tbuckley/cabot-search huggingface dataset:
Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti–PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells
Authors: Alfonso R. Sánchez-Paulete, Francisco J. Cueto, María Martínez-López, Sara Labiano, Aizea Morales-Kastresana, María E. Rodríguez-Ruiz, Maria Jure-Kunkel, Arantza Azpilikueta, M. Angela Aznar, José I. Quetglas, David Sancho, Ignacio Melero
Journal: Cancer Discovery (2015)

Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects.Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs.
Identification of Developmental Endothelial Locus-1 on Circulating Extracellular Vesicles as a Novel Biomarker for Early Breast Cancer Detection
Authors: Pyong-Gon Moon, Jeong-Eun Lee, Young-Eun Cho, Soo Jung Lee, Jin Hyang Jung, Yee Soo Chae, Han-Ik Bae, Young-Bum Kim, In-San Kim, Ho Yong Park, Moon-Chang Baek
Journal: Clinical Cancer Research (2015)

Currently, there are no molecular biomarkers for the early detection of breast cancer. This study focused on identifying surface proteins found on circulating extracellular vesicles (EVs) for detecting early-stage breast cancer.Circulating EVs, isolated from the plasma of 10 patients with breast cancer (stages I and II) and 5 healthy controls, were analyzed using LC-MS/MS. Developmental endothelial locus-1 protein (Del-1) was selected as a candidate biomarker. Two different ELISAs were used to measure Del-1 in plasma samples from healthy controls (n= 81), patients with breast cancer (n= 269), breast cancer patients after surgical resection (n= 50), patients with benign breast tumors (n= 64), and patients with noncancerous diseases (n= 98) in two cohorts.Plasma Del-1 levels were significantly higher (P< 0.0001) in patients with breast cancer than in all controls and returned to almost normal after tumor removal. The diagnostic accuracy of Del-1 was AUC, 0.961 [95% confidence interval (CI), 0.924-0.983], sensitivity of 94.70%, and specificity of 86.36% in test cohort and 0.968 (0.933-0.988), 92.31%, and 86.62% in validation cohort for early-stage breast cancer by one type of ELISA. Furthermore, Del-1 maintained diagnostic accuracy for patients with early-stage breast cancer using the other type of ELISA [0.946 (0.905-0.972), 90.90%, and 77.14% in the test cohort; 0.943 (0.900-0.971), 89.23%, and 80.99% in the validation cohort].Del-1 on circulating EVs is a promising marker to improve identification of patients with early-stage breast cancer and distinguish breast cancer from benign breast tumors and noncancerous diseases.
Double-Negative αβ T Cells Are Early Responders to AKI and Are Found in Human Kidney
Authors: Maria N. Martina, Sanjeev Noel, Ankit Saxena, Samatha Bandapalle, Richa Majithia, Chunfa Jie, Lois J. Arend, Mohamad E. Allaf, Hamid Rabb, Abdel Rahim A. Hamad
Journal: Journal of the American Society of Nephrology (2015)

