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1.
Oncologist ; 29(5): 400-406, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38339991

RESUMO

BACKGROUND: In qualitative work, patients report that seemingly short trips to clinic (eg, a supposed 10-minute blood draw) often turn into "all-day affairs." We sought to quantify the time patients with cancer spend attending ambulatory appointments. METHODS: We conducted a retrospective study of patients scheduled for oncology-related ambulatory care (eg, labs, imaging, procedures, infusions, and clinician visits) at an academic cancer center over 1 week. The primary exposure was the ambulatory service type(s) (eg, clinician visit only, labs and infusion, etc.). We used Real-Time Location System badge data to calculate clinic times and estimated round-trip travel times and parking times. We calculated and summarized clinic and total (clinic + travel + parking) times for ambulatory service types. RESULTS: We included 435 patients. Across all service day type(s), the median (IQR) clinic time was 119 (78-202) minutes. The estimated median (IQR) round-trip driving distance and travel time was 34 (17-49) miles and 50 (36-68) minutes. The median (IQR) parking time was 14 (12-15) minutes. Overall, the median (IQR) total time was 197 (143-287) minutes. The median total times for specific service type(s) included: 99 minutes for lab-only, 144 minutes for clinician visit only, and 278 minutes for labs, clinician visit, and infusion. CONCLUSION: Patients often spent several hours pursuing ambulatory cancer care on a given day. Accounting for opportunity time costs and the coordination of activities around ambulatory care, these results highlight the substantial time burdens of cancer care, and support the notion that many days with ambulatory health care contact may represent "lost days."


Assuntos
Assistência Ambulatorial , Agendamento de Consultas , Neoplasias , Humanos , Neoplasias/terapia , Feminino , Masculino , Estudos Retrospectivos , Assistência Ambulatorial/estatística & dados numéricos , Pessoa de Meia-Idade , Fatores de Tempo , Idoso , Adulto
2.
BMC Cancer ; 24(1): 201, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38350888

RESUMO

BACKGROUND: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. METHODS: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. DISCUSSION: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05673148, registered December 21, 2022.


Assuntos
Neoplasias do Colo , Neoplasias Hepáticas , Radiocirurgia , Neoplasias Retais , Humanos , Estudos Prospectivos , Radiocirurgia/métodos , Neoplasias Hepáticas/terapia
4.
Pediatr Dermatol ; 41(3): 497-500, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38173086

RESUMO

Mycobacterium avium-intracellulare (MAC) infection may have different skin manifestations, including cutaneous granulomas. Granulomatous skin reactions have distinct morphologic and histopathologic appearances. We present the case of an adolescent male with cutaneous MAC, misdiagnosed as sarcoidosis after initial biopsy results, demonstrated preservation of reticulin fibers and absence of organisms within granulomas. Sarcoidal granulomas often stain positive for reticulin fibers, which could be used to distinguish them from the infectious kind. This case should alert clinicians to the fact that the presence or quantity of intact reticular fibers may not be a reliable tool to differentiate between a sarcoidal and an infectious granuloma. Our case also highlights the diagnostic challenge of cutaneous MAC infection.


Assuntos
Infecção por Mycobacterium avium-intracellulare , Sarcoidose , Humanos , Masculino , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Diagnóstico Diferencial , Sarcoidose/diagnóstico , Adolescente , Dermatopatias Bacterianas/diagnóstico , Dermatopatias Bacterianas/microbiologia , Complexo Mycobacterium avium/isolamento & purificação , Biópsia
5.
Echocardiography ; 38(2): 222-229, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33368601

RESUMO

AIMS: The aim of this investigation was to evaluate echocardiographic parameters of cardiac function and in particular right ventricular (RV) function as a predictor of mortality in patients with coronavirus disease-2019 (COVID-19) pneumonia. METHODS AND RESULTS: This prospective observational study included 35 patients admitted to a UK district general hospital with COVID-19 and evidence of cardiac involvement, that is, raised Troponin I levels or clinical evidence of heart failure during the first wave of the COVID-19 pandemic (March-May 2020). All patients underwent echocardiography including speckle tracking for right ventricular longitudinal strain (RVLS) providing image quality was sufficient (30 out of 35 patients). Upon comparison of patients who survived COVID-19 with non-survivors, survivors had significantly smaller RVs (basal RV diameter 38.2 vs 43.5 mm P = .0295) with significantly better RV function (Tricuspid annular plane systolic excursion (TAPSE): 17.5 vs 15.3 mm P = .049; average RVLS: 24.3% vs 15.6%; P = .0018). Tricuspid regurgitation (TR) maximal velocity was higher in survivors (2.75 m/s vs 2.11 m/s; P = .0045) indicating that pressure overload was not the predominant driver of this effect and there was no significant difference in left ventricular (LV) ejection fraction. Kaplan-Meier and log-rank analysis of patients split into groups according to average RVLS above or below 20% revealed significantly increased 30-day mortality in patients with average RVLS under 20% (HR: 3.189; 95% CI: 1.297-12.91; P = .0195). CONCLUSION: This study confirms that RVLS is a potent and independent predictor of outcome in COVID-19 patients with evidence of cardiac involvement.


