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T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, i.e. the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (i) altered epigenetics, (ii) defective DNA damage responses, (iii) aberrant cell-cycle regulation, and (iv) deregulated pro-survival pathways, including TCR and JAK/STAT signaling. To further develop related pre-clinical therapeutic concepts, we studied inhibitors of (H)DACs, BCL2, CDK, MDM2, and clas-sical cytostatics, utilizing (a) single-agent and combinatorial compound testing in 20 well-characterized and molecularly-profiled primary T-PLL (validated by additional 42 cases), and (b) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single-agents and combinations (in vitro and in mice) in-cluded Cladribine, Romidepsin ((H)DAC), Venetoclax (BCL2), and/or Idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance towards MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activa-tion and down-stream signals (including enhanced accessibility of target-gene chromatin re-gions), in particular synergy with insults by Cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.
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T-cell large granular lymphocytic leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes that can result in severe neutropenia, anemia, and bone marrow failure. Strong evidence from patients and mouse models demonstrate the critical role of interleukin-15 (IL-15) in T-LGLL pathogenesis. BNZ-1 is a pegylated peptide that selectively inhibits the binding of IL-15 and other γc cytokines to their cellular receptor complex, which has demonstrated efficacy in ex vivo T-LGLL cells and transgenic mice in preclinical studies. We conducted a phase 1/2 trial of BNZ-1 in patients with T-LGLL who had hematocytopenias (anemia or neutropenia) and required therapy. Clinical responses were assessed using hematologic parameters (improvement in hematocytopenias) based on response criteria from the Eastern Cooperative Oncology Group 5998 T-LGLL trial. BNZ-1 demonstrated clinical partial responses in 20% of patients with T-LGLL with minimal toxicity and the maximum tolerated dose was not reached. Furthermore, T-LGL leukemic cells showed significantly increased apoptosis in response to BNZ-1 treatment as early as day 2, including in clinical nonresponders, with changes that remained statistically different from baseline throughout treatment (P < .005). We report first-in-human proof that T-LGL leukemic cells are dependent on IL-15 and that intervention with IL-15 inhibition with BNZ-1 in patients with T-LGLL shows therapeutic effects, which carries important implications for the understanding of the pathogenesis of this disease. This trial was registered at www.clinicaltrials.gov as #NCT03239392.
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Anemia , Leucemia Linfocítica Granular Grande , Neutropenia , Ratones , Animales , Humanos , Citocinas/metabolismo , Leucemia Linfocítica Granular Grande/patología , Interleucina-15RESUMEN
Ocular drug delivery is constrained by anatomical and physiological barriers, necessitating innovative solutions for effective therapy. Natural polymers like hyaluronic acid, chitosan, and gelatin, alongside synthetic counterparts such as PLGA and PEG, have gained prominence for their biocompatibility and controlled release profiles. Recent strides in polymer conjugation strategies have enabled targeted delivery through ligand integration, facilitating tissue specificity and cellular uptake. This versatility accommodates combined drug delivery, addressing diverse anterior (e.g., glaucoma, dry eye) and posterior segment (e.g., macular degeneration, diabetic retinopathy) afflictions. The review encompasses an in-depth exploration of each natural and synthetic polymer, detailing their individual advantages and disadvantages for ocular drug delivery. By transcending ocular barriers and refining therapeutic precision, these innovations promise to reshape the management of anterior and posterior segment eye diseases.
