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BACKGROUND: Hydatid disease is a zoonotic parasitic infection, endemic in many livestock-rearing regions, and remains a significant health concern. We report our experience managing childhood bilateral pulmonary hydatid cysts and discuss management strategies. METHODS: This was a retrospective analysis of data from the cohort of hydatid patients treated over a period of 5 years from January 2020 to December 2024. The care records were reviewed and data on clinical and radiological presentations were studied. The anesthesia and surgical management and intraoperative events were also recorded. The perioperative complications and hospital stay were studied, along with postoperative pharmacotherapy and recurrence. These patients were followed up for a minimum of 12 months. RESULTS: Out of 52 patients diagnosed with hydatid, 9 (aged 4-12 years, 66.7% male) were treated for bilateral hydatid lung. Cough was the commonest symptom, followed by fever and hemoptysis. The number of cysts ranged from one to three on either side. The cohort had low complication rates, with 88.9% avoiding major intraoperative spillage. Major intraoperative complications occurred in one patient, with one patient experiencing a mild postoperative air leak. Single-stage surgeries significantly reduced hospital stays (p = 0.049) and surgery duration per session (p = 0.013). Complication predictors, including liver involvement, cyst number, and diameter, were comparable. A follow-up between 12 and 60 months revealed recurrence in one patient on one side. CONCLUSION: Surgery remains the definitive treatment for bilateral pulmonary hydatid cysts in children. Single-stage approaches are effective in reducing hospitalization times, while postoperative medical therapy ensures low recurrence rates. Conservative methods prioritizing parenchymal preservation should remain the cornerstone of surgical management.
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Equinococose Pulmonar , Humanos , Equinococose Pulmonar/cirurgia , Equinococose Pulmonar/diagnóstico , Masculino , Criança , Pré-Escolar , Estudos Retrospectivos , Feminino , Complicações Pós-Operatórias/epidemiologia , Resultado do Tratamento , Seguimentos , Tempo de Internação/estatística & dados numéricosRESUMO
Dysregulation of DNA damage repair pathways and miRNA-mediated control play crucial targets in breast cancer therapeutics, highlighting the need for novel multi-targeted therapeutic agents. In this study, the druggability properties and biological activity of structurally distinct phytochemicals, Flavonoids (F), and Nitrogen-containing heterocyclic-compounds (N) on the DNA repair checkpoint sensor genes (MRN complex), miR-2909 expression, ROS, and cell cycle analysis in breast cancer cell models (MDA-MB-231 and MCF-7) were investigated and compared against the FDA-approved anticancer agent Palbociclib (P). Both compound classes significantly inhibited breast cancer cell proliferation, with nitrogen-containing heterocyclics showing superior cytotoxicity. Cell Cycle analyses revealed G0-G1 phase arrest upon treatment with N-compounds, while F-compounds induced Sub-G1 enrichment. N-compounds triggered greater ROS levels in the MDA-MB-231 cells than F-compounds, which showed greater ROS levels in MCF-7 cells. Similarly, DNA repair genes expression [MRN complex (MRE11, RAD50, NBN)] and miR-2909 expression analysis revealed greater regulation with N-compounds as compared to F-compounds in a cell type-specific manner, as compared to the FDA-approved anticancer agent Palbociclib. Docking simulations further confirmed compounds high-affinity interactions with MRN-complex proteins and mature miR-2909 over Palbociclib. Detailed analysis of compounds and target druggability properties through ADMET studies reflects their drug-likeness, non-mutagenic, and non-carcinogenic profiles to support their therapeutic potential. These findings suggest that phytochemicals, particularly N-compounds over F-compounds, may exert superior anticancer effects by modulating cell cycle, DNA repair markers, oxidative stress, and miR-2909 networks. This study provides a mechanistic basis and preclinical framework for developing F and N-compounds as epigenetic and genomic modulators in breast cancer.
