tbuckley/cabot-search huggingface dataset:
Ex vivo drug panel testing for response prediction in renal cell carcinoma.
Authors: Rob Ruijtenbeek, Liesbeth Houkes, Riet Hilhorst, Peter F.A. Mulders, Jeannette Oosterwijk-Wakka, Egbert Oosterwijk
Journal: Journal of Clinical Oncology (2014)

e15572 Background: Sunitinib, a potent multi-targeted receptor tyrosine kinase inhibitor of VEGFR and PDGFRβ kinases, is the first line treatment for metastatic Renal Cell Carcinoma (mRCC). With sunitinib responses and toxicity being highly variable, there is an urgent need for biomarkers predicting sunitinib response or suggesting alternative TKI’s. The aims of this study were (1) to investigate if clinical responses of mRCC patients correlate with ex vivo generated kinase activity and inhibition patterns and (2) exploring alternative treatment options. Methods: Tumor resection tissue was collected, lysed and protein concentration determined. Protein tyrosine kinase activity profiles were generated on PamChip peptide microarrays. The ex vivo effect of kinase inhibitors (sunitinib, axitinib, sorafenib, pazopanib, erlotinib and crenolanib) was determined and analyzed with BioNavigator software. A two-sample t-test applied on the inhibition ratios identified the significantly different peptide phosphorylations. Peptides were clustered according to their correlation with the grouping factor. Results: After assay optimization as low as 5 ug protein input (0.05 mm3 tissue) per kinase assay could be used. On-chip inhibition with sunitinib of 22 tumor-derived kinase activity profiles correlated positively with clinical responses, especially in the subgroup which received sunitinib as 1st line treatment: more than 15 of the 144 peptide phosphorylations monitored were more inhibited (p<0.05) in 4 responders (>9 months PR/SD) than in 4 non-responders (PD). Pathway analysis of the peptide phosphorylation patterns revealed sunitinib target involvement. Interestingly, when erlotinib, axitinib or crenolanib were spiked in the lysates the pattern was reversed: tissue from a clinical sunitinib non-responder showed more inhibition than a responder. Conclusions: The feasibility of predicting clinical response to sunitinib based on the ex vivo response to sunitinib is shown. The results merit further investigation with a larger sample set. Furthermore, the ex vivo response to a drug panel suggests that identification of novel treatment options for non-responders might be feasible.
Post-Therapy Measurable Residual Disease Monitoring in Peripheral Blood Using Overexpressed Genes in Childhood Acute Myeloid Leukemia
Authors: Anne-Sofie Skou, Kristian Juul-Dam, Maria Hansen, Anni Aggerholm, Birgitte Lausen, Charlotte Guldborg Nyvold, Hans Beier Ommen, Henrik Hasle
Journal: Blood (2018)
Exercise Programs in Older Adults—A Prescription for Fall Reduction
Authors: Ryan R. Kraemer, C. Seth Landefeld
Journal: JAMA Internal Medicine (2018)

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Abstract 16376: Brain-Dead Donor Hearts’ Storage With a Preservation Solution, Supplemented by a Mesenchymal Stem Cell Conditioned Medium, Improves Cardiac Contractility After Heart Transplantation in a Rat Model
Authors: Sevil Korkmaz-Icöz, Kunsheng Li, Mihály Ruppert, Sivakkanan Loganathan, Tamás Radovits, Matthias Karck, Gábor Szabó
Journal: Circulation (2017)

