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1.
Cureus ; 16(5): e59628, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38707754

RESUMEN

Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory disorder that affects multiple organ systems and carries a high risk of mortality if untreated. Treatment typically involves immune suppression with steroids and cytotoxic drugs. This case report details the evaluation and management of an adult female presenting with atypical symptoms, aims to improve awareness and understanding of HLH in adults, and emphasizes the urgency of timely diagnosis and intervention.

2.
Eur J Anaesthesiol ; 41(7): 513-521, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38769936

RESUMEN

BACKGROUND: Atelectasis has been reported in 68 to 100% of children undergoing general anaesthesia, a phenomenon that persists into the recovery period. Children receiving recruitment manoeuvres have less atelectasis and fewer episodes of oxygen desaturation during emergence. The optimal type of recruitment manoeuvre is unclear and may be influenced by the airway device chosen. OBJECTIVE: We aimed to investigate the different effects on lung mechanics as assessed by the forced oscillation technique (FOT) utilising different recruitment strategies: repeated inflations vs. one sustained inflation and different airway devices, a supraglottic airway device vs. a cuffed tracheal tube. DESIGN: Pragmatic enrolment with randomisation to the recruitment strategy. SETTING: We conducted this single-centre trial between February 2020 and March 2022. PARTICIPANTS: Seventy healthy patients (53 boys) aged between 2 and 16 years undergoing general anaesthesia were included. INTERVENTIONS: Forced oscillations (5 Hz) were superimposed on the ventilator waveform using a customised system connected to the anaesthesia machine. Pressure and flow were measured at the inlet of the airway device and used to compute respiratory system resistance and reactance. Measurements were taken before and after recruitment, and again at the end of surgery. MAIN OUTCOME MEASURES: The primary endpoint measured is the change in respiratory reactance. RESULTS: Statistical analysis (linear model with recruitment strategy and airway device as factors) did not show any significant difference in resistance and reactance between before and after recruitment. Baseline reactance was the strongest predictor for a change in reactance after recruitment: prerecruitment Xrs decreased by mean (standard error) of 0.25 (0.068) cmH 2 O s l -1 per  1 cmH 2 O -1  s l -1 increase in baseline Xrs ( P  < 0.001). After correcting for baseline reactance, the change in reactance after recruitment was significantly lower for sustained inflation compared with repeated inflation by mean (standard error) 0.25 (0.101) cmH 2 O ( P  = 0.0166). CONCLUSION: Although there was no significant difference between airway devices, this study demonstrated more effective recruitment via repeated inflations than sustained inflation in anaesthetised children. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12619001434189.


Asunto(s)
Anestesia General , Mecánica Respiratoria , Humanos , Anestesia General/instrumentación , Anestesia General/métodos , Niño , Masculino , Femenino , Adolescente , Preescolar , Mecánica Respiratoria/fisiología , Intubación Intratraqueal/instrumentación , Intubación Intratraqueal/métodos , Manejo de la Vía Aérea/instrumentación , Manejo de la Vía Aérea/métodos , Pulmón/fisiología , Atelectasia Pulmonar/prevención & control , Atelectasia Pulmonar/etiología , Atelectasia Pulmonar/fisiopatología , Respiración Artificial/instrumentación , Respiración Artificial/métodos
4.
Cureus ; 16(4): e58456, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38765376

