tbuckley/cabot-search huggingface dataset:
Clinical manifestations in primary ciliary dyskinesia: systematic review and meta-analysis
Authors: Myrofora Goutaki, Anna Bettina Meier, Florian S. Halbeisen, Jane S. Lucas, Sharon D. Dell, Elisabeth Maurer, Carmen Casaulta, Maja Jurca, Ben D. Spycher, Claudia E. Kuehni
Journal: European Respiratory Journal (2016)

Few original studies have described the prevalence and severity of clinical symptoms of primary ciliary dyskinesia (PCD). This systematic review and meta-analysis aimed to identify all published studies on clinical manifestations of PCD patients, and to describe their prevalence and severity stratified by age and sex. We searched PubMed, Embase and Scopus for studies describing clinical symptoms of ≥10 patients with PCD. We performed meta-analyses and meta-regression to explain heterogeneity. We included 52 studies describing a total of 1970 patients (range 10–168 per study). We found a prevalence of 5% for congenital heart disease. For the rest of reported characteristics, we found considerable heterogeneity (I 2 range 68–93.8%) when calculating the weighted mean prevalence. Even after taking into account the explanatory factors, the largest part of the between-studies variance in symptom prevalence remained unexplained for all symptoms. Sensitivity analysis including only studies with test-proven diagnosis showed similar results in prevalence and heterogeneity. Large differences in study design, selection of study populations and definition of symptoms could explain the heterogeneity in symptom prevalence. To better characterise the disease, we need larger, multicentre, multidisciplinary, prospective studies that include all age groups, use uniform diagnostics and report on all symptoms.
Margaret McCartney: Clean eating and the cult of healthism
Authors: Margaret McCartney
Journal: BMJ (2016)

The new way of eating is “eating clean”—healthy, whole, unprocessed foods. If only that were all: note the stacks of acai berries, coconut oil, cashew butter, and the expanding wheat-free shelf in the more expensive supermarkets. More choice is a good thing for people with coeliac disease—but these products aren’t aimed at them.

Bestselling cookbooks tell the public that they’ll look and feel better by avoiding wheat, dairy, and refined sugar. City centre juice bars offer similar promises to increase wellbeing (a favourite phrase).

Last month I went to a new gym …
A Two Centre Experience Of Use Of a Dual Virally Inactivated FVIII/VWF Product (Wilate®) In Patients With Von Willebrand Disease
Authors: Paul A Batty, Kate Khair, Renu Riat, Yun-Han Chen, Louise Bowles, Daniel P Hart, Ri Liesner, Sean Platton, Clive Burgess, John Pasi
Journal: Blood (2013)
Abstract 3147: Generation of exhaustion-resistant memory CD8 T-cells by simultaneous downmodulation of mTORC1 and PD-1 in activated CD8 T-cells
Authors: Alexey Berezhnoy, Agata Levay, Anugraha Rajagopalan, Yvonne Puplampu-Dove, Eli Gilboa
Journal: Cancer Research (2015)

