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1.
Cell ; 187(12): 3056-3071.e17, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38848678

RESUMO

The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.


Assuntos
Homeostase , Mucosa Intestinal , Receptores Acoplados a Proteínas G , Regeneração , Células-Tronco , Animais , Células-Tronco/metabolismo , Células-Tronco/citologia , Camundongos , Mucosa Intestinal/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Intestinos/citologia , Diferenciação Celular , Camundongos Endogâmicos C57BL , Células Epiteliais/metabolismo , Análise de Célula Única , Masculino
2.
Curr Treat Options Oncol ; 25(5): 628-643, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38649630

RESUMO

OPINION STATEMENT: Immunotherapy for glioblastoma (GBM) remains an intensive area of investigation. Given the seismic impact of cancer immunotherapy across a range of malignancies, there is optimism that harnessing the power of immunity will influence GBM as well. However, despite several phase 3 studies, there are still no FDA-approved immunotherapies for GBM. Importantly, the field has learned a great deal from the randomized studies to date. Today, we are continuing to better understand the disease-specific features of the microenvironment in GBM-as well as the exploitable antigenic characteristic of the tumor cells themselves-that are informing the next generation of immune-based therapeutic strategies. The coming phase of next-generation immunotherapies is thus poised to bring us closer to treatments that will improve the lives of patients with GBM.


Assuntos
Neoplasias Encefálicas , Imunoterapia , Microambiente Tumoral , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Glioblastoma/terapia , Glioblastoma/imunologia , Terapia Combinada/métodos , Resultado do Tratamento , Gerenciamento Clínico , Ensaios Clínicos como Assunto
3.
Mov Disord ; 38(11): 2116-2121, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37914913

RESUMO

BACKGROUND: Cervical dystonia (CD) is an intricate neurological condition with motor and nonmotor symptoms. These include disruptions in visual perception, self-orientation, visual working memory, and vestibular functions. However, the specific impact of CD on perceiving self-motion direction, especially with isolated visual or vestibular stimuli, remains largely unexplored. OBJECTIVE: This study aimed to examine the effects of CD on linear motion perception, hypothesizing impaired heading discrimination in both vestibular and visual tasks, and that such deficits correlate with the disease severity. METHODS: We employed a cutting-edge motion platform to precisely control whole-body linear motion. Through repeated two-alternative forced-choice tasks, we assessed vestibular heading direction discrimination. Participants observed dynamic star clouds in immersive virtual reality and indicated their perceived self-motion direction, evaluating visual heading direction discrimination. Sensitivity to direction variations and response accuracy errors were analyzed using robust Gaussian cumulative distribution psychometric functions. RESULTS: Heading perception is impaired in individuals with CD, particularly evident in vestibular heading discrimination. CD severity correlated with elevated thresholds for both vestibular and visual heading discrimination. Surprisingly, lateralized CD did not introduce bias in either system, suggesting widespread disruption over localized effects. CONCLUSIONS: Contrary to previous beliefs, our findings challenge the idea that CD-related heading discrimination issues mainly arise from peripheral vestibular effects. Instead, abnormal proprioceptive input from dystonic neck muscles introduces noise into the central mechanism integrating visual, vestibular, and proprioceptive signals. These insights into spatial navigation deficits have implications for future CD research. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.


Assuntos
Percepção de Movimento , Navegação Espacial , Torcicolo , Vestíbulo do Labirinto , Humanos , Estimulação Luminosa , Percepção de Movimento/fisiologia , Percepção Visual , Vestíbulo do Labirinto/fisiologia
4.
Biotechnol Bioeng ; 120(5): 1382-1398, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36639843

RESUMO

Astaxanthin (AX) is a carotenoid pigment with antioxidant properties widely used as a feed supplement. Wild-type strains of Phaffia rhodozyma naturally produce low AX yields, but we increased AX yields 50-fold in previous research using random mutagenesis of P. rhodozyma CBS6938 and fermentation optimization. On that study, genome changes were linked with phenotype, but relevant metabolic changes were not resolved. In this study, the wild-type and the superior P. rhodozyma mutant strains were grown in chemically defined media and instrumented fermenters. Differential kinetic, metabolomics, and transcriptomics data were collected. Our results suggest that carotenoid production was mainly associated with cell growth and had a positive regulation of central carbon metabolism metabolites, amino acids, and fatty acids. In the stationary phase, amino acids associated with the TCA cycle increased, but most of the fatty acids and central carbon metabolism metabolites decreased. TCA cycle metabolites were in abundance and media supplementation of citrate, malate, α-ketoglutarate, succinate, or fumarate increased AX production in the mutant strain. Transcriptomic data correlated with the metabolic and genomic data and found a positive regulation of genes associated with the electron transport chain suggesting this to be the main driver for improved AX production in the mutant strain.