Assuntos
COVID-19/epidemiologia , Ecocardiografia Tridimensional/métodos , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Pandemias , Volume Sistólico/fisiologia , Função Ventricular Direita/fisiologia , Idoso , Comorbidade , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Projetos Piloto , Prognóstico , Estudos Prospectivos , SARS-CoV-2
6.
Dev Biol ; 408(1): 41-55, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26455409

RESUMO

The C-terminal Eps15 homology domain-containing (EHD) proteins play a key role in endocytic recycling, a fundamental cellular process that ensures the return of endocytosed membrane components and receptors back to the cell surface. To define the in vivo biological functions of EHD1, we have generated Ehd1 knockout mice and previously reported a requirement of EHD1 for spermatogenesis. Here, we show that approximately 56% of the Ehd1-null mice displayed gross ocular abnormalities, including anophthalmia, aphakia, microphthalmia and congenital cataracts. Histological characterization of ocular abnormalities showed pleiotropic defects that include a smaller or absent lens, persistence of lens stalk and hyaloid vasculature, and deformed optic cups. To test whether these profound ocular defects resulted from the loss of EHD1 in the lens or in non-lenticular tissues, we deleted the Ehd1 gene selectively in the presumptive lens ectoderm using Le-Cre. Conditional Ehd1 deletion in the lens resulted in developmental defects that included thin epithelial layers, small lenses and absence of corneal endothelium. Ehd1 deletion in the lens also resulted in reduced lens epithelial proliferation, survival and expression of junctional proteins E-cadherin and ZO-1. Finally, Le-Cre-mediated deletion of Ehd1 in the lens led to defects in corneal endothelial differentiation. Taken together, these data reveal a unique role for EHD1 in early lens development and suggest a previously unknown link between the endocytic recycling pathway and regulation of key developmental processes including proliferation, differentiation and morphogenesis.


Assuntos
Endocitose , Cristalino/embriologia , Cristalino/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Catarata/complicações , Catarata/embriologia , Catarata/genética , Catarata/patologia , Diferenciação Celular , Polaridade Celular , Sobrevivência Celular , Embrião de Mamíferos/patologia , Endotélio Corneano/metabolismo , Endotélio Corneano/patologia , Células Epiteliais/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Cristalino/patologia , Camundongos Knockout , Microftalmia/complicações , Microftalmia/embriologia , Microftalmia/genética , Fenótipo , Proteínas de Transporte Vesicular/deficiência
7.
J Biol Chem ; 289(44): 30443-30458, 2014 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-25225290

RESUMO

ErbB2 overexpression drives oncogenesis in 20-30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca(2+)-dependent PKCs (α, ß1, ßII, and γ). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-α and PKC-δ together with the endocytic recycling regulator Arf6. PKC-α knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-δ knockdown. PMA-induced Erk phosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-δ but not that of PKC-α. Our results suggest that activation of PKC-α and -δ mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling.


Assuntos
Antineoplásicos/farmacologia , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C-delta/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/metabolismo , Benzoquinonas/farmacologia , Neoplasias da Mama , Carbazóis/farmacologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Endocitose/efeitos dos fármacos , Endossomos/metabolismo , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Retroalimentação Fisiológica , Feminino , Humanos , Indóis/farmacologia , Lactamas Macrocíclicas/farmacologia , Sistema de Sinalização das MAP Quinases , Fosforilação , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-delta/antagonistas & inibidores , Processamento de Proteína Pós-Traducional , Transporte Proteico
8.
Dermatol Online J ; 19(6): 18570, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24011319

RESUMO

The combination of propranolol and pulsed dye laser for the treatment of infantile hemangiomas may be superior to either alone. This case report illustrates the additive effect of propranolol and pulsed dye laser for an infantile hemangioma in a high-risk location. Although thorough clinical trials are needed, combination therapy for infantile hemangiomas may prove to be optimal for efficacy.


