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1.
Nat Immunol ; 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39289557

RESUMO

PD-1 is a key negative regulator of CD8+ T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8+ T cells in chronic infection, creating a 'sweet spot' of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1-knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8+ T cell dysfunction while avoiding excess immunopathology.

3.
Blood Adv ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093952

RESUMO

The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

4.
Transplant Cell Ther ; 2024 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-39154914

RESUMO

Despite the concurrent use of haploidentical cord (HCT) and dual cord (DCT) stem cell transplant approaches for over a decade, there have been few comparisons of their outcomes. Our objective in this study is to assess for differences in the outcomes and adverse effects associated with HCTs versus DCTs. Here we report a retrospective analysis of HCTs and DCTs at our institution. From October 2012 to October 2022, 70 HCT and 133 DCT transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. With a median follow-up of 3.6 years among survivors, there was no difference in overall survival (OS) (3 years OS 65% DCT versus 63% HCT, P = 1) or relapse-free survival (3 years RFS 62% DCT versus 64% HCT, P = .97) for all patients. Time to neutrophil recovery was faster in HCT recipients (median 17 versus 22 days, P = .021), with no difference in platelet recovery to 20,000/µL (P = .12). Median hospitalization for HCT recipients was 20 days versus 24 days for DCT recipients (P < .0001). Engraftment syndrome treated with steroids occurred in 47/133 (35%) DCT recipients versus 42/70 (60%) HCT recipients (odds ratios 0.37, P value=.001). There was a significant increase in grade 3 to 4 acute graft-versus-host disease (aGVHD) in haplo-cord recipients (P = .007), but no difference in grade 2 to 4 aGVHD (P = .11), all chronic GVHD (cGVHD) (P = .9), or moderate-severe cGVHD (P = .3). Our outcomes demonstrate faster engraftment and shorter hospitalization in HCTs relative to DCTs, but more engraftment syndrome and higher grade 3 to 4 aGVHD. When both are options, these factors should guide the choice between HCTs and DCTs.

5.
Public Health Genomics ; 27(1): 100-109, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39173603

RESUMO

INTRODUCTION: When a pathogenic BRCA1 or BRCA2 mutation is identified in a family, cascade genetic testing of family members is recommended since the results may inform screening or treatment decisions in men and women. However, rates of cascade testing are low, and men are considerably less likely than women to pursue cascade testing. To facilitate cascade testing in men, we designed a Web-based genetic education tool that addressed barriers to cascade testing, was individually tailored, delivered proactively, and could be used in lieu of pretest genetic counseling to streamline the cascade testing process. METHODS: We randomized 63 untested men from hereditary cancer families to Web-based genetic education (WGE) versus enhanced usual care (EUC). WGE participants were provided access to a genetic education website after which they could accept or decline genetic testing or opt for pretest genetic counseling. EUC participants received an informational brochure and a letter informing them of their eligibility for genetic testing and recommending they schedule genetic counseling. The primary outcome was the uptake of genetic testing. RESULTS: Men in the WGE group were more likely to complete genetic counseling and/or genetic testing (43% vs. 12.1%; χ2 [n = 63, df = 1] = 7.77, p = 0.005). WGE participants were also more likely to complete genetic testing compared to men in the EUC group (30% vs. 9.1%; χ2 [n = 63, df = 1] = 4.46, p = 0.03). CONCLUSION: This preliminary trial suggests that a streamlined approach to genetic testing using proactively delivered genetic education may reduce barriers to cascade testing for at-risk men, leading to increased uptake. These results should be interpreted cautiously given the select sample and high rate of non-response.