Assuntos
Basidiomycota , Carotenoides , Transporte de Elétrons , Carotenoides/metabolismo , Basidiomycota/genética , Basidiomycota/metabolismo , Ácidos Graxos/metabolismo
5.
Biotechnol Bioeng ; 120(11): 3276-3287, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37489850

RESUMO

Pichia pastoris (Komagataella phaffii) is a fast-growing methylotrophic yeast with the ability to assimilate several carbon sources such as methanol, glucose, or glycerol. It has been shown to have outstanding secretion capability with a variety of heterologous proteins. In previous studies, we engineered P. pastoris to co-express Escherichia coli AppA phytase and the HAC1 transcriptional activator using a bidirectional promoter. Phytase production was characterized in shake flasks and did not reflect industrial conditions. In the present study, phytase expression was explored and optimized using instrumented fermenters in continuous and fed-batch modes. First, the production of phytase was investigated under glucose de-repression in continuous culture at three dilution factors, 0.5 d-1 , 1 d-1 , and 1.5 d-1 . The fermenter parameters of these cultures were used to inform a kinetic model in batch and fed-batch modes for growth and phytase production. The kinetic model developed aided to design the glucose-feeding profile of a fed-batch culture. Kinetic model simulations under glucose de-repression and fed-batch conditions identified optimal phytase productivity at the specific growth rate of 0.041 h-1 . Validation of the model simulation with experimental data confirmed the feasibility of the model to predict phytase production in our newly engineered strain. Methanol was used only to induce the expression of phytase at high cell densities. Our results showed that high phytase production required two stages, the first stage used glucose under de-repression conditions to generate biomass while expressing phytase, and stage two used methanol to induce phytase expression. The production of phytase was improved 3.5-fold by methanol induction compared to the expression with glucose alone under de-repression conditions to a final phytase activity of 12.65 MU/L. This final volumetric phytase production represented an approximate 36-fold change compared to the flask fermentations. Finally, the phytase protein produced was assayed to confirm its molecular weight, and pH and temperature profiles. This study highlights the importance of optimizing protein production in P. pastoris when using novel promoters and presents a general approach to performing bioprocess optimization in this important production host.

6.
J Pediatr Neurol ; 21(6): 475-478, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38481935

RESUMO

DMN1L encodes for dynamin-like protein 1 (DLP1) which plays a key role in perixosomal and mitochondrial fission. Individuals with heterozygous variants in DNM1L present with a wide range of neurologic symptoms, including encephalopathy, epilepsy, and motor deficits. Here we report on a woman presenting with adolescence onset of sensory neuronopathy, spasticity, dystonia, and ataxia. Trio genome sequencing identified a heterozygous variant in DNM1L (NM_012062.3 c.121G>A/p.Val41Met) which was thought to be pathogenic. This case describes the latest known symptomatic onset of DMN1L-related disease described in literature. We highlight our approach to a challenging diagnostic workup and interpretation of a specific variant that has not been previously reported. Furthermore, the case highlights the diagnostic importance of utilizing genomic sequencing and research studies for patients with rare disease.

