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1.
Breast Cancer Res Treat ; 189(3): 665-676, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34553296

RESUMO

PURPOSE: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. METHODS: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. RESULTS: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity. CONCLUSION: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. CLINICAL TRIAL REGISTRATION: NCT01808573.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Capecitabina/uso terapêutico , Feminino , Humanos , Lapatinib/uso terapêutico , Quinolinas , Receptor ErbB-2/genética , Resultado do Tratamento
2.
Clin Cancer Res ; 27(21): 5818-5827, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380637

RESUMO

PURPOSE: Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2+) metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS. PATIENTS AND METHODS: Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models. RESULTS: Four hundred and twenty samples had successful sequencing: 34.0% had PIK3CA mutations and 5.5% had HER2 (ERBB2) mutations. In the combined patient populations, PIK3CA mutations trended toward shorter PFS [wild-type vs. mutant, HR = 0.81; 95% confidence interval (CI), 0.64-1.03], whereas HER2 mutations trended toward longer PFS [HR = 1.69 (95% CI, 0.97-3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3+ vs. 2+, HR = 0.67 (0.54-0.82); H-score ≥240 versus <240, HR = 0.77 (0.63-0.93); HERmark positive vs. negative, HR = 0.76 (0.59-0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with L+C [IHC 3+, HR = 0.64 (0.51-0.81); H-score ≥ 240, HR = 0.54 (0.41-0.72); HERmark positive, HR = 0.65 (0.50-0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm2, HR = 0.66 (0.50-0.86) vs. p95 < 2.8 RF/mm2, HR = 0.91 (0.61-1.36)]. CONCLUSIONS: PIK3CA mutations were associated with shorter PFS whereas higher HER2 expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C.

3.
Prev Med Rep ; 23: 101410, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34150472

RESUMO

Eating a healthy diet is important for managing diabetes. Although there are high rates of diabetes in low-income urban areas, these patients often have limited access to fruits and vegetables. The 15-week Fresh Prescription (Fresh Rx) program was designed to improve access and consumption of fruits and vegetables among low-income patients with diabetes in Detroit, MI. The purpose of this study was to evaluate the effects of a fruit and vegetable prescription program on changes in hemoglobin A1C (HbA1C), blood pressure (BP), and body mass index (BMI) in patients with diabetes in a randomized controlled trial at a federally qualified health center (FQHC). Patients randomized to the Fresh Rx group (n = 56) were allotted up to $80 ($10 for up to eight weeks) for purchase of produce from a farmers market based at the FQHC. The control group (n = 56) received standard treatment plus information on community resources to improve health. Outcomes were compared at baseline and within three months of program completion. There were no significant between-group differences for any of the outcomes at program completion (p > .05); however, there was a small effect size for HbA1c (partial Î·2 = 0.02). Within the Fresh Rx group, HbA1c significantly decreased from 9.64% to 9.14% (p = 0.006). However, no changes were noted within the control group (9.38 to 9.41%, p = 0.89). BMI and BP did not change from pre- to post-study in either group (p > .05). Results from this study offer preliminary evidence that produce prescription programs may reduce HbA1C in low-income patients with diabetes.

