Infectious retroviruses have been detected in 22 of 45 randomly selected patients with acquired immune deficiency syndrome (AIDS) and in other individuals from San Francisco. The AIDS-associated retroviruses (ARV) studied in detail had a type D morphology, Mg2+-dependent reverse transcriptase, and cytopathic effects on lymphocytes. The viruses can be propagated in an established adult human T cell line, HUT-78. They cross-react with antiserum to the lymphadenopathy-associated retrovirus isolated from AIDS patients in France. Antibodies to ARV were found in all 86 AIDS patients and in a high percentage of 88 other homosexual men in San Francisco. This observation indicates the widespread presence of these lymphocytopathic retroviruses and their close association with AIDS.

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Having patients, doctors, health plan managers, hospital executives, and other stakeholders participate in the design of comparative effectiveness studies can ensure that this vital research focuses on the evidence gaps most relevant to health care decision makers. Through a qualitative assessment of case studies, we identify five key principles for the effective engagement of a broad coalition of participants in research intended to improve health care and control costs. Those principles are to ensure balance among the participating stakeholders; get participants to "buy in" to the process and understand their roles; provide neutral and expert facilitators for research discussions; establish connections among the participants; and keep the participants engaged throughout the research process.

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BackgroundGenomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative.Patients and methodsHybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer.ResultsAt least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%).ConclusionsGAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.

PURPOSE A phase II trial of interferon alfa-2a (IFN) and 13-cis-retinoic acid (CRA) was conducted in patients with renal cell carcinoma (RCC). In vitro studies were performed to investigate potential mechanisms of interaction. PATIENTS AND METHODS Forty-four patients were treated. IFN was given daily at 3 MU and escalated to 6 and 9 MU if tolerated. The dose of CRA was 1 mg/kg/d. The effects of combining CRA and IFN on the proliferation of five RCC cell lines were examined, and retinoid sensitivity was correlated to the expression of retinoic acid receptors. RESULTS Thirteen (30%) of 43 assessable patients achieved a major response (three complete and 10 partial). Responding sites included bone metastases and renal primary tumors. Seven responding patients remain progression-free at 10+ to 19+ months. The response proportion was higher than in our prior experience with IFN, which was 10% in 149 patients. Eleven of 12 renal cancer cell lines were resistant to CRA alone; one, SK-RC-06, showed 90% inhibition of cell growth. CRA augmented the antiproliferative effect of IFN in several IFN-sensitive cell lines, but not in IFN-resistant lines. Northern blot analysis showed that expression of retinoic acid receptor-beta (RAR-beta) was repressed and not induced by retinoic acid in retinoic acid-insensitive RCC lines. However, RAR-beta expression was induced by retinoic acid in SK-RC-06 cells. CONCLUSION IFN and CRA showed antitumor activity in patients with advanced RCC, and the proportion and nature of response suggested CRA added therapeutic benefit to IFN. A phase III randomized trial of IFN plus CRA versus IFN alone and a phase II trial of single-agent CRA have been initiated.

Introduction Most current animal models of hindlimb ischemia use acute arterial occlusion that does not accurately reflect the pathogenesis of gradual arterial occlusion in humans. We therefore developed the first mouse model of gradual arterial occlusion and tested the hypothesis that the mechanisms regulating blood flow recovery are critically dependent on the rate of arterial occlusion. Methods Gradual arterial occlusion was induced by placing ameroid constrictors on the proximal and distal left femoral artery, and ligating the femoral arterial branches (n=36). Acute arterial occlusion was accomplished by excising the left femoral artery (n=36). The blood flow recovery was studied by laser Doppler imaging. Differential gene expression between these two models was assessed by quantitative real time PCR. Inflammatory and progenitor cells recruitment were determined by immunohistochemistry. Results We found that hypoxia-related genes increased significantly in the calf, but not in the thigh, after gradual and acute femoral arterial occlusion (p<0.05). Shear-stress dependent genes and inflammatory genes were upregulated immediately in the thigh only after acute femoral arterial occlusion (p<0.05). These differences in gene expression were consistent with increased SDF-1α expression, recruitment of macrophages and hemangiocytes, and higher blood flow recovery after acute arterial occlusion than after gradual arterial occlusion (p<0.05). Conclusion This is the first study to show the mechanisms that regulate blood flow recovery are critically dependent on the rate of arterial occlusion. This novel model of gradual arterial occlusion may more closely resemble the human diseases, and may provide more accurate mechanistic insights for creating novel molecular therapies.

Objective The goals of this study were to determine if endothelial nitric oxide synthase (eNOS) affects both early and late collateral arterial adaptation and blood flow recovery after severe limb ischemia, and to determine if eNOS-derived NO was necessary for recruitment of CXCR4+ VEGFR1+ hemangiocytes to the site of ischemia. Methods and Results Two studies were carried out. In the first study, hindlimb ischemia was induced by unilateral femoral artery excision in 3 groups: C57Bl6 (wild type), eNOS-/-, and C57Bl/6 mice treated with L-NAME from 1 day prior to excision through day 3 after excision (early L-NAME group). These 3 groups were studied on the 3rd day after induction of ischemia. In the second study, hindlimb ischemia was induced in 2 groups: C57Bl/6 mice (wild type) and C57Bl/6 mice treated with L-NAME from the 3rd through the 28th day after induction of ischemia. These 2 groups were studied on the 28th day after induction of ischemia. Dependent variables included hindlimb perfusion, collateral artery diameter, and the number and location of hemangiocytes within the ischemic hindlimb. Results In the first study, the eNOS-/- and early L-NAME treatment groups developed toe gangrene by the 2nd day of ischemia. These groups demonstrated less blood flow recovery and smaller collateral artery diameter than the wild type group. Hemangiocytes were present within the adventitia of collateral arteries in the wild type group, but were only sparsely present, in a random pattern, in the eNOS-/- and early L-NAME treatment groups. In the second study, the late L-NAME group showed less blood flow recovery and smaller collateral artery diameter on the 28th day of ischemia than the wild type group. Hemangiocytes were present in a peri-capillary distribution in the wild type group, but present only sparsely in the late L-NAME treatment group. Conclusion eNOS-derived NO is necessary for both the early (day 3) and late (day 28) adaptive responses to hindlimb ischemia. NO is necessary for normal hemangiocyte recruitment to the ischemic tissue.