7.
Am J Obstet Gynecol ; 218(6): 614.e1-614.e8, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29614276

RESUMO

BACKGROUND: Misoprostol is a common agent that is used to ripen the cervix and induce labor, yet there is no clear evidence of the optimal number of doses needed to achieve a higher rate of vaginal delivery. OBJECTIVE: Our primary objective was to compare the rate of vaginal delivery within 24 hours between a 1-dose and a multiple-dose regimen of misoprostol for the induction of labor. STUDY DESIGN: A randomized controlled trial was conducted from March 2016 to March 2017 that compared a single dose to up to 4 doses of misoprostol. Randomization was stratified by parity. Women with a singleton pregnancy ≥37 weeks gestation with intact membranes who had been admitted for labor induction with a Bishop score ≤6 were included. Our primary outcome was the rate of vaginal delivery within 24 hours. Secondary outcomes included time to vaginal delivery, cesarean delivery rate, and maternal and neonatal morbidity. Based on a power of 80%, an alpha of .05, and the assumption that 50% of women in the multiple-misoprostol group would deliver vaginally in 24 hours, a sample size of 220 patients was needed to detect a 20% increase in vaginal delivery rate within 24 hours in the 1-misoprostol group. Continuous variables were compared with the use of the Mann-Whitney test. Categoric variables were compared with the use of the Fisher's exact test. Probability values <.05 were considered statistically significant. RESULTS: Two hundred fifty women were assigned randomly. Demographics and clinical characteristics were similar between groups. In the univariate analysis, there was no difference in the rate of vaginal delivery within 24 hours between the 1-misoprostol group and the multiple-dose group (41.7% vs 44.7%, respectively; P=.698) or time to vaginal delivery (1187 min vs 1321 min, respectively; P=.202). The 1-misoprostol group had a greater cesarean delivery rate (35.8% vs 22.8%; P=.034). In a Poisson regression that controlled for Bishop score before the initiation of oxytocin, parity, gestational age, body mass index, estimated fetal weight, artificial rupture of membrane at <6 cm, and Foley balloon placement, the treatment group was no longer associated with cesarean delivery rate. Instead, a Bishop score of <4 before the initiation of oxytocin and nulliparity were associated significantly with cesarean delivery rate. CONCLUSION: In this first randomized controlled trial in the literature to compare a single with a multiple dosing of misoprostol, we found that the 1-dose regimen is an acceptable alternative for the induction for labor, especially for multiparous women and for patients with a Bishop score >4 after the first dose.


Assuntos
Cesárea/estatística & dados numéricos , Trabalho de Parto Induzido/métodos , Misoprostol , Ocitócicos , Administração Intravaginal , Adulto , Maturidade Cervical , Parto Obstétrico/estatística & dados numéricos , Relação Dose-Resposta a Droga , Feminino , Humanos , Paridade , Gravidez , Fatores de Tempo , Adulto Jovem
9.
J Appl Toxicol ; 37(5): 573-582, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27813108

RESUMO

Long-term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic (As2 O3 ) in oxidative stress-mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP-ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H2 O2 )-induced PARylation was suppressed by As2 O3 exposure in different human cancer cells. Moreover, As2 O3 treatment promoted H2 O2 -induced DNA damage and apoptosis, leading to increased cell death. We found that N-ethylmaleimide (NEM), an organic compound derived from maleic acid, could reverse As2 O3 -mediated effects, thus enhancing PARylation with attenuated cell death and increased cell survival. Pharmacologic inhibition of glutathione with l-buthionine-sulfoximine blocked the antagonistic effect of NEM on As2 O3 , thereby continuing As2 O3 -mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against As2 O3 -mediated DNA damage in a glutathione-dependent manner. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Antídotos/farmacologia , Arsenicais/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Etilmaleimida/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Óxidos/antagonistas & inibidores , Poli ADP Ribosilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Butionina Sulfoximina/farmacologia , Linhagem Celular Tumoral , Ensaio de Unidades Formadoras de Colônias , Ensaio Cometa , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Etilmaleimida/antagonistas & inibidores , Humanos , Óxidos/toxicidade
11.
Blood ; 123(6): 931-4, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24357731

RESUMO

Immune complexes consisting of heparin, platelet factor 4 (PF4), and PF4/heparin-reactive antibodies are central to the pathogenesis of heparin-induced thrombocytopenia (HIT). It is as yet unclear what triggers the initial induction of pathogenic antibodies. We identified B cells in peripheral blood of healthy adults that produce PF4/heparin-specific antibodies following in vitro stimulation with proinflammatory molecules containing deoxycytosine-deoxyguanosine (CpG). Similarly, B cells from unmanipulated wild-type mice produced PF4/heparin-specific antibodies following in vitro or in vivo CpG stimulation. Thus, both healthy humans and mice possess preexisting inactive/tolerant PF4/heparin-specific B cells. The findings suggest that breakdown of tolerance leads to PF4/heparin-specific B-cell activation and antibody production in patients developing HIT. Consistent with this concept, mice lacking protein kinase Cδ (PKCδ) that are prone to breakdown of B-cell tolerance produced anti-PF4/heparin antibodies spontaneously. Therefore, breakdown of tolerance can lead to PF4/heparin-specific antibody production, and B-cell tolerance may play an important role in HIT pathogenesis.


