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Oncolytic adenoviruses (OADVs) have emerged as promising therapeutics for cancer treatment, offering tumour-selective replication and potent antitumor effects. These genetically engineered viruses infect and lyse cancer cells while simultaneously activating antitumor immunity. OADV can be engineered with therapeutic genes and tumour-specific promoters, further enhancing their specificity and efficacy. Various researchers have explored the use of OADV in cancer treatment, integrating direct oncolysis with immune activation, hence revealing promising therapeutic effects in preclinical studies. This review provides comprehensive insights into the mechanism of OADV engineering with tumor-specific promoters and therapeutic payloads, emphasizing advances in vector design that enhance specificity and efficacy. Key evidence from preclinical and clinical studies across lungs, pancreatic, hepatic, breast, renal, and brain cancers is highlighted, demonstrating the translational impact of OADV therapy. The synergistic potential of OADVs in combination regimens, including chemotherapy, immunotherapy, and gene therapy, is critically appraised. The review further examines central hurdles such as antiviral immunity, tumor microenvironment complexity, and delivery challenges, discussing innovative strategies like genetic modulation and nanoparticle carriers to overcome these barriers. Through integrating direct oncolysis and immune modulation, OADVs offer a multifaceted approach for the treatment of resistant and heterogeneous malignancies. The future of OADV therapy requires continued refinement in vector engineering, personalized delivery systems, and multidisciplinary research, positioning OADVs as pivotal agents for enhancing patient outcomes and quality of life in cancer care.
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Adenoviridae , Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Viroterapia Oncolítica/métodos , Neoplasias/terapia , Neoplasias/inmunología , Virus Oncolíticos/genética , Adenoviridae/genética , Animales , Terapia Genética/métodos , Ingeniería Genética , Inmunoterapia/métodos , Vectores GenéticosRESUMEN
Drug repurposing is an emerging strategy in the drug discovery arena, shedding light on new therapeutic uses for already known drugs. This strategy enormously reduces the time and cost of drug development because it utilizes existing data on safety and efficacy of drugs. This review provides basic mechanisms, strategies, and challenges related to drug repurposing. Here we discuss the role of polypharmacology, potential off-target effects in the use of computational and experimental methods for identifying repurposing opportunities, and regulatory and ethical considerations in drug repurposing. Completed cases demonstrate that this approach works effectively across various therapeutic areas, from oncology to rare diseases. Challenges include the need for regulatory and clinical data. Drug repurposing is extremely promising for the rapid delivery of new treatments to patients while cooperating in the development of a more sustainable healthcare system. In-depth knowledge of biological systems and disease mechanisms will allow for drug repurposing to potentially revolutionize new treatments and patients' outcomes.
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Finding ways to increase ß-cell mass is a key goal of diabetes research. During elevated insulin demand, ß-cells turn on endoplasmic reticulum (ER) stress response pathways, and some ß-cells enter the cell cycle. ER stress response protein activating transcription factor 6 (ATF6α) induces ß-cell proliferation, but only in high glucose. The mechanism by which ATF6α increases proliferation, and the reasons for glucose dependence, remain unknown. Here we show that ATF6α activation in mouse and human islet cells increases expression of E2F1, a key cell cycle driver. E2F1 was required for ATF6α-induced proliferation in high glucose. However, E2F1 remained inactive in normal glucose, possibly because retinoblastoma (Rb), a direct E2F1 inhibitor, was in its dephosphorylated, active state. Indeed, inducing Rb phosphorylation by overexpressing cyclin-dependent kinase 4 (CDK4) allowed ATF6α to increase E2F1 activity and ß-cell proliferation in normal glucose. E2F1 expression increased in an ATF6α-dependent manner during generalized ER stress by thapsigargin treatment. Importantly, in human ß-cells, ATF6α failed to synergize with high glucose to induce proliferation, but the synergy was rescued by adding back CDK6. Taken together, this study establishes a new dual-input ß-cell proliferation regulatory mechanism integrating ER load with current glycemic conditions via CDK4/6, in which Rb phosphorylation serves as a glucose sensor that permits ATF6α-driven proliferation. ARTICLE HIGHLIGHTS: Endoplasmic reticulum stress response mediator activating transcription factor 6 (ATF6α) increases pancreatic ß-cell proliferation in a glucose-dependent manner, but the mechanism remains unknown. ATF6α activation upregulated mRNA and protein expression of E2F1, a key G1/S phase transition regulator; however, E2F1 activity only increased in high glucose. Glucose dependence of E2F1 activity was mediated by cyclin-dependent kinase 4/6 phosphorylation of retinoblastoma (Rb) protein, derepressing E2F1 in high glucose. Generalized endoplasmic reticulum stressor thapsigargin increased E2F1 abundance in an ATF6-dependent manner. ATF6α increased E2F1 expression in human ß-cells and increased human ß-cell proliferation when cyclin-dependent kinase 6 (CDK6) was coexpressed.