Assuntos
Hemangioma Capilar/radioterapia , Doenças do Prematuro/terapia , Lasers de Corante/uso terapêutico , Terapia com Luz de Baixa Intensidade , Síndromes Neoplásicas Hereditárias/radioterapia , Propranolol/uso terapêutico , Neoplasias Vulvares/radioterapia , Terapia Combinada , Feminino , Hemangioma Capilar/tratamento farmacológico , Humanos , Lactente , Recém-Nascido Prematuro , Doenças do Prematuro/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Indução de Remissão , Neoplasias Vulvares/tratamento farmacológico
9.
J Natl Cancer Inst ; 115(12): 1457-1464, 2023 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-37535679

RESUMO

The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.


Assuntos
Neoplasias Retais , Estados Unidos , Humanos , Consenso , National Cancer Institute (U.S.) , Neoplasias Retais/patologia , Quimiorradioterapia , Terapia Neoadjuvante
10.
Res Sq ; 2023 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-38196590

RESUMO

Background: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. Methods: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. Discussion: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC.

11.
J Biol Chem ; 286(9): 7379-88, 2011 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-21177873

RESUMO

The mammalian ferlins are calcium-sensing, C2 domain-containing proteins involved in vesicle trafficking. Myoferlin and dysferlin regulate myoblast fusion and muscle membrane resealing, respectively. Correspondingly, myoferlin is most highly expressed in singly nucleated myoblasts, whereas dysferlin expression is increased in mature, multinucleated myotubes. Myoferlin also mediates endocytic recycling and participates in trafficking the insulin-like growth factor receptor. We have now characterized a novel member of the ferlin family, Fer1L5, because of its high homology to dysferlin and myoferlin. We found that Fer1L5 protein is expressed in small myotubes that contain only two to four nuclei. We also found that Fer1L5 protein binds directly to the endocytic recycling proteins EHD1 and EHD2 and that the second C2 domain in Fer1L5 mediates this interaction. Reduction of EHD1 and/or EHD2 inhibits myoblast fusion, and EHD2 is required for normal translocation of Fer1L5 to the plasma membrane. The characterization of Fer1L5 and its interaction with EHD1 and EHD2 underscores the complex requirement of ferlin proteins and mediators of endocytic recycling for membrane trafficking events during myotube formation.


Assuntos
Proteínas de Transporte/metabolismo , Fusão de Membrana/fisiologia , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Proteínas de Transporte/genética , Linhagem Celular , Membrana Celular/metabolismo , Disferlina , Endossomos/metabolismo , Proteínas de Membrana/genética , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Músculo Esquelético/citologia , Mioblastos/citologia , Transporte Proteico/fisiologia , RNA Interferente Pequeno , Sarcolema/metabolismo , Proteínas de Transporte Vesicular/genética
12.
Circ Res ; 107(1): 84-95, 2010 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-20489164

RESUMO

RATIONALE: Cardiac membrane excitability is tightly regulated by an integrated network of membrane-associated ion channels, transporters, receptors, and signaling molecules. Membrane protein dynamics in health and disease are maintained by a complex ensemble of intracellular targeting, scaffolding, recycling, and degradation pathways. Surprisingly, despite decades of research linking dysfunction in membrane protein trafficking with human cardiovascular disease, essentially nothing is known regarding the molecular identity or function of these intracellular targeting pathways in excitable cardiomyocytes. OBJECTIVE: We sought to discover novel pathways for membrane protein targeting in primary cardiomyocytes. METHODS AND RESULTS: We report the initial characterization of a large family of membrane trafficking proteins in human heart. We used a tissue-wide screen for novel ankyrin-associated trafficking proteins and identified 4 members of a unique Eps15 homology (EH) domain-containing protein family (EHD1, EHD2, EHD3, EHD4) that serve critical roles in endosome-based membrane protein targeting in other cell types. We show that EHD1-4 directly associate with ankyrin, provide the first information on the expression and localization of these molecules in primary cardiomyocytes, and demonstrate that EHD1-4 are coexpressed with ankyrin-B in the myocyte perinuclear region. Notably, the expression of multiple EHD proteins is increased in animal models lacking ankyrin-B, and EHD3-deficient cardiomyocytes display aberrant ankyrin-B localization and selective loss of Na/Ca exchanger expression and function. Finally, we report significant modulation of EHD expression following myocardial infarction, suggesting that these proteins may play a key role in regulating membrane excitability in normal and diseased heart. CONCLUSIONS: Our findings identify and characterize a new class of cardiac trafficking proteins, define the first group of proteins associated with the ankyrin-based targeting network, and identify potential new targets to modulate membrane excitability in disease. Notably, these data provide the first link between EHD proteins and a human disease model.


