Five historical innovations that have shaped modern otolaryngological surgery.

Throughout history, many innovations have contributed to the development of modern otolaryngological surgery, improving patient outcomes and expanding the range of treatment options available to patients. This article explores five key historical innovations that have shaped modern otolaryngological surgery: Operative Microscope, Hopkins Rigid Endoscope, Laryngeal Nerve monitoring, Cochlear implants and Laser surgery. The selection of innovations for inclusion in this article was meticulously determined through expert consensus and an extensive literature review. We will review the development, impact and significance of each innovation, highlighting their contributions to the field of otolaryngological surgery and their ongoing relevance in contemporary and perioperative practice.

MYBPC3 D389V Variant Induces Hypercontractility in Cardiac Organoids.

BACKGROUND: MYBPC3 , encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in MYBPC3 by using human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs). METHODS: The hiPSC-derived cardiomyocytes (hiPSC-CMs) and hCOs were generated from human subjects to define the molecular, cellular, and functional changes caused by the MYBPC3 D389V variant. This variant is associated with increased fractional shortening and is highly prevalent in South Asian descendants. Recombinant C0-C2, N'-region of cMyBP-C (wildtype and D389V), and myosin S2 proteins were also utilized to perform binding and motility assays in vitro . RESULTS: Confocal and electron microscopic analyses of hCOs generated from noncarriers (NC) and carriers of the MYBPC3 D389V variant revealed the presence of highly organized sarcomeres. Furthermore, functional experiments showed hypercontractility with increased contraction velocity, faster calcium cycling, and faster contractile kinetics in hCOs expressing MYBPC3 D389V than NC hCOs. Interestingly, significantly increased cMyBP-C phosphorylation in MYBPC3 D389V hCOs was observed, but without changes in total protein levels, in addition to higher oxidative stress and lower mitochondrial membrane potential (ΔΨm). Next, spatial mapping revealed the presence of endothelial cells, fibroblasts, macrophages, immune cells, and cardiomyocytes in the hCOs. The hypercontractile function was significantly improved after treatment with the myosin inhibitor mavacamten (CAMZYOS®) in MYBPC3 D389V hCOs. Lastly, various in vitro binding assays revealed a significant loss of affinity in the presence of MYBPC3 D389V with myosin S2 region as a likely mechanism for hypercontraction. CONCLUSIONS: Conceptually, we showed the feasibility of assessing the functional and molecular mechanisms of HCM using highly translatable hCOs through pragmatic experiments that led to determining the MYBPC3 D389V hypercontractile phenotype, which was rescued by administration of a myosin inhibitor. Novelty and Significance: What Is Known?: MYBPC3 mutations have been implicated in hypertrophic cardiomyopathy. D389V is a polymorphic variant of MYBPC3 predicted to be present in 53000 US South Asians owing to the founder effect. D389V carriers have shown evidence of hyperdynamic heart, and human-induced pluripotent stem cells (hiPSC)-derived cardiomyocytes with D389V show cellular hypertrophy and irregular calcium transients. The molecular mechanism by which the D389V variant develops pathological cardiac dysfunction remains to be conclusively determined.What New Information Does This Article Contribute ?: The authors leveraged a highly translational cardiac organoid model to explore the role of altered cardiac calcium handling and cardiac contractility as a common pathway leading to pathophysiological phenotypes in patients with early HCM. The MYBPC3 D389V -mediated pathological pathway is first studied here by comparing functional properties using three-dimensional cardiac organoids differentiated from hiPSC and determining the presence of hypercontraction. Our data demonstrate that faster sarcomere kinetics resulting from lower binding affinity between D389V-mutated cMyBP-C protein and myosin S2, as evidenced by in vitro studies, could cause hypercontractility which was rescued by administration of mavacamten (CAMZYOS®), a myosin inhibitor. In addition, hypercontractility causes secondary mitochondrial defects such as higher oxidative stress and lower mitochondrial membrane potential (ΔΨm), highlighting a possible early adaptive response to primary sarcomeric changes. Early treatment of MYBPC3 D389V carriers with mavacamten may prevent or reduce early HCM-related pathology. GRAPHICAL ABSTRACT: A graphical abstract is available for this article.

Modulation of endogenous opioid signaling by inhibitors of puromycin-sensitive aminopeptidase.

