SALTT study: A retrospective analysis of 111 SAlivary gland tumors of Lung and Tracheobronchial Tree.

INTRODUCTION: Primary pulmonary salivary gland-type tumours (PPSGT) are rare lung neoplasms arising from submucosal seromucinous glands in the central airway. METHODS AND RESULTS: We retrospectively analysed the clinicopathological features of 111 PPSGTs diagnosed at our institute between 2003 and 2021. The mean age at diagnosis was 43.8 years(range 6-78 years) and a male-to-female ratio of 2:1. On imaging, 92 % of cases had centrally located tumours and 37.3 % were early stage. The histopathological types included 70 cases (63 %) of mucoepidermoid carcinoma (MEC), 31 cases (27.7 %) of adenoid cystic carcinoma (ADCC), two cases of myoepithelial carcinoma, one case each of acinic cell carcinoma (ACC), clear cell carcinoma (CCC), epithelial myoepithelial carcinoma (EMC) and 5 others [including adenocarcinoma of minor salivary gland origin(n = 3), carcinoma with sebaceous differentiation(n = 1) and poorly differentiated carcinoma of salivary gland type(n = 1)]. The size of the tumours found in the resection specimens ranged from 1 cm to 13 cm, with an average size of 4.9 cm. High-risk attributes such as lymphovascular invasion (LVI), perineural invasion (PNI), pleural involvement, positive resection margins, and nodal metastasis were identified in 15.3 %, 15.3 %, 13.6 %,15.2 % and 6.7 % of cases, respectively. These attributes were found to be more frequent in ADCC than in MEC. Surgery was the main treatment modality [68/84 (80 %) cases]. ADCC cases had more recurrence and distant metastasis than MEC cases. The 3- year overall-survival (OS) and recurrence-free survival(RFS) were better in patients with age lesser than 60 years(p-value <0.0001), low pT stage (p-value 0.00038) and lower grade of MEC(p-value-0.0067). CONCLUSION: It is crucial to have an acquaintance with the morphologic spectrum and immunophenotypic characteristics of PPSGT to recognize them in this unusual location. In tandem, it is crucial to differentiate them from conventional primary non-small cell lung carcinoma, as the management protocols and prognostic implications differ significantly.

Changes in an enzyme ensemble during catalysis observed by high-resolution XFEL crystallography.

Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser to observe catalysis in a designed mutant isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations, and formation of the thioimidate intermediate selects for catalytically competent substates. The influence of cysteine ionization on the ICH ensemble is validated by determining structures of the enzyme at multiple pH values. Large molecular dynamics simulations in crystallo and time-resolved electron density maps show that Asp17 ionizes during catalysis and causes conformational changes that propagate across the dimer, permitting water to enter the active site for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.

Clinical Utility of Stepwise Bronchoalveolar Lavage Fluid Analysis in Diagnosing and Managing Lung Infiltrates in Leukemia/Lymphoma Patients With Febrile Neutropenia.

PURPOSE: Febrile neutropenia (FN) is a serious complication in hematologic malignancies, and lung infiltrates (LIs) remain a significant concern. An accurate microbiological diagnosis is crucial but difficult to establish. To address this, we analyzed the utility of a standardized method for performing bronchoalveolar lavage (BAL) along with a two-step strategy for the analysis of BAL fluid. PATIENTS AND METHODS: This prospective observational study was conducted at a tertiary cancer center from November 2018 to June 2020. Patients age 15 years and older with confirmed leukemia or lymphomas undergoing chemotherapy, with presence of FN, and LIs observed on imaging were enrolled. RESULTS: Among the 122 enrolled patients, successful BAL was performed in 83.6% of cases. The study used a two-step analysis of BAL fluid, resulting in a diagnostic yield of 74.5%. Furthermore, antimicrobial therapy was modified in 63.9% of patients on the basis of BAL reports, and this population demonstrated a higher response rate (63% v 45%; P = .063). CONCLUSION: Our study demonstrates that a two-step BAL fluid analysis is safe and clinically beneficial to establish an accurate microbiological diagnosis. Given the crucial impact of diagnostic delays on mortality in hematologic malignancy patients with FN, early BAL studies should be performed to enable prompt and specific diagnosis, allowing for appropriate treatment modifications.

