tbuckley/cabot-search huggingface dataset:
Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression
Authors: Megan M. Kaneda, Paola Cappello, Abraham V. Nguyen, Natacha Ralainirina, Chanae R. Hardamon, Philippe Foubert, Michael C. Schmid, Ping Sun, Evangeline Mose, Michael Bouvet, Andrew M. Lowy, Mark A. Valasek, Roman Sasik, Francesco Novelli, Emilio Hirsch, Judith A. Varner
Journal: Cancer Discovery (2016)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a low 5-year survival rate, yet new immunotherapeutic modalities may offer hope for this and other intractable cancers. Here, we report that inhibitory targeting of PI3Kγ, a key macrophage lipid kinase, stimulates antitumor immune responses, leading to improved survival and responsiveness to standard-of-care chemotherapy in animal models of PDAC. PI3Kγ selectively drives immunosuppressive transcriptional programming in macrophages that inhibits adaptive immune responses and promotes tumor cell invasion and desmoplasia in PDAC. Blockade of PI3Kγ in PDAC-bearing mice reprograms tumor-associated macrophages to stimulate CD8(+) T-cell-mediated tumor suppression and to inhibit tumor cell invasion, metastasis, and desmoplasia. These data indicate the central role that macrophage PI3Kγ plays in PDAC progression and demonstrate that pharmacologic inhibition of PI3Kγ represents a new therapeutic modality for this devastating tumor type.We report here that PI3Kγ regulates macrophage transcriptional programming, leading to T-cell suppression, desmoplasia, and metastasis in pancreas adenocarcinoma. Genetic or pharmacologic inhibition of PI3Kγ restores antitumor immune responses and improves responsiveness to standard-of-care chemotherapy. PI3Kγ represents a new therapeutic immune target for pancreas cancer. Cancer Discov; 6(8); 870-85. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.
Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis
Authors: Teclegiorgis Gebremariam, Lin Lin, Mingfu Liu, Dimitrios P. Kontoyiannis, Samuel French, John E. Edwards, Scott G. Filler, Ashraf S. Ibrahim
Journal: Journal of Clinical Investigation (2016)

Patients with diabetic ketoacidosis (DKA) are uniquely predisposed to mucormycosis, an angioinvasive fungal infection with high mortality. Previously, we demonstrated that Rhizopus invades the endothelium via binding of fungal CotH proteins to the host receptor GRP78. Here, we report that surface expression of GRP78 is increased in endothelial cells exposed to physiological concentrations of β-hydroxy butyrate (BHB), glucose, and iron that are similar to those found in DKA patients. Additionally, expression of R. oryzae CotH was increased within hours of incubation with DKA-associated concentrations of BHB, glucose, and iron, augmenting the ability of R. oryzae to invade and subsequently damage endothelial cells in vitro. BHB exposure also increased fungal growth and attenuated R. oryzae neutrophil-mediated damage. Further, mice given BHB developed clinical acidosis and became extremely susceptible to mucormycosis, but not aspergillosis, while sodium bicarbonate reversed this susceptibility. BHB-related acidosis exerted a direct effect on both GRP78 and CotH expression, an effect not seen with lactic acidosis. However, BHB also indirectly compromised the ability of transferrin to chelate iron, as iron chelation combined with sodium bicarbonate completely protected endothelial cells from Rhizopus-mediated invasion and damage. Our results dissect the pathogenesis of mucormycosis during ketoacidosis and reinforce the importance of careful metabolic control of the acidosis to prevent and manage this infection.
Abstract 3710: Stanford GEMS (Girls health Enrichment Multisite Studies): Long-Term Efficacy of After-School Dance and Screen Time Reduction in Low-Income African-American Girls
Authors: Thomas N Robinson, Donna M Matheson, Helena C Kraemer, Eva Obarzanek, Darrell M Wilson, William L Haskell, Leslie A Pruitt, Nikko S Thompson, K. Farish Haydel, Michelle Fujimoto, Ann Varady, Joel D Killen
Journal: Circulation (2007)