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Neoplasias da Mama , Reparo do DNA , Flavonoides , MicroRNAs , Compostos Fitoquímicos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Feminino , Flavonoides/farmacologia , Flavonoides/química , Linhagem Celular Tumoral , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Proliferação de Células/efeitos dos fármacos , Células MCF-7 , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Piperazinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , PiridinasRESUMO
PURPOSE: Postoperative complications can significantly impact patient outcomes and quality of life, particularly in children with solid tumors. These complications may delay the commencement of adjuvant therapy. This study aimed to evaluate the severity and effects of these complications and to validate the Clavien-Dindo classification system in pediatric patients following surgery for solid tumors. METHODS: A retrospective analysis was conducted on postoperative complications in children with solid tumors at a tertiary care teaching hospital over 5 years. Patient demographics and tumor types were recorded, and complications were categorized using the Clavien-Dindo classification. The study identified key risk factors for complications and their implications for patient care. RESULTS: We included 188 patients, out of which the majority (n = 157; 83.5%) had low-grade (grade 1 or 2) postoperative complications. Higher intraoperative blood loss (p < 0.001), adjacent organ infiltration, and longer operative times were associated with more severe grade of complications. Patients with higher-grade complications also had longer hospital stays (Kendall's Tau coefficient of 0.48). Among the 26 patients with tumor recurrence, 30% had experienced severe complications (grades 3 and 4). The KaplanâMeier curve and log-rank test (p < 0.001) showed that severe complications are linked to a lower survival probability. CONCLUSIONS: The analysis of complications showed a significant effect on short-term surgical outcomes, and severe complications may also impact oncological outcomes. The Clavien-Dindo classification is a useful tool for grading postoperative complications in pediatric surgical oncology. LEVEL OF EVIDENCE: Level III.
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Neoplasias , Complicações Pós-Operatórias , Humanos , Estudos Retrospectivos , Masculino , Feminino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/classificação , Criança , Neoplasias/cirurgia , Pré-Escolar , Lactente , Adolescente , Fatores de Risco , Resultado do TratamentoRESUMO
Bronchial mucoepidermoid carcinoma in children is rare, often presenting with nonspecific respiratory symptoms, causing diagnostic delays. Complete surgical excision is the primary treatment, with excellent outcomes for low-grade tumors. Pediatric considerations include minimizing anastomotic tension and preserving lung function. The prognosis is favorable with low recurrence after R0 resection.
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We present a rare case of a 17-month-old child diagnosed with MS-stage neuroblastoma and associated chronic diarrhea due to elevated vasoactive intestinal peptide (VIP) levels. The unusual occurrence of a VIP-secreting tumor in a patient with MS neuroblastoma is a rare combination, not previously reported in the literature. The patient underwent exploratory laparotomy and excision of the tumor, leading to a significant decline in VIP levels and resolution of symptoms.
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Breast cancer, more prevalent in women, often arises due to abnormalities in the MRN-checkpoint sensor genes (MRN-CSG), responsible for DNA damage detection and repair. Abnormality in this complex is due to the suppression of various effectors such as siRNAs, miRNAs, and transcriptional factors responsible for breast tumor progression. This study analyzed breast tumor samples (n = 60) and identified four common miRNAs (miR-1-3p, miR-210-3p, miR-16-5p, miR-34a-5p) out of 12, exploring their interactions with MRN-CSG. The 3D structures of these miRNA-MRN-CSG complexes displayed strong thermodynamic stability. Screening 7711 natural compounds resulted in two natural compounds (F0870-0001 and F0922-0471) with the lowest ligand binding energies (ΔG = -8.4 to-11.6 kcal/mol), targeting two common miRNAs. Docking results showed that one natural compound (PubChem id-5 281 614) bound to all MRN-CSG components (ΔG = -6.2 to -7.3 kcal/mol), while F6782-0723 bound only to RAD50 and NBN. These compounds exhibited minimal dissociation constants (Kd and Ki) and thermodynamically stable minimum free energy (MMGBSA) values. Molecular dynamics simulations indicated highly stable natural compound-MRN-CSG complexes, with consistent RMSD, RMSF, and strong residual correlation. These top-selected compounds displayed robust intermolecular H-bonding, low carcinogenicity, low toxicity, and drug-like properties. Consequently, these compounds hold promise for regulating miRNA and MRN-CSG DNA repair mechanisms in breast cancer therapy. Insight Box: This study investigated breast tumor samples (n = 60) and identified four miRNAs (miR-1-3p, miR-210-3p, miR-16-5p, miR-34a-5p) that interact with MRN-checkpoint sensor genes (MRN-CSG), crucial for DNA damage repair. Screening 7711 natural compounds highlighted two compounds (F0870-0001 and F0922-0471) with the lowest binding energies (ΔG = -8.4 to -11.6 kcal/mol), targeting two common miRNAs (miR-1-3p and miR-34a-5p). Another natural compound (PubChem id-5 281 614, ΔG = -6.2 to -7.3 kcal/mol) bound all MRN-CSG components, while F6782-0723 targeted RAD50 and NBN. These compounds showed strong binding stability, favorable MMGBSA values, and minimal dissociation constants. Molecular dynamics simulations confirmed the stability and drug-like properties of these compounds, indicating their potential in breast cancer therapy by modulating miRNA and MRN-CSG DNA repair mechanisms.