Abstract CD8 memory T cells play a crucial role in controlling chronic infections and certain malignancies. It is possible to expand the population redirecting early-activated T-cells toward memory differentiation by altering intracellular signaling of mTORC1 pathway. Indeed, treatment with mTORC1 inhibitor rapamycin increased formation of memory cells as published previously; however, animals treated with the drug exhibited signs of immune suppression and rapamycin-generated CD8 memory T-cells failed to protect animals against melanoma challenge. We introduced highly efficient RNAi-based method to downmodulate mTORC1 signaling specifically in target cells. siRNA against raptor, a critical component of the signaling complex, was delivered in vivo into activated T-cells by conjugating to the 4-1BB-binding RNA aptamer resulting in expansion of CD8+ memory T-cells formation. Memory T-cells are generally resistant to immune suppression, yet in vivo, the population suffers from the gradual attrition mediated by PD-1 signalling. We developed the conjugate with two highly effective siRNAs against raptor and PD-1 linked to the same 4-1BB aptamer molecule. In vitro, both siRNAs efficiently dissociated from the conjugate inside target cells and simultaneously downregulated its respective mRNAs. In vivo, using OT-I adoptive transfer model, we demonstrated that treatment with 4-1BB-raptor-PD1 conjugates increased formation of memory CD8+ T-cells (as measured by absolute number of OT-1 cells 30 days after the treatment) in a rate similar to the 4-1BB-raptor conjugate. There was, however, qualitative difference between two populations, as CD8+ memory T-cells expanded with 4-1BB-raptor-PD1 conjugates expressed significantly less PD-1 on cell surface, and were, therefore, resistant to PD-1-mediated immune suppression. Thus, we introduced a new method to generate memory cells with enhanced functional potential and currently exploring its therapeutic usefulness in various models. Citation Format: Alexey Berezhnoy, Agata Levay, Anugraha Rajagopalan, Yvonne Puplampu-Dove, Eli Gilboa. Generation of exhaustion-resistant memory CD8 T-cells by simultaneous downmodulation of mTORC1 and PD-1 in activated CD8 T-cells. [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 3147. doi:10.1158/1538-7445.AM2015-3147
Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial
Authors: Donald P Tashkin, Michael D Roth, Philip J Clements, Daniel E Furst, Dinesh Khanna, Eric C Kleerup, Jonathan Goldin, Edgar Arriola, Elizabeth R Volkmann, Suzanne Kafaja, Richard Silver, Virginia Steen, Charlie Strange, Robert Wise, Fredrick Wigley, Maureen Mayes, David J Riley, Sabiha Hussain, Shervin Assassi, Vivien M Hsu, Bela Patel, Kristine Phillips, Fernando Martinez, Jeffrey Golden, M Kari Connolly, John Varga, Jane Dematte, Monique E Hinchcliff, Aryeh Fischer, Jeffrey Swigris, Richard Meehan, Arthur Theodore, Robert Simms, Suncica Volkov, Dean E Schraufnagel, Mary Beth Scholand, Tracy Frech, Jerry A Molitor, Kristin Highland, Charles A Read, Marvin J Fritzler, Grace Hyun J Kim, Chi-Hong Tseng, Robert M Elashoff
Journal: The Lancet Respiratory Medicine (2016)
Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection
Authors: Christoph Wilhelm, Oliver J. Harrison, Vanessa Schmitt, Martin Pelletier, Sean P. Spencer, Joseph F. Urban, Michelle Ploch, Thirumalai R. Ramalingam, Richard M. Siegel, Yasmine Belkaid
Journal: The Journal of Experimental Medicine (2016)

Innate lymphoid cells (ILC) play an important role in many immune processes, including control of infections, inflammation, and tissue repair. To date, little is known about the metabolism of ILC and whether these cells can metabolically adapt in response to environmental signals. Here we show that type 2 innate lymphoid cells (ILC2), important mediators of barrier immunity, predominantly depend on fatty acid (FA) metabolism during helminth infection. Further, in situations where an essential nutrient, such as vitamin A, is limited, ILC2 sustain their function and selectively maintain interleukin 13 (IL-13) production via increased acquisition and utilization of FA. Together, these results reveal that ILC2 preferentially use FAs to maintain their function in the context of helminth infection or malnutrition and propose that enhanced FA usage and FA-dependent IL-13 production by ILC2 could represent a host adaptation to maintain barrier immunity under dietary restriction.
Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling
Authors: Bo Ma, Sarah E. Wheeler, Amanda M. Clark, Diana L. Whaley, Min Yang, Alan Wells
Journal: Hepatology (2016)