4.
Am J Obstet Gynecol ; 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33974903

RESUMO

BACKGROUND: Uterine leiomyomas, commonly known as fibroids, are benign tumors in postmenarchal females. By the age of 35 years, approximately 30% of females will have fibroids, and by the age of 50 years, the prevalence approaches 70% with some studies reporting >85% prevalence in African American females. Previous studies evaluating the prevalence of fibroids have largely relied on self-reported fibroid diagnoses, which could have falsely underestimated prevalence because many females with fibroids are asymptomatic. Despite known differences in fibroid prevalence by race, there are very limited data on fibroid prevalence by ethnicity. The Latino population is the largest ethnic minority in the United States, yet there is no large study that utilizes ultrasound to confirm the presence of fibroids in Latina/Latinx females. In addition, fibroids have been associated with obesity and with diabetes mellitus, but the data have been inconsistent and at times conflicting. OBJECTIVE: The Environment, Leiomyomas, Latinas, and Adiposity Study was designed to quantify the prevalence of uterine fibroids among Latina/Latinx females and understand the relationships between obesity, glucose dysregulation, and fibroid prevalence and growth. This article presents the study's design and reports early enrollment data. STUDY DESIGN: The Environment, Leiomyomas, Latinas, and Adiposity Study is a 5-year longitudinal cohort study based in Southeast Michigan with the goal of recruiting 600 Latina/Latinx females between the ages of 21 and 50 years. Given the recruitment goals, developing a respectful, transparent, and trusting relationship between the study investigators and the community was a major priority. Thus, a community-engaged research approach was utilized in the design of the Environment, Leiomyomas, Latinas, and Adiposity Study. A community advisory board containing community leaders, largely from the Latinx community, provided input and direction during the entirety of the Environment, Leiomyomas, Latinas, and Adiposity Study design and rollout process. A minimum of 3 visits (orientation and consent, baseline, follow-up) will be conducted for each participant, with baseline and follow-up visits approximately 18 to 30 months apart. At each visit, interviewer and self-administered surveys will assess sociodemographic factors, health behaviors, health history, and social determinants of health. In addition, participants undergo a pelvic ultrasound examination and biologic samples are collected. RESULTS: Using community-engaged approaches, we have successfully enrolled 633 Latina/Latinx females. The mean participant age is 37.5±7.04 years. The mean body mass index is 30.0±6.54 kg/m2. First study visits have been initiated. CONCLUSION: The objective of the Environment, Leiomyomas, Latinas, and Adiposity Study is to address the knowledge gap regarding uterine fibroids in the Latina/Latinx population. The Environment, Leiomyomas, Latinas, and Adiposity Study will generate ultrasound-confirmed evidence of the prevalence and growth patterns of uterine fibroids in this specific population while also examining the associations between obesity and laboratory-confirmed glucose dysregulation with uterine fibroid prevalence and growth patterns.

5.
Oncologist ; 26(8): e1327-e1338, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34028126

RESUMO

BACKGROUND: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). MATERIALS AND METHODS: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. RESULTS: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. CONCLUSION: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. IMPLICATIONS FOR PRACTICE: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.


Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Sistema Nervoso Central , Feminino , Humanos , Quinolinas , Receptor ErbB-2/uso terapêutico , Resultado do Tratamento
6.
Soc Sci Med ; 280: 114027, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029864

RESUMO

RATIONALE: Social support is a key determinant of physical and mental health outcomes. Implementation of restrictive immigration policies in the U.S. under the Trump administration impacted the way mixed-status Latino families (i.e., those with varying legal statuses, including undocumented) maintained social relationships and provided social support. OBJECTIVE: This paper examines how federal immigration policies introduced after the 2016 U.S. presidential election impacted social networks and support related to health for undocumented and mixed-status Latino families. METHODS: We interviewed 23 clients and 28 service providers at two Federally Qualified Health Centers and one non-profit organization in Southeast Michigan. The interviews were audio-recorded, transcribed, and analyzed thematically. RESULTS: Policies introduced during the Trump administration increased opportunities for deportation and contributed to the isolation of mixed-status Latino families by transforming safe spaces of social interaction into prime locations for immigration enforcement activity. Despite the limitations created by these restrictive policies, mixed-status families employed alternative mechanisms to maintain access to vital informal and formal support systems while simultaneously navigating emerging immigration-related threats. CONCLUSIONS: Elections have health consequences and immigration policies are needed that promote the health and well-being of Latino immigrant communities.


Assuntos
Emigração e Imigração , Aplicação da Lei , Hispano-Americanos , Humanos , Michigan , Apoio Social
7.
Breast Cancer Res Treat ; 188(2): 449-458, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33909203

RESUMO

PURPOSE: To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. METHODS: In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan-Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. RESULTS: Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63-1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32-2.23]). CONCLUSION: In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.


Assuntos
Neoplasias da Mama , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Capecitabina/efeitos adversos , Feminino , Humanos , Quinolinas , Receptor ErbB-2/genética
8.
ChemSusChem ; 14(6): 1545-1553, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33465299

RESUMO

The deoxydehydration of carbohydrates represents a key target to leverage renewable biomass resources chemically. Using a vanadium(V)-based catalyst, it was possible to directly deoxydehydrate cyclic trans-diol substrates. Accompanying mechanistic characterisation of this process by density functional calculations pointed to an energetically tractable route for deoxydehydration of cyclic trans-diol substrates involving stepwise cleavage of the diol C-O bonds via the triplet state; experimentally, this was supported by light dependence of the reaction. Calculations also indicated that cyclic cis-diols and a linear diol substrate could additionally proceed by a concerted singlet DODH mechanism. This work potentially opens a new and cost-effective way to efficiently convert carbohydrates of trans-diol stereochemistry into alkenes.

9.
Clin Breast Cancer ; 21(1): 80-91.e7, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33183970

RESUMO

BACKGROUND: The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-positive (HR+) early-stage breast cancer (eBC). PATIENTS AND METHODS: ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2+ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤ 1 year (HR+/≤ 1-year) and > 1 year (HR+/> 1-year) post-trastuzumab. RESULTS: HR+/≤ 1-year and HR+/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR+/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR+/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported. CONCLUSION: Neratinib significantly improved iDFS in the HER2+/HR+/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.