Objective: To test the efficacy of a 2-year, community- &amp; family-based intervention to reduce weight gain in low-income, preadolescent African-American girls Design: 2 arm, parallel group, randomized controlled trial Setting: Low-income areas of Oakland, CA Participants: 8 –10 year old African-American girls Interventions: Girls were randomized to a 2 year, culturally-tailored after school dance program and a home/family-based intervention to reduce screen media use (dance/TV) versus an information-based community health education (HE) active-placebo comparison intervention Primary Outcome: Change in body mass index measured up to 5 times over the course of the study Results: 261 girls were randomized (134 dance/TV, 127 HE) and 225 (86.2%) completed 1 or more follow-up measures (118 dance/TV, 107 HE; mean ± SD follow-up = 25.7 ± 8.5 mos and 25.2 ± 9.6 mos, respectively). Intent-to-treat analysis found no statistically significant differences between groups in BMI change (mean difference in changes= .04 kg/m2 per year, 95% confidence interval [95% CI] =−.19 to .27; P=.72). Similar results were found for waist circumference and triceps skinfold. Compared to girls in HE, girls in the dance/TV group significantly reduced fasting total cholesterol levels (difference in changes = −3.49 mg/dl per year, 95% CI −5.28 to −1.70; P&lt;.001), fasting LDL-cholesterol (−3.02, 95% CI −4.74 to −1.31; P&lt;.001) and depressive symptoms (P&lt;.05). Changes between groups were not statistically significant for HDL-cholesterol, triglycerides and insulin, resting blood pressure and heart rate, dietary energy and fat, accelerometer-measured physical activity, and screen time. Moderator analysis indicated the dance/TV reduction intervention was significantly more effective than HE in reducing BMI gain for girls with single parent families, more screen time and more depressive symptoms at baseline. Conclusions: A culturally-tailored after school dance and screen time reduction intervention did not slow BMI increases more than a health education intervention in low-income African-American girls. The dance/TV intervention resulted in greater reductions in fasting total and LDL-cholesterol and depressive symptoms, but not in other cardiovascular disease risk factors.
Enzalutamide monotherapy: Phase II study results in patients with hormone-naive prostate cancer.
Authors: Bertrand Tombal, Michael Borre, Per Rathenborg, Patrick Werbrouck, Axel Heidenreich, Peter Iversen, Edwina S. Baskin-Bey, Frank Perabo, De Phung, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2013)

18 Background: Enzalutamide (ENZA) is an oral androgen receptor inhibitor that has been approved in the US and shown to increase overall survival by 4.8 months over a placebo (HR, 0.63) in patients with metastatic castration resistant prostate cancer (CRPC) previously treated with docetaxel (Scher et al, N Engl J Med 2012;367:1187). Compared with bicalutamide in nonclinical studies, enzalutamide had higher androgen receptor–binding affinity, prevented nuclear translocation, showed no DNA binding, and induced apoptosis (Tran et al, Science 2009;324:787). In contrast to previous phase II and III studies that exclusively enrolled patients with CRPC receiving androgen deprivation therapy (ie, testosterone (T) levels ≤50 ng/dL), this phase II study assessed the efficacy and safety of ENZA monotherapy in patients who had never received hormone therapy; presenting with non-castrate T levels (≥230 ng/dL). Methods: This was a 25-wk, open-label, single-arm study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy &gt;1 y. All patients received ENZA 160 mg/d without concomitment castration. Primary endpoint was PSA response (&gt;80% decrease at wk 25). Secondary endpoints included changes in endocrine levels and safety/tolerability. Results: Among 67 men enrolled, the median (range) age was 73 (48, 86) y; 39% had metastases; 36% and 24% had undergone prostatectomy or radiotherapy before study entry. The PSA response rate (&gt;80% PSA decline at wk 25) was 93%, with a median (range) decrease of −99% (−100, −57) at wk 25. Serum T and estrogen levels increased by a median (range) of 113% (−32, 300) and 58% (−49, 321) at wk 25, respectively, compared with baseline. 82% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (36%), fatigue (34%), and hot flush (18%). 7% of men experienced SAEs; none were drug-related. Conclusions: ENZA monotherapy (160 mg) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Endocrine level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT01302041.
Abstract 4233: Wnt pathway antagonist ipafricept (FZD8-Fc, OMP-54F28) inhibits tumor growth and reduces tumor-initiating cell frequency in ovarian patient-derived xenograft models
Authors: Marcus M. Fischer, Wan-Ching Yen, Chun Zheng, Randall Henner, Fiore Cattaruzza, Tracy Tang, Pete Yeung, Tanuka Biswas, John Lewicki, Austin Gurney, Ann M. Kapoun, Timothy Hoey
Journal: Cancer Research (2015)