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Factor de Transcripción Activador 6 , Proliferación Celular , Factor de Transcripción E2F1 , Glucosa , Células Secretoras de Insulina , Factor de Transcripción Activador 6/metabolismo , Factor de Transcripción Activador 6/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/citología , Factor de Transcripción E2F1/metabolismo , Factor de Transcripción E2F1/genética , Animales , Humanos , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Ratones , Glucosa/farmacología , Glucosa/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fosforilación , Proteína de Retinoblastoma/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Tapsigargina/farmacologíaRESUMEN
BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) improve survival in appendiceal carcinoma (AC) with peritoneal dissemination. However, its role in patients with concurrent peritoneal and parenchymal lesions (stage IVc) remains unclear. METHODS: A multicenter retrospective cohort study of mucinous (MAC) and non-mucinous AC (N-MAC) patients with both intra- and extraperitoneal lesions (liver, lung, or both) was conducted using the National Cancer Database (2004-2019). Overall survival (OS) was evaluated among CRS/HIPEC, surgery alone, and systemic chemotherapy (SCT) cohorts, followed by subgroup analysis performed within each tumor histology and grade. RESULTS: Out of 42,888 patients, 950 met the inclusion criteria: 186 received CRS/HIPEC, 568 - surgery alone, and 196 - SCT. Median follow-up was 58 months. Median OS after CRS/HIPEC was significantly longer than after surgery alone or SCT in low-grade MAC and N-MAC: not reached (NR) vs 50.0 (95 %CI: 17.2-82.8) vs 26.0 (95 %CI: 12.7-39.3) months (p < 0.01) and NR vs 20.0 (95 %CI: 15.4-24.6) vs 6.0 (95 %CI: 0.0-12.7) months (p < 0.01), respectively. In high-grade AC, median OS did not differ across treatment cohorts. In multivariable analysis, CRS/HIPEC positively impacted OS in low-grade MAC (HR 0.48; 95 %CI: 0.25-0.94; p = 0.03) and N-MAC (HR 0.15; 95 %CI: 0.04-0.58; p < 0.01) but not in high-grade tumors when adjusted by other factors. Younger age, private medical insurance, mucinous pathology, and liver as an extraperitoneal metastatic site were associated with CRS/HIPEC use. CONCLUSIONS: CRS/HIPEC can provide encouraging outcomes in select low-grade MAC and N-MAC patients with peritoneal and parenchymal metastases. Larger studies are required to assess its efficacy in stage IVc high-grade AC.
