Symptomatic orbital metastasis as an initial presentation of adenocarcinoma lung: A case report and review of literature.

ABSTRACT: Orbital metastasis is a rare entity in oncology. With increasing awareness and advancement, patients with initial ocular presentation can be diagnosed and treated. Ocular metastasis is more common in breast cancer followed by lung cancer. Lung cancer with ocular presentation generally have poor prognosis because of difficult diagnosis, Vision impairment and delayed management. Here, we report one such case of 59 year old female presented with painful periorbital swelling in left eye for 3 months with no pulmonary symptoms. On evaluation, she was diagnosed as ocular metastasis with primary being lung adenocarcinoma. Through this case, we enlighten the epidemiology, presentation, clinical features and evaluation of such patients which might help clinicians in further management.

A general solution for electromechanical analysis of electroelastic composite plates with arbitrary holes.

Stroh formalism provides an elegant method of solution for two-dimensional anisotropic elasticity problems through the generalized eigen relation associated with the dual coordinate system that gives the material eigen values and eigen vectors, and also the fundamental elasticity matrix and its associated Barnett-Lothe tensors. The extended Stroh-like formalism of Hwu and Hsieh has expanded the scope of basic Stroh formalism by addressing the electro-mechanical coupling effects in electro elastic plates. This paper presents an inclusive solution that addresses the two-dimensional problems in infinite electro-elastic, anisotropic, and isotropic plates with an arbitrary hole under remote arbitrary coupled electro-mechanical loading. This is achieved by adopting the Stroh formalism and its subsequent versions to consider the anisotropic and electro-elastic plates, and further, by incorporating the arbitrary biaxial loading condition into the boundary conditions, and the generalized mapping function into the basic formulation to accommodate all types of in plane loading and a variety of hole shapes respectively. Various equations of the solution are derived explicitly for easy understanding and computer implementation. The stress function is derived explicitly to satisfy the condition of traction free hole with remote electro-mechanical loading under generalized plane stress-open circuit condition. The stresses and electric displacements around the hole boundary are obtained by taking the derivative of the stress function with respect to unit normal along the hole boundary. The solution presented can be degenerated to the anisotropic or isotropic case by choosing the corresponding material properties, or appropriate values of complex parameters respectively. This general solution has exactly reproduced the results of other solutions in the literature for piezoelectric plates given by different methods. New results of stresses and electric displacements are obtained for various arbitrary holes in [PZT5H/45/-45/PZT5H]s graphite/epoxy plate and PZT 4 plates. Results for holes in piezoelectric laminates and PZT 4 piezo layer are also presented by FEM.

Neurological insights into brain-targeted cancer therapy and bioinspired microrobots.

Cancer, a multifaceted and pernicious disease, continuously challenges medicine, requiring innovative treatments. Brain cancers pose unique and daunting challenges due to the intricacies of the central nervous system and the blood-brain barrier. In this era of precision medicine, the convergence of neurology, oncology, and cutting-edge technology has given birth to a promising avenue - targeted cancer therapy. Furthermore, bioinspired microrobots have emerged as an ingenious approach to drug delivery, enabling precision and control in cancer treatment. This Keynote review explores the intricate web of neurological insights into brain-targeted cancer therapy and the paradigm-shifting world of bioinspired microrobots. It serves as a critical and comprehensive overview of these evolving fields, aiming to underscore their integration and potential for revolutionary cancer treatments.

Clinical Profile and Outcome of Adult Classical Hodgkin's Lymphoma: Real World Single Centre Experience.