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Neoplasias da Mama , Reparo do DNA , Proteínas de Ligação a DNA , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Simulação de Acoplamento Molecular , Termodinâmica , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Hidrolases Anidrido Ácido/metabolismo , Regulação Neoplásica da Expressão Gênica , Dano ao DNA , Proteína Homóloga a MRE11/metabolismo , Simulação de Dinâmica Molecular , Pessoa de Meia-Idade , Autoantígeno KuRESUMO
BACKGROUND: Neuroblastoma (NBL), is the most common, non-CNS solid tumor of childhood. This disease presents with unique biological and clinical challenges necessitating accurate diagnosis, prognosis assessment, treatment, and vigilant monitoring. Liquid biopsy is an upcoming, innovative, and non-invasive diagnostic modality. It has the potential to detect tumors and perform therapeutic monitoring through the analysis of circulating biomarkers in blood, urine, saliva, and other bodily fluids. METHODOLOGY: This scoping review offers an in-depth exploration, of the current landscape of liquid biopsy-based biomarkers in NBL. The review looks at the clinical implications, prevalent challenges, and future outlook of their clinical applications in NBL. The scoping review adhered to the guidelines of the PRISMA extension for scoping reviews, known as PRISMA-ScR, as the skeletal framework. The review involved comprehensive searches for liquid biopsy-based biomarkers in NBL across multiple databases, including PUBMED, EMBASE, SCOPUS, and WEB of Science, without restrictions. RESULTS: The scoping review process uncovered a significant body of literature (n = 201) that underwent meticulous scrutiny, ultimately leading to the final selection of studies (n = 15). The liquid biopsy biomarkers included circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and other entities in bodily fluids. Their evaluation focused on associations with clinical outcomes such as overall survival, event-free survival, and risk stratification in NBL. CONCLUSION: Our findings highlight the potential of liquid biopsy biomarkers to revolutionize NBL diagnosis and therapeutic monitoring. This rapidly evolving frontier in pediatric oncology suggests significant advancements in precision medicine for the management of NBL.
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Differential expression patterns of growth factor (EGFR, HER-2) and hormonal (ER, PR) receptors in breast cancer (BC) remain crucial for evaluating and tailoring therapeutic interventions. This study investigates differential expression profiles of hormonal and growth factor receptors in BC patients and across age groups, major subclasses, disease stages and tumor histology and survival rates, the efficacy of emerging clinical trial drugs (Dabrafenib and Palbociclib) and elucidating their molecular interaction mechanisms for efficient therapeutic strategies. Gene and protein expression analysis in the normal vs BC and across age groups and major subclasses reveals divergent patterns as EGFR and HER-2 levels are reduced in tumors versus normal tissue, while ER and PR levels are higher, particularly in luminal subtypes. However, there was no significant difference in survival rates among high and low/medium expression levels of EGFR and PR receptors. Conversely, patients with high HER-2 and ER expression exhibited poorer survival rates compared to low or medium expression levels. The in vitro findings indicate that Dabrafenib exhibits greater effectiveness than Palbociclib in suppressing various BC cells such as MCF-7 (Luminal), MDA-MB-231 (Triple-Negative), SKBR-3 (HER-2 + ) proliferation, promoting cell death, (IC50 of Dab < Pal) at 24 and 48 h, ROS production, and reduced ER and PR, elevated HER-2 with no change in EGFR expression. Molecular simulation studies revealed Dabrafenib's thermodynamically stable interactions (ΔG), tighter binding, and less structural deviation in the order EGFR > HER-2 > ER > PR as compared to Palbociclib (HER-2 > ER > PR = EGFR). These results indicate that Dabrafenib, compared to Palbociclib, more effectively regulates breast cancer cell proliferation through specific interactions with hormonal and growth factor receptors towards a repurposing approach.