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Adenocarcinoma Mucinoso , Neoplasias del Apéndice , Procedimientos Quirúrgicos de Citorreducción , Hipertermia Inducida , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Hepáticas , Neoplasias Pulmonares , Neoplasias Peritoneales , Humanos , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/terapia , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/terapia , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Adulto , Tasa de Supervivencia , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/secundario , Adenocarcinoma Mucinoso/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Terapia Combinada , Estadificación de NeoplasiasRESUMEN
Iron deficiency anemia in children is commonly managed with oral iron supplements, but liquid formulations are often associated with undesirable tooth staining. This in vitro study evaluated enamel discoloration on primary teeth after exposure to ferrous sulfate and iron polymaltose complex. Sixty extracted primary anterior teeth were divided into three groups and immersed daily for 21 days; with color change measured using a spectrophotometer and stereomicroscopy. Ferrous sulfate caused the highest degree of staining (ΔE = 12.6), followed by iron polymaltose (ΔE = 6.3), while controls showed minimal change (ΔE = 1.2). Ferrous sulfate was associated with significantly greater enamel staining, highlighting the need to prefer low-staining formulations to improve pediatric compliance and aesthetics.
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The rise of multidrug-resistant pathogens, including MRSA, underscores the urgent need for novel antibacterial agents with minimum resistance potential and enhanced potency. Herein, we report the design and synthesis of novel phenylvinylsulfonate-anchored azetidin-2-ones 8a-h & 9i-j via the reaction of (E)-2-phenylethene-1-sulfonyl chloride with differently substituted 3-hydroxy azetidin-2-ones. Structural confirmation was achieved by 1H NMR, 13C NMR, HRMS, and stereochemical elucidation based on the J-coupling values of C3-H and C4-H. Among the series, compound 9j exhibited the most potent antibacterial activity against MRSA (MIC: 7.5 µg/mL), outperforming Tetracycline. Mechanistic investigation using ROS quantification (DCFH-DA assay) revealed markedly elevated intracellular ROS (OD: 71,467), suggesting a possible ROS-mediated bacterial damage mechanism. Molecular docking interactions further supported the strong binding of 9j to penicillin-binding protein 2a (PBP2a, PDB: 1VQQ) with a docking score of -6.68 kcal/mol. Additionally, 9j exhibited selective cytotoxicity toward HCT-116 colon cancer cells with an IC50 value of 9.82 ± 0.21 µM while maintaining moderate viability (~52%) in NIH-3T3 normal fibroblast cells. Collectively, these findings highlight phenylvinylsulfonate-anchored azetidin-2-ones as promising antibacterial agents with a ROS-driven mechanism and supplementary selective cytotoxic potential.
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Antibacterianos , Antineoplásicos , Azetidinas , Especies Reactivas de Oxígeno , Ácidos Sulfónicos , Compuestos de Vinilo , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Pruebas de Sensibilidad Microbiana , Especies Reactivas de Oxígeno/metabolismo , Simulación del Acoplamiento Molecular , Humanos , Relación Estructura-Actividad , Azetidinas/farmacología , Azetidinas/química , Azetidinas/síntesis química , Estructura Molecular , Animales , Ratones , Relación Dosis-Respuesta a Droga , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Compuestos de Vinilo/farmacología , Compuestos de Vinilo/química , Compuestos de Vinilo/síntesis química , Ácidos Sulfónicos/química , Ácidos Sulfónicos/farmacología , Ácidos Sulfónicos/síntesis químicaRESUMEN
BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is often associated with extensive surgical resection and has traditionally been performed via laparotomy. Data on minimally invasive robotic approaches remain limited. We evaluated surgical safety and survival outcomes of robotic CRS/HIPEC for peritoneal surface malignancies (PSM). METHODS: A single-center propensity score-matched study was conducted using a prospectively collected database (2018-2025). PSM patients treated with robotic CRS/HIPEC were matched 1:1 to open CRS/HIPEC controls using propensity scores based on age, sex, BMI, histology, and PCI. RESULTS: Of 99 cases, 15 robotic and 71 open CRS/HIPECs were identified. After matching, 15 robotic and 15 open cases were balanced by age, sex, BMI, diagnosis, prior surgical score, and PCI. CC-0/1 rate was 100.0% in robotic and 93.3% in open CRS/HIPEC (p = 1.00). Median blood loss was lower in the robotic group (100 mL vs 250 mL, p = 0.04). Median hospital stay was shorter after robotic CRS/HIPEC (6 vs 9 days, p = 0.05). No differences were observed in major complications (26.7% vs 33.3%, p = 1.00) and reoperation (0.0% vs 6.7%, p = 1.00). No 90-day mortality was observed in either group. Median follow-up was 58 months. Median overall survival (not reached vs 52 months, p = 0.20) and progression-free survival (not reached vs 42 months, p = 0.19) did not differ between robotic and open CRS/HIPEC. CONCLUSION: In PSM patients with low tumor burden, robotic CRS/HIPEC is not associated with increased morbidity or worse survival. It may offer benefits such as reduced blood loss and shorter hospitalization. Multicenter studies are warranted to optimize patient selection.