Assuntos
Proteínas de Transporte/fisiologia , Membrana Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Transporte Vesicular/fisiologia , Proteínas de Transporte/metabolismo , Membrana Celular/química , Membrana Celular/genética , Proteínas de Ligação a DNA/fisiologia , Humanos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Família Multigênica/fisiologia , Proteínas Nucleares/fisiologia , Estrutura Terciária de Proteína/genética , Transporte Proteico/genética , Proteínas de Transporte Vesicular/metabolismo
13.
Curr Oncol ; 29(2): 465-478, 2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35200542

RESUMO

OBJECTIVE: Given the increasing risk of young-onset colorectal cancer (yCRC) among adults under 50 years, it is important to understand impacts on reproductive health. Our objective was to assess experiences with reproductive health after yCRC diagnosis among females. METHODS: We conducted a cross-sectional study among females, 18 years or older, who have been diagnosed yCRC and are able to communicate in English. Data were gathered using an online survey involving both quantitative (e.g., multiple choice) and qualitative (e.g., open-ended text) questions on pregnancy history, influence of yCRC on reproductive decisions, and experiences with reproductive healthcare. RESULTS: Altogether, 101 females with yCRC participated, including 23 who had never been pregnant and 78 who had been pregnant. yCRC influenced family planning goals for one-third of participants. Furthermore, compared to participants who completed treatment, those currently undergoing treatment had higher odds of indicating their yCRC diagnosis influenced family planning goals (adjusted odds ratio 4.93; 95% confidence interval 1.29 to 18.78). Although 53 (52.5%) participants indicated having discussions regarding reproductive health with healthcare provider(s), 44 (43.6%) did not. Content analysis of open-ended survey questions identified themes on the emotional impacts, experiences with reproductive healthcare, reproductive and family planning considerations, and the related issue of sexual health impacts of yCRC. CONCLUSIONS: Gaps in care, related to limited reproductive health discussions, influence of yCRC on family planning, and experiencing lasting reproductive health impacts highlight the need for improving reproductive healthcare, particularly for females diagnosed with yCRC.


Assuntos
Neoplasias Colorretais , Saúde Reprodutiva , Adulto , Neoplasias Colorretais/diagnóstico , Estudos Transversais , Feminino , Humanos , Gravidez , Inquéritos e Questionários
14.
Cancers (Basel) ; 13(21)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34771628

RESUMO

BACKGROUND: Adjuvant chemotherapy use in stage II colon cancer is controversial. Current prognostic risk factors do not take the tumor immune microenvironment into account. Consideration of the Immunoscore, which measures the host immune response at the tumor site, may assist clinicians in reducing adjuvant chemotherapy use in patients who are unlikely to benefit from it. This study sought to determine the potential clinical utility of the Immunoscore, via its effect on medical oncologists' recommendations for management of patients with stage II colon cancer. METHODS: De-identified vignettes of 10 patients with stage II colon cancer were presented to 25 practicing medical oncologists. Each participant completed surveys indicating recommendations for adjuvant chemotherapy and surveillance strategies. An educational session was subsequently conducted, and the same patient profiles were re-presented but included immunoscore results. Participants were again asked to provide their recommendations. A participant was counted as influenced if their responses were altered after immunoscore test results were provided. RESULTS: All but one participant (96%) altered a management recommendation for ≥1 case. For individual cases, a mean of 55% (range, 40-80%) of participants altered their recommendations for adjuvant chemotherapy and/or surveillance. For the immunoscore-high cases (low-risk of recurrence), recommendations for adjuvant chemotherapy use decreased from 60% to 31%. CONCLUSIONS: These results indicate a willingness by oncologists to integrate immunoscore information into clinical practice recommendations. Incorporation of immunoscore data resulted in the reduction of nonvalue care in the simulated population. Confirmation in prospective studies is planned.

