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1.
Am J Obstet Gynecol ; 230(3S): S669-S695, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38462252

RESUMEN

This review assessed the efficacy and safety of pharmacologic agents (prostaglandins, oxytocin, mifepristone, hyaluronidase, and nitric oxide donors) and mechanical methods (single- and double-balloon catheters, laminaria, membrane stripping, and amniotomy) and those generally considered under the rubric of complementary medicine (castor oil, nipple stimulation, sexual intercourse, herbal medicine, and acupuncture). A substantial body of published reports, including 2 large network meta-analyses, support the safety and efficacy of misoprostol (PGE1) when used for cervical ripening and labor induction. Misoprostol administered vaginally at doses of 50 µg has the highest probability of achieving vaginal delivery within 24 hours. Regardless of dosing, route, and schedule of administration, when used for cervical ripening and labor induction, prostaglandin E2 seems to have similar efficacy in decreasing cesarean delivery rates. Globally, although oxytocin represents the most widely used pharmacologic agent for labor induction, its effectiveness is highly dependent on parity and cervical status. Oxytocin is more effective than expectant management in inducing labor, and the efficacy of oxytocin is enhanced when combined with amniotomy. However, prostaglandins administered vaginally or intracervically are more effective in inducing labor than oxytocin. A single 200-mg oral tablet of mifepristone seems to represent the lowest effective dose for cervical ripening. The bulk of the literature assessing relaxin suggests this agent has limited benefit when used for this indication. Although intracervical injection of hyaluronidase may cause cervical ripening, the need for intracervical administration has limited the use of this agent. Concerning the vaginal administration of nitric oxide donors, including isosorbide mononitrate, isosorbide, nitroglycerin, and sodium nitroprusside, the higher incidence of side effects with these agents has limited their use. A synthetic hygroscopic cervical dilator has been found to be effective for preinduction cervical ripening. Although a pharmacologic agent may be administered after the use of the synthetic hygroscopic dilator, in an attempt to reduce the interval to vaginal delivery, concomitant use of mechanical and pharmacologic methods is being explored. Combining the use of a single-balloon catheter with dinoprostone, misoprostol, or oxytocin enhances the efficacy of these pharmacologic agents in cervical ripening and labor induction. The efficacy of single- and double-balloon catheters in cervical ripening and labor induction seems similar. To date, the combination of misoprostol with an intracervical catheter seems to be the best approach when balancing delivery times with safety. Although complementary methods are occasionally used by patients, given the lack of data documenting their efficacy and safety, these methods are rarely used in hospital settings.


Asunto(s)
Abortivos no Esteroideos , Misoprostol , Oxitócicos , Femenino , Humanos , Embarazo , Maduración Cervical , Dinoprostona , Hialuronoglucosaminidasa/efectos adversos , Hialuronoglucosaminidasa/farmacología , Trabajo de Parto Inducido/métodos , Mifepristona , Donantes de Óxido Nítrico/efectos adversos , Donantes de Óxido Nítrico/farmacología , Oxitocina
3.
Urol Oncol ; 42(1): 23.e1-23.e4, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38040536

RESUMEN

INTRODUCTION: Following surgical excision of pT1a renal cell carcinoma (RCC), 2% to 5% will recur, with 50% to 60% being lung metastases. The ideal surveillance strategy to identify recurrences is unclear. Guidelines are mixed, with NCCN and AUA recommending surveillance via chest x-ray (CXR) at least annually for 5 years, while EAU guidelines do not specifically recommend the use of CXR. In an effort to clarify the utility of surveillance CXR, we retrospectively evaluated pT1a patients following surgical treatment at a single institution. METHODS: We performed retrospective analysis of unique patients who underwent surgical excision of pT1 RCC between January 2000 and January 2020. In addition to demographic information, we collected RCC pathology, recurrence details, and most recent chest imaging. We excluded non-RCC pathology, and patients with pulmonary nodules on baseline imaging. RESULTS: We identified 463 unique patients (mean age 58.3 years, range 23-87) that underwent surgical excision of pT1a RCC with mean follow-up of 47.6 months (range 1-201). On the most recent pulmonary surveillance imaging, 72.4% (335/463) had CXR while 27.6% (128/463) had chest CT performed. Regardless of modality, pulmonary recurrence was not detected on any surveillance imaging (0/463). CONCLUSION: In patients without baseline preoperative lung pathology, we found that there is questionable clinical value in surveillance for pulmonary recurrence after resection of pT1a RCC.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Pulmonares , Humanos , Lactante , Preescolar , Niño , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/cirugía , Neoplasias Renales/epidemiología , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/secundario , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/epidemiología
4.
J Clin Oncol ; 42(4): 399-409, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37992266