Ischemia-reperfusion injury (IRI) is a major cause of AKI, and previous studies established important roles for conventional CD4+ T cells, natural killer T cells, and CD4+CD25+FoxP3+ Tregs in AKI pathogenesis. We recently identified CD4−CD8− (double-negative; DN) T cells as an important subset of αβ T cell receptor–positive cells residing in mouse kidney. However, little is known about the pathophysiologic functions of kidney DN T cells. In this study, we phenotypically and functionally characterized murine kidney DN T cells in the steady state and in response to IRI. Unlike CD4+ and CD8+ T cells, DN T cells in the steady state expressed high levels of CD69, CD28, and CD40L; differentially expressed IL-27 and IL-10 anti-inflammatory cytokines; spontaneously proliferated at a very high rate; and suppressed in vitro proliferation of activated CD4+ T cells. Within the first 3–24 hours after IRI, kidney DN T cells expanded significantly and upregulated expression of IL-10. In adoptive transfer experiments, DN T cells significantly protected recipients from AKI by an IL-10–dependent mechanism. DN T cells also made up a large fraction of the T cell compartment in human kidneys. Our results indicate that DN T cells are an important subset of the resident αβ+ T cell population in the mammalian kidney and are early responders to AKI that have anti-inflammatory properties.
Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma
Authors: Christina D. Pham, Catherine Flores, Changlin Yang, Elaine M. Pinheiro, Jennifer H. Yearley, Elias J. Sayour, Yanxin Pei, Colin Moore, Roger E. McLendon, Jianping Huang, John H. Sampson, Robert Wechsler-Reya, Duane A. Mitchell
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Experimental Design and Results: Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8+ PD-1+ T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1+ peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3+ T cells within the tumor microenvironment. Conclusions: This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. Clin Cancer Res; 22(3); 582–95. ©2015 AACR.
Nuclear‐Targeting MSNs‐Based Drug Delivery System: Global Gene Expression Analysis on the MDR‐Overcoming Mechanisms
Authors: Xiaoyu Li, Limin Pan, Jianlin Shi
Journal: Advanced Healthcare Materials (2015)

The biological mechanisms of nuclear-targeting mesoporous silica nanoparticles (MSNs)-based DDSs (DOX@NT-MSNs) in overcoming multidrug resistance of cancer cells are studied. It is interesting to find for the first time that DOX@NT-MSNs down-regulate the expression of apoptosis suppressor genes and inhibit DNA repair process by disturbing the p53 pathway.
The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer
Authors: Heidrun Gevensleben, Dimo Dietrich, Carsten Golletz, Susanne Steiner, Maria Jung, Thore Thiesler, Michael Majores, Johannes Stein, Barbara Uhl, Stefan Müller, Jörg Ellinger, Carsten Stephan, Klaus Jung, Peter Brossart, Glen Kristiansen
Journal: Clinical Cancer Research (2015)

Therapies targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway promote anti-tumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer.Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome.In the training cohort (n= 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67,P< 0.001), Gleason score (P= 0.004), and androgen receptor (AR) expression (P< 0.001). Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR;P= 0.004; HR, 2.37; 95% confidence interval (CI), 1.32-4.25]. In the test cohort (n= 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P= 0.011; HR, 1.49; 95% CI, 1.10-2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P< 0.001). In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P= 0.007; HR, 1.46; 95% CI, 1.11-1.92).We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1-targeted therapy might be a treatment option for hormone-naïve prostate cancers.
Chronic interstitial granulomatous dermatitis in coccidioidomycosis
Authors: A.R. Mangold, D.J. DiCaudo, J.E. Blair, A. Sekulic
Journal: British Journal of Dermatology (2015)

Coccidioides species are soil-dwelling fungi endemic to the Southwest U.S.A., especially Arizona and California and Northern Mexico. The cutaneous findings of coccidioidomycosis have a wide range of pathology, which includes organism-specific and reactive processes. Interstitial granulomatous dermatitis (IGD), a granuloma annulare-like reaction, has been described, in a limited form, in association with acute pulmonary coccidioidomycosis. We present a case of chronic, widespread IGD spanning over 9 years in association with an active coccidioidomycosis infection. Similar clinical and histopathological features have been described in association with drug reactions, connective tissue diseases, systemic vasculitis, lymphomas, other infectious diseases and inflammatory bowel disease. Our patient's dramatic presentation and chronic course expands upon the clinical spectrum of IGD occurring in association with pulmonary coccidioidomycosis. While IGD in association with coccidioidomycosis is rare, both dermatologists and general practitioners see IGD reactions, and our case highlights the importance of identifying the underlying driver.
Abstract 3737: Severe obesity and colorectal cancer patient survival
Authors: Carrie R. Daniel, Xiang Shu, Yuanqing Ye, Jian Gu, G. S. Raju, Scott Kopetz, Xifeng Wu
Journal: Cancer Research (2015)