15.
Genesis ; 48(5): 328-42, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20213691

RESUMO

The four highly homologous members of the C-terminal EH domain-containing (EHD) protein family (EHD1-4) regulate endocytic recycling. To delineate the role of EHD4 in normal physiology and development, mice with a conditional knockout of the Ehd4 gene were generated. PCR of genomic DNA and Western blotting of organ lysates from Ehd4(-/-) mice confirmed EHD4 deletion. Ehd4(-/-) mice were viable and born at expected Mendelian ratios; however, males showed a 50% reduction in testis weight, obvious from postnatal day 31. An early (Day 10) increase in germ cell proliferation and apoptosis and a later increase in apoptosis (Day 31) were seen in the Ehd4(-/-) testis. Other defects included a progressive reduction in seminiferous tubule diameter, dysregulation of seminiferous epithelium, and head abnormalities in elongated spermatids. As a consequence, lower sperm counts and reduced fertility were observed in Ehd4(-/-) males. Interestingly, EHD protein expression was seen to be temporally regulated in the testis and EHD4 levels peaked between days 10 and 15. In the adult testis, EHD4 was highly expressed in primary spermatocytes and EHD4 deletion altered the levels of other EHD proteins in an age-dependent manner. We conclude that high levels of EHD1 in the adult Ehd4(-/-) testis functionally compensate for lack of EHD4 and prevents the development of severe fertility defects. Our results suggest a role for EHD4 in the proper development of postmitotic and postmeiotic germ cells and implicate EHD protein-mediated endocytic recycling as an important process in germ cell development and testis function.


Assuntos
Proteínas de Ligação a DNA/genética , Fertilidade/genética , Proteínas Nucleares/genética , Testículo/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Feminino , Fertilidade/fisiologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Proteínas Nucleares/metabolismo , Tamanho do Órgão , Contagem de Espermatozoides , Motilidade dos Espermatozoides/genética , Motilidade dos Espermatozoides/fisiologia , Espermátides/citologia , Espermátides/metabolismo , Testículo/citologia , Testículo/crescimento & desenvolvimento , Fatores de Tempo
16.
BMC Dev Biol ; 10: 37, 2010 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-20359371

RESUMO

BACKGROUND: The C-terminal Eps15 homology domain-containing protein 1 (EHD1) is ubiquitously expressed and regulates the endocytic trafficking and recycling of membrane components and several transmembrane receptors. To elucidate the function of EHD1 in mammalian development, we generated Ehd1-/- mice using a Cre/loxP system. RESULTS: Both male and female Ehd1-/- mice survived at sub-Mendelian ratios. A proportion of Ehd1-/- mice were viable and showed smaller size at birth, which continued into adulthood. Ehd1-/- adult males were infertile and displayed decreased testis size, whereas Ehd1-/- females were fertile. In situ hybridization and immunohistochemistry of developing wildtype mouse testes revealed EHD1 expression in most cells of the seminiferous epithelia. Histopathology revealed abnormal spermatogenesis in the seminiferous tubules and the absence of mature spermatozoa in the epididymides of Ehd1-/- males. Seminiferous tubules showed disruption of the normal spermatogenic cycle with abnormal acrosomal development on round spermatids, clumping of acrosomes, misaligned spermatids and the absence of normal elongated spermatids in Ehd1-/- males. Light and electron microscopy analyses indicated that elongated spermatids were abnormally phagocytosed by Sertoli cells in Ehd1-/- mice. CONCLUSIONS: Contrary to a previous report, these results demonstrate an important role for EHD1 in pre- and post-natal development with a specific role in spermatogenesis.