RESUMEN

PURPOSE: CALGB (Alliance)/SWOG 80405 was a randomized phase III trial that in first-line patients with metastatic colorectal cancer (mCRC) treated with bevacizumab or cetuximab with chemotherapy. We aimed to discover novel mutated genes associated with prognosis and differential response to therapy with the biologics. METHODS: Primary tumor DNA from 548 patients was sequenced using FoundationOne. The effect of mutated genes and mutations on overall survival (OS) was tested adjusting for microsatellite instability status, BRAF V600E, all RAS mutations, arm, sex, and age. RESULTS: The median number (lower-upper quartile) of mutated genes was 5 (3-7), 5 (3-6) in microsatellite stable and 12.5 (4.5-32) in microsatellite instability-high tumors. Mutated KRAS and APC were more frequent in Black (53% and 85%) than White (27% and 65%, respectively) patients while BRAF V600E was less frequent in Black (5%) than White (14%) patients. The median OS in patients with BRAF non-V600E (2.2% of patients) was 31.9 months (95% CI, 15.1 to not applicable [NA]) similar to that of BRAF wild-type (WT) patients (31.2 months [95% CI, 29.0 to 33.9]). Mutated LRP1B (10.7% of patients) was associated with improved OS compared with WT LRP1B (hazard ratio, 0.57 [95% CI, 0.40 to 0.80]). RNF43 (5.6% of patients) interacted with treatment arms as, in the cetuximab arm, patients with mutated RNF43 had a median OS of 11.5 (95% CI, 10.8 to NA) months compared with 30.1 (95% CI, 24.9 to 35.3) months in patients with WT RNF43, whereas in the bevacizumab arm, patients with mutated RNF43 had a median OS of 25.0 (95% CI, 14.2 to NA) months compared with 31.3 (95% CI, 29.0 to 34.3) months in patients with WT RNF43. CONCLUSION: These results can provide new tools to predict patient outcome and improve therapeutic decisions and trial participation in patient minorities. The molecular alterations identified in this study may direct biomarker-driven studies.


Asunto(s)
Neoplasias Colorrectales , Humanos , Bevacizumab/uso terapéutico , Cetuximab , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proteínas Proto-Oncogénicas B-raf/genética , Inestabilidad de Microsatélites , Nivel de Atención , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
5.
Case Rep Ophthalmol ; 14(1): 698-705, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38090109

RESUMEN

We describe a rare case of Soemmering's ring-induced uveitis-glaucoma-hyphema (UGH) syndrome, caused by an undisplaced, in-the-bag intraocular lens (IOL) 16 years after implantation. The presenting symptoms were recurrent episodes of transient monocular vision loss, which prompted extensive unremarkable investigations. Ultrasound biomicroscopy (UBM) eventually revealed an enlarging Soemmering's ring contacting the posterior iris and causing UGH syndrome. This is a unique case because the IOL haptics remained in the bag. Anterior vitrectomy, Soemmering's ring extraction, IOL exchange to a 3-piece IOL, and implantation of a trabecular meshwork bypass microstent were performed. IOP control and both functional and structural stability were achieved long term. Soemmering's ring-induced UGH syndrome should be on the differential of a patient with previous cataract surgery and elevated IOP complaining of visual disturbances. Early diagnosis with UBM and surgical intervention may provide optimal outcomes.

6.
Nat Immunol ; 24(10): 1654-1670, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37667051

RESUMEN

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.