The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin-sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5'-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5'-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management.

Investigating the potential of catheter-assisted pulsed focused ultrasound ablation for atherosclerotic plaques.

BACKGROUND: Atherosclerosis is a condition in which an adhesive substance called plaque accumulates over time inside the arteries. Plaque buildup results in the constriction of arteries, causing a shortage of blood supply to tissues and organs. Removing atherosclerotic plaques controls the development of acute ischemic stroke and heart diseases. It remains imperative for positive patient outcomes. PURPOSE: This study sought to develop a minimally invasive technique for removing arterial plaques by applying focused ultrasound (FUS) energy on the metal surface of a nitinol catheter wire to induce inertial cavitation. The induced cavitation can deplete plaque mechanically inside the arteries, leading towards improved recanalization of blood vessels. METHODS: The enhanced cavitation effect induced by combining FUS with a metal catheter was first verified by exposing agar phantom gels with or without a 0.9-mm diameter nitinol wire to an acoustic field produced by a 0.5-MHz FUS transducer. The phenomenon was further confirmed in pork belly fat samples with or without a 3-mm diameter nitinol catheter wire. Cavitation was monitored by detecting the peaks of emitted ultrasound signals from the samples using a passive cavitation detector (PCD). Cavitation threshold values were determined by observing the jump in the peak amplitude of signals received by the PCD when the applied FUS peak negative pressure (PNP) increased. To simulate arterial plaque removal, FUS with or without a catheter was used to remove tissues from pork belly fat samples and the lipid cores of human atherosclerotic plaque samples using 2500-cycle FUS bursts at 10% duty cycle and a burst repetition rate of 20 Hz. Treatment outcomes were quantified by subtracting the weight of samples before treatment from the weight of samples after treatment. All measurements were repeated 5 times (n = 5) unless otherwise indicated, and paired t-tests were used to compare the means of two groups. A p-value of <0.05 will be considered significant. RESULTS: Our results showed that with a nitinol wire, the cavitation threshold in agar phantoms was reduced to 2.6 MPa from 4.3 MPa PNP when there was no nitinol wire in the focal region of FUS. For pork belly fat samples, cavitation threshold values were 1.0 and 2.0 MPa PNP, with and without a catheter wire, respectively. Pork belly fat tissues and lipid cores of atherosclerotic plaques were depleted at the interface between a catheter and the samples at 2 and 4 MPa FUS PNP, respectively. The results showed that with a catheter wire in the focal region of a 3-min FUS treatment session, 24.7 and 25.6 mg of lipid tissues were removed from pork belly fat and human atherosclerotic samples, respectively. In contrast, the FUS-only group showed no reduction in sample weight. The differences between FUS-only and FUS-plus-catheter groups were statistically significant (p < 0.001 for the treatment on pork belly samples, and p < 0.01 for the treatment on human atherosclerotic samples). CONCLUSION: This study demonstrated the feasibility of catheter-assisted FUS therapy for removing atherosclerotic plaques.

Molecular cloning, expression, and purification, along with in silico epitope analysis of recombinant enolase proteins (a potential vaccine candidate) from Candida albicans and Candida auris.

Candida albicans is the predominant cause of systemic candidiasis, although other non albicans Candida species are progressively becoming more widespread nowadays. Candida auris has emerged as a deadly multidrug-resistant fungal pathogen, posing a significant threat to global public health. In the absence of effective antifungal therapies, the development of a vaccine against C. auris infections is imperative. Enolase, a key glycolytic enzyme, has emerged as a promising vaccine candidate due to its immunogenic properties and essential role in fungal virulence. Herein, full-length Enolase gene sequences from C. albicans and C. auris were cloned into suitable expression vector and transformed into Escherichia coli expression hosts. Recombinant Enolase proteins were successfully expressed and purified using affinity chromatography under native conditions, followed by SDS-PAGE characterization and Western blot analysis. CD spectroscopy verified the existence of expressed proteins in soluble native conformation. Preliminary in silico studies verified the immunogenicity of recombinant Enolase proteins isolated from both C. albicans and C. auris. Furthermore, bioinformatics analysis revealed conserved B-cell and T-cell epitopes across C. albicans and C. auris Enolase proteins, suggesting potential cross-reactivity and broad-spectrum vaccine efficacy. Our findings are anticipated to play a role in advancing therapeutic as well as diagnostic strategies against systemic candidiasis.