RESUMEN

Lung cancer with brain metastasis has a high morbidity and mortality worldwide. Neurocysticercosis is a parasitic infection commonly found in regions with poor sanitation. We present a case with the coexistence of lung cancer and neurocysticercosis. A 57-year-old Caucasian female, with a history of secondhand smoke exposure, presented with a cough. Further evaluation revealed a lesion in the right upper lobe of the lung on a CT scan, a frontal lobe lesion on brain MRI, and hypermetabolic lymph nodes on a PET scan. Biopsies confirmed invasive moderately differentiated adenocarcinoma, indicating stage 4 lung cancer with a solitary brain metastasis. The patient underwent stereotactic radiosurgery for the brain lesion and subsequently received chemoradiation therapy. Upon completion of therapy, the patient showed improvement in both lung and brain lesions. Durvalumab maintenance therapy was initiated. However, a follow-up MRI of the brain revealed a new lesion in the right lateral ventricle. Stereotactic radiosurgery was performed to target this lesion. Five months later, a repeat MRI showed growth of the brain lesion. Given the atypical image finding, a biopsy of the right lateral ventricle lesion was performed, revealing an unexpected diagnosis of calcified parenchymal neurocysticercosis. The patient was referred to an infectious disease specialist who started the patient on dexamethasone without antiparasitic treatment. The co-occurrence of metastatic lung cancer to the brain and neurocysticercosis presents significant diagnostic and therapeutic complexities. Despite stereotactic radiosurgery, the patient's neurologic symptoms failed to improve, and subsequent radiographic assessments yielded inconclusive results. Consequently, a brain biopsy was performed, deviating from the usual practice in cancer management, revealing the unexpected presence of neurocysticercosis. This unforeseen diagnosis underscores the critical significance of contemplating alternative etiologies in patients exhibiting atypical clinical manifestations, particularly in regions devoid of prevalent parasitic infections. This case highlights the challenges in identifying and managing complex cases involving lung cancer and neurocysticercosis, where treatment decisions must balance the need for oncologic control and the management of parasitic infection.

5.
N Engl J Med ; 390(14): 1339-1341, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38598804
7.
J Obstet Gynaecol Can ; 46(4): 102350, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38190889

RESUMEN

OBJECTIVES: Gender and racial diversity in academic Canadian departments of obstetrics and gynecology (OBGYN) have not been previously described. We examined gender representation in leadership in academic OBGYN departments and gynecologic oncology (GO) divisions, and determined factors predictive of leadership and promotion including racialized status. METHODS: This cross-sectional study of Canadian residency-affiliated academic OBGYN departments queried institutional websites in January 2021 to compile a list of academic faculty. Subjective gender was assessed using photographs and pronouns, and racialized status was determined using photographs. Logistic regression analyses determined predictive factors for leadership roles. Fassiotto et al. rank equity indices (REI) and Hofler et al. representation ratios were calculated. RESULTS: Within 16 Canadian institutions there were 354 (33.6%) men and 699 (66.4%) women, with 18.3% racialized faculty. Men were more likely to reach full professorship (P < 0.00001) and leadership positions of department chair, vice-chair or division head (P = 0.01). Representation ratios for women in OBGYN were <1 for all administrative leadership positions, and pairwise comparisons of the probability of promotion for women OBGYNs using REI reveal significant disparities between senior and junior administrative leadership and professorial ranks. Racialized physicians were less likely to have attained full professorship (P = 0.002). Ninety-seven academic GOs were identified: 68 (70.1%) were women, 17 (17.5%) racialized. Seven GO divisions (44%) had no racialized members. On multivariate analysis, only year of completion of fellowship was predictive of leadership. CONCLUSION: In academic Canadian OBGYN departments women are underrepresented in leadership and full professor positions. Racialized faculty are underrepresented in full professorship.


Asunto(s)
Ginecología , Liderazgo , Obstetricia , Humanos , Canadá , Femenino , Masculino , Estudios Transversales , Ginecología/estadística & datos numéricos , Obstetricia/estadística & datos numéricos , Docentes Médicos/estadística & datos numéricos , Diversidad Cultural , Oncología Médica/estadística & datos numéricos
8.
J Am Acad Dermatol ; 90(4): 716-726, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38040338

RESUMEN

BACKGROUND: Pediatric melanoma presents with distinct clinical features compared to adult disease. OBJECTIVE: Characterize risk factors and negative outcomes in pediatric melanoma. METHODS: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers. RESULTS: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls. LIMITATIONS: Retrospective nature, cohort size, control selection, and potential referral bias. CONCLUSION: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Adulto , Humanos , Niño , Adolescente , Melanoma/patología , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Biopsia del Ganglio Linfático Centinela , Factores de Riesgo
10.
Br J Anaesth ; 131(6): 1043-1052, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37891122