Asunto(s)
Glioblastoma , Animales , Ratones , Humanos , Glioblastoma/metabolismo , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , Microambiente Tumoral , Transducción de Señal , Proteínas Portadoras/metabolismo , Inmunosupresores/farmacología , Línea Celular Tumoral , Células Madre Neoplásicas/metabolismo
7.
Am J Hosp Palliat Care ; : 10499091231199722, 2023 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-37651687

RESUMEN

Introduction: The hospice-in-place program at Vanderbilt University Medical Center (VUMC) is available to patients and families who elect for hospice benefits and are too unstable to be transported for hospice care. The goal of this study was to assess the satisfaction of family members of patients who died while hospitalized at VUMC and received hospice-in-place compared to the families of patients who did not receive hospice care. Methods: Next-of-kin satisfaction was measured through the administration of qualitative interviews and quantitative questionnaires. Semi-structured interviews were audio-recorded, and transcripts were analyzed using an iterative inductive-deductive approach to develop a conceptual framework. Participants were also asked to respond to a 10-question satisfaction questionnaire. Results: Forty participants were enrolled: 20 next-of-kin of patients who received hospice-in-place and 20 next-of-kin of patients who passed without hospice. Factors influencing satisfaction were organized into a conceptual framework with three categories: individual-level factors, systems-level factors, and modifying factors. For the questionnaires, the hospice-in-place group had a mean satisfaction score of 4.54 (0.76) out of five, while the non-hospice group had a mean score of 4.14 (1.00). A comparison of the two groups' responses did not show a statistically significant difference (P = 0.06). Discussion: Quantitative findings of this study showed improved satisfaction but were unable to show a significant difference in satisfaction with hospice-in-place compared to traditional care. Questionnaire results suggest that both types of care yield high satisfaction scores and are successfully supporting patients and families. The conceptual framework also adds to the understanding of end-of-life experiences at VUMC.

8.
Cancers (Basel) ; 15(13)2023 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-37444539

RESUMEN

Pediatric high-grade gliomas (pHGGs) are common malignant brain tumors without effective treatment and poor patient survival. Abnormal posttranslational modification at the histone H3 tail plays critical roles in tumor cell malignancy. We have previously shown that the trimethylation of lysine 4 at histone H3 (H3K4me3) plays a significant role in pediatric ependymoma malignancy and is associated with tumor therapeutic sensitivity. Here, we show that H3K4me3 and its methyltransferase WDR82 are elevated in pHGGs. A reduction in H3K4me3 by downregulating WDR82 decreases H3K4me3 promoter occupancy and the expression of genes associated with stem cell features, cell proliferation, the cell cycle, and DNA damage repair. A reduction in WDR82-mediated H3K4me3 increases the response of pediatric glioma cells to chemotherapy. These findings suggest that WDR82-mediated H3K4me3 is an important determinant of pediatric glioma malignancy and therapeutic response. This highlights the need for a more thorough understanding of the potential of WDR82 as an epigenetic target to increase therapeutic efficacy and improve the prognosis for children with malignant gliomas.

10.
Parkinsonism Relat Disord ; 113: 105479, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37380539

RESUMEN

INTRODUCTION: The pilot trial of deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) randomized 30 patients (medication duration 0.5-4 years; without dyskinesia or motor fluctuations) to receive optimal drug therapy alone (early ODT) or subthalamic nucleus (STN) DBS plus ODT (early DBS + ODT). This study reports long-term neuropsychological outcomes from the early DBS pilot trial. METHODS: This is an extension of an earlier study that examined two-year neuropsychological outcomes in the pilot trial. The primary analysis was conducted on the five-year cohort (n = 28), and a secondary analysis was conducted on the 11-year cohort (n = 12). Linear mixed effects models for each analysis compared overall trend in outcomes for randomization groups. All subjects who completed the 11-year assessment were also pooled to evaluate long-term change from baseline. RESULTS: There were no significant differences between groups in either the five- or 11-year analyses. Across all PD patients who completed the 11-year visit, there was significant decline in Stroop Color and Color-Word and Purdue Pegboard from baseline to 11 years. CONCLUSIONS: Previous significant differences between the groups in phonemic verbal fluency and cognitive processing speed showing more decline for early DBS + ODT subjects one year after baseline diminished as PD progressed. No cognitive domains were worse for early DBS + ODT subjects compared to standard of care subjects. There were shared declines across all subjects on cognitive processing speed and motor control, likely reflecting disease progression. More study is needed to understand the long-term neuropsychological outcomes associated with early DBS in PD.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Progresión de la Enfermedad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/psicología , Velocidad de Procesamiento , Núcleo Subtalámico/fisiología
11.
Sci Data ; 10(1): 272, 2023 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-37169799