Aspirin-Induced Massive Spontaneous Sublingual Hematoma.

Sublingual hematoma, a rare but potentially life-threatening condition, can arise spontaneously or secondary to various triggers, including trauma, dental procedures, or anticoagulant therapy. We present a case of massive spontaneous sublingual hematoma in a 45-year-old woman receiving aspirin therapy for rheumatic heart disease. Despite the absence of trauma or procedural triggers, the patient presented with bleeding from the floor of the mouth and significant submental swelling, prompting urgent intervention to secure the airway and manage coagulopathy. Conservative measures, including discontinuation of aspirin and intravenous vitamin K administration, led to gradual hematoma resolution and favorable patient outcomes. This case highlights the importance of prompt recognition and early management of sublingual hematoma, particularly in the context of aspirin therapy-induced coagulopathy.

An Analysis of the Anomalous Fissure of the Ligamentum Teres Hepatis: A Morphological Perspective in the North Indian Population.

Background The liver, being the largest internal organ of the body shows a variety of gross morphological variations about lobes, fissures and processes which may be clinically significant. Among various anatomical variations, the most found is the variant fissure for ligamentum teres hepatis. The present study was done to classify, review, compare and discuss the literature for anomalies in fissures for ligamentum teres hepatis. Methods A total of 100 formalin-preserved human livers were obtained from the Department of Anatomy of King George's Medical University, Lucknow, and studied for one year. Result In our study, 15% of the liver showed morphological variations in fissures for ligamentum teres hepatis. These were classified into four types. In type I (2%), the fissure was converted into a tunnel by pons hepatis. In type II (3%), there was an incomplete fissure for ligamentum teres hepatis extending into the diaphragmatic surface. In type III (4%), there was an incomplete fissure for ligamentum teres hepatis present only on the visceral surface. In type IV (6%), the fissure was covered by a thin membrane. Conclusion In this study of the North Indian population, 15% of liver have gross morphological variations. So thorough anatomical knowledge of the existence of variant or abnormal surface features on the liver is imperative to understanding the underlying pathology for radiologists and surgeons so that a favorable outcome can be achieved.

Adducin Regulates Sarcomere Disassembly During Cardiomyocyte Mitosis.

BACKGROUND: Recent interest in understanding cardiomyocyte cell cycle has been driven by potential therapeutic applications in cardiomyopathy. However, despite recent advances, cardiomyocyte mitosis remains a poorly understood process. For example, it is unclear how sarcomeres are disassembled during mitosis to allow the abscission of daughter cardiomyocytes. METHODS: Here, we use a proteomics screen to identify adducin, an actin capping protein previously not studied in cardiomyocytes, as a regulator of sarcomere disassembly. We generated many adeno-associated viruses and cardiomyocyte-specific genetic gain-of-function models to examine the role of adducin in neonatal and adult cardiomyocytes in vitro and in vivo. RESULTS: We identify adducin as a regulator of sarcomere disassembly during mammalian cardiomyocyte mitosis. α/γ-adducins are selectively expressed in neonatal mitotic cardiomyocytes, and their levels decline precipitously thereafter. Cardiomyocyte-specific overexpression of various splice isoforms and phospho-isoforms of α-adducin in identified Thr445/Thr480 phosphorylation of a short isoform of α-adducin as a potent inducer of neonatal cardiomyocyte sarcomere disassembly. Concomitant overexpression of this α-adducin variant along with γ-adducin resulted in stabilization of the adducin complex and persistent sarcomere disassembly in adult mice, which is mediated by interaction with α-actinin. CONCLUSIONS: These results highlight an important mechanism for coordinating cytoskeletal morphological changes during cardiomyocyte mitosis.

Fast skeletal myosin binding protein-C expression exacerbates dysfunction in heart failure.