Treatment Response to Neoadjuvant Therapy in Squamous Esophageal Cancer-Correlation Between Metabolic Response and Histopathology.

PURPOSE: Esophageal cancer is among the leading causes of cancer-related mortality worldwide. Patients presenting with localized and loco-regionally advanced cancer without distant metastases have reasonable survival with multimodality management. Adequate and comprehensive staging is the backbone for proper selection of patients fit for curative treatment. Positron emission tomography (PET) in combination with contrast-enhanced computed tomography (CECT) is utilized as the standard staging modality. Multimodality treatment has been able to achieve evaluable tumor responses including pathological complete response (pCR). It is, therefore, necessary to understand whether the impact of neoadjuvant therapy can be evaluated on imaging, i.e., standardized uptake value (SUV) on PET scan done for response assessment and if this can be correlated with histopathological response and later, with survival. Squamous cell carcinoma (SCC) is more common globally and in the Indian subcontinent; hence, we chose this subgroup to evaluate our hypothesis. METHODS: This is a single institution, retrospective study. Out of the 1967 patients who were treated between 2009 and 2019, 1369 (78.54%) patients had SCC. Out of these, 44 received NACTRT, whereas 1325 received NACT followed by curative surgery. The standardized uptake value (SUV) of 18-fluorodeoxyglucose was recorded during pre- and post-neoadjuvant treatment (NAT) using positron emission tomography (PET). The histopathology of the final resection specimen was evaluated using the Mandard tumor regression grade (TRG) criteria with response being graded from 0 to 5 as no residual tumor (NRT), scanty residual tumor (SRT), and residual tumor We attempted to find a cut-off value of the post neoadjuvant SUV of the primary tumor site which correlated with achievement of better histopathological response. RESULTS: Out of 1325 patients of SCC esophagus who underwent surgery, 943 patients had available data of TRG, and it was categorized into the 0-2 category which had 325 patients (34.5%) and 3-5 category, 618 patients (65.5%). The SUV was taken only from the PET scans done at our institution, so as to achieve a more homogenous cohort, and this was available for 186 patients, 151 from the NACT group and 35 from the NACTRT group. The ROC method was used to find the cut-off for SUV (5.05) in the NACT cohort, which depicted significant difference in the outcome. Out of these, 93 patients who underwent NACT had SUV > 5.05 and 58 had SUV < 5.05. It was found that the subjective and objective histopathological scores correlated at a p value of < 0.0001. Specifically, the majority of cases with SRT tended to be in the 3-5 category of TRG, whereas cases with NRT are predominantly in the 0-2 category. In the ≥ 5.05 category of SUV, there were 76 cases with SRT. In the NACT cohort, the < 5.05 category of SUV, there are 26 cases with SRT and 32 cases with NRT. Among cases with SRT, 74.5% had SUV ≥ 5.05, while 25.5% had SUV < 5.05. Among cases with NRT, 34.7% had SUV ≥ 5.05, while 65.3% had SUV < 5.05 (p value 0.007). No significant association was found in the radio-pathological correlation in the NACTRT group. CONCLUSION: Our study confirms the correlation of post neoadjuvant chemotherapy PET SUV with histopathological response, the cut-off of SUV being 5.05 in our cohort. This confirms the predictive value of FDG PET as demonstrated in other studies. Furthermore, its prognostic value with respect to survival has been verified in multiple other studies. With larger scale randomized studies, we may be able to identify the group of patients who have borderline operability anatomically as well as physiologically, where alternative treatment regimens may be indicated to improve outcomes.

Changes in an Enzyme Ensemble During Catalysis Observed by High Resolution XFEL Crystallography.