RESUMEN

The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables.


Asunto(s)
COVID-19 , Humanos , Actitud , COVID-19/psicología , Principios Morales , Pandemias , Encuestas y Cuestionarios , Cambio Social , Factores Socioeconómicos
12.
Ann Neurol ; 94(2): 271-284, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37177857

RESUMEN

OBJECTIVE: This study was undertaken to describe relationships between electrode localization and motor outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early stage Parkinson disease (PD) pilot clinical trial. METHODS: To determine anatomical and network correlates associated with motor outcomes for subjects randomized to early DBS (n = 14), voxelwise sweet spot mapping and structural connectivity analyses were carried out using outcomes of motor progression (Unified Parkinson Disease Rating Scale Part III [UPDRS-III] 7-day OFF scores [∆baseline➔24 months, MedOFF/StimOFF]) and symptomatic motor improvement (UPDRS-III ON scores [%∆baseline➔24 months, MedON/StimON]). RESULTS: Sweet spot mapping revealed a location associated with slower motor progression in the dorsolateral STN (anterior/posterior commissure coordinates: 11.07 ± 0.82mm lateral, 1.83 ± 0.61mm posterior, 3.53 ± 0.38mm inferior to the midcommissural point; Montreal Neurological Institute coordinates: +11.25, -13.56, -7.44mm). Modulating fiber tracts from supplementary motor area (SMA) and primary motor cortex (M1) to the STN correlated with slower motor progression across STN DBS subjects, whereas fiber tracts originating from pre-SMA and cerebellum were negatively associated with motor progression. Robustness of the fiber tract model was demonstrated in leave-one-patient-out (R = 0.56, p = 0.02), 5-fold (R = 0.50, p = 0.03), and 10-fold (R = 0.53, p = 0.03) cross-validation paradigms. The sweet spot and fiber tracts associated with motor progression revealed strong similarities to symptomatic motor improvement sweet spot and connectivity in this early stage PD cohort. INTERPRETATION: These results suggest that stimulating the dorsolateral region of the STN receiving input from M1 and SMA (but not pre-SMA) is associated with slower motor progression across subjects receiving STN DBS in early stage PD. This finding is hypothesis-generating and must be prospectively tested in a larger study. ANN NEUROL 2023;94:271-284.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Sustancia Blanca , Humanos , Núcleo Subtalámico/fisiología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/terapia , Estimulación Encefálica Profunda/métodos , Resultado del Tratamiento
13.
Rural Remote Health ; 23(1): 7591, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36935190

RESUMEN

INTRODUCTION: Telemedicine is a valuable tool to increase access to health care, especially for patients in rural areas who need to visit a specialist. In place of telemedicine robots, which are costly and complicated, hospitals have implemented successful telemedicine programs using lower-cost tablet technology; opting for tablet technology increases the organizational feasibility of a large-scale telemedicine program. METHODS: Vanderbilt University Medical Center (VUMC), in Nashville, Tennessee, USA, launched its teleneurology network program in 2014 to serve patients in surrounding community hospitals who needed a neurology consult. Consults are conducted using an iPad, including examinations and the secure sharing of images and patient information. This article reports on teleneurology consult data and the results of patient and physician satisfaction surveys. RESULTS: Between February 2014 and November 2021, the VUMC teleneurology network program provided consultations for 14 241 patients with a wide variety of neurological diagnoses presenting to 12 community-based hospitals. Patient and community physician satisfaction surveys showed that 96% of physicians were satisfied with the overall care provided, and 89% of patients reported that the telehealth visits met their medical needs. CONCLUSION: One of the goals of telemedicine programs is to increase access to care. Therefore, it is important that the technology used to implement the program also be accessible in terms of cost and complexity. Tablets are low-cost technology, and their use in telemedicine has been shown to satisfy both physicians and patients with a wide variety of diagnoses.