Assuntos
Proteína BRCA2 , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Testes Genéticos/métodos , Feminino , Pessoa de Meia-Idade , Aconselhamento Genético/métodos , Adulto , Proteína BRCA2/genética , Predisposição Genética para Doença , Proteína BRCA1/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/diagnóstico , Mutação , Educação de Pacientes como Assunto/métodos , Idoso , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico
6.
Leuk Lymphoma ; : 1-7, 2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39216505

RESUMO

Outcomes in adult and pediatric patients with acute lymphoblastic leukemia (ALL) have improved over successive generations due to rigorously conducted clinical trials and incorporation of novel therapeutic agents. Despite these advances, approximately 20% of high-risk pediatric patients and 50% of adults with ALL will fail to achieve long-term remission with frontline chemotherapy protocols, mostly due to relapse. The ability to predict which patients with ALL are more likely to relapse allows for early intensification of therapy and/or incorporation of novel immunotherapies with the goal of relapse prevention. In this review, we outline the most robust clinical predictors of relapse in ALL with a focus on measurable residual disease (MRD) and genomics. We also discuss application of these prognostic tools in different clinical settings including frontline treatment, pre-/post-allogeneic stem cell transplant, and pre-/post-Chimeric Antigen Receptor T-cell therapy.

7.
Artigo em Inglês | MEDLINE | ID: mdl-38969076

RESUMO

BACKGROUND & AIMS: Investigating the tissue-associated microbiota after surgically induced remission may help to understand the mechanisms initiating intestinal inflammation in Crohn's disease. METHODS: Patients with Crohn's disease undergoing ileocolic resection were prospectively recruited in 6 academic centers. Biopsy samples from the neoterminal ileum, colon, and rectosigmoid were obtained from colonoscopies performed after surgery. Microbial DNA was extracted for 16S rRNA gene sequencing. Microbial diversity and taxonomic differential relative abundance were analyzed. A random forest model was applied to analyze the performance of clinical and microbial features to predict recurrence. A Rutgeerts score ≥i2 was deemed as endoscopic recurrence. RESULTS: A total of 349 postoperative colonoscopies and 944 biopsy samples from 262 patients with Crohn's disease were analyzed. Ileal inflammation accounted for most of the explained variance of the ileal and colonic mucosa-associated microbiota. Samples obtained from 97 patients who were in surgically induced remission at first postoperative colonoscopy who went on to develop endoscopic recurrence at second colonoscopy showed lower diversity and microbial deviations when compared with patients who remained in endoscopic remission. Depletion of genus Anaerostipes and increase of several genera from class Gammaproteobacteria at the 3 biopsy sites increase the risk of further recurrence. Gut microbiome was able to predict future recurrence better than clinical features. CONCLUSIONS: Ileal and colonic mucosa-associated microbiome deviations precede development of new-onset ileal inflammation after surgically induced remission and show good predictive performance for future recurrence. These findings suggest that targeted microbial modulation is a plausible modality to prevent postoperative Crohn's disease recurrence.

8.
Toxicon ; 248: 108035, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39059560

RESUMO

Anterocollis (AC) and retrocollis (RC) are less common cervical dystonia (CD) subtypes that are often under-represented in CD clinical trials. Herein we describe real-world demographics, disease characteristics, and treatment response to onabotulinumtoxinA (onabotA) in AC or RC patients from an observational, multicenter, prospective registry, CD PROBE. After three onabotA treatments, outcomes (CDIP-58, PGIC, CGIC, CD severity, TWSTRS) in patients with predominant AC or RC were compared to torticollis (TC) and all CD subtypes combined. The mean dosages at each treatment ranged from 153.5 to 195.4 U (AC) to 184.0-213.4 U (RC). After treatment, AC and RC patients reported improvements in the CDIP-58. "Much" or "very much improved" on PGIC and CGIC was reported by AC patients (n = 11/23, 48%) and clinicians (n = 14/23, 61%); and by RC patients (n = 14/24, 58%) and clinicians (n = 19/24, 83%). The mean total TWSTRS decreased from 45.7 (n = 59) to 36.1 (n = 23, 21.0% improvement) for AC patients and from 40.1 (n = 55) to 31.6 (n = 23, 21.2% improvement) for RC patients; the proportion of AC and RC patients with severe CD decreased. Outcomes for AC and RC were generally consistent with those for TC and all subtypes combined. Dysphagia was reported in 4/59 (6.8%) of AC patients (one serious), 7/55 (12.7%) of RC patients (none serious), 29/494 (5.9%) of TC patients (none serious), and 64/1012 (6.3%) of all CD patients (two serious). No new safety signals were identified. In conclusion, treatment with onabotA may relieve CD symptoms in some patients with AC and RC, consistent with results for other CD subtypes and the known safety profile of onabotA for the treatment of CD.