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Sistemas de Liberación de Medicamentos , Oftalmopatías , Polímeros , Humanos , Sistemas de Liberación de Medicamentos/métodos , Oftalmopatías/tratamiento farmacológico , Polímeros/química , Ácido Hialurónico/química , Animales , Administración Oftálmica , Ojo/metabolismo , Ojo/efectos de los fármacos , Portadores de Fármacos/químicaRESUMEN
Pediatric Hepatoblastoma is a rare malignancy of the liver. This study used the National Cancer Database (NCDB) to identify 1068 patients diagnosed with hepatoblastoma from 2004 to 2020. χ 2 and Analysis of Variance testing, as well as Kaplan-Meier, Cox Regression, and multinomial logistic regression models were used. Data was analyzed using SPSS version 27, and statistical significance was set at α=0.05. Our results found Black patients experienced a significantly lower median survival rate compared with White patients, a difference which persisted after controlling for covariates. Black patients were also less likely to receive surgery and chemotherapy and more likely to be from low-income households than White patients. White patients had a significantly shorter inpatient hospital stay compared to Black patients and were more likely to receive treatment at more than 1 CoC accredited facility. There was no significant difference in grade, size of tumor, metastasis, or time of diagnosis to surgery. This study showed Black patients experienced inferior overall survival when diagnosed and treated for hepatoblastoma compared to White patients.
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Disparidades en Atención de Salud , Hepatoblastoma , Neoplasias Hepáticas , Población Blanca , Humanos , Hepatoblastoma/terapia , Hepatoblastoma/mortalidad , Hepatoblastoma/etnología , Hepatoblastoma/patología , Masculino , Femenino , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/etnología , Disparidades en Atención de Salud/estadística & datos numéricos , Disparidades en Atención de Salud/etnología , Preescolar , Niño , Lactante , Población Blanca/estadística & datos numéricos , Tasa de Supervivencia , Negro o Afroamericano/estadística & datos numéricos , Adolescente , Recién Nacido , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Percutaneous ultrasound-guided microwave ablation (MWA) for benign solid thyroid nodules is the newest modality for treatment. However, the differences in treatment outcomes between MWA and endoscopic thyroidectomy vestibular approach (TOETVA) for patients with benign euthyroid solitary nodules remain unknown. We are sharing initial results from our prospective study. METHODS: Prospective study between January 2022 and December 2023 was conducted and data were noted at 3 time points in patients planned for treatment (Preoperative, 1 week, and 12 months). Main outcome measures were clinical outcome and comparison of thyroid-related quality of life using the ThyPRO-39hin and swallowing-related quality of life using the SWAL-QoL. RESULTS: Of the 36 included patients, 20 patients underwent TOETVA and 16 underwent MWA. Both the groups were comparable in terms of demographic and clinicopathological profiles. The nodule volume reduction rate of patients at 12 months after MWA was 75.10% and 100% for TOETVA. The mean preoperative ThyPRO-39hin and SWAL-QoL scores were comparable in all domains between the two groups. Mean ThyPRO-39hin and SWAL-QoL scores on postoperative day 7 were significantly better in the MWA group in domains impaired social life (p < 0.0001) and impaired daily life (p = 0.0002). However, at the end of 12 months, mean ThyPRO-39hin and SWAL-QoL scores became significantly better in the TOETVA group as compared to the MWA group. CONCLUSION: Our findings suggest that transoral endoscopic thyroidectomy results in significant superior clinical outcome, thyroid-related quality of life, and swallowing-related quality of life in the long term.
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BACKGROUND: Pediatric endocrine disorders requiring surgical intervention are rare and so are experienced surgeons dealing with these. The aim of the current study was to investigate disease profile and perioperative outcome of pediatric patients with surgical endocrine disorders in an endocrine surgery unit. METHODS: This retrospective study (Sep 1989-Aug 2019) consisted of pediatric endocrine surgery patients (<18 years) who were managed by a team of pediatric endocrinologists and endocrine surgeons at our center. Patients were divided into three cohorts consisting of a decade each. Clinico-pathologic variables, perioperative events operative and follow-up details were recorded. RESULTS: A total of 332 children were included and their mean age was 14.6 ± 3.9 years (M:F = 1:1.6). Thyroid disorders were most prevalent (59.8%), followed by adrenal (28.2%), parathyroid (10.4%), and pancreas (1.5%). Incidence of benign, malignant, and congenital/developmental disorders were 65.4, 28.1 and 8.3, respectively. Familial association was observed in 8.9% children, which is highest among pheochromocytoma patients. Overall, 201 thyroidectomies + associated procedures, 35 parathyroidectomies, 96 adrenal and paraganglioma resections, and 5 pancreatic procedures were performed. Median hospital stay was 5.6 ± 4.1 days. The number of cases increased significantly over 3 decades. Clinical profile and outcome did not vary except for significant decrease in incidence of malignant pathology (p = 0.04) and increase in VHL cases (p = 0.04) in the last decade though overall increase in familial cases was nonsignificant (p = 0.11). No perioperative mortality was observed except for 3% after adrenalectomy. CONCLUSION: A team of dedicated endocrine surgeons and pediatric endocrinologists is effective in management of pediatric endocrine surgery.
