tbuckley/cabot-search huggingface dataset:
KRAS gene mutation status and sensitivity to pemetrexed: A retrospective analysis.
Authors: Manali K. Kamdar, Teresa Parent, Paul R. Walker
Journal: Journal of Clinical Oncology (2013)

e19154 Background: KRAS is the most frequently mutated oncogene (25%) in lung adenocarcinoma. KRAS mutations are a negative prognostic factor for survival. Recent phase II trial with a MEK inhibitor has shown promising efficacy albeit at the cost of higher adverse events. Preclinical work by Moran et al showed that antifolate therapies like pemetrexed decrease KRAS gene expression in KRAS wild type and KRAS mutant but do not do so in KRAS mutant amplified cells. Targeted therapies for EGFR, ALK and ROS1 have increased the survival for lung adenocarcinoma expressing these actionable targets. No therapies are yet approved for KRAS mutant subsets. Hence therapeutic strategies that target this cohort represent an unmet medical need. Methods: We reviewed data from patients (pts) in our thoracic oncology clinic with stage IIIB and stage IV lung adenocarcinoma with KRAS mutation positive tumours who received pemetrexed either during induction or maintenance therapy. Pt characteristics including age, sex, race, smoking history, KRAS mutation subtype and overall survival were analyzed. Results: Between April 2010 and October 2012 we treated 154 pts with stage IIIB and stage IV lung adenocarcinoma. Of these 154 pts we found 34 patients with KRAS mutation positive tumours. 10 pts out of 34 pts with KRAS mutation positive tumours received pemetrexed during induction or maintenance therapy and were analyzed further. Median age 63. 60% females. 90% Caucasians. 90% were smokers. KRAS 12C mutation was found in 2 pts, KRAS 12V in 4, KRAS 12A in 3 and KRAS 13A in 1 pt. 4(40%) patients died. Median overall survival (OS) in the KRAS 12C, 12V, 12A and 13A was 14, 9.5, 10 and 12 months respectively. Conclusions: The median OS in published series is 15.4, 14, 8 and 7 months in the KRAS 12C, 12V, 12A and 13A cohorts respectively (Rosell et al). Our analysis found that pts with KRAS 12C, 12A and 13A mutation had a survival advantage with pemetrexed therapy as compared to pts with KRAS 12V mutation. Thus this retrospective study supports the concept that KRAS mutation status affects sensitivity to antifolate therapy (pemetrexed).
Commensal microbes provide first line defense against <i>Listeria monocytogenes</i> infection
Authors: Simone Becattini, Eric R. Littmann, Rebecca A. Carter, Sohn G. Kim, Sejal M. Morjaria, Lilan Ling, Yangtsho Gyaltshen, Emily Fontana, Ying Taur, Ingrid M. Leiner, Eric G. Pamer
Journal: The Journal of Experimental Medicine (2017)

Listeria monocytogenes is a foodborne pathogen that causes septicemia, meningitis and chorioamnionitis and is associated with high mortality. Immunocompetent humans and animals, however, can tolerate high doses of L. monocytogenes without developing systemic disease. The intestinal microbiota provides colonization resistance against many orally acquired pathogens, and antibiotic-mediated depletion of the microbiota reduces host resistance to infection. Here we show that a diverse microbiota markedly reduces Listeria monocytogenes colonization of the gut lumen and prevents systemic dissemination. Antibiotic administration to mice before low dose oral inoculation increases L. monocytogenes growth in the intestine. In immunodeficient or chemotherapy-treated mice, the intestinal microbiota provides nonredundant defense against lethal, disseminated infection. We have assembled a consortium of commensal bacteria belonging to the Clostridiales order, which exerts in vitro antilisterial activity and confers in vivo resistance upon transfer into germ free mice. Thus, we demonstrate a defensive role of the gut microbiota against Listeria monocytogenes infection and identify intestinal commensal species that, by enhancing resistance against this pathogen, represent potential probiotics.
Regional Differences Between Perisynovial and Infrapatellar Adipose Tissue Depots and Their Response to Class II and Class III Obesity in Patients With Osteoarthritis
Authors: Natalia S. Harasymowicz, Nick D. Clement, Asim Azfer, Richard Burnett, Donald M. Salter, A. Hamish W. R. Simpson
Journal: Arthritis & Rheumatology (2017)