Enzymes populate ensembles of structures with intrinsically different catalytic proficiencies that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography (MISC) at an X-ray free electron laser (XFEL) to observe catalysis in a designed mutant (G150T) isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations and formation of the thioimidate catalytic intermediate selects for catalytically competent substates. A prior proposal for active site cysteine charge-coupled conformational changes in ICH is validated by determining structures of the enzyme over a range of pH values. A combination of large molecular dynamics simulations of the enzyme in crystallo and time-resolved electron density maps shows that ionization of the general acid Asp17 during catalysis causes additional conformational changes that propagate across the dimer interface, connecting the two active sites. These ionization-linked changes in the ICH conformational ensemble permit water to enter the active site in a location that is poised for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.

Anti-amyloidogenic amphipathic arginine-dehydrophenylalanine spheres capped selenium nanoparticles as potent therapeutic moieties for Alzheimer's disease.

Aggregation of both amyloid beta (Aß) peptide and hyperphosphorylated tau proteins is the major pathological hallmark of Alzheimer's disease (AD). Moieties that carry anti-amyloidogenic potency against both of the aggregating entities are considered to be promising drug candidatures for the disease. In the current work, we have synthesized amphipathic dipeptide vesicle-templated selenium nanoparticles (RΔF-SeNPs) as potential entities to combat AD. We have investigated and established their anti-amyloidogenic activity against different peptide-based amyloid models, such as the reductionist model based on the dipeptide phenylalanine-phenylalanine (FF) derived from Aß; a model based on the hexapeptide Ac-PHF6 (306VQIVYK311) derived from tau protein; and the full-length Aß42 polypeptide-based model. We also evaluated the neuroprotective characteristics of RΔF-SeNPs against FF, Ac-PHF6, and Aß42 fibril-induced toxicity in neuroblastoma, SH-SY5Y cells. RΔF-SeNPs further exhibited neuroprotective effects in streptozotocin (STZ) treated neuronal (N2a) cells carrying AD-like features. In addition, studies conducted in an intra-cerebroventricular STZ-instigated rat model of dementia revealed that RΔF-SeNP-treated animals showed improved cognitive activity and reduced Aß42 aggregate burden in brain tissues as compared with the STZ-treated group. Moreover, in vivo brain distribution studies conducted in animal models additionally demonstrated the brain-homing ability of RΔF-SeNPs. All together, these studies supported the potency of RΔF-SeNPs as efficient and propitious disease-modifying therapeutic agents for combating AD.

Caffeine improves memory and cognition via modulating neural progenitor cell survival and decreasing oxidative stress in Alzheimer's rat model.

AIMS: Caffeine possesses potent antioxidant, anti-inflammatory and anti-apoptotic activities against a variety of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). The goal of this study was to investigate the protective role of a psychoactive substance like caffeine on hippocampal neurogenesis and memory functions in streptozotocin (STZ)-induced neurodegeneration in rats. BACKGROUND: Caffeine is a natural CNS stimulant, belonging to the methylxanthine class, and is a widely consumed psychoactive substance. It is reported to abate the risk of various abnormalities that are cardiovascular system (CVS) related, cancer related, or due to metabolism dysregulation. Short-term caffeine exposure has been widely evaluated, but its chronic exposure is less explored and pursued. Several studies suggest a devastating role of caffeine in neurodegenerative disorders. However, the protective role of caffeine on neurodegeneration is still unclear. OBJECTIVE: Here, we examined the effects of chronic caffeine administration on hippocampal neurogenesis in intracerebroventricular STZ injection induced memory dysfunction in rats. The chronic effect of caffeine on proliferation and neuronal fate determination of hippocampal neurons was evaluated by co-labeling of neurons by thymidine analogue BrdU that labels new born cells, DCX (a marker for immature neurons) and NeuN that labels mature neurons. METHOD: STZ (1 mg/kg, 2 µl) was injected stereotaxically into the lateral ventricles (intracerebroventricular injection) once on day 1, followed by chronic treatment with caffeine (10 mg/kg, i.p) and donepezil (5 mg/kg, i.p.). Protective effect of caffeine on cognitive impairment and adult hippocampal neurogenesis was evaluated. RESULT: Our findings show decreased oxidative stress burden and amyloid burden following caffeine administration in STZ lesioned SD rats. Further, double immunolabeling with bromodeoxyuridine+/doublecortin+ (BrdU+/DCX+) and bromodeoxyuridine+/ neuronal nuclei+ (BrdU+/NeuN+) has indicated that caffeine improved neuronal stem cell proliferation and long term survival in STZ lesioned rats. CONCLUSION: Our findings support the neurogenic potential of caffeine in STZ induced neurodegeneration.