During heart failure, gene and protein expression profiles undergo extensive compensatory and pathological remodeling. We previously observed that fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased mouse hearts. While fMyBP-C shares significant homology with its cardiac paralog, cardiac myosin binding protein-C (cMyBP-C), there are key differences that may affect cardiac function. However, it is unknown if the expression of fMyBP-C expression in the heart is a pathological or compensatory response. We aim to elucidate the cardiac consequence of either increased or knockout of fMyBP-C expression. To determine the sufficiency of fMyBP-C to cause cardiac dysfunction, we generated cardiac-specific fMyBP-C over-expression mice. These mice were further crossed into a cMyBP-C null model to assess the effect of fMyBP-C in the heart in the complete absence of cMyBP-C. Finally, fMyBP-C null mice underwent transverse aortic constriction (TAC) to define the requirement of fMyBP-C during heart failure development. We confirmed the upregulation of fMyBP-C in several models of cardiac disease, including the use of lineage tracing. Low levels of fMyBP-C caused mild cardiac remodeling and sarcomere dysfunction. Exclusive expression of fMyBP-C in a heart failure model further exacerbated cardiac pathology. Following 8 weeks of TAC, fMyBP-C null mice demonstrated greater protection against heart failure development. Mechanistically, this may be due to the differential regulation of the myosin super-relaxed state. These findings suggest that the elevated expression of fMyBP-C in diseased hearts is a pathological response. Targeted therapies to prevent upregulation of fMyBP-C may prove beneficial in the treatment of heart failure. Significance Statement: Recently, the sarcomere - the machinery that controls heart and muscle contraction - has emerged as a central target for development of cardiac therapeutics. However, there remains much to understand about how the sarcomere is modified in response to disease. We recently discovered that a protein normally expressed in skeletal muscle, is present in the heart in certain settings of heart disease. How this skeletal muscle protein affects the function of the heart remained unknown. Using genetically engineered mouse models to modulate expression of this skeletal muscle protein, we determined that expression of this skeletal muscle protein in the heart negatively affects cardiac performance. Importantly, deletion of this protein from the heart could improve heart function suggesting a possible therapeutic avenue.

Causal gene regulatory analysis with RNA velocity reveals an interplay between slow and fast transcription factors.

Single-cell expression dynamics, from differentiation trajectories or RNA velocity, have the potential to reveal causal links between transcription factors (TFs) and their target genes in gene regulatory networks (GRNs). However, existing methods either overlook these expression dynamics or necessitate that cells be ordered along a linear pseudotemporal axis, which is incompatible with branching trajectories. We introduce Velorama, an approach to causal GRN inference that represents single-cell differentiation dynamics as a directed acyclic graph of cells, constructed from pseudotime or RNA velocity measurements. Additionally, Velorama enables the estimation of the speed at which TFs influence target genes. Applying Velorama, we uncover evidence that the speed of a TF's interactions is tied to its regulatory function. For human corticogenesis, we find that slow TFs are linked to gliomas, while fast TFs are associated with neuropsychiatric diseases. We expect Velorama to become a critical part of the RNA velocity toolkit for investigating the causal drivers of differentiation and disease.

Retrieval of high-resolution aerosol optical depth (AOD) using Landsat 8 imageries over different LULC classes over a city along Indo-Gangetic Plain, India.

Aerosol optical depth (AOD) serves as a crucial indicator for assessing regional air quality. To address regional and urban pollution issues, there is a requirement for high-resolution AOD products, as the existing data is of very coarse resolution. To address this issue, we retrieved high-resolution AOD over Kanpur (26.4499°N, 80.3319°E), located in the Indo-Gangetic Plain (IGP) region using Landsat 8 imageries and implemented the algorithm SEMARA, which combines SARA (Simplified Aerosol Retrieval Algorithm) and SREM (Simplified and Robust Surface Reflectance Estimation). Our approach leveraged the green band of the Landsat 8, resulting in an impressive spatial resolution of 30 m of AOD and rigorously validated with available AERONET observations. The retrieved AOD is in good agreement with high correlation coefficients (r) of 0.997, a low root mean squared error of 0.035, and root mean bias of - 4.91%. We evaluated the retrieved AOD with downscaled MODIS (MCD19A2) AOD products across various land classes for cropped and harvested period of agriculture cycle over the study region. It is noticed that over the built-up region of Kanpur, the SEMARA algorithm exhibits a stronger correlation with the MODIS AOD product compared to vegetation, barren areas and water bodies. The SEMARA approach proved to be more effective for AOD retrieval over the barren and built-up land categories for harvested period compared with the cropping period. This study offers a first comparative examination of SEMARA-retrieved high-resolution AOD and MODIS AOD product over a station of IGP.

LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.

Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4, but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here, we identify the domains of LRMP essential for this regulation, show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating, and demonstrate that multiple unique regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we identified the initial 227 residues of LRMP and the N-terminus of HCN4 as necessary for LRMP to associate with HCN4. We found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. Finally, we demonstrated that LRMP-regulation can be conferred to HCN2 by addition of the HCN4 N-terminus along with mutation of five residues in the S5 region and C-linker to the cognate HCN4 residues. Taken together, these results suggest that LRMP inhibits HCN4 through an isoform-specific interaction involving the N-terminals of both proteins that prevents the transduction of cAMP binding into a change in channel gating, most likely via an HCN4-specific orientation of the N-terminus, C-linker, and S4-S5 linker.

Modulation of endogenous opioid signaling by inhibitors of puromycin sensitive aminopeptidase.

The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5'-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5'-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management.

A Prospective Study on the Anatomical Variations of the Frontal Recess and its Association with Computer Tomographic Signs of Sinusitis.

The frontal recess region has a complex anatomy and HRCT scans of the paranasal sinuses (PNS) are the gold standard in evaluating it. Classification systems have been established to identify the frontal recess cells. The objectives of this study are to describe the incidence of anatomical variations, classify the anatomy of the frontal recess using the IFAC & Kuhn's classification systems, find the association between the anatomical variations and the incidence of CT signs of sinusitis. A prospective study of patients undergoing HRCT-PNS was carried out. The frontal recess region was evaluated and classified as per both classification systems. The prevalence of each frontal cell was identified; presence of CT signs of sinusitis was noted and the correlation between the two was evaluated. 272 sides of HRCT scans were evaluated. Prevalence of cells as per IFAC classification showed ANC - 98.2%, SAC-43.4%, SBC-33.1%, SAFC- 28.3%, FSC -25%, SBFC- 3.7% and SOEC- 2.2%. Prevalence of cells as per Kuhn's classification showed ANC - 98.2%, Type 1- 38.2%, SBC-32.7%, FSC -24.3%, Type 3- 16.9%, Type 2- 12.9%, Type 4- 4.8%, FBC- 2.6% and SOEC-2.2%. Sinusitis was seen in 27.2% cases. A significant association was noted between the presence of SOEC, FSC and sinusitis as per both classification systems. (P=0.049 and P<0.001 respectively). In conclusion the cells which lead to an anteriorly based drainage pathway are more common, but the presence of posteriorly based SOEC and medially based FSC have a higher association with sinusitis.

Therapeutic potential of flavonoids in ovalbumin induced asthma in mice model.

OBJECTIVES: Desmodium triquetrum DC (Fabaceae) is a plant commonly used in Indian traditional medicine to treat allergies. Asthma is a severe condition, with an estimated 300 million deaths annually, which could increase to 400 million by 2025. Flavonoids, a class of compounds found in many plants, have been found to have beneficial effects in treating asthma. In this study, researchers focused on three flavonoids, Baicalein, Naringin, and Neohesperidin, derived from Desmodium triquetrum DC, to investigate their potential as a treatment for asthma. METHODS: The study used an aerosolized ovalbumin-induced asthma model to evaluate the effects of the flavonoids on various substances in bronchoalveolar lavage fluid, including total differential leukocyte, nitrite, nitrate, TNF, IL-4, and IL-13. The researchers also measured the levels of myeloperoxidase and malondialdehyde in the lungs. RESULTS: The results showed that ovalbumin-induced airway hyper-responsiveness led to a significant increase in pro-inflammatory cytokine levels. However, the flavonoids significantly decreased the severity of airway inflammation. Histopathology results also supported the effectiveness of the flavonoids. These findings suggest that these flavonoids could be a supplementary and alternative treatment for asthma by inhibiting the pro-inflammatory pathway. CONCLUSIONS: The findings suggest that the isolated compounds have the potential to act cumulatively to decrease the levels of the tested cytokines, normalize eosinophil and activated lymphocyte counts, and significantly reduce MPO and MDA. This indicates a possible respiratory mechanism of action for the drugs.

Measured Steps: Navigating the Path of Oligoprogressive Lung Cancer with Targeted and Immunotherapies.