Assuntos
Toxinas Botulínicas Tipo A , Torcicolo , Humanos , Torcicolo/tratamento farmacológico , Toxinas Botulínicas Tipo A/uso terapêutico , Pessoa de Meia-Idade , Masculino , Feminino , Resultado do Tratamento , Adulto , Estudos Prospectivos , Idoso , Fármacos Neuromusculares/uso terapêutico
9.
Inflamm Bowel Dis ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953641

RESUMO

BACKGROUND: Almost half of patients with Crohn's disease (CD) require bowel surgeries in their lifetime. Due to the high risk of postoperative disease recurrence and high rate of previous antitumor necrosis factor (anti-TNF) failure, often alternative therapy options such as ustekinumab (UST) and vedolizumab (VDZ) are used. We aimed to evaluate the efficacy of UST and VDZ among postoperative CD patients as postoperative prophylaxis and rescue therapy. METHODS: Consented CD patients who underwent initial ileocecal resection and were treated with UST and VDZ were included in this study. Demographics, clinical characteristics, health care utilization, endoscopy scores, and surgery outcomes were collected. Postoperative early CD recurrence was defined as a Rutgeerts endoscopic score ≥i2 within the first 2 years. The rescue therapy group was defined as patients who received either UST or VDZ after having Rutgeerts endoscopic score ≥i2 postoperatively. RESULTS: During 2009 to 2019, 98 CD patients were treated with UST or VDZ postoperatively. Postoperative early recurrence rates were 5% (n = 1 out of 20) and 6% (1 out of 15) for the UST and VDZ groups, respectively. Two patients from the UST group and 1 patient from the VDZ group required bowel surgery during follow-up with median drug exposure of 51 (95% confidence interval [CI], 29-61) and 30 (95% CI, 14-63) months, respectively; 55% and 69% of patients had at least 1 point of improvement on postoperative endoscopic Rutgeerts score, respectively, for UST and VDZ. Only 3 out of 40 and 1 out of 23 patients required bowel surgery during follow-up while receiving UST and VDZ as rescue therapy. CONCLUSIONS: Both UST and VDZ were effective as postoperative therapies either as prophylaxis or rescue therapy.


This retrospective 11-year data examines the efficacy of ustekinumab and vedolizumab among postoperative Crohn's disease patients. When utilizing postoperative Rutgeerts score, this study confirms that both ustekinumab and vedolizumab were effective as postoperative therapies either as prophylaxis or rescue therapy.

10.
bioRxiv ; 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38895459

RESUMO

Biological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.