Robotic esophagectomy and 3-field lymphadenectomy with intraoperative nerve monitoring.

The standard of care for esophageal malignancies has evolved over the years from open transthoracic esophagectomy to a minimally invasive approach due to the reduction in surgical trauma and significant impact on postoperative outcomes. Minimally invasive approaches include video-assisted thoracoscopic surgery and robot-assisted thoracoscopic surgery. These minimally invasive approaches have an attendant learning curve that early-career surgeons are required to negotiate before achieving proficiency in the procedure. Recurrent laryngeal nerve injury is a particularly significant problem, especially in the presence of enlarged supracarinal lymph nodes, which mandate a 3-field lymphadenectomy. With technological advances and the use of intraoperative nerve monitoring, iatrogenic nerve injury can at best be avoided or at least be recognized, and corrective measures can be undertaken to reduce postoperative morbidity. In this video tutorial, we demonstrate a standard robot-assisted esophagectomy and a 3-field lymphadenectomy with the use of intraoperative nerve monitoring followed by an esophagogastric anastomosis with the triangulating stapling technique.

Angiotensin-Converting Enzyme 2 Activation Mitigates Behavioral Deficits and Neuroinflammatory Burden in 6-OHDA Induced Experimental Models of Parkinson's Disease.

Hypertension is reported to cause major brain disorders including Parkinson's disease (PD), apart from cardiovascular and chronic kidney disorders. Considering this, for the first time, we explored the effect of modulation of the ACE2/Ang (1-7)/MasR axis using diminazene aceturate (DIZE), an ACE2 activator, in 6-hydroxydopamine (6-OHDA) induced PD model. We found that DIZE treatment improved neuromuscular coordination and locomotor deficits in the 6-OHDA induced PD rat model. Further, the DIZE-mediated activation of ACE2 led to increased tyrosine hydroxylase (TH) and dopamine transporters (DAT) expression in the rat brain, indicating the protection of dopaminergic (DAergic) neurons from 6-OHDA induced neurotoxicity. Moreover, 6-OHDA induced activation of glial cells (astrocytes and microglia) and release of neuroinflammatory mediators were attenuated by DIZE treatment in both in vitro as well as in vivo models of PD. DIZE exerted its effect by activating ACE2 that produced Ang (1-7), a neuroprotective peptide. Ang (1-7) conferred its neuroprotective effect upon binding with the G-protein-coupled MAS receptor that led to the upregulation of cell survival proteins while downregulating apoptotic proteins. Importantly, these findings were further validated by using A-779, a MasR antagonist. The result showed that treatment with A-779 reversed the antioxidative and anti-inflammatory effects of DIZE by decreasing glial activation and neuroinflammatory markers. Although the role of ACE2 in PD pathology needs to be additionally confirmed using transgenic models in either ACE2 overexpressing or knockout mice, still, our study demonstrates that enhancing ACE2 activity could be a novel approach for ameliorating PD pathology.

Isoformononetin, a dietary isoflavone protects against streptozotocin induced rat model of neuroinflammation through inhibition of NLRP3/ASC/IL-1 axis activation.