Obesity is associated with an increased risk of developing osteoarthritis (OA), which is postulated to be secondary to adipose tissue-dependent inflammation. Periarticular adipose tissue depots are present in synovial joints, but the association of this tissue with OA has not been extensively explored. The aim of this study was to investigate differences in local adipose tissue depots in knees with OA and characterize the changes related to class II and class III obesity in patients with end-stage knee OA.Synovium and the infrapatellar fat pad (IPFP) were collected during total knee replacement from 69 patients with end-stage OA. Histologic changes, changes in gene and protein expression of adiponectin, peroxisome proliferator-activated receptor γ (PPARγ), and Toll-like receptor 4 (TLR-4), and immune cell infiltration into the adipose tissue were investigated.IPFP and synovium adipose tissue depots differed significantly and were influenced by the patient's body mass index. Compared to adipocytes from the IPFP and synovium of lean patients, adipocytes from the IPFP of obese patients were significantly larger and the synovium of obese patients displayed marked fibrosis, increased macrophage infiltration, and higher levels of TLR4 gene expression. The adipose-related markers PPARγ in the IPFP and adiponectin and PPARγ in the synovium were expressed at lower levels in obese patients compared to lean patients. Furthermore, there were increased numbers of CD45+ hematopoietic cells, CD45+CD14+ total macrophages, and CD14+CD206+ M2-type macrophages in both the IPFP and synovial tissue of obese patients.These differences suggest that IPFP and synovium may contain 2 different white adipose tissue depots and support the theory of inflammation-induced OA in patients with class II or III obesity. These findings warrant further investigation as a potentially reversible, or at least suppressible, cause of OA in obese patients.
Identification of functional modulators of platinum resistance using isogenically matched ovarian cancer cell line models.
Authors: Euan Stronach, Nona Rama, Hani Gabra
Journal: Cancer Research (2008)

699  Resistance to platinum based chemotherapy is a major factor in the poor prognosis associated with advanced stage ovarian cancer. We hypothesised that by taking advantage of the reduced variance associated with the use of isogenic resources, gene expression profiling could be used to identify molecular alterations characteristic of the platinum resistant phenotype. Using cDNA microarrays we have measured gene expression levels for four clinically derived, isogenically matched cell line pairs representing platinum sensitivity and resistance, for which we have demonstrated stable reflection of clinical resistance in vitro by calculation of IC50s for cisplatin (average between pair difference in IC50= 5.8 fold). Microarray hybridisations were performed in quadruplicate employing a dye swap design. Analysis of loess normalised data identified 65 genes commonly upregulated in resistant cells and 92 genes commonly downregulated in resistant cells by applying the following criteria: =>1.5 fold change in 3 out of 4 pairs; t-test p
<i>IGHV</i> mutational status testing in chronic lymphocytic leukemia
Authors: Jennifer Crombie, Matthew S. Davids
Journal: American Journal of Hematology (2017)