Assuntos
Formação de Anticorpos/imunologia , Anticoagulantes/efeitos adversos , Linfócitos B/imunologia , Heparina/efeitos adversos , Fator Plaquetário 4/metabolismo , Proteína Quinase C-delta/fisiologia , Trombocitopenia/imunologia , Adulto , Animais , Anticoagulantes/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Células Cultivadas , Heparina/metabolismo , Humanos , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator Plaquetário 4/imunologia , Prognóstico , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo
12.
Cryobiology ; 73(1): 63-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27256663

RESUMO

PURPOSE: To evaluate the cytokine transforming growth factor beta 1 (TGF-ß1) as a predictor of oncological outcomes in patients after cryoablation. MATERIALS AND METHODS: Perioperative blood samples from prostate cancer (PC) patients who underwent total gland cryoablation between October 2011 and March 2013 were collected prospectively. Plasma TGF-ß1 levels were quantified using magnetic bead immunoassay. The perioperative change in TGF-ß1 was defined as the change in TGF-ß1 from before surgery to 1-2 months after surgery. Biochemical recurrence (BCR) was defined according to the Phoenix criteria. The Mann-Whitney U, Kruskal-Wallis rank sum, and Chi-square test were used to compare the clinical characteristics of the subsets. The Cox proportional hazard model was applied for the comparison of recurrence risk among the groups. RESULTS: A total of 75 PC patients were included. During a median follow-up period of 12 months (range: 2.5-47 months), 11 patients had BCR, and 64 patients did not. Significantly greater changes in the perioperative TGF-ß1 levels (median: 470.3 vs. 78.9 pg/ml) were observed in patients with than without BCR (p < 0.05). According to the changes in TGF-ß1 levels, the patients were further divided into 4 groups, which were determined in the quartile categories of perioperative TGF-ß1 levels. Group 4 (≥430) predicted the worst BCR outcome. CONCLUSIONS: Perioperative plasma TGF-ß1 levels were associated with BCR after prostate cryoablation for localized PC. Increase in postoperative plasma TGF-ß1 may be a novel predictor for poor oncological outcomes and prompt a more aggressive follow-up or earlier salvage treatment.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Próstata/sangue , Fator de Crescimento Transformador beta1/biossíntese , Idoso , Criocirurgia/métodos , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Modelos de Riscos Proporcionais , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Fator de Crescimento Transformador beta1/sangue
13.
OTO Open ; 8(1): e119, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38420351

RESUMO

Objective: The aim of this study is to evaluate the association between race and the treatment of laryngeal dysplasia and early-stage laryngeal squamous cell carcinoma (LSCC). Study design: Retrospective Cohort Study. Setting: Large multispecialty academic medical center. Methods: Patients were treated for laryngeal dysplasia or LSCC between September 2019 and September 2022. A retrospective chart review was conducted to collect demographic and clinical information. Two-sample t tests, chi-square tests, and linear regression models were used to compare characteristics (α = 0.05). Analyses were performed in STATA 17. Results: Sixty-five patients were identified that underwent potassium titanyl phosphate (KTP) transoral laser microsurgery for management of early-stage LSCC (n = 29) or dysplasia (n = 36). The cohort consisted of 23 Black and 42 White patients. No significant difference was found in age, alcohol or tobacco use, rate of adjuvant radiotherapy, stage of disease, nor insurance status between the 2 groups. White patients underwent more procedures to address initial disease and subsequent recurrent dysplasia on average than Black patients (2.52 vs 1.52, P = .02). This remained true after adjusting for demographic and clinical characteristics and insurance status in a linear regression model. While Black patients were more likely to be lost to follow-up than White patients (30.4% vs 9.5%, P = .03), the average number of procedures between the groups still differed significantly (2.63 vs 1.56, P = .04) when controlling for those lost to follow-up. Conclusion: The findings presented here highlight potential inequities that exist for racial minorities at early stages of treatment and in addressing premalignant conditions, which may contribute to the known downstream disparities in laryngeal cancer outcomes.