Asunto(s)
Neurología , Médicos , Telemedicina , Humanos , Telemedicina/métodos , Derivación y Consulta , Encuestas y Cuestionarios
14.
Neuromodulation ; 26(2): 451-458, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36567243

RESUMEN

OBJECTIVE: The deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5-4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (ODT) (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report the 11-year outcomes of patients who completed the DBS in early-stage PD pilot clinical trial. MATERIALS AND METHODS: Attempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed-effects: assigned treatment, year, their interaction; random-effect: subject) to account for repeated measures. RESULTS: Twelve subjects participated in this 11-year follow-up study (n = 8 early ODT, n = 4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n = 4). Three early ODT subjects received STN-DBS as standard of care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (Unified Parkinson's Disease Rating Scale [UPDRS]-IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference = 3.5 points; pinteraction = 0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, Parkinson Disease Questionnaire-39 (PDQ-39), and levodopa equivalent daily dose (LEDD). CONCLUSIONS: Eleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution because only 40% of pilot trial subjects participated in this 11-year follow-up study. The Food and Drug Administration has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016). CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00282152.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Anciano , Enfermedad de Parkinson/tratamiento farmacológico , Estudios de Seguimiento , Estimulación Encefálica Profunda/métodos , Levodopa/uso terapéutico , Núcleo Subtalámico/fisiología , Resultado del Tratamiento
15.
Urology ; 172: 111-114, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36481202

RESUMEN

OBJECTIVE: To address historical concerns surrounding vasectomy in childless men, we sought to evaluate for the level of regret in this unique cohort. METHODS: The records of patients who underwent vasectomy via single surgeon between 2006 and 2021 were retrospectively reviewed and those who had not fathered children in any capacity at time of vasectomy were selected. We devised a 6-question survey inquiring about regret and thoughts on vasectomy reversal and assisted reproductive technology (ART). The questions are listed in Table 1. Patients were queried via a telephone call to rate their level of regret, both immediately after vasectomy and present day. The cohort was analyzed via age at time of vasectomy, time since vasectomy and marital status. RESULTS: There were 4812 overall patients who underwent vasectomy in this interval, with 205 (4.3%) who were childless. The response rate was 33.2% (68/205). Average age was 36.6 years with average time since vasectomy at time of phone call was 5.51 years. Regret rate was 4.4% immediately following vasectomy and 7.4% at time of telephone interview. A confirmatory, second consultation before vasectomy was present in 6.8% (14/205). The majority of patients 150/205 (73.1%) were married. When patients were stratified by marital status, there was no significant difference in any of the questions. The majority of patients were satisfied with their decision, with few contemplating or pursuing reversal or ART (Table 1). CONCLUSION: Regret in childless patients who undergo vasectomy is very rare, with the majority of patients feeling that their life was improved.


Asunto(s)
Vasectomía , Vasovasostomía , Masculino , Niño , Humanos , Adulto , Estudios Retrospectivos , Emociones , Técnicas Reproductivas Asistidas
16.
Cancers (Basel) ; 14(22)2022 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-36428586

RESUMEN

Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in preclinical research are of therapy-naïve tumors. Here, we describe the development of therapy-resistant IDH-wildtype glioblastoma patient-derived xenografts (PDX) through orthotopic engraftment of therapy naïve PDX in athymic nude mice, and repeated in vivo exposure to the therapeutic modalities most often used in treating glioblastoma patients: radiotherapy and temozolomide chemotherapy. Post-temozolomide PDX became enriched for C>T transition mutations, acquired inactivating mutations in DNA mismatch repair genes (especially MSH6), and developed hypermutation. Such post-temozolomide PDX were resistant to additional temozolomide (median survival decrease from 80 days in parental PDX to 42 days in a temozolomide-resistant derivative). However, temozolomide-resistant PDX were sensitive to lomustine (also known as CCNU), a nitrosourea which induces tumor cell apoptosis by a different mechanism than temozolomide. These PDX models mimic changes observed in recurrent GBM in patients, including critical features of therapy-driven tumor evolution. These models can therefore serve as valuable tools for improving our understanding and treatment of recurrent glioma.