Liver is one of the most common sites of cancer metastasis. Once disseminated, the prognosis is poor as these tumors often display generalized chemoresistance, particularly for carcinomas that derive not from the aerodigestive tract. When these cancers seed the liver, the aggressive cells usually undergo a mesenchymal to epithelial reverting transition that both aids colonization and renders the tumor cells chemoresistant. In vitro studies demonstrate that hepatocytes drive this phenotypic shift. However, the in vivo evidence and the molecular signals that protect these cells from induced death are yet to be defined. Herein, we report that membrane surface E‐cadherin‐expressing prostate cancer cells were resistant to cell death by chemotherapeutic drugs but E‐cadherin null cells or those expressing E‐cadherin only in the cytoplasm were sensitive to death signals and chemotherapies both in vitro and in vivo . While cell‐cell E‐cadherin ligandation reduced mitogenesis, this chemoprotection was proliferation‐independent as killing of both 5‐ethynyl‐2′‐deoxyuridine‐positive (or Ki67 + ) and 5‐ethynyl‐2′‐deoxyuridine‐negative (Ki67 ‐ ) cells was inversely related to membrane‐bound E‐cadherin. Inhibiting the canonical survival kinases extracellular signal‐regulated protein kinases, protein kinase B, and Janus kinase, which are activated by chemotherapeutics in epithelial cell‐transitioned prostate cancer, abrogated the chemoresistance both in cell culture and in animal models of metastatic cancer. For disseminated tumors, protein kinase B disruption in itself had no effect on tumor survival but was synergistic with chemotherapy, leading to increased killing. Conclusion: Liver microenvironment‐driven phenotypic switching of carcinoma cells and subsequent survival signaling results in activation of canonical survival pathways that protect the disseminated prostate cancer liver micrometastases in a proliferation‐independent manner, and these pathways can be targeted as an adjuvant treatment to improve the efficacy of traditional chemotherapeutics (H epatology 2016;64:1725‐1742)
Prognostic Impact Of Somatic NOTCH2 Mutation In Splenic Marginal Zone Lymphoma
Authors: Caroline Algrin, Gabriel Brisou, Kheira Beldjord, Nicolas Mounier, Francoise Berger, Lucile Baseggio, Aurélie Verney, Gilles Andre Salles, Bertrand Coiffier, Josette Briere, Alexandra Traverse-Glehen, Catherine Thieblemont
Journal: Blood (2013)
Abstract 2670: Non-metabolic function of asparagine in regulating global protein translation
Authors: Ji Zhang, Natalya Pavlova, Richard White, Craig Thompson
Journal: Cancer Research (2016)

Abstract Cancer cells rely on extracellular glutamine for growth and survival. Previously, we showed that asparagine, a nonessential amino acid that can be synthesized de novo from glutamine, is both necessary and sufficient for glutamine-dependent cell survival. In addition, asparagine synthetase (ASNS) expression positively correlates with the progression of the disease in human glioma patients, suggesting a critical role of asparagine during tumor progression. Interestingly, mammalian cells cannot catabolize asparagine for use as either a nitrogen source or a bioenergetic substrate, potentially due to the loss of asparaginase activity during evolution. Ectopic expression of yeast or zebrafish asparaginase restores the capacity of mammalian cells to utilize asparagine as both bioenergetic and biosynthetic substrates to support cell growth. Furthermore, asparagine restores translation of fast-turn-over proteins under glutamine starvation. Together, the data suggests that asparagine has been evolved to be a metabolic reserve to regulate cellular adaptation to nonessential amino acid limitation in mammalian cells and is therefore a potential target for cancer therapy. Citation Format: Ji Zhang, Natalya Pavlova, Richard White, Craig Thompson. Non-metabolic function of asparagine in regulating global protein translation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2670.
Association of response to programmed death 1 receptor or ligand (PD1/PDL1) blockade with immune-related gene expression profiling across three cancer-types.
Authors: Alejandro Navarro, Ana Arance, Noemi Reguart, Laia Paré, Patricia Galván, Alex Martinez Marti, Paolo Nuciforo, Nuria Pardo Aranda, Susana Cedres Perez, Lydia Gaba, Iván Victoria, Nuria Vinolas, Ana Vivancos, Aleix Prat, Enriqueta Felip
Journal: Journal of Clinical Oncology (2016)