Hodgkin's lymphoma treatment outcomes have been the true success story of modern medicine. Various data from western as well as Indian studies are available for classical Hodgkin's lymphoma (cHL). Here we report treatment outcomes from a tertiary cancer care centre in Karnataka over a 5 year period. This was a retrospective review of cHL cases aged 15 years and above diagnosed between January 2015 and December 2019 at Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India. The case files of the patients were retrieved and relevant data was collected. Two hundred patients of cHL were included in this study. Median age was 28 years with male to female ratio of 1.56:1. B symptoms were present in 58% cases. Mixed cellularity (46.5%) was the most common histological subtype. Majority patients had advanced stage at presentation (stage III/IV) (62.5%). Extranodal disease was present in 19.5% cases. GHSG early-favourable cases were 15.5%, early-unfavourable cases were 22.0%, while 62.5% were advanced cases. The most common chemotherapy regimen used was ABVD. Eighty-three (41.5%) patients received radiation therapy. Median follow-up was 34.2 months (range 4.1-67.8). The rates for complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were 84.5%, 8.5%, 5.0% and 2.0% respectively. PFS and OS rate at 6 years were 69.5% and 84.1% respectively. HL is one of the malignancies with high cure rate. The treatment outcome at our centre is comparable to western data and data from other tertiary centres from India.

Exploring GPCR signaling pathway networks as cancer therapeutic targets.

GPCR signaling can contribute to establishing the tumor microenvironment and influence the progression and metabolism of tumors. Arora et al.1 describe a systems-level approach to investigate the patterns of co-expression of GPCR signaling pathway networks across diverse tumors and identify network components that correlate with patient-survival data across different cancer types.

Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion.

T cell exhaustion is linked to persistent antigen exposure and perturbed activation events, correlating with poor disease prognosis. Tumor-mediated T cell exhaustion is well documented; however, how the nutrient-deprived tumor niche affects T cell receptor (TCR) activation is largely unclear. We show that methionine metabolism licenses optimal TCR signaling by regulating the protein arginine methylome, and limiting methionine availability during early TCR signaling promotes subsequent T cell exhaustion. We discovered a novel arginine methylation of a Ca 2+ -activated potassium transporter, KCa3.1, prevention of which results in increased Ca 2+ -mediated NFAT1 activation, NFAT1 promoter occupancy, and T cell exhaustion. Furthermore, methionine supplementation reduces nuclear NFAT1 in tumor-infiltrating T cells and augments their anti-tumor activity. These findings demonstrate metabolic regulation of T cell exhaustion determined during TCR engagement.

Intrinsic disorder: A term to define the specific physicochemical characteristic of protein conformational heterogeneity.

In his commentary in this issue of Molecular Cell,1 Struhl reasons that the term "intrinsically disordered regions" represents a vague and confusing concept for protein function. However, the term "intrinsically disordered" highlights the important physicochemical characteristic of conformational heterogeneity. Thus, "intrinsically disordered" is the counterpart to the term "folded, " with neither term having specific functional implications.

Mechanistic insights into the potential role of dietary polyphenols and their nanoformulation in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aß biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

Peptide-scFv antigen recognition domains effectively confer CAR T cell multiantigen specificity.

The emergence of immune escape is a significant roadblock to developing effective chimeric antigen receptor (CAR) T cell therapies against hematological malignancies, including acute myeloid leukemia (AML). Here, we demonstrate feasibility of targeting two antigens simultaneously by combining a GRP78-specific peptide antigen recognition domain with a CD123-specific scFv to generate a peptide-scFv bispecific antigen recognition domain (78.123). To achieve this, we test linkers with varying length and flexibility and perform immunophenotypic and functional characterization. We demonstrate that bispecific CAR T cells successfully recognize and kill tumor cells that express GRP78, CD123, or both antigens and have improved antitumor activity compared to their monospecific counterparts when both antigens are expressed. Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations.

Orchestration and theranostic applications of synthetic genome with Hachimoji bases/building blocks.