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Introduction: Leiomyomatosis peritonealis disseminate (LPD) is an entity with uncertain biological behavior, characterized by multiple smooth muscle intra-abdominal and pelvic nodules that may recur after apparently complete resection. LPD has been predominantly described in childbearing age females. Most case reports with short term follow-up describe this as a benign entity. Only isolated case reports indicate the malignant potential of the disease. A comprehensive collation of cases is lacking in literature.Methods: We present a case of malignant transformation of LPD, confirmed by histology and imaging, occurring over two decades. This patient was originally diagnosed with uterine atypical smooth muscle tumor but developed frank malignancy during follow-up. An increasingly malignant aggressive disease course resulted in ultimate development of liver and lung metastases almost 23 years after original diagnoses, resulting in her demise. A comprehensive literature review was performed, and 213 cases of LPD were described, including the present case. Patients were divided into G1 (reportedly benign), G2 (malignant at presentation), and G3 (malignant transformation).Results: Compared to G1, G2 at presentation were more likely to be symptomatic (73%/88%), larger sized (4.1/8.4 cm), and older aged (38/44). In G1, G2, and G3, the average age was 38.5, 44.3, and 37.5 years, respectively; while the disease specific survival was 100%, 71%, and 40%, respectively. The mean number of surgeries performed in G1, G2, and G3 was 1.6, 1.8, and 3.8, respectively. Hormone receptors were found in 24.4% of cases. The mean reported follow-up time in G1, G2, and G3, respectively, was 44.9, 13.1, and 70.5 months. This suggests with longer follow-up, even apparently benign tumors may develop malignancy. The transformation time to malignancy in G3 was 77.8 months, which is more than the average reported follow-up in G1 (44.9 months).Conclusions: LPD is a potentially malignant condition with long latency prior to transformation. Lifelong surveillance should be considered even in cases originally presumed to be benign. Loss of hormone receptor expression may serve as a marker for this transformation. Circulating Tumor DNA (ctDNA) levels may be associated with development of hematogenous metastases and may be a useful biomarker.