14.
J Am Geriatr Soc ; 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38944677

RESUMO

BACKGROUND: Sensory disability in older adults is associated with increased rates of depressive symptoms and loneliness. Here, we examined the impact of hearing, vision, and olfaction disability on mental health outcomes in older US adults. METHODS: We studied respondents from the first three rounds (2005/6, 2010/11, and 2015/16) of the National Social Life, Health and Aging Project, a nationally representative, longitudinal study of older US adults. Sensory function was assessed by structured interviewer ratings (hearing and vision) and objective assessment (olfaction). Cox proportional hazards models and one degree of freedom tests for trend were utilized to analyze the relationships between sensory disability and self-rated mental health, frequent depressive symptoms, frequent perceived stress, frequent anxiety symptoms, and frequent loneliness symptoms over time, adjusting for demographics, health behaviors, comorbidities, and cognitive function. RESULTS: We analyzed data from 3940 respondents over 10 years of follow-up. A greater number of sensory disabilities was associated with greater hazard of low self-rated mental health, frequent depressive symptoms, frequent perceived stress, and frequent loneliness symptoms over time (p ≤ 0.003, all). After adjusting for covariates, older adults with a greater number of sensory disabilities had greater hazard of low self-rated mental health (HR = 1.22, CI = [1.08, 1.38], p = 0.002) and loneliness symptoms (HR = 1.13, CI = [1.05, 1.22], p = 0.003) over time in our tests for trend. In our Cox proportional hazards model, older adults with vision disability had greater hazard of low self-rated mental health (HR = 1.34, 95% CI = [1.05, 1.72], p = 0.02) and loneliness symptoms (HR = 1.21, CI = [1.04, 1.41], p = 0.01). CONCLUSIONS: Older US adults with greater numbers of sensory disabilities face worse subsequent mental health. Future longitudinal studies dissecting the relationship of all five classical senses will be helpful in further understanding how improving sensory function might improve mental health in older adults.

15.
Artigo em Inglês | MEDLINE | ID: mdl-38305427

RESUMO

BACKGROUND AND OBJECTIVES: Asleep, image-guided deep brain stimulation (DBS) is a modern alternative to awake, microelectrode recording (MER) guidance. Studies demonstrate comparable efficacy and complications between techniques, although some report lower stimulation thresholds for side effects with image guidance. In addition, few studies directly compare the risk of postoperative transient confusion (pTC) across techniques. The purpose of this study was to compare clinical efficacy, stimulation thresholds for side effects, and rates of pTC with MER-guided DBS vs intraoperative 3D-fluoroscopy (i3D-F) guidance in Parkinson's disease and essential tremor. METHODS: Consecutive patients from 2006 to 2021 were identified from the departmental database and grouped as having either MER-guided DBS or i3D-F-guided DBS insertion. Directional leads were used once commercially available. Changes in Unified Parkinson's Disease Rating Scale (UPDRS)-III scores, levodopa equivalent daily dose, Fahn-Tolosa-Marin scores, and stimulation thresholds were assessed, as were rates of complications including pTC. RESULTS: MER guidance was used to implant 487 electrodes (18 globus pallidus interna, GPi; 171 subthalamic nucleus; 76 ventrointermediate thalamus, VIM) in 265 patients. i3D-F guidance was used in 167 electrodes (19 GPi; 25 subthalamic nucleus; 41 VIM) in 85 patients. There were no significant differences in Unified Parkinson's Disease Rating III Scale, levodopa equivalent daily dose, or Fahn-Tolosa-Marin between groups. Stimulation thresholds for side effects were higher with i3D-F guidance in the subthalamic nucleus (MER, 2.80 mA ± 0.98; i3D-F, 3.46 mA ± 0.92; P = .002) and VIM (MER, 2.81 mA ± 1.00; i3D-F, 3.19 mA ± 1.03; P = .0018). Less pTC with i3D-F guidance (MER, 7.5%; i3D-F, 1.2%; P = .034) was also found. CONCLUSION: Although clinical efficacy between MER-guided and i3D-F-guided DBS was comparable, thresholds for stimulation side effects were higher with i3D-F guidance and the rate of pTC was lower. This suggests that image-guided DBS may affect long-term side effects and pose a decreased risk of pTC.

16.
bioRxiv ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38915559

RESUMO

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of treatment. CAR-mediated trogocytosis (CMT) is a potential tumor escape mechanism in which cell surface proteins transfer from tumor cells to CAR T cells. CMT results in the emergence of antigen-negative tumor cells, which can evade future CAR detection, and antigen-positive CAR T cells, which is hypothesized to lead to CAR T cell fratricide and dysfunction. Using a system to selectively degrade trogocytosed antigen in CAR T cells, we show that the presence of trogocytosed antigen in CAR T cells directly causes CAR T cell fratricide and exhaustion. By performing a small molecule screening using a custom high throughput CMT-screening assay, we identified the cysteine protease cathepsin B (CTSB) as a key driver of CMT. We show that overexpression of cystatin A (CSTA), an endogenous human inhibitor of CTSB, reduces trogocytosis resulting in prolonged antitumor activity and increased CAR T cell expansion/persistence. Overall, we show that targeting CMT is an effective approach to enhance CAR T cell function, which may improve their clinical efficacy.