Synthetic genomics is a novel field of chemical biology where the chemically modified genetic alphabets have been considered in central dogma of life. Tweaking of chemical compositions of natural nucleotide bases could be developed as novel building blocks of DNA/RNA. The modified bases (dP, dZ, dS, and dB etc.) have been demonstrated to be adaptable for replication, transcription and follow Darwinism law of evolution. With advancement of chemical biology especially nucleotide chemistry, synthetic genetic codes have been discovered and Hachimoji nucleotides are the most important and significant one among them. These additional nucleotide bases can form orthogonal base-pairing, and also follow Darwinian evolution and other structural features. In the Hachimoji base pairing, synthetic building blocks are formed using eight modified nucleotide (DNA/RNA) letters (hence the name "Hachimoji"). Their structural conformations, like polyelectrolyte backbones and stereo-regular building blocks favor thermodynamic stability and confirm Schrodinger aperiodic crystal. From the structural genomics aspect, these synthetic bases could be incorporated into the central dogma of life. Researchers have shown Hachimoji building blocks were transcribed to its RNA counterpart as a functional fluorescent Hachimoji aptamer. Apart from several unnatural nucleotide base pairs maneuvered into its in vitro and in vivo applications, this review describes future perspective towards the development and therapeutic utilization of the genetic codes, a primary objective of synthetic and chemical biology.

Dynamic conformational changes of a tardigrade group-3 late embryogenesis abundant protein modulate membrane biophysical properties.

A number of intrinsically disordered proteins (IDPs) encoded in stress-tolerant organisms, such as tardigrade, can confer fitness advantage and abiotic stress tolerance when heterologously expressed. Tardigrade-specific disordered proteins including the cytosolic-abundant heat-soluble proteins are proposed to confer stress tolerance through vitrification or gelation, whereas evolutionarily conserved IDPs in tardigrades may contribute to stress tolerance through other biophysical mechanisms. In this study, we characterized the mechanism of action of an evolutionarily conserved, tardigrade IDP, HeLEA1, which belongs to the group-3 late embryogenesis abundant (LEA) protein family. HeLEA1 homologs are found across different kingdoms of life. HeLEA1 is intrinsically disordered in solution but shows a propensity for helical structure across its entire sequence. HeLEA1 interacts with negatively charged membranes via dynamic disorder-to-helical transition, mainly driven by electrostatic interactions. Membrane interaction of HeLEA1 is shown to ameliorate excess surface tension and lipid packing defects. HeLEA1 localizes to the mitochondrial matrix when expressed in yeast and interacts with model membranes mimicking inner mitochondrial membrane. Yeast expressing HeLEA1 shows enhanced tolerance to hyperosmotic stress under nonfermentative growth and increased mitochondrial membrane potential. Evolutionary analysis suggests that although HeLEA1 homologs have diverged their sequences to localize to different subcellular organelles, all homologs maintain a weak hydrophobic moment that is characteristic of weak and reversible membrane interaction. We suggest that such dynamic and weak protein-membrane interaction buffering alterations in lipid packing could be a conserved strategy for regulating membrane properties and represent a general biophysical solution for stress tolerance across the domains of life.

Assessment of cyclone risk and case study of Gaja cyclone using GIS techniques and machine learning algorithms in coastal zone of Tamil Nadu, India.

Cyclones can cause devastating impacts, including strong winds, heavy rainfall, storm surges, and flooding. The aftermath includes infrastructure damage, loss of life, displacement of communities, and ecological disruptions. Timely response and recovery efforts are crucial to minimize the socio-economic and environmental consequences of cyclones. To accelerate the time-consuming risk assessment process, particularly in geographically diverse regions, a blend of multi-criteria decision-making and machine learning models was utilized. This novel approach swiftly assessed cyclone risk and the impact of the Gaja cyclone in Nagapattinam, India. The method involved assigning weights to distinct criteria, unveiling notable vulnerability aspects like elevation, slope, proximity to the coast, distance from cyclone tracts, Lu/Lc, population density, proximity to cyclone shelters, household density, accessibility to healthcare facilities, NDVI, and levels of awareness. Daddavari, Ettugudi, Kodikarai, Vedharanyam, Velankanni, and Thirupoondi face high/extreme cyclone risk. Nagore, Nagapattinam, Pillai, Enangudi, and Sannanllur have low/no threat. To further enhance the precision of the study, machine learning algorithms like SVM, SAM, and MLC were deployed. These models were instrumental in generating pre- and post-cyclone land use maps. The influence of Gaja cyclones effects shows decreasing of agriculture land from 34% to 30%, aquaculture increase 1%, barren land decrease from 8% to 6%, Built-up land decrease from 15% to 13%, land with scrub and salt pan also decrease from 21% to 17% and 10%-8%. Mostly effect of Gaja cyclone is dramatic increase of water body from 8% to 21%. Conducting cyclone risk zone analysis and pre/post-cyclone Land Use Land Cover (LULC) detection in Nagapattinam offers valuable insights for disaster preparedness, infrastructure planning, and climate resilience. This study can enhance understanding of vulnerability and aid in formulating strategies to mitigate cyclone impacts, ensuring sustainable development in the region.