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Neoplasias de las Glándulas Suprarrenales , Procedimientos Quirúrgicos Endocrinos , Enfermedades del Sistema Endocrino , Feocromocitoma , Cirujanos , Humanos , Niño , Adolescente , Estudios Retrospectivos , Feocromocitoma/cirugía , Enfermedades del Sistema Endocrino/epidemiología , Enfermedades del Sistema Endocrino/cirugía , Neoplasias de las Glándulas Suprarrenales/cirugíaRESUMEN
Pirfenidone, initially indicated for lung fibrosis, has gone beyond its original purpose, and shown promise in eye care. This detailed review tracks its evolution from lung treatment to aiding eye healing as evidenced by published literature. Pirfenidone's multifaceted attributes extend to mitigating corneal fibrosis, inflammation, and trauma. Through rigorous investigations, its efficacy emerges in diabetic retinopathy, macular degeneration, and postoperative glaucoma interventions. As an unheralded protagonist, pirfenidone reshapes ocular care paradigms, inviting renewed research opportunities.
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Piridonas , Cicatrización de Heridas , Piridonas/farmacología , Piridonas/uso terapéuticoRESUMEN
BACKGROUND: The Déjerine-Roussy syndrome is caused by a stroke in the posterior lateral nuclei of the thalamus. It has a 17 to 18% prevalence after a stroke involving the inferior lateral thalamus. METHODS: We reported a case of a 65-year-old, diabetic and hypertensive male who presented with sudden onset of superficial hemianesthesia, allodynia, severe and paroxysmal pain on the right side of the body with choreoathetoid movements in the upperN limb, along with slured speech, and unsteadiness while walking. CONCLUSIONS: It is characterized by superficial hemianesthesia, allodynia, severe paroxysmal pain, and choreoathetoid movements in the limbs on the paralyzed side. A posterior lateral thalamic lesion can present with ataxia hemiparesis contralateral to the side of the lesion.
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BACKGROUND: A dysregulation of cholesterol homeostasis is often seen in various cancer cell types, and elevated cholesterol content and that of its metabolites appears to be crucial for cancer progression and metastasis. Cholesterol is a precursor of various steroid hormones and a key plasma membrane component especially in lipid-rafts, also modulating many intracellular signaling pathways. METHODS: To provide an insight of dysregulated cholesterol regulatory genes, their transcript levels were analyzed in different cancers and their influence was correlated with the overall survival of cancer patients using cancer database analysis. RESULTS: This analysis found a set of genes (e.g., ACAT1, RXRA, SOAT1 and SQLE) that were not only often dysregulated, but also had been associated with poorer overall survival in most cancer types. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed elevated SQLE and SOAT1 transcript levels and downregulated expression of RXRA and ACAT1 genes in triple negative breast cancer tissues compared to adjacent control tissues, indicating that this dysregulated expression of the gene signature is a diagnostic marker for breast cancer. CONCLUSION: For the first time, the present study identified a gene signature associated with the dysregulation of cholesterol homeostasis in cancer cells that may not only be used as a diagnostic marker, but also comprise a promising drug target for the advancement of cancer therapy.