3038 Background: Anti-PD1/PDL1 drugs show consistent activity across various solid tumors. However, a substantial proportion of patients show primary resistance, and those who benefit do not benefit to the same extend. Here, we explored the predictive ability of immune-related gene expression in advanced lung cancer, head and neck and melanoma. Methods: Treatment-naive (n = 45) or pre-treated (n = 31) tumor samples from 76 patients with lung non-squamous (n = 28), squamous cell lung cancer (n = 20), head and neck (n = 5) and melanoma (n = 23) were evaluated. RNA from formalin-fixed paraffin-embedded tissue sections was analyzed using the NanoString PanCancer Immune Panel (730 genes). Patients were treated with pembrolizumab (n = 35), nivolumab (n = 28) or atezolizumab (n = 13). All genes, and 16 immune cell-type signatures, were linked to response and progression-free survival (PFS). Logistic regression models for overall response rate (ORR; defined as partial or complete response at 6-8 weeks) and non-progressive rate (NPR; non-progressive vs. progressive disease at 6-8 weeks), and Cox models for PFS, were used. Results: The ORR and NPR were 32.9% and 61.8%, respectively. Median PFS was 5.57 months (3.20-7.67). No gene was found significantly associated with ORR (False Discovery Rate [FDR] < 5%). Expression of 374 genes, including PD1 and PDL1, was found significantly associated with NPR (FDR = 0%). Six signatures (T-cells, CD8-T cells, NK-cells, CD4-activated, T-regulated and Th1-cells) showed significant associations with both NPR and PFS. The median PFS of the Th1-cells high-tertile group was 12.3 months compared to 2.6 months of the Th1-cells low-tertile group (hazard ratio = 0.26, 0.10-0.65,P= 0.004). These associations were independent of sample timing, drug used or cancer-type. Conclusions: Expression of immune-related genes in tumor samples identifies patients likely to have primary resistance to anti-PD1/PDL1 monotherapy. Results are consistent with the hypothesis that identification of a preexisting and stable adaptive immune response predicts clinical outcome regardless of cancer-type or anti-PD1/PDL1 inhibitor.
Targeting KRAS mutant non-small cell lung cancer (NSCLC) with deltarasin: A small molecule inhibitor of KRAS-PDEδ interaction.
Authors: Jun Zhang, Ke Xu, Dong Moon Shin, Xingming Deng
Journal: Journal of Clinical Oncology (2015)

e13597 Background: As oncogenic KRAS relies on the correct spatial localization to exert its function, disrupting the transport of KRAS to the cell membrane may provide a new approach to target KRAS mutant NSCLC. Recent study has shown deltarasin, a small molecular inhibitor, can suppress oncogenic KRAS signaling by disrupting the interaction between KRAS and its transporter PDEδ, thereby altering its localization to endomembranes (Zimmermann et al, Nature 2013). Here we investigated whether deltarain has anti-tumor effect on KRAS mutant NSCLC. Methods: NSCLC cell lines with various KRAS mutations (Calu-1, H358, H1792, H157, H460 and A549) or wild type KRAS (H292 and H1975), as well as immortalized bronchial epithelial cell line Beas2B (wild type KRAS) were used in the study. MTT and SRB assays were used to analyze cell proliferation and IC50. Flow cytometry and immunoblotting were used to investigate relevant signaling pathways as well as potential mechanisms involved in cell death. Results: Probably due to small sample size, the difference of IC50 between the KRAS mutant vs. wild type cell lines was not statistically significant. However, after we treated the cells with 5µM deltarasin for 48 hrs, 5 out of 6 KRAS mutant NSCLC lines had cell viability below 20%, but all 3 cell lines with wild type KRAS (including Beas2B) were above 20% (p = 0.0476), suggesting potential mutant-selective effect of deltarasin. When we compared KRAS mutant (H358) vs. wild type (H292) NSCLC cells in parallel, treatment with 3µM of deltarasin for 48 hrs resulted in ~ 6 times more apoptotic cells of H358 (p < 0.01), but less than 2 folds of H292 cells (p > 0.05) comparing to their baseline levels. This observation correlated to the potent inhibition of both phospho-ERK and phospho-AKT, as well as significant induction of cleaved PARP in H358 cells, which did not happen in H292 cells under similar condition. Interestingly, treatment with deltarasin didn't change the levels of total RAS and KRAS. This is consistent with the known effect of deltarasin – it targets RAS localization rather than RAS itself. Conclusions: Deltarasin, a small molecule inhibitor of KRAS-PDEδ interaction, provides a unique opportunity to target KRAS mutant NSCLC.
Abstract 272: Metformin enhances the anti-prostate cancer activity of abiraterone and enzalutamide
Authors: Yi Xie, Linbo Wang, Arif Hussain
Journal: Cancer Research (2016)