17.
J Med Chem ; 65(23): 15642-15662, 2022 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-36410047

RESUMEN

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.


Asunto(s)
Neoplasias Encefálicas , Indolamina-Pirrol 2,3,-Dioxigenasa , Humanos , Animales , Ratones , Triptófano , Quimera Dirigida a la Proteólisis , Neoplasias Encefálicas/tratamiento farmacológico
18.
F1000Res ; 11: 1010, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36324813

RESUMEN

Median survival of patients with glioblastoma (GBM) treated with standard of care which consists of maximal safe resection of the contrast-enhancing portion of the tumor followed by radiation therapy with concomitant adjuvant temozolomide (TMZ) remains 15 months. The tumor microenvironment (TME) is known to contain immune suppressive myeloid cells with minimal effector T cell infiltration. Stimulator of interferon genes (STING) is an important activator of immune response and results in production of Type 1 interferon and antigen presentation by myeloid cells. This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches in gliomas.


Asunto(s)
Glioma , Proteínas de la Membrana , Humanos , Glioma/tratamiento farmacológico , Interferones , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Microambiente Tumoral
19.
Disaster Med Public Health Prep ; 17: e287, 2022 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-36229959

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic challenged not only the health-care industry, but also the public health infrastructure in new and wide-ranging ways. Environmental health (EH) professionals have proven to be an essential component of the interdisciplinary public health solution required to prevent, respond, and recover from the COVID-19 pandemic. The Indian Health Service's Division of Environmental Health Services is a community-based program offering a broad scope of environmental health services and technical assistance. Significant COVID-19 workload activities were recorded from March 2020 through March 2021. A total of 62.7% of the Division's federal staff completed a 24-question survey in February/March 2021. Primary roles relating to community-based EH, institutional EH, and incident command system support/teams became apparent. Results indicated Division of Environmental Health Services staff provided critical leadership and used their established, trusted, interdisciplinary partnerships to help ensure critical resources and services were available in Indian Country.


Asunto(s)
COVID-19 , Humanos , COVID-19/epidemiología , Pandemias/prevención & control , Personal de Salud , Salud Pública
20.
J Vet Med Educ ; : e20220049, 2022 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-36166193

RESUMEN

Work-based learning (WBL) provides relevant contemporary experience of working environments. Potential benefits for students include developing invaluable skills (clinical, personal, cultural, and professional) and gaining greater awareness of the profession and future career opportunities. However, there are also challenges related to running and sustaining a successful WBL program. In the context of this study, WBL refers to external placements undertaken by final-year students. The aims of the study were to identify ways to optimize the benefits while managing the challenges in delivering WBL in a veterinary curriculum. An in-depth study was undertaken at Chattogram Veterinary and Animal Sciences University (CVASU), Bangladesh, where a WBL program has been in place for 20 years. Final-year veterinary students at CVASU were surveyed to ascertain WBL experiences; survey findings were further explored in focus groups with students, recent graduates, faculty, and placement providers. Most agreed that they had sufficient opportunities to observe, assist, and directly handle pet and farm animals with top skills learned, including clinical diagnosis and communication, and recognized the value of learning in professional workplaces. Based on suggested areas of improvement, the following recommendations can be made: carefully selecting placements, adjusting time allocation, improving communication and building strong collaborations with placement providers, allowing students to customize more placements to align with their career preferences, and staffing adequately to arrange placements and manage a WBL program. Overall, results suggest the current WBL arrangements at CVASU are reasonably good, but there are some specific areas for improvement.

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