11.
J Neurosurg ; : 1-8, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38941635

RESUMO

OBJECTIVE: The objective of this study was to develop a nomogram to predict long-term facial nerve (FN) function after vestibular schwannoma (VS) resection. METHODS: A retrospective cohort study of two tertiary academic skull base referral centers was performed. Consecutive adults > 18 years of age with sporadic unilateral VS who underwent resection between September 2016 and May 2021 were included. FN function in the immediate postoperative period and at the most recent evaluation was measured. RESULTS: A total of 306 patients (mean age 49 years, 63% female) were included, with a mean follow-up of 18 months. The mean maximum tumor diameter was 19 mm (range 1-50 mm), and 80 (26.1%) tumors were > 25 mm. Overall, 85% of patients showed good immediate postoperative FN function (House-Brackmann [HB] grade I or II) and 89% maintained good FN function at > 12 months of follow-up. An intraoperative FN electromyographic (EMG) response ≥ 100 µV to 0.05 mA of stimulation (OR 18.6, p < 0.001) was the strongest predictor of good HB grade in the immediate postoperative period. EMG response ≥ 100 µV (OR 5.70, p < 0.001), tumor size ≤ 25 mm (OR 3.09, p < 0.05), and better immediate postoperative HB grade (OR 1.48, p = 0.005) predicted good long-term FN function on multivariable analysis. A point-of-care nomogram based on these data predicted long-term FN function with a sensitivity of 89% and specificity of 69%. CONCLUSIONS: Better immediate postoperative HB grade, intraoperative FN EMG response ≥ 100 µV, and tumor size ≤ 25 mm strongly predicted good long-term FN function after VS resection. A point-of-care nomogram based on these variables could serve as a useful tool for postoperative counseling and prognosis of long-term FN recovery.

12.
Leuk Lymphoma ; 65(6): 800-807, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38814858

RESUMO

Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/genética , Contagem de Leucócitos , Pessoa de Meia-Idade , Masculino , Feminino , Prognóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Quimioterapia de Indução/métodos , Resultado do Tratamento , Adulto Jovem , Transplante de Células-Tronco Hematopoéticas/métodos
13.
Otol Neurotol ; 45(6): 684-689, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38769097

RESUMO

OBJECTIVE: To evaluate quality-of-life outcomes for patients with vestibular schwannomas (VS) undergoing a middle cranial fossa (MCF) approach. STUDY DESIGN: Prospective study from 2018 to 2023. SETTING: Tertiary academic institution. PATIENTS: Adults with sporadic VS. INTERVENTIONS: MCF. MAIN OUTCOME MEASURES: The primary outcome measure was the change in preoperative and 1-year postoperative Penn Acoustic Neuroma Quality-of-life (PANQOL) scores. Secondary outcome measures included hearing preservation and facial nerve function. RESULTS: Of the 164 patients who underwent MCF for sporadic VS, 78 patients elected to voluntarily complete preoperative PANQOL assessments prior to surgery. Seventy-one (91%) of those 78 patients completed postoperative PANQOL surveys. Fifty (70%) of the respondents were female and the median age was 48 years (range, 27-71 years). Overall, at 1-year postsurgery, a minimal clinically important difference (MCID) was obtained in the hearing (mean difference, 10.5; 95% confidence interval [CI], 4.3-16.7) and anxiety (mean difference, 18.8; 95% CI, 11.7-25.9) domains. For patients with hearing preservation (n = 48, 68%), MCIDs were reached in the hearing (mean difference, 13.4; 95% CI, 6.3-20.6), anxiety (mean difference, 20.8; 95% CI, 11.8-29.9), energy (mean difference, 13.7; 95% CI, 3.6-23.8), pain (mean difference, 13.7; 95% CI, 3.6-23.8) domains, and overall PANQOL scores (mean difference, 12.7; 95% CI, 7.1-18.3). Postoperatively, 64 (90%) patients maintained a House-Brackmann I. CONCLUSIONS: To our knowledge, this is the largest study examining disease-specific QOL for VS patients undergoing MCF. Based on our institution's experience, MCF approach for small VS is associated with clinically meaningful improvements in QOL, hearing preservation, and excellent facial nerve outcomes.