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Biomarcadores de Tumor , Transformación Celular Neoplásica , Leiomiomatosis , Neoplasias Peritoneales , Neoplasias Uterinas , Femenino , Humanos , Transformación Celular Neoplásica/patología , Leiomiomatosis/patología , Estudios Longitudinales , Neoplasias Peritoneales/patología , Neoplasias Uterinas/patología , Resultado FatalRESUMEN
BACKGROUND: Radiation-induced biologic bystander effects (RIBBEs) where non-irradiated cells display radiation like responses are well established in the context of external beam radiotherapy. However, their presence and characteristics in radionuclide therapy have been explored in only a limited number of studies. With the growing application of radionuclide therapy, this study was designed to investigate RIBBEs using a targeting agent labeled with three different types of emitters, aiming to quantify the varying biological effects attributable to each radionuclide and to devise strategies for achieving maximum therapeutic effect.Trastuzumab antibody targeting human epidermal growth factor receptor 2 (HER2) was labeled with radionuclides of varying energy profile; Y-90 (ß-emitter), Lu-177 (ß-/γ-emitter), and I-125 (Auger electron emitter). The radiolabeled conjugates were characterized, and their specificity was evaluated. Studies to evaluate both direct and bystander effects in (HER2) receptor overexpressing cell lines were performed via a media transfer protocol. RESULTS: The study highlights distinct cellular responses depending on the radionuclide employed, with significant bystander induced reductions in clonogenic survival observed for all radiolabeled formulations. Notably, HER2-overexpressing SK-OV-3 and SK-BR-3 cells displayed dose-dependent variations in survival, with 90Y and 177Lu demonstrating greater bystander toxicity than 125I. The survival fraction of recipient cells, which were exposed solely to media containing bystander factors, decreased significantly, indicating the potency of bystander factors in influencing therapeutic outcomes. Additionally, cytotoxicity assays revealed that higher doses of 90Y and 177Lu induced substantial apoptosis and necrosis, whereas 125I exhibited lower cytotoxicity, consistent with its lower energy emission profile. Reactive oxygen species (ROS) generation assays corroborated these findings, showing elevated ROS levels in direct and donor cell groups treated with 90Y and 177Lu, while recipient cells exhibited relatively lower ROS induction. CONCLUSIONS: This study elucidates the complex interplay of direct and bystander effects in targeted radionuclide therapy, demonstrating that the therapeutic efficacy and cellular response depend on the specific radionuclide and its energy profile. The findings emphasize the need for further exploration of RIBBEs to optimize radionuclide-based cancer therapies to enhance their clinical efficacy.
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Mitochondrial targeting is of particular interest to researchers, as it presents as a personalized medicine approach in cancer cell metabolism and survival. By specifically targeting mitochondria, targeted therapies can disrupt energy production, induce apoptosis, and overcome drug resistance in cancer cells, potentially improving therapeutic outcomes. This review discusses the advancements in mitochondrial drug delivery over the last decade. It explores the potential of mitochondrial targeting using mitocurcumin (MTC), a novel small molecule curcumin analog that has been engineered to specifically target mitochondria in cancer cells, thereby augmenting its therapeutic efficacy. The antiproliferative activity of MTC demonstrates its ability to induce reactive oxygen species (ROS) production and promote oxidative stress-mediated apoptosis, oxidative damage, and cellular senescence in diverse cancer cell lines, thereby enhancing its specificity for cancer cells. Despite these encouraging attributes, current research on MTC remains limited. Further comprehensive investigations are imperative to fully elucidate the efficacy and potential applications of mitochondrial targeting, especially MTC, in oncological therapeutics, including in vivo efficacy trials, pharmacokinetic profiling, toxicology studies, and combination therapy assessments. Although mitochondrial targeting presents a promising avenue for cancer therapy, rigorous scientific inquiry is essential to validate its clinical potential and optimize its therapeutic application for improved patient compliance.