Abstract As the therapeutic landscape for chronic lymphocytic leukemia (CLL) continues to expand, biological predictors of response to therapy are becoming increasingly important. One such predictive biomarker is the mutational status of the variable region of the immunoglobulin heavy chain ( IGHV ) gene, which is a powerful predictor of duration of response and overall survival with chemoimmunotherapy (CIT). As this test may influence choice of therapy between CIT and novel agents, it is critical that providers understand how mutational status is determined and the limitations of testing. Here, we describe the details of IGHV mutational status testing, highlighting the appropriate way to interpret this information and best apply it to the care of patients with CLL.
The relationship of circulating relaxin‐2 concentrations with short‐term prognosis in patients with acute heart failure: the RELAHF study
Authors: Pablo Herrero-Puente, Belén Prieto-García, María García-García, Pere Llorens, Francisco Javier Martín-Sánchez, Javier Jacob, Alexandre Mebazaa, Christian Mueller, Alan S. Maisel, Víctor Gil, Pablo García-Hernandez, Òscar Miró
Journal: European Journal of Heart Failure (2017)
Cases of ALK-Rearranged Lung Cancer with 5-Year Progression-Free Survival with Crizotinib as Initial Precision Therapy
Authors: Deepa Rangachari, Xiuning Le, Meghan Shea, Mark S. Huberman, Paul A. VanderLaan, Susumu S. Kobayashi, Daniel B. Costa
Journal: Journal of Thoracic Oncology (2017)
Type 3 innate lymphoid cell-derived lymphotoxin prevents microbiota-dependent inflammation
Authors: Yuan Zhang, Tae-Jin Kim, Joanna A Wroblewska, Vera Tesic, Vaibhav Upadhyay, Ralph R Weichselbaum, Alexei V Tumanov, Hong Tang, Xiaohuan Guo, Haidong Tang, Yang-Xin Fu
Journal: Cellular and Molecular Immunology (2017)
SAT0161 Menatetrenone acts directly on circulating human osteoclast precursors
Authors: T Hirayama, H Taira, O Kudo, I Itonaga, T Torisu, Y Fujikawa
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Vitamin K is known to be an essential cofactor in the post-translational gamma-carboxylation of clotting factors. Since the gamma-carboxyglutamic acid-containing protein, osteocalcin, was discovered in bone matrix, vitamin K was thought to play a role in bone metabolism. Both <i>in vitro</i> and <i>in vivo</i> studies have shown that menatetrenone, a vitamin K2 homologue, can act directly on bone metabolism. <h3>Objectives</h3> Although the relationship between menatetrenone and bone resorption appears clear,<sup>1,2</sup> it is still not certain whether menatetrenone act directly on osteoclast precursors to influence their differentiation into osteoclasts. In this study, we have invetgated whether menatetrenone has a direct effect on circulating osteoclast precursors to influence osteoclast differentiation. <h3>Methods</h3> Monocytes were cultured with osteoprotegerin ligand (OPGL) in the presence of macrophage stimulating factor (M-CSF) on glass coverslips and dentine slices. Menatetrenone or vitamin K1 was then added to the cultures in 10–7, -6, -5 (M) respectively. Geranylgeraniol or phytol (alcohol forms of the respective side chain of menatetrenone and vitamin K1) was also added to the cultures. After 7 and 14 days incubation, cultures were assessed for cytochemical and functional evidence of osteoclast differentiation. <h3>Results</h3> The number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) and the area of lacunar resorption were decreased when menatetrenone was added. Dose-dependent inhibition of osteoclast formation and lacunar resorption was seen. Vitamin K1, however, did not inhibite the formation of TRAP positive MNCs nor lacunar resorption. The addition of geranylgeraniol in the cultures inhibited osteoclast formation in a dose dependent manner. Phytol did not affect the number of TRAP-positive MNCs nor lacunar resorption. <h3>Conclusion</h3> Menatetrenone not only influence osteoclast formation in the presence of bone stromal cells but also act directly on circulating osteoclast precursors to influence osteoclast differentiation. The inhibitory effect of menatetrenone on osteoclast formation is not due to gamma-carboxylation and the side chain of menatetrenone may play an important role in this inhibitory effect. <h3>References</h3> Akiyama Y, Hara K, Tajima T, Murota S, Morita I. Effect of vitaminK2 (menatetrenone) on osteoclast-like cell formation in mouse bone marrow culture. Eur J Pharmacol. 1994;263:181–5 Hara K, Akiyama Y, Ohkawa I, Tajima T. The effect of menatetrenone on prednisolone-induced bone loss in rats. Bone 1993;14: 813–18
Sodium Reduction in US Households’ Packaged Food and Beverage Purchases, 2000 to 2014
Authors: Jennifer M. Poti, Elizabeth K. Dunford, Barry M. Popkin
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> Initiatives to reduce sodium in packaged foods have been launched in the United States, yet corresponding changes in the amount of sodium that US households obtain from packaged foods have not been evaluated, to our knowledge. <h3>Objective</h3> To assess 15-year changes in the amount of sodium that US households acquire from packaged food purchases, the sodium content of purchases, and the proportion of households that have purchases with optimal sodium density. <h3>Design, Setting, and Participants</h3> Longitudinal study of US households in the 2000 to 2014 Nielsen Homescan Consumer Panel, a population-based sample of households that used barcode scanners to record all packaged foods purchased throughout the year. Time-varying brand- and product-specific nutrition information was used for 1 490 141 products. <h3>Main Outcomes and Measures</h3> Sociodemographic-adjusted changes in mean sodium per capita (mg/d) and sodium content (mg/100 g), overall and for top food group sources of sodium, and the proportion of households that have total purchases with sodium density of 1.1 mg/kcal or less. <h3>Results</h3> In a nationwide sample of 172 042 US households (754 608 year-level observations), the amount of sodium that households acquired from packaged food and beverage purchases decreased significantly between 2000 and 2014 by 396 mg/d (95% CI, −407 to −385 mg/d) per capita. The sodium content of households' packaged food purchases decreased significantly during this 15-year period by 49 mg/100 g (95% CI, −50 to −48 mg/100 g), a 12.0% decline; decreases began in 2005 and continued through 2014. Moreover, the sodium content of households' purchases decreased significantly for all top food sources of sodium between 2000 and 2014, including declines of more than 100 mg/100 g for condiments, sauces, and dips (−114 mg/100 g; 95% CI, −117 to −111 mg/100 g) and salty snacks (−142 mg/100 g; 95% CI, −144 to −141 mg/100 g). However, in all years, less than 2% of US households had packaged food and beverage purchases with sodium density of 1.1 mg/kcal or less. <h3>Conclusions and Relevance</h3> In this nationwide study, significant reductions in sodium from packaged food purchases were achieved in the past 15 years. Nonetheless, most US households had food and beverage purchases with excessive sodium density. Findings suggest that more concerted sodium reduction efforts are needed in the United States.
Probing supramolecular protein assembly using covalently attached fluorescent molecular rotors
Authors: Markéta Kubánková, Ismael López-Duarte, James A. Bull, Devkee M. Vadukul, Louise C. Serpell, Marie de Saint Victor, Eleanor Stride, Marina K. Kuimova
Journal: Biomaterials (2017)