AIMS: Isoformononetin (IFN), a methoxyl isoflavone present in most of human dietary supplements. However, being a highly potent antioxidant and anti-inflammatory molecule, its activity against neuronal oxidative stress and neuroinflammation has not been explored till now. The present study was inquested to assess the antioxidant, anti-apoptotic and anti-inflammatory activity of IFN against streptozotocin induced neuroinflammation in different brain regions of rat. MAIN METHODS: Four groups of animals were subjected to treatment as control, toxic control (STZ; single intracerebrovascular injection), third group (STZ + IFN; 20 mg/kg p.o.), fourth group (IFN) for 14 days. The different brain regions of rats were evaluated for inflammatory, apoptotic and biochemical antioxidant markers. The brain tissues were further assessed for gene expression, immunohistochemical and western blotting examination for localization of inflammasome cascade expression that plays a pivotal role in neuroinflammation. KEY FINDINGS: The modulation in oxidant/antioxidant status after exposure of STZ was significantly balanced after administration of IFN to rats. Further, IFN was also found to be an apoptotic agent as it modulates the apoptotic gene (Bax) and anti-apoptotic gene (BcL2) expression. IFN significantly curtailed the augmented protein expression of NLRP3, NLRP2, ASC, NFκBP65, IL-1ß and caspase-1 due to STZ administration in cortex and hippocampus rat brain regions. SIGNIFICANCE: The aforementioned results proclaim the neuroprotective functioning of IFN against STZ induced inflammation. IFN significantly prevents the neuroinflammation by decreasing the generation of ROS that reduces the activation of NLRP3/ASC/IL-1 axis thereby exerting neuroprotection as evidenced in rat model of STZ induced neuroninflammation.

Video-assisted mediastinoscopic lymphadenectomy (VAMLA): A video vignette.

Mediastinal staging in potentially resectable non-small cell lung cancer is of paramount importance since it impacts the survival of the patient. With increasing nodal stage, survival was noted to precipitously decline. Nodal status also determined the use of neoadjuvant/adjuvant therapy and other treatment modalities. Various methods of obtaining lymphatic tissue from the mediastinum for staging purposes have been described in the literature, although mediastinoscopic lymph node evaluation remains the gold standard. Endoscopic methods of mediastinal staging, like the endobronchial ultrasound guided and esophageal ultrasound guided fine-needle aspiration techniques, although minimally invasive, provide the highest levels of accuracy when used in conjunction with surgical mediastinal staging. Video-assisted mediastinoscopic lymphadenectomy (VAMLA) provides clear advantages, as far as ergonomics and training are concerned, over conventional mediastinoscopy. Access to stations 2R, 2L, 4R, 4L, and 7 is feasible with VAMLA. In this video vignette, we present the step-by-step technique of a standard VAMLA, with an overview of relevant anatomical relationships, for the effective and safe clearance of lymph node stations for the purposes of staging and defining appropriate therapy.

Uniportal VATS left lower lobectomy: Fissure first technique.

This video tutorial describes a left lower lobectomy performed by the uniportal approach. A single 2-cm incision in the lateral chest wall is used as the utility port. The procedure begins with division of the inferior pulmonary ligament and isolation of the inferior pulmonary vein. This patient has densely adherent interlobar nodes, which are then dissected to demonstrate the interlobar pulmonary artery. Then we proceed to divide the anterior part of the fissure after identifying and safeguarding the lingular branches of the pulmonary artery. This step is followed by the division of the posterior part of the fissure after identification of the posterior branches of the pulmonary artery to the upper lobe. Then we identify the basilar trunk and divide it using endostaplers. Other branches of the interlobar artery are clearly identified, and the apicobasal artery is taken separately. This is followed by division of the inferior pulmonary vein and a systematic mediastinal nodal dissection.

COVID-19 Pandemic and Its Gendered Impact on Indian Physicians.