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Neoplasias de la Mama , Colesterol , Humanos , Femenino , Colesterol/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Metabolismo de los Lípidos , Genes Reguladores , Biomarcadores/metabolismoRESUMEN
INTRODUCTION: Digital Mammography (DM) is extensively used for breast imaging however, lesion visibility is often limited by overlapping tissues, which affects lesion characterization. Digital breast tomosynthesis (DBT) reduces the effect of overlapping tissues and helps in revealing obscured findings. We aimed to describe the mammographic findings in granulomatous and non-granulomatous mastitis and assess the utility of adjunctive DBT in lesion characterization. MATERIALS AND METHODS: DM and DBT images of histo-pathologically diagnosed cases of granulomatous (GM) and non-granulomatous mastitis (NGM) were reviewed according to the BI-RADS lexicon. Presence of contiguous/ interconnected lesions, tubular densities, interspersed hypodensities/fat densities within the involved areas were also assessed. The perceived utility of adjunct DBT was scored from 0-2. RESULTS: Of 33 reviewed patients (24 GM, 9 NGM; median age 39 years, range 24-78); 13/33 (39.4%) were under 35 years of age. DBT detected masses in 24/33 (72.7%), whereas only 15/33 (45.4%) were visible on DM alone. Contiguous or inter-connected lesions were found in 10/33 (30.3%) cases. Tubular extensions were seen in 14 cases and interspersed hypodensities in 15. None of the enlarged lymph nodes had irregular shape or indistinct margins or loss of fatty hilum. DBT was able to categorize more lesions as BIRADS 4a or below, as compared to DM alone. CONCLUSIONS: Mammographic presence of multiple contiguous iso-dense masses, reniform contour of axillary lymph nodes with preserved fatty hilum despite a large area of breast involvement favour a benign etiology; especially if DBT reveals tubular extensions or lesions with inhomogenous low density areas within.
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Neoplasias de la Mama , Mastitis Granulomatosa , Femenino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Mamografía , Mama/diagnóstico por imagen , Mama/patología , Márgenes de Escisión , Mastitis Granulomatosa/diagnóstico por imagen , Axila , Neoplasias de la Mama/patología , Estudios RetrospectivosRESUMEN
NK cells are innate immune cells that reside within tissue and circulate in peripheral blood. They interact with a variety of microenvironments, yet how NK cells engage with these varied microenvironments is not well documented. The adhesome represents a molecular network of defined and predicted integrin-mediated signaling interactions. In this study, we define the integrin adhesome expression profile of NK cells from human tonsil, peripheral blood, and those derived from human hematopoietic precursors through stromal cell coculture systems. We report that the site of cell isolation and NK cell developmental stage dictate differences in expression of adhesome associated genes and proteins. Furthermore, we define differences in cortical actin content associated with differential expression of actin regulating proteins, suggesting that differences in adhesome expression are associated with differences in cortical actin homeostasis. These data provide understanding of the diversity of human NK cell populations and how they engage with their microenvironment.
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Integrinas , Internado y Residencia , Humanos , Integrinas/genética , Células Asesinas Naturales , Transducción de SeñalRESUMEN
Bioconversion of fruit waste (FW) and sewage sludge (SS) sludge mixtures into valuable products was investigated using black soldier fly (Hermetia illucens) larvae (BSFL) under a lab-scale trial. For that, five different setups of FW and SS mixtures (100FW; 100SS; 70SS+30FW; 50SS+50FW; 70FW+30SS) were prepared and changes in larval biomass, feed loss, and residual waste physicochemical properties were estimated until the emergence of fly in all waste mixtures. BSFL caused a significant decrease in total organic carbon (11.71-34.79%) and carbon-to-nitrogen ratio (C/N ratio) while the increase in total nitrogen (8.35-123.30%), total phosphorus (17.02-143.36%), and total potassium (19.40-48.87%) contents in the feedstock. The germination index and C/N ratio of frass were below the standards decided for manure quality in a few setups suggesting the non-stability of frass for agronomic applications due to the short duration (20 d) of composting. Larval biomass yield, feed conversion ratio and nutrient mineralization were found to be higher in 50SS+50FW and 70FW+30SS feedstock combinations suggesting their suitability as ideal feedstock for optimal BSFL cultivation. The impact of toxic substances in sewage on BSFL survival, growth and waste stabilization processes, and frass metal enrichment could be investigated in future studies.