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The extensive use of plasticizers in various industries has made Diethyl phthalate (DEP), a serious threat to the environment and ecological water security, owing to its complex-structure and low-biodegradability. Thus, the present study aimed to design a sustainable sand-coated nano glutathione (GSH) -Fe3O4-loaded/activated carbon (AC) bionanocomposite (AC-GSH-Fe3O4@sand bionanocomposite) for effective removal of DEP from water. Characterization results suggested bionanocomposites' rough and irregular texture due to the uneven distribution of AC and Fe3O4 nanoparticles over the sand. The XRD spectra indicated high crystallinity of bionanocomposites, while the FTIR spectra confirmed the presence of all individual components, i.e., GSH, AC, Fe3O4, and sand. EDX-mapping, AFM, and TGA further verified its elemental composition, topographical changes and thermal stability. The inï¬uence of pH (3, 7, 9), bed height (2, 4, 6) cm, and flow rate (2.5, 3.5, 4.5) mL min-1 were studied in a dynamic system with an initial DEP concentration of 50 mg L-1 to investigate the removal behavior of the bionanocomposites. The best DEP removal efficiency (90.18 %) was achieved over 28-h at pH 9, bed-height-4 cm, and flow-rate-3.5 mL min-1, with an optimum qmax-200.25 mg g-1 as determined through Thomas-model. Breakthrough curves were predicted using various column models, and the corresponding parameters essential for column-reactor process design were calculated. The high reusability up to the 10th cycle (≥83.32%) and the effective treatment in complex matrices (tap-water: 90.11 %, river-water: 89.72 %, wastewater: 83.83%) demonstrated bionanocomposites' prominent sustainability. Additionally, the production cost at 6.64 USD per Kg, underscores its potentiality for industrial application. Phytotoxicity assessment on mung-bean revealed better root (5.02 ± 0.27 cm) and shoot (17.64 ± 0.35 cm) growth in the bionanocomposite-treated DEP samples over the untreated samples. Thus, AC-GSH-Fe3O4@sand bionanocomposites could be considered a highly-sustainable, low-cost technique for the effective removal of DEP and other phthalate-esters from contaminated matrices.
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Glutationa , Nanocompostos , Ácidos Ftálicos , Poluentes Químicos da Água , Ácidos Ftálicos/química , Poluentes Químicos da Água/química , Nanocompostos/química , Glutationa/química , Carvão Vegetal/química , Areia/química , Purificação da Água/métodosRESUMO
Introduction: Neuroglioma, a classification encompassing tumors arising from glial cells, exhibits variable aggressiveness and depends on tumor grade and stage. Unraveling the EGFR gene alterations, including amplifications (unaltered), deletions, and missense mutations (altered), is emerging in glioma. However, the precise understanding of emerging EGFR mutations and their role in neuroglioma remains limited. This study aims to identify specific EGFR mutations prevalent in neuroglioma patients and investigate their potential as therapeutic targets using FDA-approved drugs for repurposing approach. Methods: Neuroglioma patient's data were analyzed to identify the various mutations and survival rates. High throughput virtual screening (HTVS) of FDA-approved (1615) drugs using molecular docking and simulation was executed to determine the potential hits. Results: Neuroglioma patient samples (n=4251) analysis reveals 19% EGFR alterations with most missense mutations at V774M in exon 19. The Kaplan-Meier plots show that the overall survival rate was higher in the unaltered group than in the altered group. Docking studies resulted the best hits based on each target's higher docking score, minimum free energy (MMGBSA), minimum kd, ki, and IC50 values. MD simulations and their trajectories show that compounds ZINC000011679756 target unaltered EGFR and ZINC000003978005 targets altered EGFR, whereas ZINC000012503187 (Conivaptan, Benzazepine) and ZINC000068153186 (Dabrafenib, aminopyrimidine) target both the EGFRs. The shortlisted compounds demonstrate favorable residual interactions with their respective targets, forming highly stable complexes. Moreover, these shortlisted compounds have drug- like properties as assessed by ADMET profiling. Conclusion: Therefore, compounds (ZINC000012503187 and ZINC000068153186) can effectively target both the unaltered/altered EGFRs as multi-target therapeutic repurposing drugs towards neuroglioma.