Changes in microscopic viscosity and macromolecular crowding accompany the transition of proteins from their monomeric forms into highly organised fibrillar states. Previously, we have demonstrated that viscosity sensitive fluorophores termed 'molecular rotors', when freely mixed with monomers of interest, are able to report on changes in microrheology accompanying amyloid formation, and measured an increase in rigidity of approximately three orders of magnitude during aggregation of lysozyme and insulin. Here we extend this strategy by covalently attaching molecular rotors to several proteins capable of assembly into fibrils, namely lysozyme, fibrinogen and amyloid-β peptide (Aβ(1-42)). We demonstrate that upon covalent attachment the molecular rotors can successfully probe supramolecular assembly in vitro. Importantly, our new strategy has wider applications in cellulo and in vivo, since covalently attached molecular rotors can be successfully delivered in situ and will colocalise with the aggregating protein, for example inside live cells. This important advantage allowed us to follow the microscopic viscosity changes accompanying blood clotting and during Aβ(1-42) aggregation in live SH-SY5Y cells. Our results demonstrate that covalently attached molecular rotors are a widely applicable tool to study supramolecular protein assembly and can reveal microrheological features of aggregating protein systems both in vitro and in cellulo not observable through classical fluorescent probes operating in light switch mode.
Copy-number and targeted sequencing analyses to identify distinct prognostic groups: Implications for patient selection to targeted therapies amongst anti-endocrine therapy resistant early breast cancers.
Authors: Jane Bayani, Elizabeth Kornaga, Cheryl Crozier, Gun Ho Jang, Irina Kalatskaya, Quang M Trinh, Cindy Q Yao, Julie Livingstone, Annette Hasenburg, Dirk G Kieback, Christos Markopoulos, Luc Dirix, Paul Christopher Boutros, Melanie Spears, Lincoln D. Stein, Daniel Rea, John Bartlett
Journal: Journal of Clinical Oncology (2017)

524 Background: Hormone receptor positive breast cancer is a therapeutic challenge. Despite optimal anti-endocrine therapies, most breast cancer deaths follow a diagnosis of early luminal cancer. To understand the impact of multiple aberrations in the context of current therapy, we assessed the prognostic ability of genomic signatures as a putative stratification tool to targeted therapies. Methods: This a priori study is based on molecular pathways which might predict response to targeted therapies. DNA from 420 patients from the phase III TEAM pathology cohort were used. Patients with a distant recurrence within 5 years were matched by clinical variables to those disease-free at follow up. Copy number analysis was performed using the Affymetrix Oncoscan Assay. Targeted sequencing was performed in a subset of samples for genes based on signaling cassettes mined from the ICGC. Pathways were identified as aberrant if there were copy number variations (CNVs) and/or mutations in any of the pre-determined pathway genes: 1) CCND1/CCND2/CCND3/CDK4/CDK6; 2) FGFR1/FGFR2/FGFR2/FGFR4; and 3) AKT1/AKT2/PIK3CA/PTEN. Kaplan-Meier and log-rank analyses were used for DFS between groups. Hazard ratios were calculated using the Cox proportional hazard models adjusted for age, tumour size, grade, lymph node and HER2 status. Results: 390/420 samples passed informatics QC filters. For the CCND/CDK pathway, patients with no CNV changes experienced a better DFS (HR = 1.7, 95% CI 1.3-2.3, p &lt; 0.001). For the FGFR/FGF pathway, a similar outcome is seen among patients without CNVs (HR = 1.5, 95% CI 1.1-2.0; p = 0.005). For AKT/PIK3CA, a decrease in DFS was seen in those with aberrations (HR = 1.4, 95% CI 1.0-1.8, p = 0.03). Conclusions: We demonstrated that CNVs of genes within CDK4/CCND, PIK3CA/AKT and FGFR pathways are independently linked to high risk of relapse following endocrine treatment, with implications for identifying those patients who are at high-risk for recurrence despite optimal anti-endocrine therapy and linking molecular features driving these cancers to targeted therapies.
Pathologic complete response (pCR) rates after neoadjuvant pertuzumab (P) and trastuzumab (H) administered concomitantly with weekly paclitaxel (T) and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy for clinical stage I-III HER2-positive breast cancer.
Authors: Julia Foldi, Sarah Schellhorn Mougalian, Andrea Silber, Donald R. Lannin, Brigid K. Killelea, Anees B. Chagpar, Nina Ruth Horowitz, Courtney Frederick, Lawrence Rispoli, Maysa M. Abu-Khalaf, Kert D. Sabbath, Tara Beth Sanft, Neal A. Fischbach, Debra S. Brandt, Erin Wysong Hofstatter, Michael DiGiovanna, Lajos Pusztai
Journal: Journal of Clinical Oncology (2017)