RESUMEN

BACKGROUND: Obstructive sleep apnoea (OSA) and perioperative respiratory adverse events are significant risks for anaesthesia in children undergoing adenotonsillectomy. Upper airway collapse is a crucial feature of OSA that contributes to respiratory adverse events. A measure of upper airway collapsibility to identify undiagnosed OSA can help guide perioperative management. We investigated the utility of pharyngeal closing pressure (PCLOSE) for predicting OSA and respiratory adverse events. METHODS: Children scheduled for elective adenotonsillectomy underwent in-laboratory polysomnography 2-12 weeks before surgery. PCLOSE measurements were obtained while the child was anaesthetised and breathing spontaneously just before surgery. Logistic regression was used to assess the predictive performance of PCLOSE for detecting OSA and perioperative respiratory adverse events after adjusting for potential covariates. RESULTS: In 52 children (age, mean [standard deviation] 5.7 [1.8] yr; 20 [38%] females), airway collapse during PCLOSE was observed in 42 (81%). Of these, 19 of 42 (45%) patients did not have OSA, 15 (36%) had mild OSA, and eight (19%) had moderate-to-severe OSA. All 10 children with no evidence of airway collapse during the PCLOSE measurements did not have OSA. PCLOSE predicted moderate-to-severe OSA (odds ratio [OR] 1.71; 95% confidence interval [CI]: 1.2-2.8; P=0.011). All children with moderate-to-severe OSA could be identified at a PCLOSE threshold of -4.0 cm H2O (100% sensitivity), and most with no or mild OSA were ruled out (64.7% specificity; receiver operating characteristic/area under the curve=0.857). However, there was no significant association between respiratory adverse events and PCLOSE (OR 1.0; 95% CI: 0.8-1.1; P=0.641). CONCLUSIONS: Measurement of PCLOSE after induction of anaesthesia can reliably identify moderate or severe OSA but not perioperative respiratory adverse events in children before adenotonsillectomy. CLINICAL TRIAL REGISTRATION: ANZCTR ACTRN 12617001503314.


Asunto(s)
Apnea Obstructiva del Sueño , Tonsilectomía , Femenino , Humanos , Niño , Masculino , Apnea Obstructiva del Sueño/diagnóstico , Faringe , Respiración , Polisomnografía , Tonsilectomía/efectos adversos
11.
Antibiotics (Basel) ; 12(9)2023 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-37760736

RESUMEN

In the context of epidemiology, host response, disease presentation, diagnosis, and treatment management, the manifestation of Helicobacter pylori (H. pylori) infection diverges between children and adults. H. pylori infection stands out as one of the most prevalent bacterial infections globally, and its prevalence in both children and adults is decreasing in many developing countries but some still struggle with a high prevalence of pediatric H. pylori infection and its consequences. The majority of infected children are asymptomatic and pediatric studies do not support the involvement of H. pylori in functional disorders such as recurrent abdominal pain. The pathophysiology of H. pylori infection relies on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors. This interaction gives rise to diverse gastritis phenotypes, which subsequently influence the potential development of various gastroduodenal pathologies. In clinical settings, the diagnosis of this infection in childhood requires an upper gastrointestinal endoscopic exam with mucosal biopsy samples for histology and culture, or Polymerase Chain Reaction (PCR) at the very least. When warranted, eradication treatment should be given when good compliance is expected, and there should be systematic use of a treatment adapted to the antimicrobial susceptibility profile. To combat the burgeoning threat of multidrug resistance, vigilant surveillance of resistance patterns and strategic antibiotic management are paramount.