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Dípteros , Animales , Larva , Aguas del Alcantarillado , Frutas , Carbono , NitrógenoRESUMEN
INTRODUCTION: Tumor-infiltrating lymphocytes (TILs) are gaining recognition as an important immunological biomarker with therapeutic potential in breast cancer. In this cohort study conducted on patients with advanced breast cancer treated with primary systemic therapy (PST), the TILs concentration was correlated with response to PST and survival outcomes. METHODS: Patients with primary breast cancer treated with PST between 2016 and 2020 were included in this study, approved by IEC, and registered on ClinicalTrials.gov (NCT05250336). Tumor core biopsies obtained prior to starting treatment from 489 patients were assessed for the proportion of stromal TILs by standardized method and categorized into low (0-10% immune cells), intermediate (11-59%), and high (≥ 60%) TILs. TIL concentration and complete pathological response (pCR), disease-free survival (DFS), and overall survival (OS) were correlated. RESULTS: Of the 489 patients, 372 matched the eligibility criteria for assessment of TILs and made the final study cohort. Among these, 135 were luminal, 129 HER2-enriched, and 108 triple-negative breast cancers (TNBC). Proportions of patients with high TILs were greater in TNBC (15.7%) and HER2-enriched (9.3%), compared to luminal cancers (4.4%). High TIL concentration was correlated with higher pCR in all subtypes. A pCR was achieved in 33.3, 50, and 52.9% of high TIL patients in luminal, HER2-enriched, and TNBC subtypes, respectively (p < 0.05). High TILs were linked to longer DFS and OS in TNBC and HER2-enriched breast cancers. CONCLUSION: In this first study of its kind from a low- and middle-income country, high TILs concentration was found to be a predictor of response to PST across all breast cancer subtypes. TILs concentration was found predictive of better DFS and OS in TNBC and HER2-enriched cancers. Prognostic role of TILs in luminal cancers was not so apparent.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Pronóstico , Linfocitos Infiltrantes de Tumor/química , Linfocitos Infiltrantes de Tumor/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Estudios de Cohortes , Supervivencia sin Enfermedad , Terapia Neoadyuvante , Biomarcadores de TumorRESUMEN
BACKGROUND: Margin assessment is an essential component of breast conservation surgery (BCS). Re-excision of infiltrated margin(s) detected on paraffin section histology (PSH) needs reoperation, adding time, inconvenience and cost. Intra-operative assessment of margins using frozen section histology (IFSH) can potentially obviate need for re-operation, thus facilitating one-step oncologically complete BCS. METHODS: IFSH and PSH reports of consecutive patients undergoing BCS (2010-2020) were reviewed. Accuracy and cost-efficacy of IFSH were assessed, considering PSH as gold standard. Cost of achieving oncologically complete BCS in whole cohort with IFSH (Scenario-A) was calculated and compared using appropriate statistical tests, with hospital costs for the cohort in a hypothetical Scenario-B, where IFSH was presumed not to have been used and all patients with infiltrated margin(s) on PSH would have been re-operated. RESULTS: Of the 367 patients screened, 39 were excluded due to incomplete IFSH data. Of 328 patients analyzed, 59 (18%) had one or more margins were reported infiltrated on IFSH, managed by re-excision or mastectomy in the same sitting, thus avoiding a reoperation. Additional 8 (2.4%) had involved margins on PSH (False negative IFSH). Significantly higher number of reoperations (p < 0.001) would have been needed in scenario-B. Average cost of the first operation with use of IFSH was Indian Rupees (INR) 25791 which included INR660 as IFSH cost. The average cost of reoperation was INR23724 which could be avoided in 59 (18%) by use of IFSH. The average cost per patient to achieve oncologically complete surgery in scenario A utilizing IFSH was significantly lower (p = 0.001) by INR3101 (11.7%), c.w. that in scenario B. Significant cost-saving with IFSH was maintained in cost-efficacy analysis undertaken with various higher and lower costs assumptions. CONCLUSIONS: Use of IFSH facilitates one-step oncologically complete BCS in majority of patients and results in considerable cost saving, resulting in avoidance of reoperations, besides preventing patient anxiety and delay in adjuvant treatment. TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI/2021/08/035896).