Introduction: Often heart transplantation is the only treatment in end-stage heart failure. Currently, the pool of heart donors is restricted to brain-dead (BD) donors. However, hemodynamic instability demonstrated in BD donors could affect the posttransplant graft function after ischemia/reperfusion (IR). Previous studies have suggested that mesenchymal stem cell (MSC) administration, or their conditioned medium (MSC CM), protects the heart against IR injury. Hypothesis: BD donor hearts’ preservation by Custodiol-supplemented MSC CM improves in vivo left ventricular (LV) graft function following cold ischemia followed by warm reperfusion injury in the transplant setting in rats. Methods: In donor rats, BD was induced by a subdurally placed, and inflated balloon catheter. Controls were sham-operated. Sham-operated and BD donors were monitored for 5h. Then, hearts were perfused with a cold preservation solution (Custodiol), explanted, stored at 4°C in a Custodiol supplemented medium vehicle (BD Custodiol-M...
High-dose chemotherapy and autologous peripheral blood stem cell (PBSC) transplantation with non-cryopreserved PBSCs in multiple myeloma.
Authors: Hakan Goker, Eylem Eliacik, Yahya Buyukasik, Ibrahim C Haznedaroglu, Mehmet Turgut, Salih Aksu, Nilgun Sayinalp, Gursel Gunes, Haluk Demiroglu, Osman I. Ozcebe
Journal: Journal of Clinical Oncology (2014)

e19577 Background: Peripheral blood stem cells (PBSCs) are commonly used as the graft source during hematopoietic cell transplantation(HCT). The aim of this retrospective evaluation was to compare the impact of non-cryopreserved, autologous CD34+ PBSCs or cryopreserved CD34+ autologous PBSC (auto-PBSC) transplantation in terms of their effect on the hematopoietic recovery and engraftment kinetics in HCT. Methods: We have retrospectively analyzed 78 myeloma patients who underwent auto-PBSC transplantation; i.e. 57 patients cryopreserved and 21 freshly collected (non-cryopreserved) CD34+ auto-PBSCs, respectively. All patients, provided written informed consent for the procedure. For all the patients, conditioning was done with intravenous (IV) melphalan 200 mg/m2. CD34+ auto-PBSCs were collected from the patients after chemotherapy or G-CSF mobilization. Collected PBSCs are stored at 40 C, and infused next day after IV HD melphalan. Successful engraftment time was defined as neutrophils>0.5x 109 cells/L, platelets>20 x109 cells/L for three consecutive days. SPSSincver. 20 used for statistics. Results: All of the 78 patients were engrafted promptly without any problem, and no early or late engraftment was noted. The mean amount of cryopreserved autologous CD34+ PBSC was 8,5 x 10e6/kg versus freshly collected infused were 5,9 x 10e6/kg, respectively. Median times to the neutrophil engraftment to >0,5x 109/L were 9,6 and 9,4 days for the cryopreserved autoPBSC and freshly collected auotologous PBSC transplantation, respectively (p=0,8). However, median times to the platelet engraftment to >20x 109/L were 11.6 and 9.5 days for the cryopreserved autoPBSC and freshly collected auto-PBSC transplantation, respectively (p=0,012). Though, the platelet engraftment times was somewhat delayed in the recipients of autologous cryopreserved PBSCs; this observation was not clinically relevant, since all were engrafted. Conclusions: When there is need due to the logistical reasons; after high-dose IV melphalan therapy in multiple myeloma patients with no renal failure, non-cryopreserved autologous PBSC transplantation can be performed safely and successfully.
A phase 1 expansion cohort of the fibroblast growth factor receptor (FGFR) inhibitor AZD4547 in patients (pts) with advanced gastric (GC) and gastroesophageal (GOJ) cancer.
Authors: Hendrik-Tobias Arkenau, Matilde Saggese, Antoine Hollebecque, Alastair Mathewson, Charlotte Rose Lemech, Donal Landers, Paul Frewer, Elaine Kilgour, Nigel Brooks
Journal: Journal of Clinical Oncology (2014)