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Antineoplásicos , Curcumina , Mitocondrias , Neoplasias , Humanos , Curcumina/análogos & derivados , Curcumina/farmacología , Curcumina/administración & dosificación , Curcumina/uso terapéutico , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Animales , Sistemas de Liberación de Medicamentos , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacosRESUMEN
BACKGROUND Epithelioid angiosarcoma arising in a schwannoma is an exceedingly rare and aggressive malignancy, with less than 25 cases reported in the English-language literature. Histopathologically, it combines the spindle cell characteristics of schwannomas with the epithelioid, vascular nature of angiosarcomas. The presence of SMARCB1 frameshift loss-of-function (LOF) mutations impairs gene function, contributing to various aggressive cancers. CASE REPORT A 58-year-old man presented with slow-growing masses on the back and arm. Ultrasound and MRI findings were suspicious for nerve sheath tumor. He underwent surgical resection and biopsy, with results revealing SOX10-positive, S100-positive, CD31-positive, excisional margins-positive characteristics of high-grade epithelioid angiosarcoma arising in a schwannoma. A PET scan suggested metastasis to intrathoracic lymph nodes. Tempus molecular profiling showed SMARCB1 frameshift LOF. He was treated with weekly paclitaxel and tazemetostat, with slight improvement in pain; however, he developed symptomatic disease progression. Due to extensive metastatic disease precluding surgical resection, palliative radiation was added to the systemic treatment regimen. After several cycles of treatments with worsening symptoms, he decided to enter hospice care. CONCLUSIONS Presentation of high-grade angiosarcoma arising in schwannoma can be non-specific, posing a diagnostic challenge. Histopathology and immunohistochemistry are essential in the diagnosis and may be characterized by the presence of SMARCB1 frameshift LOF as a prognostic biomarker. Surgical resection with negative margins is the cornerstone of treatment supplemented by chemotherapy and radiotherapy. Patients should be monitored closely for recurrence or metastasis.
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Hemangiosarcoma , Neurilemoma , Proteína SMARCB1 , Humanos , Masculino , Neurilemoma/patología , Neurilemoma/genética , Persona de Mediana Edad , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Hemangiosarcoma/terapia , Proteína SMARCB1/genética , Mutación del Sistema de Lectura , MutaciónRESUMEN
Background Arteriovenous fistulas (AVFs) remain the preferred vascular access for hemodialysis patients due to their superior long-term patency and lower complication rates. However, AVF dysfunction due to stenosis and thrombosis remains a significant clinical challenge. Color duplex ultrasound (CDUS) has emerged as a valuable, non-invasive tool for AVF assessment, but its accuracy compared to digital subtraction angiography (DSA) remains debated. This study aims to evaluate the diagnostic reliability of CDUS in detecting AVF dysfunction and compare its findings with DSA. Methods A prospective observational study was conducted over 18 months at Shri Guru Ram Rai Institute of Medical & Health Sciences, Dehradun, including 57 hemodialysis patients undergoing AVF evaluation. CDUS parameters, including peak systolic velocity (PSV), flow volume (FV), and draining vein diameter, were assessed and compared with DSA findings. Diagnostic performance, inter-method agreement, and key hemodynamic determinants of AVF function were analyzed. Results CDUS demonstrated high sensitivity (93.35%) and specificity (92.86%) in detecting stenosis, with 100% agreement with DSA in identifying stenosis location and severity. Functional AVFs had larger draining vein diameters (6±1.1 mm vs. 2.9±0.7 mm, p=0.001) and lower FVs, emphasizing the importance of hemodynamic balance in AVF maturation. Stenotic length significantly impacted FV, with longer stenotic segments (>6 cm) associated with reduced flow (p=0.023). Conclusion CDUS is a highly accurate and non-invasive modality for AVF surveillance, demonstrating strong agreement with DSA. Given the absence of standardized Doppler criteria, further research should focus on refining hemodynamic thresholds and integrating AI-assisted ultrasound analysis for improved diagnostic precision.
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This study reports the isolation and characterisation of a biosurfactant-producing endophytic strain, Bacillus safensis subsp. safensis FO-36b (T) MTCC 25740 (RSS2), from Phyllanthus niruri L. Among 52 screened endophytes, RSS2 was the most potent biosurfactant producer, yielding rhamnolipid congeners predominantly comprising dirhamnolipids (RhaRhaC10C10). The purified biosurfactant exhibited a critical micelle concentration of 0.79 mg/mL and was structurally confirmed by HPLC, LC-MS, FTIR, and NMR. Cytotoxicity against Jurkat (T lymphoblast) cells showed a dose-dependent response (IC50: 356.63 µM), with non-significant effects on normal PBMCs. Apoptosis analysis revealed 22.6% early and 73.2% late apoptosis respectively in leukaemia cells after 24 h, confirming selective pro-apoptotic activity. These findings highlight the potential of B. safensis derived rhamnolipids as natural, apoptosis-inducing anticancer agents. The study explores the promising role of biosurfactants in therapeutic development, and advocates future research on production optimisation, mechanistic insights into anticancer action, and the development of targeted biomedical formulations.
