Toxicity to immune checkpoint inhibitors presenting as pulmonary arterial vasculopathy and rapidly progressing right ventricular dysfunction

Introduction: Immune Checkpoint Inhibitors (ICIs) are antitumor drugs associated with a number of serious immune-related adverse events (IRAEs). ICIs enhance anti-tumor immunity, thereby  energized  patient's immune system to fight cancer. IRAEs may affect functions of various organs, including heart, and may lead to morbidity and, to some  extent  mortality. Left ventricle (LV) myocarditis with dysfunction is a known side effect of this class of drugs. However, right ventricle (RV) myocarditis and pulmonary vasculitis are an unknown entity and has not been previously reported.  Here, we present the first case of  IRAEs causing selective RV involvement with dysfunctions, attributed to immune checkpoint inhibitors described till date in medical literature.Presentation of Case: A 58-year male presented  with history of low-grade fever and  weight loss. On palpation, he had diffuse cervical lymphadenopathy. Histopathology evaluation of  lymph node revealed  metastatic lesions of Renal Cell Carcinoma (RCC).Conclusion: Fatal cardiovascular adverse events can occur as a side effect of ICI. The combination of RV myocarditis with progressive pulmonary hypertension is fatal. Treatment with high dose corticosteroids and immunomodulators may help in patient survival. Physicians treating patients with ICIs should be aware of their lethal cardiotoxic side effects  to reduce adverse cardiac outcomes. Because the number of patients exposed to this new immune therapy is expected to increase remarkably in the near future, our study encourages further work to define guidelines for cardiovascular monitoring and management

Metabolism of 2-Chloro-4-Nitrophenol in a Gram Negative Bacterium, Burkholderia sp. RKJ 800

A 2-Chloro-4-nitrophenol (2C4NP) degrading bacterial strain designated as RKJ 800 was isolated from a pesticide contaminated site of India by enrichment method and utilized 2C4NP as sole source of carbon and energy. The stoichiometric amounts of nitrite and chloride ions were detected during the degradation of 2C4NP. On the basis of thin layer chromatography, high performance liquid chromatography and gas chromatography-mass spectrometry, chlorohydroquinone (CHQ) and hydroquinone (HQ) were identified as major metabolites of the degradation pathway of 2C4NP. Manganese dependent HQ dioxygenase activity was observed in the crude extract of 2C4NP induced cells of the strain RKJ 800 that suggested the cleavage of the HQ to γ-hydroxymuconic semialdehyde. On the basis of the 16S rRNA gene sequencing, strain RKJ 800 was identified as a member of genus Burkholderia. Our studies clearly showed that Burkholderia sp. RKJ 800 degraded 2-chloro-4-nitrophenol via hydroquinone pathway. The pathway identified in a gram negative bacterium, Burkholderia sp. strain RKJ 800 was differed from previously reported 2C4NP degradation pathway in another gram-negative Burkholderia sp. SJ98. This is the first report of the formation of CHQ and HQ in the degradation of 2C4NP by any gram-negative bacteria. Laboratory-scale soil microcosm studies showed that strain RKJ 800 is a suitable candidate for bioremediation of 2C4NP contaminated sites

Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?

PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments

Direct Ubiquitin Independent Recognition and Degradation of a Folded Protein by the Eukaryotic Proteasomes-Origin of Intrinsic Degradation Signals

Eukaryotic 26S proteasomes are structurally organized to recognize, unfold and degrade globular proteins. However, all existing model substrates of the 26S proteasome in addition to ubiquitin or adaptor proteins require unstructured regions in the form of fusion tags for efficient degradation. We report for the first time that purified 26S proteasome can directly recognize and degrade apomyoglobin, a globular protein, in the absence of ubiquitin, extrinsic degradation tags or adaptor proteins. Despite a high affinity interaction, absence of a ligand and presence of only helices/loops that follow the degradation signal, apomyoglobin is degraded slowly by the proteasome. A short floppy F-helix exposed upon ligand removal and in conformational equilibrium with a disordered structure is mandatory for recognition and initiation of degradation. Holomyoglobin, in which the helix is buried, is neither recognized nor degraded. Exposure of the floppy F-helix seems to sensitize the proteasome and primes the substrate for degradation. Using peptide panning and competition experiments we speculate that initial encounters through the floppy helix and additional strong interactions with N-terminal helices anchors apomyoglobin to the proteasome. Stabilizing helical structure in the floppy F-helix slows down degradation. Destabilization of adjacent helices accelerates degradation. Unfolding seems to follow the mechanism of helix unraveling rather than global unfolding. Our findings while confirming the requirement for unstructured regions in degradation offers the following new insights: a) origin and identification of an intrinsic degradation signal in the substrate, b) identification of sequences in the native substrate that are likely to be responsible for direct interactions with the proteasome, and c) identification of critical rate limiting steps like exposure of the intrinsic degron and destabilization of an unfolding intermediate that are presumably catalyzed by the ATPases. Apomyoglobin emerges as a new model substrate to further explore the role of ATPases and protein structure in proteasomal degradatio

An investigation into the age and origin of Suranga in the foothills of the Western Ghats of India