Assuntos
Fossa Craniana Média , Craniotomia , Neuroma Acústico , Qualidade de Vida , Humanos , Neuroma Acústico/cirurgia , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Fossa Craniana Média/cirurgia , Idoso , Estudos Prospectivos , Craniotomia/efeitos adversos , Resultado do Tratamento
14.
PM R ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38813838

RESUMO

INTRODUCTION: Upper and lower limb spasticity is commonly associated with central nervous system disorders including stroke, traumatic brain injury, multiple sclerosis, cerebral palsy, and spinal cord injury, but little is known about the concurrent treatment of upper and lower limb spasticity with botulinum toxins. OBJECTIVE: To evaluate onabotulinumtoxinA (onabotA) utilization and to determine if concurrent onabotA treatment of the upper and lower limbs has supported improvements in participants with spasticity. DESIGN: Sub-analysis of a 2-year, international, prospective, observational registry (ASPIRE, NCT01930786). SETTING: International clinic sites (54). PARTICIPANTS: Adult spasticity participants across etiologies, who received ≥1 concurrent onabotA treatment of the upper and lower limbs during the study. INTERVENTION: Participants were treated with onabotA at the clinician's discretion. OUTCOMES: Baseline characteristics and outcomes of disability (Disability Assessment Scale [DAS]), pain (Numeric Pain Rating Scale [NPRS]), participant satisfaction, physician satisfaction, and quality of life (QoL; Spasticity Impact Assessment [SIA]) were evaluated. Adverse events were monitored throughout the study. RESULTS: Of 744 participants enrolled, 730 received ≥1 dose of onabotA; 275 participants received treatment with onabotA in both upper and lower limbs during ≥1 session; 39.3% of participants were naïve to onabotA for spasticity. The mean (SD) total dose per treatment session ranged from 421.2 (195.3) to 499.6 (188.6) U. The most common baseline upper limb presentation was clenched fist (n = 194, 70.5%); lower limb was equinovarus foot (n = 219, 66.9%). High physician and participant satisfaction and improvements in pain, disability and QoL were reported after most treatments. Nine participants (3.3%) reported nine treatment-related adverse events; two participants (0.7%) reported three serious treatment-related severe adverse events. No new safety signals were identified. CONCLUSION: More than a third of enrolled participants received at least one concurrent onabotA treatment of the upper and lower limbs, with reduced pain, disability, and improved QoL after treatment, consistent with the established safety profile of onabotA for the treatment of spasticity.

15.
Toxicon ; 241: 107678, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38447766

RESUMO

According to prescribing information, potency units are not interchangeable between botulinum toxin A products. This exploratory study compared real-world dosing and utilization of onabotulinumtoxinA and abobotulinumtoxinA in adults with upper limb spasticity. In this retrospective study, 101 clinicians provided chart data via online surveys for 215 US post-stroke patients treated for upper limb spasticity with ≥3 onabotulinumtoxinA or abobotulinumtoxinA doses (phase 1: 9/18/2020-12/10/2020; phase 2: 9/30/2021-12/7/2021). Most participating clinicians were physicians (70.3%) specializing in neurology (71.3%) or physiatry (20.8%). In the onabotulinumtoxinA (n = 107) and abobotulinumtoxinA (n = 108) groups, ∼75% of patients had moderate-to-severe spasticity. A range of onabotulinumtoxinA:abobotulinumtoxinA dose ratios (1:2.2 [95% CI: 1.8, 2.6] to 1:4.1 [95% CI: 3.0, 6.0]) was observed across muscles. For the most recent dose, mean number of muscles injected was greater for onabotulinumtoxinA (4.3) versus abobotulinumtoxinA (3.1; P = 0.0003). For onabotulinumtoxinA versus abobotulinumtoxinA, the proportion of injections was 81.3% versus 63.9% (P = 0.0067) in forearm muscles and 23.4% versus 3.7% (P = 0.0001) in hand muscles. Mean injection intervals were similar (onabotulinumtoxinA: 102.0 days; abobotulinumtoxinA: 99.1 days). Differences in real-world dosing and utilization of onabotulinumtoxinA and abobotulinumtoxinA for upper limb spasticity were observed. There was no standard dose-conversion ratio, consistent with each product's prescribing information.