Abstract Background: More than one-third of all U.S. adults are obese (BMI &amp;gt;30); and 15% of middle-aged adults, the group most commonly diagnosed and treated for colorectal and other cancers, meet the criteria for class II obesity (BMI&amp;gt; = 35). In contrast to the large and consistent body of evidence for obesity and increased colorectal cancer risk, several recent meta-analyses indicate that the association with colorectal patient survival is poorly defined. Some evidence suggests that moderate adiposity may be protective. In a prospective cohort of well-characterized CRC patients, we evaluated class I and class II obesity in relation to 5-year and 10-year survival outcomes. Methods: Histologically-confirmed colorectal adenocarcinoma patients (n = 634) evaluated at the University of Texas MD Anderson Cancer Center were followed for a median period of 4 years. We collected epidemiological data through questionnaires and abstracted treatment, anthropometric, and clinicopathologic data from patients’ electronic medical records. Overall survival (OS) and progression/recurrence-free survival (PFS) were calculated from the date of pathologic diagnosis until disease progression, first recurrence, or death. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in multivariable Cox proportional hazards models adjusted for demographics, lifestyle factors, tumor characteristics, and treatment modality. Results: We observed a 1.5-fold increased risk of death among class II obese (BMI&amp;gt; = 35), as compared to overweight CRC patients in multivariable-adjusted models. Among patients who reported stable weight and among stage I-III patients, the association between class II obesity and OS was more pronounced [BMI&amp;gt; = 35 vs. BMI 25-29.9 (ref), HR and 95% CI: 3.49 (1.68-7.22) and 2.40 (1.33-4.31), respectively], but no associations were observed among metastatic patients or among patients who experienced recent weight loss. Similar associations were observed with PFS, but few reached statistical significance. Conclusions: Severe adiposity defined as class II obesity (BMI &amp;gt; = 35) was associated with significantly higher mortality among CRC patients. Clarifying what is not a healthy weight for cancer patients and survivors remains both a clinically relevant and timely concern. Understanding and targeting this relationship may improve long-term outcomes among growing numbers of obese patients and cancer survivors. Citation Format: Carrie R. Daniel, Xiang Shu, Yuanqing Ye, Jian Gu, G. S. Raju, Scott Kopetz, Xifeng Wu. Severe obesity and colorectal cancer patient survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3737. doi:10.1158/1538-7445.AM2015-3737
Preoperative Mobilization of Circulating Dendritic Cells by Flt3 Ligand Administration to Patients With Metastatic Colon Cancer
Authors: Michael A. Morse, Smita Nair, Monica Fernandez-Casal, Yuping Deng, Michelle St Peter, Rhonda Williams, Amy Hobeika, Paul Mosca, Tim Clay, R. Ian Cumming, Eva Fisher, Pierre Clavien, Alan D. Proia, Donna Niedzwiecki, Dania Caron, H. Kim Lyerly
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To evaluate preoperative dendritic cell (DC) mobilization and tumor infiltration after administration of Flt3 ligand (Flt3L) to patients with metastatic colon cancer. PATIENTS AND METHODS: Twelve patients with colon cancer metastatic to the liver or lung received Flt3L (20 μg/kg/d subcutaneously for 14 days for one to three cycles at monthly intervals) before attempted metastasectomy. The number and phenotype of DCs mobilized into peripheral-blood mononuclear cells (PBMCs) were evaluated by flow cytometry. After surgical resection, metastatic tumor tissue was evaluated for DC infiltration. In vivo immune responses to recall antigens were measured. RESULTS: After Flt3L administration, on average, the total number of leukocytes in the peripheral blood increased from 5.9 ± 1.0 × 10 3 /mm 3 to 11.2 ± 3.8 × 10 3 /mm 3 (mean ± SD, P = .0001). The percentage of CD11c + CD14 − DCs in PBMCs increased from 2.4% ± 1.8% to 8.8% ± 4.7% (P = .004). Delayed-type hypersensitivity (DTH) responses to recall antigens (Candida, mumps, and tetanus) showed marginally significant increases in reactivity after Flt3L administration (P = .06, P = .03, and P = .08, respectively). An increase in the number of DCs was observed at the periphery of the tumors of patients who received Flt3L compared with those of patients who had not. CONCLUSION: Flt3L is capable of mobilizing DCs into the peripheral blood of patients with metastatic colon cancer and may be associated with increases in DC infiltration in the peritumoral regions. Flt3L mobilization is associated with a trend toward increased DTH responses to recall antigens in vivo. The use of Flt3L to increase circulating DCs for cancer immunotherapy should be considered.
The Contemporary Safety and Effectiveness of Lower Extremity Bypass Surgery and Peripheral Endovascular Interventions in the Treatment of Symptomatic Peripheral Arterial Disease
Authors: Thomas T. Tsai, Thomas F. Rehring, R. Kevin Rogers, Susan M. Shetterly, Nicole M. Wagner, Rajan Gupta, Omid Jazaeri, Nasim Hedayati, W. Schuyler Jones, Manesh R. Patel, P. Michael Ho, Alan S. Go, David J. Magid
Journal: Circulation (2015)