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[177Lu]-Lu-DOTA-Trastuzumab is currently under clinical evaluation for radioimmunotherapy (RIT) for HER2-positive breast cancer. This study aimed to enhance its internalization by modifying Trastuzumab with a nuclear localization signal (NLS: PKKKRKV). The NLS, bearing a terminal azide group, was synthesized via solid-phase peptide synthesis. DOTA, a chelator for 177Lu, was incorporated at the α-amino group of lysine at the NLS's proline end, allowing UV-vis-based drug-to-antibody ratio (DAR) estimation. Both DOTA-Trastuzumab and DOTA-NLS-Trastuzumab, along with their [177Lu]-Lu-labeled counterparts, were synthesized. In vitro studies in HER2-positive SK-OV-3 and SK-BR-3 cells showed an enhanced internalization of the NLS-modified conjugate. However, ex vivo and in vivo evaluation in SCID mice revealed lower tumor and nontarget organ accumulation for [177Lu]-Lu-DOTA-NLS-Trastuzumab compared to [177Lu]-Lu-DOTA-Trastuzumab, indicating altered biodistribution despite improved cellular uptake.
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Cellular senescence is emerging as one of the leading underlying mechanisms of ageing. Senescent cells are observed in most tissues and organs with advancing age, which augments tissue dysfunction and inflammatory disorders. Extracellular vesicles (EVs) are nanoscale sacs released by almost all cells, which carry cell-type dependent molecular cargo that can exhibit pharmacological effects in recipient cells. Since senescence represents a global phenomenon in an organism, and EVs are released by various cell types, this review attempts to delineate their intricate interactions in regulating various facets of cellular senescence and age-related diseases, as well as potential diagnostic avenues, research gaps, and challenges. EVs released by senescent cells are biophysically different and can not only promote bystander senescence in healthier cells but can also accelerate the development of age-dependent chronic disorders by promoting a pro-tumorigenic and pro-inflammatory environment. Conversely, EVs isolated from healthy cells, typically stem cells, can suppress senescence, promote inflammatory homeostasis, and improve lifespan in vivo. Novel non-mammalian sources of EVs, including the gut microbiota and dietary plants, are also being recognised with potentially senescence-modulatory effects. A previously unknown role of EVs in modulating immune cell response during senescence is also developing, and EVs-based biomarkers are identified with the aim of early prediction and diagnosis of senescence. However, several challenges remain at the technical and translational end of EVs, and future research should focus on the identification of EVs in senescent cell subtypes and immune cells, understanding non-mammalian sources of EVs in modulating senescence, and establishing the safety of EVs to fully comprehend their pathological, therapeutic, and diagnostic potential in regulating cellular senescence.
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Senescencia Celular , Vesículas Extracelulares , Humanos , Vesículas Extracelulares/metabolismo , Animales , Envejecimiento/patología , Inflamación , Biomarcadores/metabolismoRESUMEN
Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumour metabolism in patients has not been closely examined. We developed a parallel workflow to analyse [U-13C]glucose tracing and metabolomics data from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labelling, similar to levels in human brain tumours. Although levels of TCA cycle labelling in PDXs were similar to those in the original patient tumours, PDXs had higher labelling in glycolytic metabolites. Through metabolomics, we observed consistent alterations of 100 metabolites among PDXs and patient tumours that reflected species-specific differences in diet, host physiology and microbiota. Despite these differences, most of nearly 200 PDXs retained a 'metabolic fingerprint' largely durable over six passages and often traceable back to the patient tumour of origin. This study identifies both high- and low-fidelity metabolites in the PDX model system, providing a resource for cancer metabolism researchers.