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Humanos , Femenino , Mastectomía , Secciones por Congelación , Neoplasias de la Mama/cirugía , Mastectomía Segmentaria/métodos , Reoperación , Carcinoma Ductal de Mama/cirugía , Estudios Retrospectivos , Márgenes de EscisiónRESUMEN
BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are catecholamine producing tumors of chromaffin cell origin, known to cause varied cardiovascular manifestations from hypertension to myocardial infarction. This study sought to objectively evaluate the cardiac changes in PPGL patients and their reversal following curative surgery. METHODS: The PheoCard study was registered in ClinicalTrials.gov (NCT05082311) and involved 35 consecutive PPGL patients managed as per standard protocol involving alpha blockade followed by curative surgery. They underwent detailed cardiac evaluation using 2D-echocardiography and speckle tracking echocardiography at the time of diagnosis, 7-10 days after alpha blockade, and at 7 days, 3 months, and 6 months after surgical removal. Age- and gender-matched essential hypertensives and healthy individuals (10 in each group) served as two control groups. RESULTS: Patients with PPGLs had significantly higher mean blood pressure, left ventricle end-diastolic dimension and volume (LVEDD, LVEDV), left ventricle end-systolic volume (LVESV), septal wall thickness, LV hypertrophy, lower mean LV ejection fraction (LVEF), early diastolic mitral annular velocity (E/A), decreased amplitude of LV longitudinal strain, and increased circumferential strain (p < 0.001) when compared with the control groups at baseline. After alpha blockade, there was marked reduction in the mean LVEDD, LVEDV, LVESV, and normalization of E/A ratio (p < 0.001) in the PPGL patients. Following curative surgery (normalization of fractionated urinary metanephrines at 7-10 days post-operatively), there was early improvement in all echocardiographic parameters and it continued to improve even at 6 months after surgery. There was marked improvement in the global longitudinal strain as seen on serial speckle tracking echocardiography with recovery of most of the segments of LV depicting the reversal of subclinical endocardial dysfunction (p < 0.001). CONCLUSION: PPGL patients despite normal systolic function have subclinical LV diastolic dysfunction which is reversed after curative surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05082311.
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Neoplasias de las Glándulas Suprarrenales , Hipertensión , Paraganglioma , Feocromocitoma , Disfunción Ventricular Izquierda , Humanos , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/cirugía , Ecocardiografía/métodos , Paraganglioma/complicaciones , Paraganglioma/diagnóstico por imagen , Paraganglioma/cirugía , Feocromocitoma/complicaciones , Feocromocitoma/diagnóstico por imagen , Feocromocitoma/cirugía , Estudios Prospectivos , Volumen Sistólico/fisiologíaRESUMEN
1. The current investigation was to develop and validate the LC-MS/MS method in order to analyse the various pharmacokinetic parameters of S019-0385. A sensitive, selective, and robust LC-MS/MS approach was established and validated for measuring S019-0385 in female mice plasma and tissue, using optimal multiple reaction monitoring (MRM) transition m/z 488.25/329.12 on positive mode. On a Waters Symmetry Shield C18 column, the analyte was separated using acetonitrile and deionised water with formic acid within 6 min at 0.7 mL/min. Linearity (R2 ≥ 0.99) was observed across 0.195-100 ng/mL concentration range using linear least-squares regression.2. Blood-to-plasma ratio and plasma protein drug binding (%) in mice and human was assessed and found to be less than 1 and >83%, respectively. Absolute bioavailability (%F) of S019-0385 in female Swiss mice was exhibited to be 6.90%. Percent dose excreted S019-0385 in unchanged form through urine and faecal was found to be less than 2% and 0.5%, respectively.3. Following oral administration at 5 mg/kg, the concentration of S019-0385 in tissue distribution was found to be in the order of C small intestine > C bone > C lung > C spleen > C kidney > C liver > C heart > C brain.