Assuntos
Toxinas Botulínicas Tipo A , Fármacos Neuromusculares , Adulto , Humanos , Toxinas Botulínicas Tipo A/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Espasticidade Muscular/tratamento farmacológico , Extremidade Superior , Fármacos Neuromusculares/uso terapêutico
16.
J Exp Med ; 221(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38411617

RESUMO

In vivo T cell screens are a powerful tool for elucidating complex mechanisms of immunity, yet there is a lack of consensus on the screen design parameters required for robust in vivo screens: gene library size, cell transfer quantity, and number of mice. Here, we describe the Framework for In vivo T cell Screens (FITS) to provide experimental and analytical guidelines to determine optimal parameters for diverse in vivo contexts. As a proof-of-concept, we used FITS to optimize the parameters for a CD8+ T cell screen in the B16-OVA tumor model. We also included unique molecular identifiers (UMIs) in our screens to (1) improve statistical power and (2) track T cell clonal dynamics for distinct gene knockouts (KOs) across multiple tissues. These findings provide an experimental and analytical framework for performing in vivo screens in immune cells and illustrate a case study for in vivo T cell screens with UMIs.


Assuntos
Linfócitos T CD8-Positivos , Animais , Camundongos , Técnicas de Inativação de Genes
17.
Qual Life Res ; 33(1): 253-265, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37589772

RESUMO

PURPOSE: The assumption that patient-provider communication may mediate patients' sense of control over cancer to affect health outcomes has limited evidence. This study examines whether patient-perceived cancer care communication quality (PPCQ) mediates stress appraisal and coping behavior, affecting physical functioning across different racial groups. METHODS: Two hundred and twenty Chinese American and 216 non-Hispanic White (NHW) women (ages 28-80) with stage 0-III breast cancer, 1-5 years post-diagnosis, and without recurrence, enrolled and completed a cross-sectional telephone survey. Physical functioning was measured by the NIH-PROMIS short form. Validated measures of PPCQ, patients' evaluation of their socioeconomic well-being, stress appraisal (perceived severity and control), use of coping strategies, treatment-related symptoms, and comorbidities were also assessed. Path analyses were used to examine the mediation for each racial group. RESULTS: Regardless of race, treatment-related symptoms, comorbidities, and socioeconomic well-being were all directly related to physical functioning (p < 0.05). The impact of PPCQ on physical functioning was mediated by perceived control in the Chinese American group (p < 0.05), but not in the NHW group. Perceived severity and coping were not mediators of physical functioning in either group. CONCLUSIONS: The mediational pathway from PPCQ to perceived control to physical functioning in Chinese American survivors may be partially explained by their lower socioeconomic well-being and culturally valued conformity to physicians as a medical authority. These sociocultural dynamics reinforce the importance of cancer care communication. For NHW survivors, the impact of treatment-related symptoms and socioeconomic well-being on physical functioning outweighed their PPCQ and perceived control.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Feminino , Humanos , Neoplasias da Mama/terapia , China , Comunicação , Capacidades de Enfrentamento , Estudos Transversais , Qualidade de Vida/psicologia , Fatores Raciais , Sobreviventes , Brancos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais
18.
Nat Biotechnol ; 42(4): 582-586, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37291427

RESUMO

Full-length RNA-sequencing methods using long-read technologies can capture complete transcript isoforms, but their throughput is limited. We introduce multiplexed arrays isoform sequencing (MAS-ISO-seq), a technique for programmably concatenating complementary DNAs (cDNAs) into molecules optimal for long-read sequencing, increasing the throughput >15-fold to nearly 40 million cDNA reads per run on the Sequel IIe sequencer. When applied to single-cell RNA sequencing of tumor-infiltrating T cells, MAS-ISO-seq demonstrated a 12- to 32-fold increase in the discovery of differentially spliced genes.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Isoformas de RNA , DNA Complementar/genética , Isoformas de RNA/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Isoformas de Proteínas/genética , Análise de Sequência de RNA/métodos , Transcriptoma , Perfilação da Expressão Gênica/métodos , RNA/genética
19.
Otol Neurotol ; 45(1): 92-99, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38085765