10.
Public Health Nutr ; 24(3): 549-560, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32993845

RESUMO

OBJECTIVE: To develop and implement a community-tailored, food agency-based cooking programme at a community health centre (CHC) and evaluate the effect of the intervention on cooking confidence and food waste. DESIGN: This study used an exploratory, sequential mixed methods design. Focus groups (n 38) were conducted to inform the development of a cooking intervention, then six cooking classes (n 45) were planned and piloted in the health centre's teaching kitchen. Changes in cooking confidence and related outcomes were assessed using pre- and post-class surveys. Follow-up interviews (n 12) were conducted 2-4 months post-intervention to assess satisfaction and short-term outcomes. SETTING: A CHC in Detroit, MI. PARTICIPANTS: Spanish- and English-speaking adults aged ≥18 years recruited at the CHC. RESULTS: In the formative focus groups, patients identified multiple barriers to cooking healthy meals, including trade-offs between quality, cost and convenience of food, chronic disease management and lack of time and interest. Each cooking class introduced a variety of cooking techniques and food preservation strategies. Participants demonstrated increased confidence in cooking (P 0·004), experimenting with new ingredients (P 0·006) and knowing how to make use of food before it goes bad (P 0·017). In post-class interviews, participants reported that they valued the social interaction and participatory format and that they had used the recipes and cooking techniques at home. CONCLUSIONS: A community-tailored, hands-on cooking class was an effective way to engage patients at a CHC and resulted in increased cooking confidence.


Assuntos
Culinária/métodos , Adulto , Idoso , Centros Comunitários de Saúde , Feminino , Educação em Saúde , Humanos , Masculino , Refeições , Pessoa de Meia-Idade , Eliminação de Resíduos
11.
Elife ; 92020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33216713

RESUMO

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1ß and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered an attractive therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown. Chloride efflux is suggested as an important step in NLRP3 activation, but which chloride channels are involved is still unknown. We used chemical, biochemical, and genetic approaches to establish the importance of chloride channels in the regulation of NLRP3 in murine macrophages. Specifically, we identify LRRC8A, an essential component of volume-regulated anion channels (VRAC), as a vital regulator of hypotonicity-induced, but not DAMP-induced, NLRP3 inflammasome activation. Although LRRC8A was dispensable for canonical DAMP-dependent NLRP3 activation, this was still sensitive to chloride channel inhibitors, suggesting there are additional and specific chloride sensing and regulating mechanisms controlling NLRP3.


Assuntos
Alarminas/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Proteínas de Membrana/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Cloretos/imunologia , Feminino , Humanos , Inflamassomos/genética , Inflamação/genética , Macrófagos/imunologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pressão Osmótica
12.
iScience ; 23(9): 101474, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32905878

RESUMO

Through in vitro kinase assays and docking studies, we report the synthesis and biological evaluation of a phenothiazine analog J54 with potent TLK1 inhibitory activity for prostate cancer (PCa) therapy. Most PCa deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa. Treatments that can suppress the conversion to mCRPC have high potential to be rapidly implemented in the clinics. ADT results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DNA damage response that typically results in temporary cell-cycle arrest of androgen-responsive PCa cells, whereas its abrogation leads to apoptosis. We studied J54 as a potent inhibitor of this axis and as a mediator of apoptosis in vitro and in LNCaP xenografts, which has potential for clinical investigation in combination with ADT. J54 has low affinity for the dopamine receptor in modeling and competition studies and weak detrimental behavioral effects in mice and C. elegans.

13.
Am J Community Psychol ; 66(3-4): 325-336, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32776579

RESUMO

This paper applies the Minority Stress framework to data collected from an ongoing community-based participatory research project with health and social service agencies in Southeast Michigan. We examine the stressors and coping strategies employed by undocumented Latinx immigrants and their families to manage immigration-related stress. We conducted in-depth interviews with 23 immigrant clients at Federally Qualified Health Care Centers (FQHC) in Southeast Michigan and 28 in-depth interviews with staff at two FQHC's and a non-profit agency serving immigrants. Findings suggest that immigrants face heightened anxiety and adverse mental health outcomes because of unique minority identity-related stressors created by a growing anti-immigrant social environment. Chronic stress experienced stems from restrictive immigration policies, anti-immigrant rhetoric in the media and by political leaders, fear of deportation, discriminatory events, concealment, and internalized anti-immigrant sentiment. Though identity can be an important effect modifier in the stress process, social isolation in the immigrant community has heightened the impact of stress and impeded coping strategies. These stressors have resulted in distrust in community resources, uncertainty about future health benefits, delayed medical care, and adverse mental health outcomes. Findings provide a framework for understanding the unique stressors experienced by immigrants and strategies for interventions by social service agencies.