Abstract Ovarian cancer is the deadliest gynecologic malignancy and the fifth leading cause of death from cancer in women in the U.S. The Wnt/beta-catenin pathway, which signals through the Frizzled (FZD) receptor family and several co-receptors, has long been implicated in cancer. We have developed ipafricept (FZD8-Fc, OMP-54F28), a recombinant fusion protein consisting of the ligand-binding domain of FZD8 and a human IgG1 Fc fragment. This fusion protein blocks Wnt signaling induced by multiple Wnt family members by binding and sequestering WNT. Using minimally passaged ovarian patient-derived xenograft tumors (PDX), we demonstrate that ipafricept is efficacious in combination with chemotherapy in four of eight ovarian cancer PDX tumors examined. Utilizing an in vivo serial transplantation assay, we quantified a reduction of the tumor initiating cell frequency by ipafricept in combination with paclitaxel. Additionally, we have discovered that pre-treatment with ipafricept several days prior to paclitaxel therapy enhances the activity of both agents when compared to delivering the drugs simultaneously. The anti-tumor effect observed is directly associated with a modulation of Wnt pathway gene sets. In responsive tumors, we discovered that a large number of WNT target genes were significantly down-regulated by ipafricept (e.g, AXIN2, LRP5/6, and FZD8). Conversely, in non-responsive tumors, these genes were either unchanged or up-regulated by the combination therapy. Histologic analysis revealed that total beta-catenin protein levels were reduced by ipafricept alone and in combination with paclitaxel in responsive tumors but were unchanged in non-responsive tumors. We are using these tumors to develop biomarkers that can be used clinically. Our data demonstrates the potential therapeutic benefit of targeting Wnt signaling in ovarian cancer. A Phase 1b clinical trial is currently examining ipafricept in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Citation Format: Marcus M. Fischer, Wan-Ching Yen, Chun Zheng, Randall Henner, Fiore Cattaruzza, Tracy Tang, Pete Yeung, Tanuka Biswas, John Lewicki, Austin Gurney, Ann M. Kapoun, Timothy Hoey. Wnt pathway antagonist ipafricept (FZD8-Fc, OMP-54F28) inhibits tumor growth and reduces tumor-initiating cell frequency in ovarian patient-derived xenograft models. [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 4233. doi:10.1158/1538-7445.AM2015-4233
Factors associated with depression and anxiety symptoms in family caregivers of patients with incurable cancer
Authors: R.D. Nipp, A. El-Jawahri, J.N. Fishbein, E.R. Gallagher, J.M. Stagl, E.R. Park, V.A. Jackson, W.F. Pirl, J.A. Greer, J.S. Temel
Journal: Annals of Oncology (2016)
Phase Ib Study Of Combination Epigenetic Therapy With 5-Azacitidine and Vorinostat In Patients With Relapsed Or Refractory DLBCL
Authors: Tiffany Tang, Peter Martin, Rebecca L. Elstrom, Jia Ruan, Richard R. Furman, Arcania Garcia, June Greenberg, Amelyn Rodriguez, Alison Bender, Jessica Lewis, Ari Melnick, Leandro Cerchietti, John P. Leonard
Journal: Blood (2013)
Treatment of Burns--I
Authors: J. P. Bull, D. M. Jackson
Journal: BMJ (1952)

This article is concerned chiefly with the hospital treat- ment of burned patients, including skin grafting.Although of prime interest to residents and registrars, we believe that many general practitioners will welcome this account of current methods of treatment.Some will be glad of it for more immediately practical reasons, as they may have charge of such patients in cottage hospitals or privately.]
Mitotic index, microvascular proliferation, and necrosis define 3 pathological subgroups of prognostic relevance among 1p/19q co-deleted anaplastic oligodendrogliomas
Authors: Dominique Figarella-Branger, Karima Mokhtari, Caroline Dehais, Catherine Carpentier, Carole Colin, Anne Jouvet, Emmanuelle Uro-Coste, Fabien Forest, Claude-Alain Maurage, Jean-Michel Vignaud, Marc Polivka, Emmanuèle Lechapt-Zalcman, Sandrine Eimer, Gabriel Viennet, Isabelle Quintin-Roué, Marie-Hélène Aubriot-Lorton, Marie-Danièle Diebold, Delphine Loussouarn, Catherine Lacroix, Valérie Rigau, Annie Laquerrière, Fanny Vandenbos, Sophie Michalak, Henri Sevestre, Michel Peoc'H, François Labrousse, Christo Christov, Jean-Louis Kemeny, Marie-Pierre Chenard, Danchristian Chiforeanu, François Ducray, Ahmed Idbaih, Jean-Yves Delattre, Pola Network
Journal: Neuro-Oncology (2016)
Radium-223 in metastatic castration resistant prostate cancer: Progression free survival and pain scores—Real-world single-institution experience.
Authors: Amarnath Challapalli, Serena Hilman, Sue Cowley, Susan Masson, Dorothy Grifiths, Rajendra Persad, Kathryn Mitchell, Rebecca Huckett, Rosemary Greenwood, Eleanor Compton, Amit Bahl
Journal: Journal of Clinical Oncology (2016)