PURPOSE: The 2018 WHO health workforce report analyzing gender equity in 104 countries reported that although women constituted 70% of the workers, they were less likely to be employed full-time and faced a 28% gender pay gap. The ongoing COVID-19 pandemic has affected professional as well as personal lives of physicians. We conducted a survey among Indian physicians to understand this impact. METHODS: A 31-point anonymized survey to evaluate the impact of the COVID-19 pandemic and resultant lockdown on physicians' domestic responsibilities was disseminated via e-mail and text messaging applications. Our aim was to evaluate whether the impact was gender-based and to look for differences in aspects of domestic work, childcare, and professional commitments. RESULTS: We obtained 1,041 responses, of which 643 identified themselves as men and 393 as women. An increase in the domestic responsibilities during the lockdown was confirmed by 90% of the women compared with 82% men. More women than men were solely responsible for domestic chores (38.7% v 23.7%), managed their children's education (74% v 31%), and felt an adverse impact of the pandemic on their professional work (60.8% v 42.6%). Fewer women's spouses (57/359) than men's (174/594, P = .00001) were forced to take leave or work reduced hours, and double the proportion of women (3.5% v 1.5%) had to quit their jobs to manage responsibilities at home. CONCLUSION: As the COVID-19 pandemic and the lockdown measures threw newer challenges, more women physicians than men (81% v 63%) shouldered the burden of increased domestic work and childcare. This survey highlights the need to re-examine the specific challenges faced by women physicians and identify means to support and empower them.

Fluorescent Dopamine-Tryptophan Nanocomposites as Dual-Imaging and Antiaggregation Agents: New Generation of Amyloid Theranostics with Trimeric Effects.

The aggregation of neurotoxic amyloid-ß (Aß) polypeptides into aberrant extracellular senile plaques is the major neuropathological hallmark of Alzheimer's disease (AD). Inhibiting aggregation of these peptides to control the progression of this deadly disease can serve as a viable therapeutic option. In the current work, inherently fluorescent theranostic dopamine-tryptophan nanocomposites (DTNPs) were developed and investigated for their amyloid inhibition propensity along with their ability to act as a cellular bioimaging agent in neuronal cells. The antiaggregation potency of the nanocomposites was further investigated against an in vitro established reductionist amyloid aggregation model consisting of a mere dipeptide, phenylalanine-phenylalanine (FF). As opposed to large peptide/protein-derived robust and high-molecular-weight amyloid aggregation models of Alzheimer's disease, our dipeptide-based amyloid model provides an edge over others in terms of the ease of handling, synthesis, and cost-effectiveness. Results demonstrated positive antiaggregation behavior of the DTNPs toward both FF-derived amyloid fibrils and preformed Aß-peptide fibers by means of electron microscopic and circular dichroism-based studies. Our results further pointed toward the neuroprotective effects of the DTNPs in neuroblastoma cells against FF amyloid fibril-induced toxicity and also that they significantly suppressed the accumulation of Aß42 oligomers in both cortex and hippocampus regions and improved cognitive impairment in an intracerebroventricular streptozotocin (ICV-STZ)-induced animal model of dementia. Besides, DTNPs also exhibited excellent fluorescent properties and light up the cytoplasm of neuroblastoma cells when being coincubated with cells, confirming their ability to serve as an intracellular bioimaging agent. Overall, these results signify the potency of the DTNPs as promising multifunctional theranostic agents for treating AD.

Mechanistic exploration of quercetin against metronidazole induced neurotoxicity in rats: Possible role of nitric oxide isoforms and inflammatory cytokines.

AIM: Metronidazole, a nitroimidazole derived antibiotic used to treat many bacterial infections, is reported to penetrate the blood brain barrier after long term administration resulting into neuronal toxicity. Further, quercetin, a polyphenol flavonoid is reported to exhibit neuroprotective activity but its pharmacodynamics interaction against metronidazole induced neurotoxicity. Therefore, the present study was designed to evaluate the postulated mechanism of metronidazole induced neurotoxicity and potential neuroprotective role of quercetin. MAIN METHODS: Animals (Sprague Dawley) rats were randomly divided into five groups such as control, metronidazole (135 mg/kg), quercetin (100 mg/kg), metronidazole (135 mg/kg) + quercetin (50 mg/kg), and metronidazole (135 mg/kg) + quercetin (100 mg/kg). The brain tissues were evaluated for tissue cyclo-oxygenase, lipoxygenase, nitrite levels, inflammatory and antioxidant biomarkers. The brain tissues were further scrutinized histopathologically for neuronal degeneration. Western blotting analysis was performed for the localization of protein expression for Bax, Bcl2, iNOS, eNOS and caspase-3. KEY FINDINGS: The metronidazole significantly alters the antioxidant levels, inflammatory mediators and morphological changes in the brain tissue. Metronidazole also induces iNOS, Bax and caspase 3 protein expressions whilst decreases the expression of Bcl2 and eNOS in the brain tissue. Metronidazole administration causes a momentous increase in tissue inflammatory markers. SIGNIFICANCE: The metronidazole (oral) administration causes remarkably neurotoxicity effects and the same could be attributed to the fact that metronidazole has the ability to cross the blood brain barrier and transforms the enzymatic activity of various biomarkers present in the brain. From the results, it could be hypothesized that metronidazole causes neurotoxicity by hindering the proportion of antioxidants in the brain tissue and inducing nitric oxide synthesis along with apoptosis. However, quercetin demonstrated a significant protective effect on neuronal toxicity precipitated through metronidazole.