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Emergency endovascular and percutaneous urological interventions encompass various diagnostic and therapeutic procedures to address various genitourinary conditions. These urological interventions are life-saving in addressing complications following biopsy, post-nephrectomy, post-transplant, and post-trauma. Compared to other surgical fields, there are relatively fewer urological emergencies. However, they require prompt radiological diagnosis and urgent interventions. This pictorial essay emphasizes various urological emergencies and urgent interventional management.
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Procedimentos Endovasculares , Doenças Urológicas , Humanos , Doenças Urológicas/diagnóstico por imagem , Doenças Urológicas/terapia , Emergências , Radiografia IntervencionistaRESUMO
Objectives The objective of the study was to identify accurate site of liver biopsy under ultrasound and elastography guidance and compare the shear wave elastography (SWE) and transient elastography (TE) diagnostic accuracy with histopathological correlation. Methods This was a prospective single-center study where patients scheduled for nonfocal liver biopsy were divided into two groups (group U: ultrasound; group E elastography) by sequential nonrandom selection of patients. Elastography was performed before the biopsy and biopsies from the maximum stiffness segment were taken. Results There was no significant difference of intersegmental liver stiffness with mean velocity; however, biopsy segment velocities show significant difference with mean liver stiffness suggestive of heterogenous distribution of fibrosis. The rho ( r ; Spearman's correlation) value between biopsy segments and mean velocities shows excellent correlation. The diagnostic performance of TE was good for fibrosis stages F2, F3, and F4, while SWE was fair for the diagnosis of fibrosis stages F1 and F2 and fairly equal for the diagnosis stages F2 and F3. Area under the curve (AUC) values in differentiating mild (F1) or no fibrosis from significant fibrosis (≥F2) were 95.5 with cutoff value of at least 1.94 m/s. Conclusions The diagnostic performance of SWE is comparable with TE in liver fibrosis staging and monitoring. Fibrosis is heterogeneously distributed in different segments of the right lobe liver. Therefore, elastography at the time of biopsy may help in defining the accurate site for biopsy and improve histopathological yield in detecting liver fibrosis in patients with chronic liver disease. Advances in Knowledge Elastography-guided biopsy is helpful to determine the ideal site of biopsy.
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Breast cancer ranks as one of the most prevalent forms of cancer and stands as the primary global cause of mortality among women. Overexpression of EGFR and ER receptors or their genomic alterations leads to malignant transformation, disease aggression and is linked to poor patient survival outcomes. The clinical breast cancer patient's genomic expression, survival analysis, and computational drug-targeting approaches were used to identify best-hit phytochemicals for therapeutic purposes. Breast cancer patients have genomic alterations in EGFR (4%, n = 5699) and ER (9%, n = 8461), with the highest proportion being missense mutations. No statistically significant difference was observed in the patient survival rates between the altered and unaltered ER groups, unlike EGFR, with the lowest survival rates in the altered group. Computational screening of natural compound libraries (7711) against each EGFR (3POZ) and ER (3ERT) receptor shortlists the best-hit 3 compounds with minimum docking score (ΔG = -7.9 to -10.8), MMGBSA (-40.16 to -51.91 kcal/mol), strong intermolecular H-bonding, drug-like properties with least kd, and ki. MD simulation studies display stable RMSD, RMSF, and good residual correlation of best-hit common compounds (PubChem ID: 5281672 and 5280863) targeting both EGFR and ER receptors. In vitro, studies revealed that these common drugs exhibited a high anti-proliferative effect on MCF-7 and MDA-MB-231 breast cancer cells, with effective IC50 values (15-40 µM) and lower free energy, kd, and ki (5281672 > 5280863 > 5330286) much affecting HEK-293 non-cancerous cells, indicating the safety profile. The experimental and computational correlation studies suggest that the highly expressed EGFR and ER receptors in breast cancer patients having poor survival rates can be effectively targeted with best-hit common potent drugs with a multi-target therapeutic approach. Insight Box: The findings of this study provide valuable insights into the genomic/proteomic data, breast cancer patient's survival analysis, and EGFR and ER receptor variants structural analysis. The genetic alterations analysis of EGFR and ER/ESR1 in breast cancer patients reveals the high frequency of mutation types, which affect patient's survival rate and targeted therapies. The common best-hit compounds affect the cell survival patterns with effective IC50, drug-like properties having lower equilibrium and dissociation constants demonstrating the anti-proliferative effects. This work integrates altered receptor structural analysis, molecular interaction-based simulations, and ADMET properties to illuminate the identified best hits phytochemicals potential efficacy targeting both EGFR and ER receptors, demonstrating a multi-target therapeutic approach.