250 Background: Radium-223 (Ra223) is a novel alpha-emitting radiopharmaceutical agent approved for use in patients with metastatic castration resistant prostate cancer (mCRPC) and bone metastases based on ALSYMPCA results. We report our early experience in this setting. Methods: 36 patients were treated with Ra223 from Feb 2014 - Aug 2015. The patients were planned to receive 6 injections at a dose of 50 kBq/kg every 4 weekly. The pain was assessed using the visual analogue score (VAS). The effect of 6 cycles of Ra223 on blood counts, serum alkaline phosphatase (SAP), PSA, VAS and progression free survival (PFS) were evaluated. Results: At baseline (BL) median age was 79years; 66% of patients were ECOG 0-1; median VAS was 6. 53% had received prior docetaxel. 18 patients (50%) received all the scheduled 6 cycles of Ra223. In these patients there was a significant reduction in the pain scores both after the first cycle and after 6 cycles compared to the BL score (p &lt; 0.05 &amp; p &lt; 0.001, respectively). A 30% reduction in the SAP levels was seen (p = 0.03). The reduction in pain scores was independent of the PSA response. The treatment was well tolerated with no grade 3,4 toxicity. Discontinuation rate was 50% (18/36) and was due to disease progression. Prior docetaxel use was associated with a higher discontinuation rate (12/18), as was albumin level &lt; 34g/dL (60% vs. 43%). 7 (19%) required blood transfusions during the course. The median PFS was 6.1 months. It was significantly longer in those who completed 6 cycles of treatment and in patients with SAP &lt; 220 U/L (10.97vs.5.2 &amp; 10.33vs.6.4 months, respectively: p &lt; 0.0001). There was a non-significant trend towards longer PFS in patients who had no prior docetaxel (10.33vs.6.5m; p = 0.05) and in patients with Albumin &gt; 34 (8.9vs.6.4m; p = 0.06). Conclusions: Ra223 is a safe and effective treatment for mCRPC with bone metastases. Completion of 6 cycles is associated with a significantly better PFS, reduction in pain scores and in SAP levels. Prior docetaxel use and lower albumin levels were associated with a higher discontinuation rate and this should be considered in the decision process for optimising therapy sequencing.
Supporting the next generation
Authors: Tom Moberly
Journal: BMJ (2016)

Last week the government and the BMA stepped back from the brink in the escalating dispute over the new contract for junior doctors in England (doi:10.1136/bmj.i2635). The five day “pause” for further negotiations offers a last ditch opportunity to tackle outstanding areas of disagreement (doi:10.1136/bmj.i2572), and junior doctors will have the chance to vote on any proposals (doi:10.1136/bmj.i2663).

Before the pause, the government maintained that there was only one substantive area of …
The Association of Chemotherapy-Induced Peripheral Neuropathy Symptoms and the Risk of Falling
Authors: Noah A. Kolb, A. Gordon Smith, J. Robinson Singleton, Susan L. Beck, Gregory J. Stoddard, Summer Brown, Kathi Mooney
Journal: JAMA Neurology (2016)

