A STAT3 Degrader Demonstrates Pre-clinical Efficacy in Venetoclax resistant Acute Myeloid Leukemia.

Unlabelled: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that continues to have poor prognosis despite recent therapeutic advances. Venetoclax (Ven), a BCL2-inhibitor has shown a high response rate in AML; however, relapse is invariable due to mitochondrial dysregulation that includes upregulation of the antiapoptotic protein MCL1, a central mechanism of Ven resistance (Ven-res). We have previously demonstrated that the transcription factor STAT3 is upregulated in AML hematopoietic stem and progenitor cells (HSPCs) and can be effectively targeted to induce apoptosis of these aberrant cells.

Mechanisms of resistance to hypomethylating agents and BCL-2 inhibitors.

Myeloid malignancies such as myelodysplastic syndrome (MDS) & acute myeloid leukemia (AML) are clonal diseases that emerge and progress due to the expansion of disease-initiating aberrant hematopoietic stem cells, that are not eliminated by conventional cytotoxic therapies. Hypomethylating agents(HMA), azacytidine and decitabine are the first line agents for treatment of MDS and a combination with BCL-2 inhibitor, venetoclax, is approved for AML induction in patients above 75 years and is also actively being investigated for use in high risk MDS. Resistance to these drugs has become a significant clinical challenge in treatment of myeloid malignancies.

Association between Single-Nucleotide Polymorphisms and Treatment Response to Inhaled Corticosteroids and a Long-Acting Beta-Agonist in Asthma.

has been linked to airway structural changes in patients with asthma, leading to airway hyperresponsiveness, narrowing, and ultimately poor treatment responsiveness. This study aimed to evaluate the genetic association of SNPs with asthma, disease severity, and treatment responsiveness to ICS+LABA in the South Indian population. In this case-control study (486 controls and 503 cases), we performed genotyping using MassArray for six SNPs of , namely rs2280091, rs2787094, rs3918396, rs67044, rs2853209, and rs3918392.

Therapeutic targeting of the inflammasome in myeloid malignancies.

Even though genetic perturbations and mutations are important for the development of myeloid malignancies, the effects of an inflammatory microenvironment are a critical modulator of carcinogenesis. Activation of the innate immune system through various ligands and signaling pathways is an important driver of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The DAMPs, or alarmins, which activate the inflammasome pathway via the TLR4/NLR signaling cascade causes the lytic cell death of hematopoietic stem and progenitor cells (HSPCs), ineffective hematopoiesis, and β-catenin-induced proliferation of cancer cells, leading to the development of MDS/AML phenotype.

The evolution of epigenetic therapy in myelodysplastic syndromes and acute myeloid leukemia.

Mutations in the group of epigenetic modifiers are the largest group of mutated genes in Myelodysplastic Syndromes (MDS) and are very frequently found in Acute Myeloid Leukemia (AML). Our advancements in the understanding of epigenetics in these diseases have helped develop groundbreaking therapeutics that have changed the treatment landscape of MDS and AML, significantly improving outcomes. In this review we describe the most common epigenetic aberrations in MDS and AML, and current treatments that target mutations in epigenetic modifiers, as well as novel treatment combinations, from standard therapies to investigational treatments.

Genetic variations in olfactory receptor gene OR2AG2 in a large multigenerational family with asthma.

It is estimated from twin studies that heritable factors account for at-least half of asthma-risk, of which genetic variants identified through population studies explain only a small fraction. Multi-generation large families with high asthma prevalence can serve as a model to identify highly penetrant genetic variants in closely related individuals that are missed by population studies. To achieve this, a four-generation Indian family with asthma was identified and recruited for examination and genetic testing.

Haplotype analysis of polymorphisms in asthma: A pilot study.

Background & Objectives: ADAM33 is implicated as a potentially strong candidate gene for asthma and bronchial hyper-responsiveness. Many polymorphisms of ADAM33 have been studied along with ADAM33 expression in various cells of the lungs. Haplotype analysis also showed association with asthma in different populations across the world.

Chemical chaperones mitigate experimental asthma by attenuating endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress and consequent unfolded protein response (UPR) are important in inflammation but have been poorly explored in asthma. We used a mouse model of allergic airway inflammation (AAI) with features of asthma to understand the role of ER stress and to explore potential therapeutic effects of inhaled chemical chaperones, which are small molecules that can promote protein folding and diminish UPR. UPR markers were initially measured on alternate days during a 7-day daily allergen challenge model.