12.
Transplantation ; 107(7): 1630-1641, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-36949034

RESUMEN

BACKGROUND: Urine CXCL10 (C-X-C motif chemokine ligand 10, interferon gamma-induced protein 10 [IP10]) outperforms standard-of-care monitoring for detecting subclinical and early clinical T-cell-mediated rejection (TCMR) and may advance TCMR therapy development through biomarker-enriched trials. The goal was to perform an international multicenter validation of a CXCL10 bead-based immunoassay (Luminex) for transplant surveillance and compare with an electrochemiluminescence-based (Meso Scale Discovery [MSD]) assay used in transplant trials. METHODS: Four laboratories participated in the Luminex assay development and evaluation. Urine CXCL10 was measured by Luminex and MSD in 2 independent adult kidney transplant trial cohorts (Basel and TMCT04). In an independent test and validation set, a linear mixed-effects model to predict (log 10 -transformed) MSD CXCL10 from Luminex CXCL10 was developed to determine the conversion between assays. Net reclassification was determined after mathematical conversion. RESULTS: The Luminex assay was precise, with an intra- and interassay coefficient of variation 8.1% and 9.3%; showed modest agreement between 4 laboratories (R 0.96 to 0.99, P < 0.001); and correlated with known CXCL10 in a single- (n = 100 urines, R 0.94 to 0.98, P < 0.001) and multicenter cohort (n = 468 urines, R 0.92, P < 0.001) but the 2 assays were not equivalent by Passing-Bablok regression. Linear mixed-effects modeling demonstrated an intercept of -0.490 and coefficient of 1.028, showing Luminex CXCL10 are slightly higher than MSD CXCL10, but the agreement is close to 1.0. After conversion of the biopsy thresholds, the decision to biopsy would be changed for only 6% (5/85) patients showing acceptable reclassification. CONCLUSIONS: These data demonstrate this urine CXCL10 Luminex immunoassay is robust, reproducible, and accurate, indicating it can be readily translated into clinical HLA laboratories for serial posttransplant surveillance.


Asunto(s)
Trasplante de Riñón , Adulto , Humanos , Trasplante de Riñón/efectos adversos , Quimiocina CXCL10 , Biomarcadores , Interferón gamma , Inmunoensayo , Rechazo de Injerto/diagnóstico
13.
Am J Obstet Gynecol ; 228(5): 553.e1-553.e8, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36791986

RESUMEN

BACKGROUND: Surgeon-administered transversus abdominis plane block is a contemporary approach to providing postoperative analgesia, and this approach is performed by transperitoneally administering local anesthetic in the plane between the internal oblique and transversus abdominis muscles to target the sensory nerves of the anterolateral abdominal wall. Although this technique is used in many centers, it has not been studied prospectively in patients undergoing a midline laparotomy. OBJECTIVE: This study aimed to evaluate whether surgeon-administered transversus abdominis plane block reduces postoperative opioid requirements and improves clinical outcomes. STUDY DESIGN: In this double-blind, randomized, placebo-controlled trial, patients with a suspected or proven gynecologic malignancy undergoing surgery through a midline laparotomy at 1 Canadian tertiary academic center were randomized to either the bupivacaine group (surgeon-administered transversus abdominis plane blocks with 40 mL of 0.25% bupivacaine) or the placebo group (surgeon-administered transversus abdominis plane blocks with 40 mL of normal saline solution) before fascial closure. The primary outcome was the total dose of opioids (in morphine milligram equivalents) received in the first 24 hours after surgery. The secondary outcomes included opioid doses between 24 and 48 hours, pain scores, postoperative nausea and vomiting, incidence of clinical ileus, time to flatus, and hospital length of stay. The exclusion criteria included contraindications to study medication, history of chronic opioid use, significant adhesions on the anterior abdominal wall preventing access to the injection site, concurrent nonabdominal surgical procedure, and the planned use of neuraxial anesthesia or analgesia. To detect a 20% decrease in opioid requirements with a 2-sided type 1 error of 5% and power of 80%, a sample size of 36 patients per group was calculated. RESULTS: From October 2020 to November 2021, 38 patients were randomized to the bupivacaine arm, and 41 patients were randomized to the placebo arm. The mean age was 60 years, and the mean body mass index was 29.3. A supraumbilical incision was used in 30 of 79 cases (38.0%), and bowel resection was performed in 10 of 79 cases (12.7%). Patient and surgical characteristics were evenly distributed. The patients in the bupivacaine group required 98.0±59.2 morphine milligram equivalents in the first 24 hours after surgery, whereas the patients in the placebo group required 100.8±44.0 morphine milligram equivalents (P=.85). The mean pain score at 4 hours after surgery was 3.1±2.4 (0-10 scale) in the intervention group vs 3.1±2.0 in the placebo group (P=.93). Clinically significant nausea or vomiting was reported in 1 of 38 patients (2.6%) in the intervention group vs 1 of 41 patients (2.4%) in the placebo group (P=.95). Time to first flatus, rates of clinical ileus, and length of stay were similar between groups. Subgroup analysis of patients with a body mass index of <25 and patients who received an infraumbilical incision showed similarly comparable outcomes. CONCLUSION: Surgeon-administered transversus abdominis plane block with bupivacaine was not found to be superior to the placebo intervention in reducing postoperative opioid requirements or improving other postoperative outcomes for patients undergoing a midline laparotomy. These results differed from previous reports evaluating the ultrasound-guided transversus abdominis plane block approach. Surgeon-administered transversus abdominis plane block should not be considered standard of care in postoperative multimodal analgesia.