2620 Background: AZD4547 is a potent selective inhibitor of FGFR 1, 2, and 3 tyrosine kinases. Pre-clinically, gastric cancer cell lines and patient-derived xenograft models with FGFR2 gene amplification were sensitive to AZD4547, resulting in reduced cell proliferation and tumor regression. Methods: A multicentre phase-1 study assessed the safety, pharmacokinetics, pharmacodynamics (PD) and antitumor activity of AZD4547 (80 mg bd) in an expansion cohort of pts with advanced/metastatic GC/GOJ cancer (NCT00979134) who were prospectively selected for FGFR1/2 amplification using fluorescent in situ hybridization (FISH) analysis of archival or fresh tumors. Results: 238 GC/GOJ pts were pre-screened, of which 38 pts (16%) had the pre-specified FGFR1/2 amplification (FGFR:Centromeric ratio ≥2). 13 pts were treated (9 m: 4 f, mean age 57yrs). 6 had high FGFR amplification (FGFR:Centromeric ratio ≥ 2.8), 3 had low amplification (FGFR:Centromeric ratio >2 to < 2.8), and 4 were of a cluster type (FGFR gene amplification clusters in > 10% cells). A total of 136 treatment-emergent adverse events (CTC-AE all grades) were reported including vomiting (8 pts; 61.5%), decreased appetite and diarrhoea (7 pts each; 53.9%), fatigue and nausea (6 pts each; 46.2%), hyperphosphatemia, constipation and dry eye (4 pts each, 30.7%). 8 pts (61.5%) reported epithelial and mucosal dryness, 5 pts (38.5%) stomatitis, and 4 pts (30.8%) retinal pigment epithelial detachment. Preliminary exploratory analysis revealed an increase in serum phosphate following dosing. 1 PR was observed in a patient with a tumor that had clusters of FGFR gene amplification and 4 pts had stable disease (3 with high FGFR amplification and 1 with clusters). Conclusions: AZD4547 was well-tolerated in pts with FGFR1 amplified advanced/metastatic GC/GOJ cancer but did not meet its pre-specified efficacy endpoint, in terms of overall response rate, for continuation. The increase in plasma phosphate concentration observed in this study, provides evidence that AZD4547 at this dose and schedule causes pharmacologic target inhibition. Clinical trial information: NCT00979134.
Outcomes of surgical management for borderline (BR)/locally advanced (LA) pancreatic adenocarcinoma (PAC) after neoadjuvant FOLFIRINOX chemotherapy: Results of an AGEO/French multicenter study.
Authors: Daniel Pietrasz, Lysiane Marthey, Mathilde Wagner, Jean-Frédéric Blanc, Eric Terrebonne, Antonio Sa Cunha, Romain Coriat, Isabelle Trouilloud, Nicolas Regenet, Pascal Artru, Eric Francois, Lilian Schwarz, David Malka, Jean-Christophe Vaillant, Jean Baptiste Bachet, Mehdi Karoui
Journal: Journal of Clinical Oncology (2014)

e15250 Background: FOLFIRINOX has been shown to increase survival in patients with metastatic PAC with an objective response rate of 32%. In BR and LA PAC, a resection rate of 36% has been reported in a retrospective study. The aim of our study was to analyse post-operative outcomes in patients resected for BR or LA PAC who received neoadjuvant treatment based on FOLFIRINOX. Methods: Data of patients who underwent a curative intent resection after neoadjuvant FOLFIRINOX in 18 French centers were reviewed in this retrospective study. BR or LA PAC were classified following the National Comprehensive Cancer Network classification using CT-scan by investigators. Post-operative morbidity was graded according to the Dindo classification. Disease free survival (DFS) and overall survival (OS) were analysed using Kaplan Meier method from the date of surgical resection. Results: From November 2010 to December 2013, 58 patients (36 men, median age of 59 years, 34 BR and 24 LA at baseline CT-scan staging) underwent a pancreatic resection after a median number of 6 cycles (1-30) of FOLFIRINOX. Additional preoperative chemoradiotherapy was administred in 42 patients (72%). Initial median tumor size was 31 mm (16-66) with 79% located in the pancreatic head. 24% (n=14) of tumors required en bloc vascular resection. Post-operative mortality and severe morbidities (grade 3-4) were 3.4% and 19%, respectively. R0 resection was achieved in 86% of patients. The histological complete response (ypT0N0) rate was 19%. After a median follow-up of 11.0 months (0.4-37.2) from surgery, a recurrence occurred in 15 patients (local n=5; metastatic n=9; both n=1) including 9 deaths during follow-up. Median DFS and OS were not reached. One year DFS and OS rates were 53% (16/34) and 71% (9/34), respectively. Conclusions: In this retrospective study, pancreatic resection after neoadjuvant FOLFIRINOX was safe even when combined with radiochemotherapy. Rates of R0 resection and histological complete response were high suggesting that this strategy should be further evaluated in a prospective manner in patients with BR/ LA PAC.
Epigenetic silencing of <i>Ndrg2 </i>synergizes with deregulated <i>p53</i> to promote gastric cancer metastasis.
Authors: Zhiqiang Ling, Xin Zhu, Lianlian Hong, Xiaoxiao Lu, Pei Li, Xianhua Fang, Shi Wang, Jing Han, Jiangliu Yu
Journal: Journal of Clinical Oncology (2014)