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Neoplasias da Mama , Flavonas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Taxa de Sobrevida , Proteômica , Células HEK293 , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/uso terapêutico , Pirimidinas/uso terapêutico , Flavonas/uso terapêutico , Simulação de Acoplamento MolecularRESUMO
The study intends to repurpose FDA drugs and investigate the mechanism of (5HT2BR) activation by comprehending inter-residue interactions. The 5HT2BR is a novel thread, and its role in reducing seizures in Dravet syndrome is emerging. The crystal structure (5HT2BR) is a chimera with mutations; hence 3D-structure is modeled (4IB4: 5HT2BRM). The structure is cross-validated to simulate the human receptor using enrichment analysis (ROC: 0.79) and SAVESv6.0. Virtual screening of 2456 approved drugs yielded the best hits that are subjected to MM/GBSA and molecular dynamic (MD) simulations. The 2 top drugs Cabergoline (-53.44 kcal/mol) and Methylergonovine (-40.42 kcal/mol), display strong binding affinity, and ADMET/SAR analysis also suggests their non-mutagenic or non-carcinogenic nature. Methylergonovine has a weaker binding affinity and lower potency than standards [Ergotamine (agonist) and Methysergide (antagonist)] due to its higher Ki (1.32 M) and Kd (6.44 ×10-8 M) values. Compared to standards, Cabergoline has moderate binding affinity and potency [Ki = 0.85 M and Kd = 5.53 × 10-8 M]. The top 2 drugs primarily interact with conserved residues (ASP135, LEU209, GLY221, ALA225, and THR140) as in agonists, unlike the antagonist. The top 2 drugs, upon binding to the 5HT2BRM, modify the helices VI, V, and III and shift the RMSD 2.48 Å and 3.07 Å. LEU209 forms a latch with residues 207-214 (forms a lid) in the 5HT2BRM receptor, which enhances agonist binding and prevents drug escape. Methylergonovine and Cabergoline interact more stongly with ALA225 than the antagonist. The post-MD analysis of Cabergoline suggests a better MM/GBSA value (-89.21 kcal/mol) than Methylergonovine (-63.54 kcal/mol). In this study, Cabergoline and Methylergonovine's agonistic mechanism and solid binding properties suggest their strong role in regulating the 5HT2BR and might target drug-resistant epilepsy.
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Epilepsia , Metilergonovina , Humanos , Cabergolina , Reposicionamento de Medicamentos , Simulação de Dinâmica MolecularRESUMO
Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase involved in the homeostasis of cellular energy. AMPK has developed as an appealing clinical target for the diagnosis of multiple metabolic diseases such as diabetes mellitus, obesity, inflammation, and cancer. Genetic and pharmacological studies indicate that AMPK is needed in response to glucose deficiency, dietary restriction, and increased physical activity for preserving glucose homeostasis. After activation, AMPK influences metabolic mechanisms contributing to enhanced ATP production, thus growing processes that absorb ATP simultaneously. In this review, several natural products have been discussed which enhance the sensitivity of AMPK and alleviate sub complications or different pathways by which such AMPK triggers can be addressed. AMPK Natural products as potential AMPK activators can be developed as alternate pharmacological intervention to reverse metabolic disorders including type 2 diabetes.