Abstract The standard treatment for advanced castration sensitive prostate cancer (CSPC) is androgen deprivation therapy (ADT), generally in the form of suppression of gonadally produced androgens via medical or surgical castration. The selective inhibitor of androgen biosynthesis Abiraterone (Abi), and the androgen receptor (AR) antagonist Enzalutamide (MDV3100), are second line hormonal therapies used to treat PC patients failing ADT. However, these drugs provide treatment response for a limited duration of time due to the development of resistance to them. Included among the mechanisms leading to resistance to ABI or MDV is the expression of the AR variant AR-V7. Metformin, a widely used oral anti-diabetic drug, has been reported to reduce prostate cancer mortality in PC patients with type II diabetes. In this study, we explored the effects of ABI, MDV and metformin in a pre-clinical model of PC. Both Abi and MDV inhibited cell proliferation and the expression of prostate specific antigen (PSA) in androgen-sensitive LNCaP cells. However, neither induced cell death, and in fact MDV appeared to actually inhibit apoptosis in LNCaP cells. Both agents increased AR and AR-V7 expression, which in part may account for development of resistance to ABI or MDV. In contrast, metformin inhibited AR, AR-V7 and PSA expression in a dose-dependent manner, and induced apoptotic cell death in PC cells. Metformin, in combination with ABI or MDV, further enhanced apoptosis and inhibited expression of PSA than it did as single agent. Interestingly, at near physiological concentrations metformin induced apoptosis in a caspase-independent manner rather than by a caspase-dependent apoptotic program that is reported to occur with high doses of metformin. In conclusion, Abi or MDV inhibits AR signaling and PC cell proliferation, but also induces AR and AR-V7 expression. Metformin decreases AR and AR-V7 expression and induces apoptotic cell death. The combination of metformin with androgen biosynthesis/AR inhibitors results in caspase-independent apoptotic cell death in addition to inhibition of both cell proliferation and AR signaling. Further studies will be needed to evaluate the clinical efficacy of these combination treatments in patients with PC. Citation Format: Yi Xie, Linbo Wang, Arif Hussain. Metformin enhances the anti-prostate cancer activity of abiraterone and enzalutamide. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 272.
Abstract 1838: Differential CXCL13 and CXCR5 expression mediated by down-regulation of select miRNAs in prostate cancer
Authors: Denise E. Hinton, James Lillard
Journal: Cancer Research (2016)

Abstract Chemokines and their receptors are involved in the inflammatory response by attracting immune cells to sites of infection and wound healing. Chemokines have also been implicated in the progression of prostate cancer (PCa). We have previously shown a positive correlation between the expression of CXCL13 and CXCR5 proteins with PCa progression; in particular, the CXCR5 protein is expressed to a greater extent by prostate tumors isolated from African Americans than compared to those from European Americans. In the present study, we sought: (i) to determine whether CXCL13 and CXCR5 mRNA expression patterns correlated with overall and/or disease-free survival in PCa cases and (ii) to identify the possible molecular mechanisms that govern this association. CXCL13 and CXCR5 mRNA levels and PCa survival rates were evaluated using The Cancer Genome Atlas (TCGA) data sets and the CbioPortal, respectively. CXCR5 and CXCL13 mRNA expression did not correlate with prostate tumor stage or grade and was not associated with overall PCa survival. However, CXCR5 mRNA expression was significantly associated with poor disease-free survival. Gene map analysis using the UCSC Genome Browser revealed consensus sequence binding sites for four miRNA's (miR-192/215, miR-486, and miR-494) that could bind the 3’ UTR of the cxcr5 transcript. Our results showed that miR-494 was frequently deleted or down-regulated, confirming other reports that miR-494 is down-regulated in high-grade PCa cases. Of note, miR-494 also targets cxcr4 mRNA and suppresses migration of PCa cells. Others have shown that miR-486 is associated with p53 and PI3K-Akt pathways and miR-186 has a putative binding site in the 3’ UTR region of the cxcl13 transcript. This miRNA was down-regulated in PCa patients with initial metastasis. These results confirm our previous studies demonstrating a correlation between tumor expression and PCa progression and reveal new mechanisms of post-translational regulation of this chemokine receptor. Citation Format: Denise E. Hinton, James Lillard. Differential CXCL13 and CXCR5 expression mediated by down-regulation of select miRNAs in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1838.
Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics
Authors: Yair Shemesh, Oren Forkosh, Mathias Mahn, Sergey Anpilov, Yehezkel Sztainberg, Sharon Manashirov, Tamar Shlapobersky, Evan Elliott, Laure Tabouy, Gili Ezra, Elaine S Adler, Yair J Ben-Efraim, Shosh Gil, Yael Kuperman, Sharon Haramati, Julien Dine, Matthias Eder, Jan M Deussing, Elad Schneidman, Ofer Yizhar, Alon Chen
Journal: Nature Neuroscience (2016)