly, leucine supplement or Bcat1 knockdown promoted the activation of the mTOR signaling in the brains of AD mice or neurons. Subsequently, mTOR was critically involved in leucine and Bcat1 knockdown-mediated phosphorylation of Tau. Taken together, our findings demonstrated that diabetes-related BCAA accumulation in the brain tissues led to the phosphorylation of Tau and, subsequently, the development of diabetes-related AD.