Antibody-drug conjugates in cancer therapy: innovations, challenges, and future directions.

The emergence of antibody-drug conjugates (ADCs) as a potential therapeutic avenue in cancer treatment has garnered significant attention. By combining the selective specificity of monoclonal antibodies with the cytotoxicity of drug molecules, ADCs aim to increase the therapeutic index, selectively targeting cancer cells while minimizing systemic toxicity. Various ADCs have been licensed for clinical usage, with ongoing research paving the way for additional options. However, the manufacture of ADCs faces several challenges. These include identifying suitable target antigens, enhancing antibodies, linkers, and payloads, and managing resistance mechanisms and side effects. This review focuses on the strategies to overcome these hurdles, such as site-specific conjugation techniques, novel antibody formats, and combination therapy. Our focus lies on current advancements in antibody engineering, linker technology, and cytotoxic payloads while addressing the challenges associated with ADC development. Furthermore, we explore the future potential of personalized medicine, leveraging individual patients' molecular profiles, to propel ADC treatments forward. As our understanding of the molecular mechanisms driving cancer progression continues to expand, we anticipate the development of new ADCs that offer more effective and personalized therapeutic options for cancer patients.

Molecular determinants of ligand efficacy and potency in GPCR signaling.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses through conformational changes. Despite their importance as drug targets, the molecular origins of pharmacological properties such as efficacy (maximum signaling response) and potency (the ligand concentration at half-maximal response) remain poorly understood for any ligand-receptor-signaling system. We used the prototypical adrenaline-ß2 adrenergic receptor-G protein system to reveal how specific receptor residues decode and translate the information encoded in a ligand to mediate a signaling response. We present a data science framework to integrate pharmacological and structural data to uncover structural changes and allosteric networks relevant for ligand pharmacology. These methods can be tailored to study any ligand-receptor-signaling system, and the principles open possibilities for designing orthosteric and allosteric compounds with defined signaling properties.

Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling.

The limited availability of cytokines in solid tumours hinders maintenance of the antitumour activity of chimeric antigen receptor (CAR) T cells. Cytokine receptor signalling pathways in CAR T cells can be activated by transgenic expression or injection of cytokines in the tumour, or by engineering the activation of cognate cytokine receptors. However, these strategies are constrained by toxicity arising from the activation of bystander cells, by the suboptimal biodistribution of the cytokines and by downregulation of the cognate receptor. Here we show that replacement of the extracellular domains of heterodimeric cytokine receptors in T cells with two leucine zipper motifs provides optimal Janus kinase/signal transducer and activator of transcription signalling. Such chimeric cytokine receptors, which can be generated for common γ-chain receptors, interleukin-10 and -12 receptors, enabled T cells to survive cytokine starvation without induction of autonomous cell growth, and augmented the effector function of CAR T cells in vitro in the setting of chronic antigen exposure and in human tumour xenografts in mice. As a modular design, leucine zippers can be used to generate constitutively active cytokine receptors in effector immune cells.