577 Background: Inclusion of H with chemotherapy has increased pathologic complete response (pCR) rates in HER2 positive breast cancer, and dual HER2 blockade involving H + P further increased efficacy. With dual HER2 blockade and taxane-based (+/-carboplatin followed by anthracycline) chemotherapies, pCR rates reach, 75% in estrogen receptor (ER) negative and 45% in ER+ patients. HER2 targeted therapies also increase the efficacy of anthracyclines but are not routinely combined due to potential cardiotoxicity. The goal of this phase II study was to assess pCR rate when H+P is administered during the entire treatment duration, including the anthracycline phase, of weekly T (80 mg/m 2 ) x 12 followed by FE(75 mg/m 2 )C x 4 neoadjuvant chemotherapy. Methods: pCR (ypT0/is and ypN0) rate was assessed separately in ER+ and ER- cancers following Simon’s two-stage design to detect improvement in pCR rates to 90% and 70% in the ER- and ER+ cohorts, respectively. Eligibility included age &lt;65, stage I-III, HER2+ disease, and normal cardiac function. Results: The ER- cohort completed full accrual of 25 patients: 23 completed therapy and surgery, 2 patients are still receiving treatment. The pCR rate is 78% (n=18, 95% CI:58-90%). The ER+ cohort was closed after 23 patients were accrued to the first stage due to lower than expected pCR of 26% (n=6, 95% CI:13-46%) at interim analysis. The incidence of grade 3/4 adverse events was 48% (n=24/50), the most common being neutropenia (n=12) and diarrhea (n=7). No patient experienced symptomatic congestive heart failure, one patient had a drop in LVEF to &lt; 50% following completion of chemotherapy. Thirteen patients (27%) had a &gt;10% asymptomatic drop in their LVEF but remained above 50%, LVEF returned to baseline by the next assessment in half of these cases. Conclusions: Neoadjuvant P and H administered concomitantly with weekly T followed by FEC resulted in 78% pCR rate in ER-/HER2+ cancers. This pCR rate is among the highest reported in the literature. The pCR rate was substantially lower in ER+ cancers. Clinical trial information: NCT01855828.
Functional and phenotypic analysis of basophils allows determining distinct subtypes in patients with chronic urticaria
Authors: M. M. Rauber, J. Pickert, L. Holiangu, C. Möbs, W. Pfützner
Journal: Allergy (2017)

Abstract Background Chronic urticaria ( CU ) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, Fcε RI , and the therapeutic efficacy of anti‐IgE antibodies imply that IgE‐mediated mechanisms also play an important role in CU . Methods Reactivity of CU patients’ peripheral blood basophils (n=60) to specific anti‐Fcε RI and IgE‐independent fMLP stimulation was determined by basophil activation test in comparison with patients suffering from IgE‐mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (Fcε RI , Fcγ RII ) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria‐related symptoms were assessed by both UCT and CU ‐Q 2 oL. Results Stimulating CU patients’ basophils via Fcε RI , we identified three distinct immunologic phenotypes. One subgroup of patients’ basophils reacted to Fcε RI stimulation, whereas the others had anti‐Fcε RI nonreactive basophils. Among the latter, a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum‐induced basophil activation, increased levels of autoantibodies against thyroid peroxidase, and also exhibited the strongest disease impact on their quality of life. Conclusions Patients with CU can be categorized into three immunologic subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology.