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91.
Jun Xu Xiangdong Cui Jiehua Li Panagiotis Koutakis Iraklis Pipinos Edith Tzeng Alex Chen Ulka Sachdev 《Journal of vascular surgery》2018,67(3):910-921
Objective
We have previously shown that exogenous administration of the nuclear protein high mobility group box 1 (HMGB1) improves angiogenesis after tissue ischemia. Antagonizing HMGB1 prolongs muscle necrosis and deters regeneration. In this study, we evaluated HMGB1 expression in peripheral arterial disease (PAD) and the mechanisms that promote its release in a murine model of hindlimb ischemia. Specifically, we investigated how chloroquine (CQ), a commonly employed disease-modifying antirheumatic drug, promotes HMGB1 release from muscle. We hypothesized that CQ could increase HMGB1 locally and systemically, allowing it to mediate recovery from ischemic injury.Methods
Muscle biopsies were performed on patients undergoing lower extremity surgery for non-PAD-related disease as well as for claudication and critical limb ischemia. Clinical symptoms and ankle-brachial indices were recorded for each patient. HMGB1 was detected in muscle sections using immunohistochemical staining. Unilateral femoral artery ligation was performed on both wild-type and inducible HMGB1 knockout mice. Wild-type mice were administered intraperitoneal CQ 2 weeks before and after femoral artery ligation. Laser Doppler perfusion imaging was used to determine perfusion recovery. Serum and tissue levels of HMGB1 were measured at designated time points. In vitro, cultured C2C12 myoblasts were treated with increasing doses of CQ. HMGB1, autophagosome formation, p62/SQSTM1 accumulation, caspase-1 expression and activity, and lactate dehydrogenase levels were measured in supernatants and cell lysates.Results
Nuclear expression of HMGB1 was prominent in patients with claudication and critical limb ischemia (P < .05) compared with controls. CQ-treated mice had elevated serum HMGB1 and diffuse HMGB1 staining in muscle (P < .01). In wild-type mice, CQ treatment resulted in higher laser Doppler perfusion imaging ratios in the ischemic limb at 7 days (P < .03) and less fat replacement after 2 weeks (P < .03). In cultured myoblasts, CQ induced autophagosome accumulation, inhibited p62/SQSTM-1 degradation, and activated caspase-1.Conclusions
HMGB1 is prominently expressed in PAD muscle but mostly confined to the nucleus. Our in vivo data suggest that HMGB1 mobilization into the sarcoplasm and serum can be increased with CQ, possibly through caspase-1-mediated pathways. Whereas HMGB1 can be released by many cell types, these studies suggest that the muscle may be an important additional source that is relevant in PAD. 相似文献92.
Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. 总被引:11,自引:0,他引:11
PURPOSE: To determine the efficacy and toxicity of the drug combination of carboplatin, paclitaxel, and gemcitabine in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Patients eligible included those with advanced urothelial malignancy of any histology, no previous chemotherapy for metastatic disease, Southwest Oncology Group performance status of 2 or less, serum creatinine levels of 2 mg/dL or less, and adequate bone marrow and hepatic function. Treatment consisted of paclitaxel 200 mg/m2, carboplatin (target area under the curve = 5) on day 1, and gemcitabine 800 mg/m2 on days 1 and 8, repeated every 21 days. RESULTS: Forty-nine patients (44 men and five women) were enrolled; the patients' median age was 63 years, and their median creatinine clearance was 78 mL/min (range, 26 to 165 mL/min). Forty-three patients had transitional cell carcinoma, and six had squamous cell carcinoma or mixed histology. Ten patients had metastases to lymph nodes only, six had locally advanced disease, four had locally recurrent disease, 24 patients had visceral metastases, and five had soft tissue metastases. Twenty-one patients had disease in one site, 16 in two sites, and 12 in three sites. A total of 272 cycles were administered (median, six cycles; range, 1 to 15 cycles). Major toxicities were grade 3 and 4 neutropenia in 17 and 19 patients, respectively; grade 3 and 4 thrombocytopenia in 15 and six patients, respectively; grade 3 and 4 anemia in 10 and two patients, respectively; grade 3 neuropathy in four patients; and diarrhea in two patients. The incidence of febrile neutropenia was 1.4%; no patients died of drug toxicity. Forty-seven of the 49 patients were assessable for response. Fifteen (32%) patients experienced a complete response, and 17 (36%) patients experienced a partial response (32 of 47 patients, 68%; 95% confidence interval, 56.27 to 82.86). Responses were seen in all sites, including 15 (68%) of 22 patients with visceral metastases. The median survival was 14.7 months, with a 1-year survival of 59%. CONCLUSION: Combination paclitaxel, carboplatin, and gemcitabine is active; an encouraging number of patients with advanced urothelial carcinoma treated with this regimen experienced complete remission. 相似文献
93.
Overall survival benefit with a docetaxel and prednisone regimen in metastatic androgen-independent prostate cancer marked a major advance in the management of prostate cancer. Immunotherapy, antiangiogenic therapies and targeted agents are areas of active research interest. Simultaneous progress in palliative and supportive care has enabled us to improve the quality of life of advanced prostate cancer patients. Multiple predictors of outcome have been reported, and systemic therapy is being actively explored in localized disease. This review attempts to summarize the risk profiling strategy in prostate cancer and the existing therapies in high-risk prostate cancer, including some of the novel agents under investigation. 相似文献
94.
95.
Arthur E. Frankel Keith T. Flaherty George J. Weiner Robert Chen Nilofer S. Azad Michael J. Pishvaian John A. Thompson Matthew H. Taylor Daruka Mahadevan A. Craig Lockhart Ulka N. Vaishampayan Jordan D. Berlin David C. Smith John Sarantopoulos Matthew Riese Mansoor N. Saleh Chul Ahn Eugene P. Frenkel 《The oncologist》2017,22(4):369-374
Multiple factors critical to the effectiveness of academic phase I cancer programs were assessed among 16 academic centers in the U.S. Successful cancer centers were defined as having broad phase I and I/II clinical trial portfolios, multiple investigator‐initiated studies, and correlative science. The most significant elements were institutional philanthropic support, experienced clinical research managers, robust institutional basic research, institutional administrative efforts to reduce bureaucratic regulatory delays, phase I navigators to inform patients and physicians of new studies, and a large cancer center patient base. New programs may benefit from a separate stand‐alone operation, but mature phase I programs work well when many of the activities are transferred to disease‐oriented teams. The metrics may be useful as a rubric for new and established academic phase I programs. 相似文献
96.
Jennifer Derebery MD Eli Meltzer MD Robert A. Nathan MD Paul E. Stang PhD Ulka B. Campbell PhD Marlo Corrao MPH Richard Stanford PharmD MS 《Otolaryngology--head and neck surgery》2008,139(2):198-205
OBJECTIVE: To assess the burden of nasal symptoms in the United States (U.S.) and the comorbid conditions associated with nasal symptoms. SUBJECTS AND METHODS: A self-administered screening questionnaire and follow-up survey was sent to targeted households from a representative sample of 15,000 households in the U.S. Subjects with comorbid asthma completed the Asthma Control Test (ACT). RESULTS: Out of 7024 evaluable subjects who responded, 3831 subjects were classified as rhinitis "sufferers." Individuals with active rhinitis symptoms were 1.5 to 4.5 times more likely to suffer from comorbid conditions including asthma, conjunctivitis, otitis media, sinusitis, eczema, food and insect bite allergies, migraine, and depression. Almost half of all respondents with moderate or severe rhinitis symptoms and comorbid asthma had poorly controlled asthma as defined by an ACT score of < or =19. CONCLUSIONS: A strong relationship exists between rhinitis symptoms and various comorbidities, including asthma, in the U.S. population. Poorly controlled rhinitis contributes to the public health burden of rhinitis and asthma. 相似文献
97.
98.
J Bengtsson M Hartmann M Unterseher P Vaishampayan K Abarenkov L Durso EM Bik JR Garey KM Eriksson RH Nilsson 《Research in microbiology》2012,163(6-7):407-412
Metagenomic libraries represent subsamples of the total DNA found at a study site and offer unprecedented opportunities to study ecological and functional aspects of microbial communities. To examine the depth of a community sequencing effort, rarefaction analysis of the ribosomal small subunit (SSU/16S/18S) gene in the metagenome is usually performed. The fragmentary, non-overlapping nature of SSU sequences in metagenomic libraries poses a problem for this analysis, however. We introduce a software package - Megraft - that grafts SSU fragments onto full-length SSU sequences, accounting for observed and unobserved variability, for accurate assessment of species richness and sequencing depth in metagenomics endeavors. 相似文献
99.
100.
Andrea Necchi Gregory R. Pond Marco Moschini Elizabeth R. Plimack Gunter Niegisch Evan Y. Yu Aristotelis Bamias Neeraj Agarwal Ulka Vaishampayan Christine Theodore Srikala S. Sridhar Jonathan E. Rosenberg Joaquim Bellmunt Andrea Gallina Renzo Colombo Francesco Montorsi Alberto Briganti Matthew D. Galsky 《Clinical genitourinary cancer》2019,17(1):7-14.e3