This document is the Accepted Manuscript version. The final publication is available at Springer via: https://doi.org/10.1007/s12685-015-0125-yThis paper presents the evidence for determining the age and origin of suranga irrigation found mainly in southern Karnataka and northern Kerala in the foothills of the Western Ghats of south India. It draws on on-going research that has attempted to use an interdisciplinary approach to date the system using Indian Archives, British and Portuguese colonial archives, etymology, oral testimony archaeology, phenology and palaeo dating techniques. The results from this study put the origins of the system at around 1900–1940 CE. These results are compared with the current academic discourse that supports the view that the system originates from ancient Persia and qanat technology, because of the long established trade links with Persia and the Arabian Peninsula in the Malabar region. We argue that a new ‘origin discourse’ should be framed around these much more recent dates. The methodological constraints behind both theories are discussed throughout to enable the reader to appreciate the limitations of both arguments.Peer reviewedFinal Accepted Versio

Antisense oligonucleotide and thyroid hormone conjugates for obesity treatment

Using the principle of antibody-drug conjugates that deliver highly potent cytotoxic agents to cancer cells for cancer therapy, we here report the synthesis of antisense-oligonucleotides (ASO) and thyroid hormone T3 conjugates for obesity treatment. ASOs primarily target fat and liver with poor penetrance to other organs. Pharmacological T3 treatment increases energy expenditure and causes weight loss, but is contraindicated for obesity treatment due to systemic effects on multiple organs. We hypothesize that ASO-T3 conjugates may knock down target genes and enrich T3 action in fat and liver. Two established ASOs are tested. Nicotinamide N-methyltransferase (NNMT)-ASO prevents diet- induced obesity in mice. Apolipoprotein B (ApoB)-ASO is an FDA approved drug for treating familial hypercholesterolemia. NNMT-ASO and ApoB-ASO are chemically conjugated with T3 using a non- cleavable sulfo-SMCC linker. Both NNMT-ASO-T3 (NAT3) and ApoB-ASO-T3 (AAT3) enhance thyroid hormone receptor activity. Treating obese mice with NAT3 or AAT3 decreases adiposity and increases lean mass. ASO-T3 enhances white fat browning, decreases genes for fatty acid synthesis in liver, and shows limited effects on T3 target genes in heart and muscle. Furthermore, AAT3 augments LDL cholesterol-lowering effects of ApoB-ASO. Therefore, ASO and hormone/drug conjugation may provide a novel strategy for obesity and hyperlipidemia treatment

Multiscale Simulations Suggest a Mechanism for the Association of the Dok7 PH Domain with PIP-Containing Membranes

Dok7 is a peripheral membrane protein that is associated with the MuSK receptor tyrosine kinase. Formation of the Dok7/MuSK/membrane complex is required for the activation of MuSK. This is a key step in the complex exchange of signals between neuron and muscle, which lead to neuromuscular junction formation, dysfunction of which is associated with congenital myasthenic syndromes. The Dok7 structure consists of a Pleckstrin Homology (PH) domain and a Phosphotyrosine Binding (PTB) domain. The mechanism of the Dok7 association with the membrane remains largely unknown. Using multi-scale molecular dynamics simulations we have explored the formation of the Dok7 PH/membrane complex. Our simulations indicate that the PH domain of Dok7 associates with membranes containing phosphatidylinositol phosphates (PIPs) via interactions of the β1/β2, β3/β4, and β5/β6 loops, which together form a positively charged surface on the PH domain and interact with the negatively charged headgroups of PIP molecules. The initial encounter of the Dok7 PH domain is followed by formation of additional interactions with the lipid bilayer, and especially with PIP molecules, which stabilizes the Dok7 PH/membrane complex. We have quantified the binding of the PH domain to the model bilayers by calculating a density landscape for protein/membrane interactions. Detailed analysis of the PH/PIP interactions reveal both a canonical and an atypical site to be occupied by the anionic lipid. PH domain binding leads to local clustering of PIP molecules in the bilayer. Association of the Dok7 PH domain with PIP lipids is therefore seen as a key step in localization of Dok7 to the membrane and formation of a complex with MuSK

Genetic variation and diversity of pearl millet [Pennisetum glaucum (L.)] genotypes assessed for millet head miner, Heliocheilus albipunctella resistance, in West Africa

Pearl millet (Pennisetum glaucum L.), the major source of minerals and dietary energy for people living in the semi-arid regions of Sahel, is regularly damaged by millet head miner, Heliocheilus albipunctella. In order to identify the plant-based resistance sources for millet head miner along with high grain Fe and Zn, we have screened forty pearl millet genotypes, using an artificial infestation method. Analysis of variance revealed significant differences in the genotypes tested for head miner resistance. The genotypes Gamoji, ICMP 177001, ICMP 177002, ICMV 177003, ICMV IS 90311, LCIC9702, Souna 3, ICMV IS 94206 and PE08043 exhibited antibiosis resistance mechanism to Heliocheilus albipunctella with appreciable agronomy and grain yield when compared with the susceptible check ICMV IS 92222. The genotypes Faringuero, ICMV 167005, ICMV IS 99001, Sadore local, SOSAT-C88, and ICMP 177004 exhibited tolerance to head miner damage with good per se performance. The genotypes ICMP 177001, ICMP 177002, ICMV 177003, and Moro exhibited resistance to millet head miner and had consistent grain Fe content across seasons (ranging from 44 to 70 ppm). Association between the head miner resistance and morphological traits showed a positive and significant correlation of larval production index (%) with head miner damage (r = 0.59**). Grain Fe and Zn contents exhibited negative association with panicle length and grain yield indicating proper care should be taken in breeding for these traits. Hence, the identified resistance sources can be effectively utilized in breeding head miner resistant pearl millet OPV’s/ hybrids, with high grain yield including Fe and Zn concentrations, to overcome the hunger and malnutrition seen in populations living in the semi-arid tropics