Asunto(s)
Neoplasias de los Genitales Femeninos , Cirujanos , Humanos , Femenino , Persona de Mediana Edad , Analgésicos Opioides , Neoplasias de los Genitales Femeninos/cirugía , Neoplasias de los Genitales Femeninos/complicaciones , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Dolor Postoperatorio/etiología , Laparotomía , Flatulencia/inducido químicamente , Flatulencia/complicaciones , Flatulencia/tratamiento farmacológico , Canadá , Bupivacaína/uso terapéutico , Anestésicos Locales/uso terapéutico , Músculos Abdominales , Método Doble Ciego , Derivados de la Morfina/uso terapéutico , Morfina
14.
Breast Cancer Res Treat ; 197(3): 461-478, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36473978

RESUMEN

PURPOSE: Inflammatory breast cancer (IBC) is characterized by numerous tumor emboli especially within dermal lymphatics. The explanation remains a mystery. METHODS: This study combines experimental studies with two different IBC xenografts with image algorithmic studies utilizing human tissue microarrays (TMAs) of IBC vs non-IBC cases to support a novel hypothesis to explain IBC's sina qua non signature of florid lymphovascular emboli. RESULTS: In the human TMAs, compared to tumor features like nuclear grade (size), mitosis and Ki-67 immunoreactivity which show that IBC is only modestly more proliferative with larger nuclei than non-IBC, what really sets IBC apart is the markedly greater number of tumor emboli and distinctly smaller emboli whose numbers indicate geometric or exponential differences between IBC and non-IBC. In the experimental xenograft studies, Mary-X gives rise to tight spheroids in vitro which exhibit dynamic budding into smaller daughter spheroids whereas Karen-X exhibits only loose non-budding aggregates. Furthermore Mary-X emboli also bud dramatically into smaller daughter emboli in vivo. The mechanism that regulates this involves the generation of E-cad/NTF1, a calpain-mediated cleavage 100 kDa product of 120 kDa full length membrane E-cadherin. Inhibiting this calpain-mediated cleavage of E-cadherin by blocking either the calpain site of cleavage (SC) or the site of binding (SB) with specific decapeptides that both penetrate the cell membrane and mimic either the cleavage site or the binding site on E-cadherin, inhibits the generation of E-cad/NTF1 in a dose-dependent manner, reduces spheroid compactness and decreases budding. CONCLUSION: Since E-cad/NFT1 retains the p120ctn binding site but loses the α-and ß-catenin sites, promoting its 360° distribution around the cell's membrane, the vacilating levels of this molecule trigger budding of both the spheroids as well as the emboli. Recurrent and geometric budding of parental emboli into daughter emboli then would account for the plethora of emboli seen in IBC.


Asunto(s)
Neoplasias de la Mama , Neoplasias Inflamatorias de la Mama , Células Neoplásicas Circulantes , Femenino , Humanos , Cadherinas/metabolismo , Calpaína , Neoplasias Inflamatorias de la Mama/patología , Células Neoplásicas Circulantes/patología , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Animales
15.
Gynecol Oncol Rep ; 44: 101079, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36249904

RESUMEN

Background: Desmoplastic small round cell tumors are exceedingly rare, usually involve abdominal organs and predominantly affect male patients. We describe the first reported case arising from the uterine cervix and provide a summary of 20 previously reported cases involving gynecologic organs. Case: A 54 year-old was diagnosed with a rapidly growing 13 cm desmoplastic small round cell tumor of the cervix. She was treated through a multimodal approach involving neoadjuvant chemotherapy and surgery. She subsequently recurred, and this was successfully treated with radiation therapy. She is well and without evidence of disease 22 months after initial diagnosis. Conclusion: We report successful treatment through multidisciplinary and multimodal management. This can guide management of future patients as no gold-standard treatment has yet been described.