Controversies in preoperative therapy in esophageal cancer: Current evidence and ongoing research.

Esophageal cancer incidence is growing worldwide, especially adenocarcinomas in the western world. Outcomes overall are universally poor, with the best survival seen in earlier stages of the disease, where surgery is the mainstay of treatment. Although squamous cell cancers and adenocarcinomas of the esophagus have different etiology, clinical features, biological behavior and prognosis, earlier research studies have frequently combined the two histologies. Several trials in the past three decades have been carried out in the neoadjuvant, adjuvant and perioperative settings in attempts to improve survival further. Most of the initial studies were small and underpowered, and showed no benefit with neoadjuvant or adjuvant treatment over surgery alone. More recent well-designed trials have now established that the neoadjuvant (in squamous and adenocarcinomas) and the perioperative (in adenocarcinomas) strategies result in superior outcomes compared to surgery alone. However, the optimum neoadjuvant strategy has still not been identified, with both neoadjuvant chemotherapy and chemoradiotherapy (both followed by surgery) showing superior outcomes over surgery alone. Direct comparisons of these two neoadjuvant protocols have not shown a clear benefit of one over the other, although more trials are ongoing and may settle this debate. Future studies using personalized medicine and immunotherapy are required to evaluate their role in the management of esophageal cancers.

Mix-and-inject XFEL crystallography reveals gated conformational dynamics during enzyme catalysis.

How changes in enzyme structure and dynamics facilitate passage along the reaction coordinate is a fundamental unanswered question. Here, we use time-resolved mix-and-inject serial crystallography (MISC) at an X-ray free electron laser (XFEL), ambient-temperature X-ray crystallography, computer simulations, and enzyme kinetics to characterize how covalent catalysis modulates isocyanide hydratase (ICH) conformational dynamics throughout its catalytic cycle. We visualize this previously hypothetical reaction mechanism, directly observing formation of a thioimidate covalent intermediate in ICH microcrystals during catalysis. ICH exhibits a concerted helical displacement upon active-site cysteine modification that is gated by changes in hydrogen bond strength between the cysteine thiolate and the backbone amide of the highly strained Ile152 residue. These catalysis-activated motions permit water entry into the ICH active site for intermediate hydrolysis. Mutations at a Gly residue (Gly150) that modulate helical mobility reduce ICH catalytic turnover and alter its pre-steady-state kinetic behavior, establishing that helical mobility is important for ICH catalytic efficiency. These results demonstrate that MISC can capture otherwise elusive aspects of enzyme mechanism and dynamics in microcrystalline samples, resolving long-standing questions about the connection between nonequilibrium protein motions and enzyme catalysis.

Prospective Evaluation of Surgical Outcome After Transoral CO2 Laser Resection of Potentially Malignant and Early Oral Malignancy.

A prospective observational study was done at the Regional Cancer Centre, Thiruvananthapuram, a tertiary referral center for cancer care in India with an aim to assess the surgical outcomes of CO2 laser resection of oral lesions in terms of operative time, blood loss, hospital stay, postoperative pain, time to re-epithelization, pathological margins achieved and the postoperative scar. The excision was performed in 30 patients with a diagnosis of either potentially malignant lesions (leucoplakia, erythroplakia) or early cancers, i.e., carcinoma in situ or T1/T2 squamous cell carcinoma of the anterior oral cavity (tongue, buccal mucosa), adhering to standard oncological principles, and the resultant defect was left for secondary healing.