<h3>Importance</h3> Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neurotoxic chemotherapy resulting in pain, sensory loss, and decreased quality of life. Few studies have prospectively examined the relationship between sensory neuropathy symptoms, falls, and fall-related injuries for patients receiving neurotoxic chemotherapy. <h3>Objective</h3> To determine the association between the symptoms of CIPN and the risk of falls for patients receiving neurotoxic chemotherapy. <h3>Design, Setting, and Participants</h3> In this secondary analysis of a prospective study, 116 patients with breast, ovarian, or lung cancer who were beginning neurotoxic chemotherapy with a taxane or platinum agent were recruited from oncology clinics. These patients would call a novel automated telephone system daily for 1 full course of chemotherapy. The telephone system (SymptomCare@Home) used a series of relevant CIPN questions to track symptoms on a 0 to 10 ordinal scale and contained a questionnaire about falls. Those reporting a numbness and tingling severity score of 3 or greater for at least 10 days were considered to have significant CIPN symptoms and were compared with those patients who did not. Data analysis was performed in November 2015. <h3>Exposure</h3> Chemotherapy with a neurotoxic taxane or platinum agent. <h3>Main Outcomes and Measures</h3> Patient-reported falls or near falls and fall-related injuries. The hypothesis was generated after data collection but prior to data analysis. <h3>Results</h3> Of the 116 patients who started neurotoxic chemotherapy (mean [SD] age was 55.5 [11.9] years, and 109 [94.0%] were female), 32 met the predetermined criteria for CIPN symptoms. The mean duration of follow-up was 62 days, with 51 telephone calls completed per participant. Seventy-four falls or near falls were reported. The participants with CIPN symptoms were nearly 3 times more likely to report a fall or near fall than the participants without CIPN symptoms (hazard ratio, 2.67 [95% CI, 1.62-4.41];<i>P</i> &lt; .001). The participants with CIPN symptoms were more likely than the participants without CIPN symptoms to obtain medical care for falls (8 of 32 participants with CIPN symptoms [25.0%] vs 6 of 84 participants without CIPN symptoms [7.1%];<i>P</i> = .01). <h3>Conclusions and Relevance</h3> These findings suggest that the sensory symptoms of CIPN are an indicator of an increased risk of falling and an increased use of health care resources. This study demonstrates the utility of a novel telephone-based system to track neuropathy symptoms. Careful monitoring and coaching of patients receiving neurotoxic chemotherapy for new sensory symptoms may facilitate more effective fall prevention strategies.
Fibroblast Growth Factor Receptor 3 Inhibits Osteoarthritis Progression in the Knee Joints of Adult Mice
Authors: Junzhou Tang, Nan Su, Siru Zhou, Yangli Xie, Junlan Huang, Xuan Wen, Zuqiang Wang, Quan Wang, Wei Xu, Xiaolan Du, Hangang Chen, Lin Chen
Journal: Arthritis & Rheumatology (2016)

Objective Fibroblast growth factor (FGF) signaling is involved in articular cartilage homeostasis. This study was undertaken to investigate the role and mechanisms of FGF receptor 3 (FGFR‐3) in the pathogenesis of osteoarthritis (OA) caused by surgery and aging in mice. Methods FGFR‐3 was conditionally deleted or activated in articular chondrocytes in adult mice subjected to surgical destabilization of the medial meniscus (DMM). A mouse model of human achondroplasia was also used to assess the role of FGFR‐3 in age‐associated spontaneous OA. Knee joint cartilage was histologically evaluated and scored using the Osteoarthritis Research Society International system. The expression of genes associated with articular cartilage maintenance was quantitatively evaluated in hip cartilage explants. The effect of inhibiting Indian hedgehog (IHH) signaling in Fgfr3 ‐deficient explants was analyzed. Results Conditional Fgfr3 deletion in mice aggravated DMM‐induced cartilage degeneration. Matrix metalloproteinase 13 and type X collagen levels were up‐regulated, while type II collagen levels were down‐regulated, in the articular cartilage of these mice. Conversely, FGFR‐3 activation attenuated cartilage degeneration induced by DMM surgery and age. IHH signaling and runt‐related transcription factor 2 levels in mouse articular chondrocytes were up‐regulated in the absence of Fgfr3 , while inhibition of IHH signaling suppressed the increases in the expression of Runx2 , Mmp13 , and other factors in Fgfr3 ‐deficient mouse cartilage explants. Conclusion Our findings indicate that FGFR‐3 delays OA progression in mouse knee joints at least in part via down‐regulation of IHH signaling in articular chondrocytes.
Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial
Authors: M Irem Baharoglu, Charlotte Cordonnier, Rustam Al-Shahi Salman, Koen de Gans, Maria M Koopman, Anneke Brand, Charles B Majoie, Ludo F Beenen, Henk A Marquering, Marinus Vermeulen, Paul J Nederkoorn, Rob J de Haan, Yvo B Roos
Journal: The Lancet (2016)