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Espectrometría de Masas en Tándem , Humanos , Ratones , Femenino , Animales , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Distribución Tisular , Disponibilidad Biológica , Heces , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: We have performed an updated meta-analysis of randomized controlled trials (RCT) comparing total thyroidectomy (TT) with less than total thyroidectomy (LTT) for benign multinodular non-toxic goiter (BMNG). OBJECTIVES: The objective was to evaluate the effects and outcomes of TT as compared to LTT. METHODS: Eligibility criteria: RCTs comparing TT vs LTT. INFORMATION SOURCES: PubMed, Embase, Cochrane Library and online registers were searched for articles comparing TT with LTT. Risk of bias: Articles were assessed for risk of bias using the Cochrane's revised tool to assess risk of bias in randomized trials (RoB 2 tool). SYNTHESIS OF RESULTS: The main summary measures were risk difference using a random effects model. RESULTS: Five randomized controlled trials were included in the meta-analysis. Recurrence rate was lower for TT compared to LTT. Adverse events like temporary or permanent recurrent laryngeal nerve (RLN) palsy and permanent hypoparathyroidism were similar in both groups except for the rate of temporary hypoparathyroidism which was lower in the LTT group. DISCUSSION: All studies had unclear risk of bias for blinding of the participants and personnel and high risk of bias for certain selective reporting. This meta-analysis did not show any clear benefit or harm of either procedure (TT vs LTT) for goiter recurrence and re-operation rates (for both recurrence and incidental thyroid cancer). However, re-operation for goiter recurrence was significantly higher in the LTT group based on a single RCT. Evidence suggests increased rates of temporary hypoparathyroidism with TT but there was no difference in the rate of RLN palsy and permanent hypoparathyroidism between the two methods. The overall quality of evidence was low to moderate.
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Bocio Nodular , Hipoparatiroidismo , Parálisis de los Pliegues Vocales , Humanos , Bocio Nodular/cirugía , Bocio Nodular/etiología , Tiroidectomía/efectos adversos , Tiroidectomía/métodos , Recurrencia Local de Neoplasia/cirugía , Hipoparatiroidismo/etiología , Parálisis de los Pliegues Vocales/etiologíaRESUMEN
BACKGROUND: Tumor neo-angiogenesis plays an important role in the development and growth of breast cancers, but its detection by imaging is challenging. A novel microvascular imaging (MVI) technique, Angio-PLUS, promises to overcome the limitations of color Doppler (CD) in detecting low-velocity flow and small diameter vessels. PURPOSE: To determine the utility of the Angio-PLUS technique for detecting blood flow in breast masses and compare it with CD for differentiating benign from malignant masses. MATERIAL AND METHODS: A total of 79 consecutive women with breast masses were prospectively evaluated using CD and Angio-PLUS techniques, and biopsied as per BI-RADS recommendations. Vascular imaging scores were assigned using three factors (number, morphology, and distribution) and vascular patterns were divided into five groups: internal-dot-spot, external-dot-spot, marginal, radial, and mesh patterns. The independent samples t-test, Mann-Whitney U test, Wilcoxon signed rank test, or Fisher's exact test were used to compare the two groups as appropriate. Area under the receiver operating characteristic (ROC) curve (AUC) methods were used to assess diagnostic accuracy. RESULTS: Vascular scores were significantly higher on Angio-PLUS than CD (median=11, [IQR=9-13] vs. 5 [IQR=3-9], P < 0.001). Malignant masses had higher vascular scores than benign masses on Angio-PLUS (P < 0.001). AUC was 80% (95% CI=70.3-89.7; P < 0.001) for Angio-PLUS and 51.9% for CD. Using Angio-PLUS at a cutoff value of ≥9.5, sensitivity was 80% and specificity was 66.7%. Vascular pattern descriptors on AP showed good correlation with histopathological results (PPV mesh 95.5%, radial 96.9%, and NPV of marginal orientation 90.5%). CONCLUSION: Angio-PLUS was more sensitive in detecting vascularity and superior in differentiating benign from malignant masses compared to CD. Vascular pattern descriptors on Angio-PLUS were useful.