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Xenoinjertos , Melanoma , Neoplasias , Humanos , Animales , Ratones , Metabolómica/métodos , Fenotipo , Xenoinjertos/metabolismo , Melanoma/metabolismo , Neoplasias/metabolismo , Metaboloma , Glucólisis , Ciclo del Ácido Cítrico , Glucosa/metabolismoRESUMEN
Organic pollutants have an antagonistic impact on the ecosystem and human health, as these pollutants and their exposure lead to many health effects, including cancer, immune deficiency disorders, genotoxicity, neurological disorders, etc. Among the several techniques, the eviction of organic toxins via sorption or photocatalysis utilizing graphene or its derivatives such as graphene oxide, reduced graphene oxide, and graphene aerogel are one of the most enthralling aspects of the current research on account of their huge surface active area, sterling mechanical strength, intriguing physicochemical properties, ability to attain π-π stacking, and meso-porosity within the layer structures, which facilitate the sorption of noxious pollutants as well as potent photocatalysts to degrade organic hazardous pollutants. Furthermore, the inclusion of a large degree of oxygen-derived functional groups sequentially improves their pollutant degradation rates due to increased hydrophilicity, thus increasing the degree of molecular interactions. Therefore, this review ruminates on a summary of graphene and its derivative-based platforms for eradicating organic pollutants, their synthesis procedures, modus operandi, and modifications employed to boost selectivity and efficiency, along with their current status and future aspects.
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Contaminantes Ambientales , Grafito , Compuestos Orgánicos , Grafito/química , Catálisis , Adsorción , Compuestos Orgánicos/química , Procesos Fotoquímicos , Contaminantes Ambientales/químicaRESUMEN
Breast cancer is the most common and deadly cancer affecting women globally. While traditional treatments - surgery, chemotherapeutic agents, radiotherapy - are used, factors damage their effectiveness: tumor heterogeneity, drug resistance, and non-targeted actions on cancer cells. Postbiotics, a newer category of biotics, confer benefits without living microorganisms and show promise against cancer. This review summarizes the link between gut microbiota and BC, postbiotic mechanisms against cancer, and their potential for personalized medicine. Postbiotics modulate the host immune system and inflammation in BC management. They target apoptotic signaling pathways, such as mitochondrial-dependent and death receptor-dependent pathways, interrupt the cell cycle, inhibit cancer cell growth, and regulate immune responses. In cancer, integrative approaches for therapies include microbiome analysis to provide personalized medical treatment, highlighting the microbiome's impact on cancer. Compared to probiotics, postbiotics have advantages, including better bioavailability, stability, and safety profiles. However, research should continue to address clinical evidence and extended studies in their production and application. The use of postbiotics as adjunctive agents in BC treatment has been highlighted for their potential to enhance standard therapy outcomes.
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Neoplasias de la Mama , Microbioma Gastrointestinal , Probióticos , Humanos , Neoplasias de la Mama/terapia , Neoplasias de la Mama/microbiología , Neoplasias de la Mama/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Medicina de Precisión/métodos , Femenino , Probióticos/uso terapéuticoRESUMEN
Background: Oral Submucous Fibrosis (OSMF) is a chronic, progressive disorder leading to fibrosis, trismus, and burning sensation. Physiotherapy is a non-invasive approach aimed at improving oral mobility. Materials and Methods: A total of 50 OSMF patients underwent daily physiotherapy exercises using ice cream sticks for six months. Mouth opening was measured at baseline, 1 month, 3 months, and 6 months. Pain levels were assessed using the Visual Analogue Scale (VAS). Results: Physiotherapy led to a moderate increase in mouth opening, but pain relief and symptom improvement were limited. Compliance was a challenge due to patient discomfort. Conclusion: Physiotherapy is a viable conservative treatment for OSMF but should be combined with adjunct therapies for better symptom management and long-term effectiveness.