Assuntos
Hispano-Americanos/psicologia , Saúde Mental , Grupos Minoritários/psicologia , Estresse Psicológico/etnologia , Imigrantes Indocumentados/psicologia , Adaptação Psicológica , Ansiedade/etnologia , Pesquisa Participativa Baseada na Comunidade , Medo , Feminino , Acesso aos Serviços de Saúde , Humanos , Masculino , Michigan , Pesquisa Qualitativa , Serviço Social
14.
Gynecol Oncol ; 159(1): 150-156, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32723675

RESUMO

OBJECTIVE: Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors. METHODS: Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety. RESULTS: Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations. CONCLUSIONS: Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population. TRIAL REGISTRATION NUMBER: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).


Assuntos
Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Neoplasias do Colo do Útero/tratamento farmacológico , Administração Oral , Adulto , Diarreia/induzido quimicamente , Diarreia/diagnóstico , Diarreia/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Náusea/induzido quimicamente , Náusea/diagnóstico , Náusea/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Receptor ErbB-2/genética , Critérios de Avaliação de Resposta em Tumores Sólidos , Índice de Gravidade de Doença , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade
15.
J Clin Oncol ; 38(27): 3138-3149, 2020 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-32678716

RESUMO

PURPOSE: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/metabolismo , Neoplasias da Mama Masculina/patologia , Capecitabina/administração & dosagem , Diarreia/induzido quimicamente , Feminino , Humanos , Estimativa de Kaplan-Meier , Lapatinib/administração & dosagem , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Intervalo Livre de Progressão , Qualidade de Vida , Quinolinas/administração & dosagem , Receptor ErbB-2/metabolismo , Retratamento , Taxa de Sobrevida
16.
J Chem Inf Model ; 60(8): 3901-3909, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32628846

RESUMO

Small molecule compounds which form colloidal aggregates in solution are problematic in early drug discovery; adsorption of the target protein by these aggregates can lead to false positives in inhibition assays. In this work, we probe the molecular basis of this inhibitory mechanism using molecular dynamics simulations. Specifically, we examine in aqueous solution the adsorption of the enzymes ß-lactamase and PTP1B onto aggregates of the drug miconazole. In accordance with experiment, molecular dynamics simulations observe formation of miconazole aggregates as well as subsequent association of these aggregates with ß-lactamase and PTP1B. When complexed with aggregate, the proteins do not exhibit significant alteration in protein tertiary structure or dynamics on the microsecond time scale of the simulations, but they do indicate persistent occlusion of the protein active site by miconazole molecules. MD simulations further suggest this occlusion can occur via surficial interactions of protein with miconazole but also potentially by envelopment of the protein by miconazole. The heterogeneous polarity of the miconazole aggregate surface seems to underpin its activity as an invasive and nonspecific inhibitory agent. A deeper understanding of these protein/aggregate systems has implications not only for drug design but also for their exploitation as tools in drug delivery and analytical biochemistry.


Assuntos
Inibidores Enzimáticos , Simulação de Dinâmica Molecular , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas , beta-Lactamases/metabolismo
17.
PLoS One ; 15(6): e0233839, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502193

RESUMO

Immigration- and enforcement-related policies and laws have significantly and negatively impacted the health and well-being of undocumented immigrants. We examine barriers and facilitators to healthcare and social services among undocumented Latino(a)/Latinx immigrants specifically in the post 2016 US presidential election socio-political climate. By grounding our study on the perspectives of frontline providers, we explore their challenges in meeting the needs of their undocumented clients. These include client access to healthcare and social services, the barriers providers face in providing timely and effective services, and avenues to reduce or overcome factors that impede service provision to improve quality of care for this population. Data are from 28 in-depth interviews with frontline healthcare and social service providers. Based on data analysis, we found that the domains of the Three Delays Model used in obstetric care provided a good framework for organizing and framing the responses. Our findings suggest that these undocumented clients encounter three phases of delay: delay in the decision to seek care, delay in identifying and traveling to healthcare facilities, and delay in receiving adequate and appropriate care at healthcare facilities. Given the current socio-political climate for immigrants, healthcare and social services organizations that serve undocumented clients should adapt existing services or introduce new services, including those that are not site-based.