16.
PLoS Biol ; 20(10): e3001858, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36279312

RESUMEN

Cancer cells survive chemotherapy and cause lethal relapse by entering a senescent state that facilitates expression of many phagocytosis/macrophage-related genes that engender a novel cannibalism phenotype. We used biosensors and live-cell imaging to reveal the basic steps and mechanisms of engulfment by senescent human and mouse tumor cells. We show filamentous actin in predator cells was localized to the prey cell throughout the process of engulfment. Biosensors to various phosphoinositide (PI) species revealed increased concentration and distinct localization of predator PI(4) P and PI(4,5)P2 at the prey cell during early stages of engulfment, followed by a transient burst of PI(3) P before and following internalization. PIK3C2B, the kinase responsible for generating PI(3)P, was required for complete engulfment. Inhibition or knockdown of Clathrin, known to associate with PIK3C2B and PI(4,5)P2, severely impaired engulfment. In sum, our data reveal the most fundamental cellular processes of senescent cell engulfment, including the precise localizations and dynamics of actin and PI species throughout the entire process.


Asunto(s)
Citoesqueleto de Actina , Actinas , Ratones , Animales , Humanos , Actinas/metabolismo , Citoesqueleto de Actina/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Fagocitosis/fisiología
17.
Elife ; 112022 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-35506657

RESUMEN

De novo-designed receptor transmembrane domains (TMDs) present opportunities for precise control of cellular receptor functions. We developed a de novo design strategy for generating programmed membrane proteins (proMPs): single-pass α-helical TMDs that self-assemble through computationally defined and crystallographically validated interfaces. We used these proMPs to program specific oligomeric interactions into a chimeric antigen receptor (CAR) that we expressed in mouse primary T cells and found that both in vitro CAR T cell cytokine release and in vivo antitumor activity scaled linearly with the oligomeric state encoded by the receptor TMD, from monomers up to tetramers. All programmed CARs stimulated substantially lower T cell cytokine release relative to the commonly used CD28 TMD, which we show elevated cytokine release through lateral recruitment of the endogenous T cell costimulatory receptor CD28. Precise design using orthogonal and modular TMDs thus provides a new way to program receptor structure and predictably tune activity for basic or applied synthetic biology.


Asunto(s)
Antígenos CD28 , Receptores Quiméricos de Antígenos , Animales , Antígenos CD28/metabolismo , Citocinas/metabolismo , Ratones , Dominios Proteicos , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Bioorg Med Chem Lett ; 71: 128807, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35605837

RESUMEN

SST5 receptor activation potently inhibits insulin secretion from pancreatic ß-cells, and an orally available nonpeptide selective SST5 agonist may be used to effectively manage the blood glucose levels of congenital HI patients to avoid severe hypoglycemia. Our medicinal chemistry efforts have led to the discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridine analogs as potent SST5 agonists. This class of molecules exhibits excellent human SST5 potency and selectivity against SST1, SST2, SST3 and SST4 receptors. Leading compound 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl-5-fluorobenzonitrile (28, CRN02481) showed limited off-target activity and good pharmacokinetic profiles in both male Sprague Dawley rats and Beagle dogs to advance into further preclinical evaluations.


Asunto(s)
Hiperinsulinismo Congénito , Somatostatina , Animales , Hiperinsulinismo Congénito/tratamiento farmacológico , Perros , Humanos , Masculino , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Somatostatina/agonistas , Somatostatina/farmacología , Somatostatina/fisiología
19.
Gynecol Oncol ; 166(1): 154-161, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35606168