RESUMO

OBJECTIVE: Cystic vestibular schwannomas (cVSs) have more variable and less favorable clinical outcomes after microsurgical resection compared with solid VS (sVS). This study compares the preoperative presentation and postoperative outcomes between cVS and sVS. STUDY DESIGN: Retrospective cohort study. SETTING: Two tertiary skull base referral centers. METHODS: Consecutive adult patients who underwent VS resection from 2016 to 2021 were included. Univariate and multivariate analyses compared differences in baseline symptoms and postoperative outcomes between cVS and sVS. RESULTS: There were a total of 315 patients (64% female; mean age, 54 yrs) and 46 (15%) were cystic. cVS were significantly larger than sVS (maximum diameter, 28 vs. 18 mm, p < 0.001) and had higher rates of dysphagia and dysphonia preoperatively (p < 0.02). cVSs were more likely to undergo translabyrinthine resection (76 vs. 50%, p = 0.001) and have a higher rate of subtotal resection (STR) compared with sVS (30 vs. 13%, p = 0.003). At latest follow-up, fewer cVS achieved good facial nerve (FN) outcome (House-Brackmann [HB] I/II) (80 vs. 90%, p = 0.048). Subanalysis of cVS and sVS matched in tumor size, and surgical approach did not show differences in the rate of STR or FN outcomes (HB I/II, 82 vs. 78%, p = 0.79). CONCLUSION: In this large multi-institutional series, cVSs represent a distinct entity and are characterized by larger tumor size and higher incidence of atypical symptoms. Although cVSs were more likely to undergo STR and portend worse FN outcomes than sVSs, this may be due to their larger tumor size rather than the presence of the cystic component.


Assuntos
Neuroma Acústico , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Neuroma Acústico/patologia , Estudos Retrospectivos , Resultado do Tratamento , Seguimentos , Procedimentos Neurocirúrgicos/efeitos adversos , Nervo Facial/cirurgia , Complicações Pós-Operatórias/etiologia
20.
J Natl Compr Canc Netw ; 21(12): 1261-1268.e14, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38081141

RESUMO

BACKGROUND: Germline genetic testing is recommended for men with metastatic or high-risk prostate cancer to inform treatment and risk management for other cancers and inform genetic testing in at-risk relatives. However, relatively few patients with prostate cancer undergo genetic testing. Given the low rate of testing and increasing demands on genetic service providers, strategies are needed that reduce barriers to testing while conserving genetic counseling resources. The primary goal of this study was to determine whether a proactive and streamlined "traceback" approach could yield increased genetic testing participation among prostate cancer survivors. METHODS: We randomized 107 survivors of metastatic and high-risk prostate cancer to streamlined testing (ST) versus enhanced usual care (EUC). ST participants were proactively provided with print genetic education materials and the option to proceed to genetic testing without pre-test genetic counseling. EUC participants were sent a letter from their physician advising them of their eligibility for genetic testing and recommending they schedule genetic counseling. The primary outcome was genetic testing participation. Secondary outcomes were distress, knowledge, decision satisfaction, and regret. RESULTS: In the ST group, 41.5% of participants completed genetic testing compared with 27.8% in the EUC group. After adjusting for education and marital status, the odds of testing were more than twice as high for the ST group as for the EUC group (odds ratio, 2.57; 95% CI, 1.05-6.29). The groups did not differ on any of the psychosocial outcomes at the 3-month follow-up. CONCLUSIONS: Proactive outreach paired with streamlined genetic testing delivery may be a safe, effective, and resource-efficient approach to facilitate traceback genetic testing in prostate cancer survivors.


Assuntos
Sobreviventes de Câncer , Neoplasias da Próstata , Humanos , Masculino , Aconselhamento Genético , Testes Genéticos , Mutação , Projetos Piloto , Próstata , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética
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