17.
bioRxiv ; 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38370665

RESUMO

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin α4 (A4ko), an adhesion molecule essential for migration across the blood-brain barrier. A4ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells.

18.
Parkinsonism Relat Disord ; 111: 105433, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37141688

RESUMO

INTRODUCTION: COVID-19 infection is known to cause various neurological symptoms, and potentially increases the risk of developing subsequent neurodegenerative conditions including parkinsonism. To our knowledge, no study to date has used a large data set in the United States to ascertain the risk of developing incident Parkinson disease in patients with history of COVID-19 infection compared to the risk amongst those without prior COVID-19 infection. METHODS: We utilized data from TriNetX electronic health records network which includes 73 healthcare organizations and over 107 million patients. We compared adult patients with and without COVID-19 infection, with health records from January 1, 2020 through July 26, 2022, to determine the relative risk of developing Parkinson disease stratified by 3-month intervals. We used propensity score matching to control for patients' age, sex, and smoking history. RESULTS: We collected data on 27,614,510 patients meeting our study criteria: 2,036,930 patients with a positive COVID-19 infection (COVID-19) and 25,577,580 without a positive COVID-19 infection (non-COVID-19). After propensity score matching, age, sex, and smoking history differences became non-significant, with 2,036,930 patients in each cohort. After propensity score matching, we found significantly increased odds of new onset Parkinson disease in the COVID-19 cohort at three, six, nine, and twelve months from the index event, with peak odds ratio at six months. After twelve months there is no significant difference between the COVID-19 group and non-COVID-19 group. CONCLUSIONS: There may be a transiently increased risk of developing Parkinson disease in the first year following COVID-19 infection.


Assuntos
COVID-19 , Doença de Parkinson , Adulto , Humanos , Estados Unidos , SARS-CoV-2 , Estudos Retrospectivos , Doença de Parkinson/epidemiologia , Registros Eletrônicos de Saúde
19.
iScience ; 26(10): 107865, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37766975

RESUMO

The circadian rhythm pacemaker, the suprachiasmatic nucleus (SCN), mediates light entrainment via vasoactive intestinal peptide (VIP) neurons (SCNVIP). Yet, how these neurons uniquely respond and connect to intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin (Opn4) has not been determined functionally in freely behaving animals. To address this, we first used monosynaptic tracing from SCNVIP neurons in mice and identified two SCNVIP subpopulations. Second, we recorded calcium changes in response to ambient light, at both bulk and single-cell levels, and found two unique activity patterns in response to high- and low-intensity blue light. The activity patterns of both subpopulations could be manipulated by application of an Opn4 antagonist. These results suggest that the two SCNVIP subpopulations connect to two types of Opn4-expressing ipRGCs, likely M1 and M2, but only one is responsive to red light. These findings have important implications for our basic understanding of non-image-forming circadian light processing.

20.
Int J Gen Med ; 16: 1591-1602, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37152273

RESUMO

Background: Few reports have investigated chatbots in patient care. We aimed to assess the current applications, limitations, and challenges in the literature on chatbots employed in oncological care. Methods: We queried the PubMed database through April 2022 and included studies that investigated the use of chatbots in different phases of oncological care. The search used five different combinations of the specific terms "chatbot", "cancer", "oncology", and "conversational agent". Inclusion criteria were chatbot use in any aspect of oncological care-prevention, patient education, treatment, and surveillance. Results: The initial search yielded 196 records, 21 of which met inclusion criteria. The identified chatbots mostly focused on breast and ovarian cancer (n=8), with the second most common being cervical cancer (n=3). Good patient satisfaction was reported among 14 of 21 chatbots. The most reported chatbot applications were cancer screening, prevention, risk stratification, treatment, monitoring, and management. Of 12 studies examining efficacy of care via chatbot, 9 demonstrated improvements compared to standard care. Conclusion: Chatbots used for oncological care to date demonstrate high user satisfaction, and many have shown efficacy in improving patient-centered communication, accessibility to cancer-related information, and access to care. Currently, chatbots are primarily limited by the need for extensive user-testing and iterative improvement before widespread implementation.

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