RESUMEN

INTRODUCTION: Frailty is increasingly recognized as a predictor of postoperative morbidity and oncologic outcomes. Evidence of the predictive value of frailty assessment in gynecologic oncology remains sparse. OBJECTIVES: To evaluate the National Surgical Quality Improvement Program (NSQIP) comorbidity-based modified Frailty Index-5 (mFI-5) as predictor of severe postoperative complications, non-completion of chemotherapy and other patient-centered outcomes in gynecologic oncology patients >70 years-old undergoing surgery. METHODS: Prospectively-collected NSQIP data and retrospective chart review of patients undergoing elective laparotomies for gynecologic malignances at a tertiary academic center in Ontario, Canada, between 01/2016-09/2020 were reviewed. Primary outcome was rate of 30-day Clavien-Dindo (Clavien) grade III-V complications. Secondary outcomes included Clavien II-V complications, postoperative length of stay (LOS), non-home discharge and non-completion of chemotherapy. Logistic regression analyses and receiver-operator curves were performed. RESULTS: Two-hundred and fifty-nine patients were included; 103 were planned to receive adjuvant chemotherapy. Fifty-three patients (20.5%) had an mFI ≥ 2 and were categorized as frail. On multivariable analyses, frailty independently predicted grade III-V complications (OR 24.49, 95%CI 9.72-70.67, p < 0.0001), grade II-V complications (OR 4.64, 95%CI 2.31-9.94, p < 0.0001), non-home discharge (OR 7.37, 95%CI 2.81-20.46, p < 0.0001), LOS ≥ 7d (OR 3.6, 95% CI 1.54-8.6, p = 0.003) and non-completion of chemotherapy (OR 8.42, 95%CI 2.46-32.79, p = 0.001). Adjusted C-statistics demonstrated strong predictive value of the mFI-5 for grade III-V (0.92, 95%CI 0.86-0.97) and grade II-V (0.74, 95%CI 0.68-0.8) complications as well as non-home discharge (0.86, 95%CI 0.78-0.95) and chemotherapy non-completion (0.87, 95%CI 0.8-0.95). CONCLUSION: Frailty as assessed with the mFI-5 predicted adverse postoperative and chemotherapy outcomes in gynecologic oncology patients aged ≥70 undergoing a laparotomy. The mFI-5 is a concise tool that can be used for routine frailty screening and risk stratification.


Asunto(s)
Fragilidad , Neoplasias de los Genitales Femeninos , Anciano , Femenino , Fragilidad/complicaciones , Fragilidad/epidemiología , Neoplasias de los Genitales Femeninos/complicaciones , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Neoplasias de los Genitales Femeninos/cirugía , Humanos , Ontario , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo
20.
Int J Gynecol Cancer ; 32(5): 583-589, 2022 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-35304410

RESUMEN

OBJECTIVE: Despite increased participation of women in academic medicine in recent decades, gender disparities persist. The gender gap in authorship and editorial boards in gynecologic oncology, and impact of the COVID-19 pandemic, have not been recently evaluated. We examined gender representation and the impact of COVID-19 on authorship and editorial boards of two major peer-reviewed gynecologic oncology journals. METHODS: We conducted a bibliometric analysis of original articles published in Gynecologic Oncology and the International Journal of Gynecological Cancer, comparing the most contemporary 5-year period (2016-2020) to single years in the two prior decades (1996, 2006). To assess the early impact of COVID-19, we compared publications from May 2020-April 2021 to 2019. Editorial boards were analyzed for gender composition. First names, pronouns, and institutional photographs were used to determine gender. RESULTS: There were 3022 original articles published between 2016 and 2020, 763 in 2006, and 203 in 1996. Gender was identified for 91.3% of first authors (3641 articles) and 95.6% of senior authors (3813 articles). Men comprised the majority of the editorial boards in 2021 at 57% and 61% for Gynecologic Oncology and the International Journal of Gynecological Cancer, respectively. Men were overrepresented as senior authors across all study periods: 93% in 1996, 77% in 2006, and 58% in 2016-2020. Over time, representation of women as first and senior authors increased (7% in 1996, 42% in 2016-2020, p<0.00001). There was no immediate impact of the early pandemic on gender distribution of authorship. CONCLUSIONS: Despite greater representation of women over time as authors in gynecologic oncology journals, there remains gender disparity in senior authorship and editorial board representation. This presents an opportunity for the academic publishing community to advocate for deliberate strategies to achieve gender parity. Although no impact of the early COVID-19 pandemic was found, this requires ongoing surveillance.


Asunto(s)
COVID-19 , Neoplasias de los Genitales Femeninos , Autoria , COVID-19/epidemiología , Femenino , Neoplasias de los Genitales Femeninos/epidemiología , Neoplasias de los Genitales Femeninos/terapia , Humanos , Masculino , Pandemias , Sexismo
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