Population dynamics and reproductive biology of Barilius bendelisis (Cyprinidae: Cypriniformes) from river Gaula, Central Indian Himalaya / Dinámica poblacional y biología reproductiva de Barilius bendelisis (Cyprinidae: Cypriniformes) en el río Gaula del Himalaya Central, India

Abstract:The Indian hill trout cyprinid, Barilius bendelisis is a member of family Cyprinidae that dwells in shallow, cold, and clear water. In this study, growth parameters and reproductive biology of Indian hill trout, Barilius bendelisis from river Gaula, Central Himalaya region, India, were studied. The length-frequency data were grouped sex wise and were analyzed to determine the growth and mortality parameters using the computer software programme, FAO-ICLARM Stock Assessment Tool (FISAT II). Altogether, 501 individuals were collected from river Gaula (November 2013-October 2014) and were preserved in formalin for further analysis. The results showed that the female outnumbered the male population. The minimum GSI of females was observed in the month of October (4.93 ± 0.26) and for males in the month of June and July (0.093 ± 0.12), whereas, the maximum value was in the month of April for both females (13.47 ± 0.52) and males (1.21 ± 0.12). Fluctuation in GSI values had a bimodal pattern showing two peaks during March-May and August-September in both the sexes, indicating the common spawning period of fish. The slope of regression showed the negative allometric growth for both males and females (b= 2.65 for male and b= 2.5 for female). A significant relationship between length and weight was observed in the present study (p < 0.05). The ELEFAN-I estimated L∞ and K of the von Bertalanffy growth factor for males (17.33 cm and 0.310 per year), females (17.33 cm and 0.3 per year) and pooled sexes (17.33 cm and 0.240 per year). The results indicated that Barilius bendelisis is a small sized fish having negative allometric growth that spawns twice a year. Thus, the present study on biological traits represents the baseline information for effective production, conservation and restoration planning. Rev. Biol. Trop. 64 (3): 1287-1295. Epub 2016 September 01.

ResumenBarilius bendelisis es un miembro de la familia Cyprinidae que habita en agua superficial, fría y clara. En esta investigación se estudiaron los parámetros de crecimiento y la biología reproductiva de Barilius bendelisism en el río Gaula, Himalaya Central, India. Los datos talla-frecuencia fueron agrupados por sexo, y analizados para determinar parámetros de crecimiento y mortalidad usando el programa de computador, FAO-ICLARM Stock Asseessment Toll (FISAT II). En total, 501 individuos fueron recolectados en el río Gaula (Noviembre 2013-Octubre 2014) y fueron preservados en formalina para futuros análisis. Los resultados mostraron que la población de hembras supera en número la población de machos. El GSI mínimo en hembras fue observado en octubre (4.93 ± 0.26) y en machos en Junio y Julio (0.093 ± 0.12), mientras, el valor máximo en abril para ambos, hembras (13.47 ± 0.52) y machos (1.21 ± 0.12). La fluctuación en los valores del GSI tenía un patrón bimodal mostrando dos picos durante Marzo-Macho y Agosto-Septiembre en ambos sexos, indicando el periodo de desove común del pez. La pendiente de regresión muestra crecimiento alométrico negativo tanto para machos como para hembras (b= 2.65 para machos y b= 2.5 para hembras). Se observó una significativa relación entre talla y peso en el presente estudio (p < 0.05). El ELEFAN-I estimó L∞ y K del factor de crecimiento von Bertalanffy para machos (17. 33 cm y 0.310 por año), hembras (17.33 cm y 0.3 por año) y sexos combinados (17.33 cm y 0.240 por año). Los resultados indicaron que Barilius bendelisis es un pez de talla pequeña con un crecimiento alométrico negativo que desova dos veces al año. Además, el presente estudio de rasgos biológicos representa la información de base para la efectiva producción, conservación y planeamiento de la restauración.