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Amy A. Mericle Adam W. Carrico Jordana Hemberg Ronald Stall Douglas L. Polcin 《Journal of substance use》2019,24(2):140-146
Background: Gay, bisexual, and other men who have sex with men (MSM) face unique recovery challenges. Recovery housing may play an important role in improving outcomes among MSM, but little is known about their experiences in these settings. Methods: This study examined 3-month outcomes among MSM (N = 22) living in a group of recovery residences in Texas, one of which is a home specifically designated for gay and bisexual men. Upon intake, adult MSM were recruited to participate in the study, which involved a baseline and 3-month phone interview and allowing study staff to access records maintained by the program about their stay. Results: At follow-up, only two (9.1%) reported used of any substances in the past 30 days. The vast majority (73%) had attended outpatient substance use treatment in the past three months, and 86% reported working for pay during the past 30 days. All participants reported attending four or more 12-step meetings in the past 30 days. Use of dysfunctional coping strategies significantly decreased, however, so did scores on health-related quality of life. Conclusions: MSM have complex treatment needs. Recovery housing may help improve outcomes among MSM by bridging formal substance use treatment with community-based recovery support. 相似文献
995.
Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors 总被引:4,自引:0,他引:4
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996.
The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase 总被引:3,自引:0,他引:3
997.
Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia 总被引:12,自引:3,他引:12
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Kantarjian H Gandhi V Cortes J Verstovsek S Du M Garcia-Manero G Giles F Faderl S O'Brien S Jeha S Davis J Shaked Z Craig A Keating M Plunkett W Freireich EJ 《Blood》2003,102(7):2379-2386
In a phase 2 study, 62 patients with relapsed and refractory acute myeloid leukemia (AML; n = 31), myelodysplastic syndrome (MDS; n = 8), chronic myeloid leukemia in blastic phase (CMLBP; n = 11), and acute lymphocytic leukemia (ALL; n = 12) received 40 mg/m2 clofarabine intravenously over 1 hour daily for 5 days, every 3 to 6 weeks. Twenty patients (32%) achieved complete response (CR), 1 had a partial response (PR), and 9 (15%) achieved CR but without platelet recovery (CRp), for an overall response rate of 48%. In AML, responses were noted in 2 (18%) of 11 patients in first salvage with short first CR (= 12 months), in 7 (87%) of 8 patients with longer first CR, and in 8 (67%) of 12 patients in second or subsequent salvage. Responses were observed in 4 of 8 patients with high-risk MDS (50%), in 7 (64%) of 11 with CML-BP, and in 2 (17%) of 12 with ALL. Severe reversible liver dysfunction was noted in 15% to 25%. After the first clofarabine infusion, responders accumulated more clofarabine triphosphate in blasts compared with nonresponders (median 18 vs 10 microM; P =.03). This increased only in responders (median, 1.8-fold; P =.008) after the second clofarabine infusion. In summary, clofarabine is active in acute leukemias and MDS; cellular pharmacokinetics may have prognostic significance. 相似文献
998.
Langenbacher AD Dong Y Shu X Choi J Nicoll DA Goldhaber JI Philipson KD Chen JN 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(49):17699-17704
Cardiac fibrillation, a form of cardiac arrhythmia, is the most common cause of embolic stroke and death associated with heart failure. The molecular mechanisms underlying cardiac fibrillation are largely unknown. Here we report a zebrafish model for cardiac fibrillation. The hearts of zebrafish tremblor (tre) mutants exhibit chaotic movements and fail to develop synchronized contractions. Calcium imaging showed that normal calcium transients are absent in tre cardiomyocytes, and molecular cloning of the tre mutation revealed that the tre locus encodes the zebrafish cardiac-specific sodium-calcium exchanger (NCX) 1, NCX1h. Forced expression of NCX1h or other calcium-handling molecules restored synchronized heartbeats in tre mutant embryos in a dosage-dependent manner, demonstrating the critical role of calcium homeostasis in maintaining embryonic cardiac function. By creating mosaic zebrafish embryos, we showed that sporadic NCX1h-null cells were not sufficient to disrupt normal cardiac function, but clustered wild-type cardiomyocytes contract in unison in tre mutant hearts. These data signify the essential role of calcium homeostasis and NCX1h in establishing rhythmic contraction in the embryonic zebrafish heart. 相似文献
999.
Clinical brain proton magnetic resonance spectroscopy for management of Alzheimer's and sub-cortical ischemic vascular dementia in older people 总被引:4,自引:0,他引:4
Waldman AD Rai GS McConnell JR Chaudry M Grant D 《Archives of gerontology and geriatrics》2002,35(2):137-142
This study examined the clinical usefulness of magnetic resonance spectroscopy (MRS) performed using an automated single voxel technique at 1.0 T field strength in a district general hospital magnetic resonance (MR) scanner in the assessment of older people referred to a memory clinic with suspected dementia. Of 50 elderly subjects (M:F 20:30) examined and followed-up clinically over more than 2 years, 20 had clinical Alzheimer's disease (AD), 18 had clinical vascular dementia, six had mixed features and three were normal. Three normal volunteers were also studied. MRS was performed at the same time as structural magnetic resonance imaging (MRI), added <15 min to the examination and was well-tolerated in all patients studied. Patients with AD had significantly higher myoinositol/creatine (MI/Cr) ratios (mean +/- S.D.: 0.82 +/- 0.04) compared to those with vascular dementia (mean +/-S. D.: 0.71 +/- 0.07, P<0.00001) and normal subjects (mean +/- S.D.: 0.72 +/- 0.036, P<0.0002); there was little overlap between the AD and vascular groups. The mixed dementia group also had significantly higher MI/Cr ratios (mean +/- S.D.: 0.80 +/- 0.05) than vascular dementia (P<0.01) and normal (P<0.03) groups, but with considerable overlap. No significant differences were shown for N-acetyl aspartate or choline/creatine ratios between the different clinical groups. These data suggest that MI/Cr ratios can distinguish patients with AD from normal subjects and those with sub-cortical ischemic vascular dementia and that MRS will be useful to clinicians managing persons with AD in a district general hospital setting. 相似文献
1000.
Xiaonan Dong Adam Cheng Zhongju Zou Yih-Sheng Yang Rhea M. Sumpter Jr. Chou-Long Huang Govind Bhagat Herbert W. Virgin Sergio A. Lira Beth Levine 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(11):2994-2999
The ubiquitin-proteasome system degrades viral oncoproteins and other microbial virulence factors; however, the role of endolysosomal degradation pathways in these processes is unclear. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, and a constitutively active viral G protein-coupled receptor (vGPCR) contributes to the pathogenesis of KSHV-induced tumors. We report that a recently discovered autophagy-related protein, Beclin 2, interacts with KSHV GPCR, facilitates its endolysosomal degradation, and inhibits vGPCR-driven oncogenic signaling. Furthermore, monoallelic loss of Becn2 in mice accelerates the progression of vGPCR-induced lesions that resemble human Kaposi’s sarcoma. Taken together, these findings indicate that Beclin 2 is a host antiviral molecule that protects against the pathogenic effects of KSHV GPCR by facilitating its endolysosomal degradation. More broadly, our data suggest a role for host endolysosomal trafficking pathways in regulating viral pathogenesis and oncogenic signaling.Phagocytosis and autophagy are two processes that deliver microbes and their constituent proteins to the lysosome for degradation, thereby contributing to the clearance of pathogens and to the presentation of peptide antigens to T cells (1, 2). However, it is not known whether endocytic internalization and lysosomal targeting of virus-encoded cell-surface receptors contributes to the control of viral infection and disease.Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of AIDS-related and other forms of Kaposi’s sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s disease (3–5). KS is a multifocal tumor characterized by proliferating spindle cells (possibly of endothelial origin), angiogenesis, vascular slits, erythrocyte extravasation, and inflammatory cells. Proinflammatory signaling by the dominant KS cell, the spindle cell, is considered the driving force in KS lesions (6). The risk of KSHV-associated malignancies increases with increased lytic viral replication (7–9), suggesting that KSHV-induced oncogenesis may be related to the levels of expression of viral oncoproteins.The oncogenic KSHV G protein-coupled receptor (vGPCR), encoded by the KSHV ORF74 lytic gene, is a constitutively active chemokine receptor expressed in patients with KSHV-associated tumors (10). At least in animal studies, there are strong data that vGPCR substantially contributes to the onset and progression of KSHV-associated neoplasia in vivo (11–19). Although only a small proportion of tumor cells express vGPCR (10), they are both sufficient and necessary for KSHV-induced sarcomagenesis. The endothelial-specific expression of vGPCR (but of neither KSHV latent genes, such as vCyclin, vFlip, and Kaposin, nor other KSHV lytic genes, such as vBcl-2 or vIRF1) or injection of murine endothelial cells stably expressing vGPCR (but not other KSHV genes, such as vCyclin, vFlip, Kaposin, LANA, vIL-6, vBcl-2, and K1) causes multifocal KS-like tumors in mice (15, 18). Furthermore, injection of a small number of endothelial cells expressing vGPCR increases the tumorigenic potential, in a paracrine fashion, of endothelial cells expressing other KSHV latent genes (vCyclin and vFlip), whereas eradication of the small number of vGPCR-expressing cells in established mix-cell tumors induces tumor regression (15, 18). Moreover, in a nude mouse model of KS driven by transfection of a KSHV bacterial artificial chromosome into bone marrow endothelial-lineage cells, siRNA interference (RNAi)-mediated suppression of vGPCR expression dramatically reduces angiogenesis and tumor formation (19). In addition, immunocompetent mice that transgenically express doxycycline (DOX)-inducible KSHV GPCR in endothelial cells (hereafter referred to as ikGPCR+) manifest lesions that strongly resemble human Kaposi’s sarcoma (16, 17). Importantly, the progression of lesions in ikGPCR+ mice is reversible because DOX withdrawal leads to significant regression of vGPCR-induced lesions (17), suggesting that vGPCR-driven oncogenesis is highly dependent on sustained vGPCR expression and signaling.Based on these previous observations in animal models regarding KSHV GPCR and oncogenesis, we developed the hypothesis that cell-intrinsic mechanisms that decrease vGPCR protein levels may function as an important host defense mechanism for controlling viral oncogenesis. Recently, we showed that the autophagy protein, Beclin 2 (but not the related autophagy protein Beclin 1) is essential for the endolysosomal degradation of certain cellular GPCRs that are regulated by GASP1 rather than by ubiquitination and the endosomal sorting complexes required for the transport pathway (20). This function of Beclin 2, but not Beclin 1, regulates mouse brain cannabinoid receptor levels and metabolism in vivo (20). Therefore, we investigated whether Beclin 2 may play a role in the endolysosomal degradation of viral GPCRs and thereby represent an important host defense mechanism against KSHV GPCR-induced oncogenic effects. Our results demonstrate a crucial role for Beclin 2 in KSHV GPCR trafficking, proinflammatory signaling, and in vivo tumorigenicity, and thus represent a previously undescribed role for endolysosomal trafficking in innate immunity and the control of viral GPCR-driven oncogenesis. 相似文献