e22042 Background: N-myc downstream regulated gene 2 (Ndrg2) promoter methylation was recently shown to be frequent in human cancers and was suggested as a candidate suppressor of cancer metastasis. The aim of this study was to investigate the mechanistic roles of Ndrg2 promoter methylation and its clinical relevance in gastric cancer (GC). Ndrg2 promoter methylation was assessed in human GC cell lines and 300 GC tissues. Methods: Ndrg2 mRNA and protein levels were measured in relation to Ndrg2 promoter methylation. The effects of forced Ndrg2 expression on tumorigenesis were studied using in vitro and in vivo assays. The association between Ndrg2 promoter methylation and clinical relevance of GC patients was determined. Results: Ndrg2 promoter methylation is tumor-specific and frequently found in GC cell lines and tissues, resulting in the down-regulation of Ndrg2mRNA and protein levels. Forced expression of Ndrg2 in gastric cancer cell lines promoted an epithelial phenotype, featuring decreased proliferation, migration, invasion, anchorage-independent growth and blocked metastasis. Ndrg2 down-regulation alone or Ndrg2-by-p53 interaction-mediated processes could contribute to GC metastasis via epithelial-mesenchymal transition (EMT). However, no additive effect of Ndrg2 and p53 coinactivation in promoting GC metastasis. DNA microarray analyses suggested critical downstream genes that are associated with cancer cell proliferation, invasion or metastasis. In a mouse xenograft model, Ndrg2 inhibited tumorigenesis and metastasis. Finally, Ndrg2 promoter methylation was associated with worse prognosis of GC patients (P<0.05) and also with poor differentiation (P<0.05). Conclusions: Ndrg2 promoter methylation is a frequent and tumor-specific event in GC progression. That this epigenetic silencing of Ndrg2 synergizes with deregulated p53 to promote gastric cancer metastasis may have clinical ramifications in the diagnosis and treatment of GC patients.
Bacterial secretion of histamine within the gut influences immune responses within the lung
Authors: Weronika Barcik, Benoit Pugin, Marina Sabaté Brescó, Patrick Westermann, Arturo Rinaldi, David Groeger, Dries Van Elst, Milena Sokolowska, Krzysztof Krawczyk, Remo Frei, Ruth Ferstl, Marcin Wawrzyniak, Can Altunbulakli, Cezmi A. Akdis, Liam O'Mahony
Journal: Allergy (2018)

Histamine is an important immunomodulator influencing both the innate and adaptive immune system. Certain host cells express the histidine decarboxylase enzyme (HDC), which is responsible for catalysing the decarboxylation of histidine to histamine. We and others have shown that bacterial strains can also express HDC and secrete histamine; however, the influence of bacterial-derived histamine on the host immune responses distant to the gut is unclear.The Escherichia coli BL21 (E coli BL21) strain was genetically modified to express the Morganella morganii (M morganii)-derived HDC gene (E coli BL21_HTW). E coli BL21 and E coli BL21_HTW were gavaged to ovalbumin (OVA) sensitized and challenged mice to investigate the effect of bacterial-derived histamine on lung inflammatory responses.Oral administration of E coli BL21_HTW, which is able to secrete histamine, to wild-type mice reduced lung eosinophilia and suppressed ex vivo OVA-stimulated cytokine secretion from lung cells in the OVA respiratory inflammation mouse model. In histamine receptor 2 (H2R)-deficient mice, administration of histamine-secreting bacteria also reduced inflammatory cell numbers in bronchoalveolar lavage (BAL). However, the suppressive effect of bacterial-derived histamine on BAL inflammation was lost in HDC-deficient mice. This loss of activity was associated with increased expression of histamine degrading enzymes and reduced histamine receptor expression.Histamine secretion from bacteria within the gut can have immunological consequences at distant mucosal sites, such as within the lung. These effects are influenced by host histamine receptor expression and the expression of histamine degrading enzymes.
Preclinical characterization of GPA512: A prodrug of a direct STAT3 inhibitor for the treatment of prostate cancer.
Authors: Martin Hans Johansson, Rebecka Hellsten, Giacomo Canesin, Susan Evans-Axelsson, Zilma Escobar, Anders Bjartell, Olov Sterner
Journal: Journal of Clinical Oncology (2014)