Assuntos
Espermatogênese , Proteínas de Transporte Vesicular/metabolismo , Animais , Endocitose , Feminino , Infertilidade Masculina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Testículo/metabolismo
17.
BMC Cell Biol ; 10: 84, 2009 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-19948031

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) controls a wide range of cellular processes, and altered EGFR signaling contributes to human cancer. EGFR kinase domain mutants found in non-small cell lung cancer (NSCLC) are constitutively active, a trait critical for cell transformation through activation of downstream pathways. Endocytic trafficking of EGFR is a major regulatory mechanism as ligand-induced lysosomal degradation results in termination of signaling. While numerous studies have examined mutant EGFR signaling, the endocytic traffic of mutant EGFR within the NSCLC milieu remains less clear. RESULTS: This study shows that mutant EGFRs in NSCLC cell lines are constitutively endocytosed as shown by their colocalization with the early/recycling endosomal marker transferrin and the late endosomal/lysosomal marker LAMP1. Notably, mutant EGFRs, but not the wild-type EGFR, show a perinuclear accumulation and colocalization with recycling endosomal markers such as Rab11 and EHD1 upon treatment of cells with endocytic recycling inhibitor monensin, suggesting that mutant EGFRs preferentially traffic through the endocytic recycling compartments. Importantly, monensin treatment enhanced the mutant EGFR association and colocalization with Src, indicating that aberrant transit through the endocytic recycling compartment promotes mutant EGFR-Src association. CONCLUSION: The findings presented in this study show that mutant EGFRs undergo aberrant traffic into the endocytic recycling compartment which allows mutant EGFRs to engage in a preferential interaction with Src, a critical partner for EGFR-mediated oncogenesis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Endocitose , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Mutação , Quinases da Família src/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Células Cultivadas , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Proteínas de Membrana Lisossomal/metabolismo , Ligação Proteica , Transporte Proteico , Transdução de Sinais , Transferrina/metabolismo
18.
Indian J Psychiatry ; 60(3): 307-311, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405256

RESUMO

CONTEXT AND AIMS: Dysfunction of cognition and emotion is known in alcohol dependence; however, their relationship in alcohol dependence is unknown. Thus, this study aimed to know the level of emotional dysregulation and cognitive functions and their correlation in patients with alcohol dependence. MATERIALS AND METHODS: In this hospital-based cross-sectional study, 120 patients with alcohol dependence were consecutively recruited and assessed with sociodemographic and clinical pro forma, Montreal Cognitive Assessment (MoCA), and Difficulty in Emotional Regulation Scale-Short Form (DERS-SF). STATISTICAL ANALYSIS: Descriptive statistical, Kruskal-Wallis H, and regression analysis. RESULTS: Results revealed a mild level of cognitive impairment (mean MoCA score = 0 23.76) and high levels of emotional dysregulation (mean DERS-SF score = 0 26.90). On linear regression analysis (R 2 = 0.266, df = 0 1, F = 0 42.782, P =0.000), the score on MoCA had statistically significant negative association with score on DERS-SF (P = 0.001). CONCLUSIONS: Cognitive impairment and emotional dysregulation are inversely related in patients with alcohol dependence. Improving the dysfunction may improve the outcome of alcohol dependence.

19.
Indian J Psychiatry ; 60(Suppl 4): S506-S509, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29540922

RESUMO

Substance abuse and addictive disorders are very common in the community. Patients with addictive disorders frequently experience sexual dysfunctions and chronic use of substances tends to adversely affect all stages of sexual response, in both male and female abusers. An important aspect in the management of sexual dysfunction is psychosocial intervention. In addictive disorders, sexual dysfunction is of high clinical relevance, as it often leads to treatment non adherence and sexual or marital disharmony. Instead of a disease-centred approach, a couple and relationship centred approach of management is desirable. A detailed history about the sexual dysfunction, the addictive disorder and enquiry into various psychosocial aspects is mandatory for adequate management of the same. Sexual therapy, behavioural techniques, systematic sensitization and desensitization are some of the techniques used in the management of sexual dysfunction in addictive disorders. The assessment and treatment need to be tailored depending upon the various psychosocial aspects of the individual.

20.
Indian J Psychiatry ; 60(Suppl 4): S510-S513, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29540923

RESUMO

Addiction is the term employed not only for excess consumption of substances, but also for problem behaviours like eating disorders, pathological gambling, computer addiction and pathological preoccupation with video games and sexual acts. No clear diagnostic criterion has been established with validity for behavioral addictions. Sexual addiction, including addiction to pornography is not included as a separate entity because of a lack of strong empirical evidence in this area. Different scales can be used for assessment of sexual addiction. Since there is an absence of established diagnostic criteria, the significance of validity of these scales is doubted. Several of the questions in these scales do not yield information about whether the diagnostic criteria are met or not. Pharmacotherapy, together with psychotherapy proves to have a better outcome in such patients as it helps to synthesize the role of developmental antecedents, reduce current anxiety, depression, guilt and to improve social adjustment.

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