Assuntos
Acesso aos Serviços de Saúde , Hispano-Americanos , Serviço Social , Imigrantes Indocumentados , Atenção à Saúde , Feminino , Pessoal de Saúde , Humanos , Entrevistas como Assunto , Masculino , Michigan , Tempo para o Tratamento
18.
Health Soc Care Community ; 28(6): 2004-2012, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32462702

RESUMO

Rising hostility towards immigrants characterised the 2016 Presidential election in the United States (US) and subsequent policy priorities by the new presidential administration. The political shift towards aggressive policies targeting undocumented immigrants is far-reaching and extends into other communities that convive con-or coexist with-immigrant communities. Our study aims to examine the rippling effects of these anti-immigrant policies and rhetoric on health and social service providers in Southeast Michigan who predominantly serve Latino immigrants. Between April and August 2018, we conducted in-depth individual interviews in two Federally Qualified Health Centers and a non-profit social service agency at a county health department. We interviewed 28 frontline health and social service providers. After coding and thematic analyses, we found that staff members' experiences in supporting immigrant clients was congruent with definitions of secondary trauma stress and compassion fatigue, whereby exposure to clients' trauma combined with job burden subsequently impacted the mental health of providers. Major themes included: (a) frontline staff experienced a mental and emotional burden in providing services to immigrant clients given the restrictive anti-immigrant context; and (b) this burden was exacerbated by the increased difficulties in providing these services to their clients. Staff described psychological and emotional distress stemming from exposure to clients' immigration-related trauma and increased mental health needs. This distress was exacerbated by an increased demand to meet clients' needs, which involved explaining or translating documents into English, assisting with legal paperwork, referring clients to mental health resources, addressing increased transportation barriers, and reestablishing trust with the community. Our findings add qualitative data on the mental health implications for frontline providers who support Latino immigrant clients impacted by immigration and highlights the need for further research and resources that address the workplace-related stress generated by heightened immigration enforcement.


Assuntos
Emigrantes e Imigrantes/psicologia , Pessoal de Saúde/psicologia , Saúde Mental , Políticas , Assistentes Sociais/psicologia , Adulto , Fadiga por Compaixão/epidemiologia , Feminino , Hispano-Americanos/psicologia , Humanos , Entrevistas como Assunto , Masculino , Michigan/epidemiologia , Política , Provedores de Redes de Segurança/organização & administração , Estresse Psicológico/epidemiologia , Estados Unidos/epidemiologia
19.
Heliyon ; 6(3): e03474, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32258449

RESUMO

Appropriate hygiene practices and vaccine acceptance are key factors impacting the health of homeless individuals. A recent outbreak of hepatitis A in Michigan, especially impacting Detroit, prompted us to investigate the practices and attitudes of Detroit's homeless population toward hygiene measures and vaccinations, as well as barriers to such resources. We developed a questionnaire as a means to collect our data, and participants were interviewed at shelters and soup kitchens. While the majority of participants adhered to healthy hygiene practices, approximately 89% reported barriers to accessing public showers. More than half the participants (64%) reported receiving their hepatitis A vaccine prior to the study, while 23% reported previously refusing or hesitating to receive vaccinations. Despite an overall favorable adherence to hygiene practices, substantial barriers are yet to be overcome. Moreover, active measures should be taken to establish higher levels of trust between providers and the homeless to encourage vaccine acceptance.

20.
Methods Mol Biol ; 2114: 339-353, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32016902

RESUMO

There is significant potential for electronic structure methods to improve the quality of the predictions furnished by the tools of computer-aided drug design, which typically rely on empirically derived functions. In this perspective, we consider some recent examples of how quantum mechanics has been applied in predicting protein-ligand geometries, protein-ligand binding affinities and ligand strain on binding. We then outline several significant developments in quantum mechanics methodology likely to influence these approaches: in particular, we note the advent of more computationally expedient ab initio quantum mechanical methods that can provide chemical accuracy for larger molecular systems than hitherto possible. We highlight the emergence of increasingly accurate semiempirical quantum mechanical methods and the associated role of machine learning and molecular databases in their development. Indeed, the convergence of improved algorithms for solving and analyzing electronic structure, modern machine learning methods, and increasingly comprehensive benchmark data sets of molecular geometries and energies provides a context in which the potential of quantum mechanics will be increasingly realized in driving future developments and applications in structure-based drug discovery.


Assuntos
Descoberta de Drogas/métodos , Preparações Farmacêuticas/química , Algoritmos , Desenho de Fármacos , Humanos , Ligantes , Proteínas/química , Teoria Quântica
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