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The 5HT2BR, class-A GPCR is a new target, and its significance for seizure reduction in Dravet syndrome is just now gaining interest, suggesting its specific role in epileptic seizure management. Homology modeling of human 5HT2BR (P41595), was performed using a template 4IB4, the modeled structure was cross-validated (stereo chemical hindrance, Ramachandran plot, enrichment analysis) to mimic a closer native structure. Virtual screening (8532 compounds), drug-likeliness, mutagenicity, and carcinogenicity profiling prioritized six compounds for molecular dynamics (500 ns), Rgyr, DCCM. The receptor's C-alpha fluctuation upon bound agonist (6.91 Å), known antagonist (7.03 Å), and LAS 52115629 (5.83 Å) binding varies, leading to receptor stabilization. The residues C-alpha side-chain in active site strongly interacts (hydrogen bonds) with bound agonist (100% interaction: ASP135), known antagonist (95%:ASP135), and LAS 52115629 (100%:ASP135). The Rgyr for receptor-ligand complex, LAS 52115629 (25.68 Å), lies close to bound agonist-Ergotamine, and DCCM analysis also shows strong positive correlations for LAS 52115629 as compared to known drugs. LAS 52115629 is less likely to cause toxicity than known drugs. The structural parameters in the modeled receptor's conserved motifs (DRY, PIF, NPY) were altered for receptor activation upon ligand-binding, which otherwise was in the in-activated state. The ligand (LAS 52115629)-binding further alters the helices-III, V, VI (G-protein bound), and VII, which form potential interacting sites with the receptor and are proven necessary for activating the receptor. Therefore, LAS 52115629 can act as a potential 5HT2BR agonist, targeting drug-resistant epilepsy.Communicated by Ramaswamy H. Sarma.
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Epilepsia Resistente a Medicamentos , Humanos , Ligantes , Estrutura Secundária de Proteína , Simulação de Dinâmica Molecular , Descoberta de Drogas , Sítios de LigaçãoRESUMO
Background and aim: Severe cholangitis secondary to biliary obstruction carries high mortality unless biliary drainage is performed urgently. Owing to various patient-related and logistical issues, bedside biliary drainage is considered a salvage therapeutic option. This study aims to evaluate the safety and efficacy of ultrasonography (USG)-guided biliary drainage at the bedside in patients with severe cholangitis admitted to the intensive care unit (ICU). Materials and methods: A total of 20 patients with severe cholangitis admitted to ICU who underwent bedside percutaneous transhepatic biliary drainage (PTBD) under USG guidance were retrospectively evaluated. Clinical outcomes, details about the PTBD procedure, and complications were recorded and analyzed. Results: Among 20 patients, 13 were male and 7 were female with a mean age of 50.5 years. The most common cause of biliary obstruction was gall bladder malignancy (45%, n = 9) followed by cholangiocarcinoma (25%, n = 5). Left- and right-sided PTBD was performed in 40% (n = 8) and 35% (n = 7) patients, respectively, while 25% (n = 5) of patients underwent bilateral PTBD. The technical success rate was 100%. A total of 65% (n = 13) of patients were discharged from ICU upon improvement while the remaining 35% (n = 7) died despite bedside PTBD. None of the patients had any major procedure-related complications. Conclusions: Ultrsound-guided bedside PTBD seems to be a safe and effective option in critically ill patients with severe cholangitis when shifting of patients is not feasible. How to cite this article: Singh J, Tripathy TP, Patel R, Chandel K. Is Ultrasound-guided Bedside Percutaneous Transhepatic Biliary Drainage Safe and Feasible in Critically Ill Patients with Severe Cholangitis? A Preliminary Single-center Experience. Indian J Crit Care Med 2023;27(1):16-21.