Treatment for symptomatic peripheral artery disease includes lower extremity bypass surgery (LEB) and peripheral endovascular interventions (PVIs); however, limited comparative effectiveness data exist between the 2 therapies. We assessed the safety and effectiveness of LEB and PVI in patients with symptomatic claudication and critical limb ischemia.
Five‐year recurrence rate of lentigo maligna after treatment with imiquimod
Authors: A.C. Kai, T. Richards, A. Coleman, R. Mallipeddi, R. Barlow, E.E. Craythorne
Journal: British Journal of Dermatology (2015)

The current recommended treatment for lentigo maligna (LM) is surgical resection, which can cause significant scarring. The reported recurrence rate after Mohs micrographic surgery is 0-6·25%. There is little published data on long-term outcome after imiquimod therapy. Several reports record progression to LM melanoma during treatment. Clinical assessment of clearance is difficult. Histological confirmation is preferred but risks sampling error and missing areas of invasion. Confocal microscopy can be used to assess entire lesions.To assess the 5-year recurrence rate of LM after imiquimod treatment.Forty patients with LM were treated with imiquimod between 2002 and 2007. Their previous treatments included cryotherapy, incomplete surgical excision and radiotherapy. All applied imiquimod three times per week for 6 weeks; 25 (62·5%) experienced inflammation. The other 15 (37·5%) then applied imiquimod five times per week for a further 4 weeks; all experienced inflammation. All patients were subsequently examined and biopsied. Clinical clearance did not always correlate with histological clearance. Eleven patients (27·5%) had residual LM on histology and underwent surgical excision. At the time of this study, three patients had died (deaths were unrelated to LM). Eighteen of the 27 patients (66·7%) who were clear on biopsy after imiquimod attended for the study and were assessed using confocal microscopy (Vivascope 1500 and 3000).The recurrence rate of LM in patients who were clear on histology after imiquimod treatment who attended for this follow-up study was 0% (n = 18).Imiquimod is an effective long-term treatment for LM. Its use avoids potentially disfiguring surgical resection.
Single Dose of Ebola Vaccine May Be Protective
Authors: Anita Slomski
Journal: JAMA (2015)

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Popularity does not equal peer review
Authors: R. M Pitkin
Journal: BMJ (1995)

EDITOR,--In announcing the death of biomedical journals, Ronald E LaPorte and colleagues extol the potential of the information superhighway for the transmission, compilation, and retrieval of data.1 The presumption seems to be that expanded access is one of the most ardent desires of readers of biomedical journals. An electronic research communication system in physics, which has grown to 40000 users in just four years, is given as evidence. Perhaps physicists are different from physicians. I don't know any medical …