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Neoplasias de la Mama , Ultrasonografía Mamaria , Femenino , Humanos , Ultrasonografía Mamaria/métodos , Sensibilidad y Especificidad , Mama/diagnóstico por imagen , Mama/patología , Ultrasonografía , Neoplasias de la Mama/patología , Neovascularización Patológica/diagnóstico por imagen , Neovascularización Patológica/patología , Diagnóstico Diferencial , Ultrasonografía Doppler en ColorRESUMEN
A novel, quick and precise RP-UHPLC analytical method for the simultaneous determination of moxifloxacin (MFX), voriconazole (VCZ) and pirfenidone (PIR) was developed and validated according to the International Conference on Harmonization guidelines using a QbD-driven response surface Box-Behnken design. The developed method was validated considering the selectivity, sensitivity, linearity, accuracy-precision, robustness, stability, limit of detection and limit of quantification, respectively. Resolution between MFX, VCZ and PIR was achieved using a gradient elution protocol against a Waters Symmetry Shield C18 column (150 × 4.6 mm2 , 5 µm) using an Agilent 1290, Infinity II series LC system. The method was applied to quantitatively estimate proprietary and in-house prepared pharmaceutical topical ophthalmic formulations containing MFX, VCZ and PIR at wavelength (λmax ) of 296, 260 and 316 nm. The method is sensitive enough to detect up to 0.1 ppm of analytes in the formulation. The method was further exploited to study and identify the possible degradation products of the analytes. The proposed chromatographic method is simple, economical, reliable and reproducible. In conclusion, the developed method could be applicable for routine quality control analysis of single or combined MFX, VCZ and PIR-containing units or bulk dosage forms in pharmaceutical industries and research organizations working on drug discovery and development.
Asunto(s)
Voriconazol , Moxifloxacino , Cromatografía Líquida de Alta Presión/métodos , Preparaciones FarmacéuticasRESUMEN
The eye, an intricate organ comprising physical and physiological barriers, poses a significant challenge for ophthalmic physicians seeking to treat serious ocular diseases affecting the posterior segment, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Despite extensive efforts, the delivery of therapeutic drugs to the rear part of the eye remains an unresolved issue. This comprehensive review delves into conventional and innovative formulation strategies for drug delivery to the posterior segment of the eye. By utilizing alternative nanoformulation approaches such as liposomes, nanoparticles, and microneedle patches, researchers and clinicians can overcome the limitations of conventional eye drops and achieve more effective drug delivery to the posterior segment of the eye. These innovative strategies offer improved drug penetration, prolonged residence time, and controlled release, enhancing therapeutic outcomes for ocular diseases. Moreover, this article explores recently approved delivery systems that leverage diverse polymer technologies, such as chitosan and hyaluronic acid, to regulate drug-controlled release over an extended period. By offering a comprehensive understanding of the available formulation strategies, this review aims to empower researchers and clinicians in their pursuit of developing highly effective treatments for posterior-segment ocular diseases.