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BACKGROUND: Breast cancer, an emerging global challenge, is evidenced by recent studies of miRNAs involvement in DNA repair gene variants (MRE11, RAD50, and NBN as checkpoint sensor genes (CSG) - MRN-CSG). The identification of various mutations in MRN-CSG and their interactions with miRNAs is still not understood. The emerging studies of miR-2909 involvement in other cancers led us to explore its role as molecular mechanistic marker in breast cancer. MATERIALS AND METHODS: The genomic and proteomic data of MRN-CSG of breast cancer patients (8426 samples) was evaluated to identify the mutation types linked with the patient's survival rate. Additionally, molecular, 3D-structural and functional analysis was performed to identify miR-2909 as regulator of MRN-CSG. RESULTS: The genomic and proteomic data analysis shows genetic alterations with majority of missense mutations [RAD50 (0.7%), MRE11 (1.5%), and NBN (11%)], though with highest MRE11 mRNA expression in invasive ductal breast carcinoma as compared to other breast cancer types. The Kaplan-Meier survival curves suggest higher survival rate for unaltered groups as compared to the altered group. Network analysis and disease association of miR-2909 and MRN-CSG shows strong interactions with other partners. The molecular hybridization between miR-2909-RAD50 and miR-2909-MRE11 complexes showed thermodynamically stable structures. Further, argonaute protein, involved in RNA silencing, docking studies with miR-MRE11-mRNA and miR-RAD50-mRNA hybridized complexes showed strong binding affinity. CONCLUSION: The results suggest that miR-2909 forms strong thermodynamically stable molecular hybridized complexes with MRE11 and RAD50 mRNAs which further strongly interacts with argonaute protein to show potential molecular mechanistic role in breast cancer.
Assuntos
Neoplasias da Mama , MicroRNAs , Feminino , Humanos , Hidrolases Anidrido Ácido , Proteínas Argonautas/metabolismo , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/metabolismo , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , MicroRNAs/genética , Proteína Homóloga a MRE11/genética , Proteína Homóloga a MRE11/metabolismo , Proteínas Nucleares/metabolismo , Proteômica , RNA Mensageiro , Análise de SobrevidaRESUMO
Tuberose (Polianthes tuberosa) is an ornamental flowering crop of the Amaryllidaceae family. Tuberose mild mosaic virus (TuMMV) and tuberose mild mottle virus (TuMMoV), members of the genus Potyvirus, are ubiquitously distributed in most tuberose growing countries worldwide with low biological incidence. Here, we report the first coding-complete genomic RNA of TuMMV and TuMMoV obtained through high-throughput sequencing (HTS) and further, the presence of both the viruses were confirmed using virus-specific primers in RT-PCR assays. Excluding the poly (A) tail, the coding-complete genomic RNA of TuMMV and TuMMoV was 9485 and 9462 nucleotides (nts) in length, respectively, and contained a single large open reading frame (ORF). Polyprotein encoded by both the viral genomes contained nine putative cleavage sites. BLASTn analysis of TuMMV and TuMMoV genomes showed 72.40-76.80% and 67.95-77% nucleotide sequence similarities, respectively, with the existing potyviral sequences. Phylogenetic analysis based on genome sequences showed that TuMMV and TuMMoV clustered in a distinct clade to other potyviruses. Further studies are required to understand the mechanism of symptom development, distribution, genetic variability, and their possible threat to tuberose production in India.
RESUMO
The RNA viruses are marked by high genetic diversity, which allows them to quickly adapt to new and resistant hosts. The pathogenic turnip mosaic virus (TuMV) infects Brassicaceae plant species all over the world. AIM: To study the evolution and host expansion of a TuMV for the first time in India using molecular population genetic framework. MATERIALS AND RESULTS: Here, we decipher the complete genome sequences of two TuMV world-B3 strains infecting yellow and black mustard in India through high-throughput RNA sequencing subjecting ribosomal RNA depleted mRNA isolated from leaves exhibiting puckering and mosaic symptoms with 100% incidence and high severity in the experimental field. The viral genomes of the two isolates were 9817 and 9829 nucleotides long. They featured two open reading frames (ORFs), one of which encoded a polyprotein comprised of 3164 amino acids and the other of which encoded a PIPO protein of 62 amino acids. CONCLUSIONS: The two TuMV strains from New Delhi region shared identity with the world-B pathotype and subpathotype world B3 showcasing its emergence first time in South Asia. In contrast, other isolates reported previously from South Asia were all Asian-BR pathotypes. SIGNIFICANCE AND IMPACT OF THE STUDY: According to our knowledge, this is the first instance of TuMV association with black mustard naturally. Their geographical prevalence justifies a lower degree of genetic differentiation and higher rate of gene flow calculated between the world-B and Asian-BR pathotypes. This study provides insights on population structuring, expansions and evolution, level of genetic heterogeneity and variability of worldwide prevalent isolates of TuMV which will further aid in understanding virus epidemiology and help prevent losses.