PURPOSE OF REVIEW: This review discusses the definitions, treatment modalities, management, future directions, and ongoing clinical trials of oligoprogressive disease in oncogene-driven and non-oncogene-driven NSCLC. RECENT FINDINGS: During the last decades, diagnostic and treatment modalities for oligometastatic NSCLC have advanced significantly, leading to improved survival. Additionally, our understanding of the tumor biology of oligoprogressive disease has expanded. However, despite the efforts of organizations, such as EORTC, ESTRO, and ASTRO proposing definitions for oligometastatic and oligoprogressive disease, heterogeneity in definitions persists in (ongoing) trials. Recognizing the significance of subclassification within oligoprogressive disease in NSCLC and the varying risks associated with subsequent metastatic spread, there is a call for tailored management strategies. A consensus on standardized criteria for the definition of oligoprogressive disease is urgently needed and will not only facilitate meaningful comparisons between studies but also pave the way for the development of personalized treatment plans that take into account the heterogeneous nature of oligoprogressive disease.

S6K1 deficiency in tumor stroma impairs lung metastasis of melanoma in mice.

Accumulating data suggest that ribosomal protein S6 kinase 1 (S6K1), an effector in the mammalian target of rapamycin (mTOR) pathway, plays pleiotropic roles in tumor progression. However, to date, while the tumorigenic function of S6K1 in tumor cells has been well elucidated, its role in the tumor stroma remains poorly understood. We recently showed that S6K1 mediates vascular endothelial growth factor A (VEGF-A) production in macrophages, thereby supporting tumor angiogenesis and growth. As macrophage-derived VEGF-A is crucial for both tumor cell intravasation and extravasation across the vascular endothelium, our previous findings suggest that stromal S6K1 signaling is required for tumor metastatic spread. Therefore, we aimed to determine the impact of host S6K1 depletion on tumor metastasis using a murine model of pulmonary metastasis (S6k1-/- mice implanted with B16F10 melanoma). The ablation of S6K1 in the host microenvironment significantly reduced the metastasized B16F10 melanoma cells on the lung surface in both spontaneous and intravenous lung metastasis mouse models without affecting the incidence of metastasis to distant lymph nodes. In addition, stromal S6K1 loss decreased the number of tumor cells circulating in the peripheral blood of mice bearing B16F10 xenografts without affecting the vascular leakage induced by VEGF-A in vivo. These observations demonstrate that S6K1 signaling in host cells other than endothelial cells is required to modulate the host microenvironment to facilitate the metastatic spread of tumors via blood circulation, thus revealing its novel role in the tumor stroma during tumor progression.

4-1BB immunotherapy: advances and hurdles.

Since its initial description 35 years ago as an inducible molecule expressed in cytotoxic and helper T cells, 4-1BB has emerged as a crucial receptor in T-cell-mediated immune functions. Numerous studies have demonstrated the involvement of 4-1BB in infection and tumor immunity. However, the clinical development of 4-1BB agonist antibodies has been impeded by the occurrence of strong adverse events, notably hepatotoxicity, even though these antibodies have exhibited tremendous promise in in vivo tumor models. Efforts are currently underway to develop a new generation of agonist antibodies and recombinant proteins with modified effector functions that can harness the potent T-cell modulation properties of 4-1BB while mitigating adverse effects. In this review, we briefly examine the role of 4-1BB in T-cell biology, explore its clinical applications, and discuss future prospects in the field of 4-1BB agonist immunotherapy.

Potential therapies for obesity management: Exploring novel frontiers.

Humans are becoming less active in the current age of technological advancement, which leads to poor health. Many factors, including unregulated diet, lack of exercise, environmental pollution and genetic factors are contributing to an increase in overweight. Obesity is a chronic condition that disturbs the physical health of a person, resulting in various other complications including cardiac, respiratory, and psychosocial issues. According to WHO, the current trend of obesity has shown a sharp increase in recent years. Methods ranging from as simple as regulating the diet to as complex as surgery are available. There are many approved drugs to treat the obesity majority of them works as suppressing the appetite and making the patient satisfy. Some of other agents works by insulinotropic activity. However, these agents need to be taken for longer period of time thus are associated with significant adverse drug reactions. Thus, the motive of this study is to understand obesity and the various methods available to manage it using the recent pharmacological and non-pharmacological approaches.