e22186 Background: The transcription factor STAT3 is a promising target for the treatment of castration-resistant prostate cancer (CRPC) as STAT3 is implicated in drug resistance, the progression of androgen independent growth, metastatic spread, immune-avoidance and tumor growth. Galiellalactone (GL) is a direct inhibitor of STAT3 that prevents DNA binding, inhibits the proliferation of DU145 prostate cancer cells and induces apoptosis by down-regulation of STAT3 activated genes. In this study we aimed to characterize a prodrug of GL, GPA512, with improved drug-like properties and to demonstrate its effect on tumor growth in a xenograft model of prostate cancer following oral administration. Methods: Stability studies were performed in 0.1 M PBS buffer (pH 7.4) and in plasma at 37 °C. The systemic exposure of galiellalactone in mice was studied following a single oral dose of GPA512 or GL (both 10 mg/kg). The plasma concentrations of GL were determined by LC-MS/MS. For the xenograft study NMRI-nude male mice were inoculated subcutaneously with DU145 cells in the flank region. After four weeks the mice were divided in two groups with ten mice in each. Mice were treated orally with 40 mg/kg GPA512 daily five times/week for four weeks. Tumor growth was measured by caliper and at the end of the study tumors were harvested for subsequent analyses. Results: In vitro studies showed that GPA512 is rapidly converted to GL in plasma with no species variability and that GPA512 is stable in buffer solution. The pharmacokinetics of GPA512 following a single oral dose indicated that the compound was rapidly absorbed and converted to GL with a tmax of 15 min. Oral administration of GPA512 in mice increased the plasma exposure (AUC) of the active parent compound 20-fold compared to when GL was dosed orally. GPA512 treated mice bearing subcutaneous DU145 tumors had significantly smaller tumors compared to mice treated with vehicle. No adverse effects or weight loss were observed. Conclusions: The favorable drug-like properties and safety profile of the prodrug GPA512 and galiellalactone’s specific inhibition of STAT3, warrant further studies of GPA512 as a drug candidate for treatment of patients with CRPC.
Omalizumab in patients with antihistamine‐resistant CSU
Authors: F. Bérard, M.C. Ferrier le Bouedec, L. Bouillet, Z. Reguiai, A. Barbaud, F. Cambazard, B. Milpied, B. Pelvet, I. Kasujee, H. Gharbi, J.P. Lacour
Journal: British Journal of Dermatology (2019)

This study from France concerned itself with the biologic drug, omalizumab, as treatment for chronic spontaneous urticaria (CSU). CSU causes troublesome, even debilitating, itchy weals like nettle stings (urticaria), together with swelling of deeper tissues (angioedema) that commonly affects the lips, tongue and eyelids. Omalizumab is licensed for severe CSU that does not respond to high-dose antihistamines. One hundred and thirty-six patients with CSU were enrolled and 124 completed the study. They were given three standard doses of omalizumab, every four weeks for 12 weeks. Half the patients also took other medication, usually an antihistamine, to treat their CSU. Researchers and participants knew that all participants were getting omalizumab, and there was no placebo group. Two scoring methods used to assess improvement – the established 7-day urticaria activity score UAS7 and the newer urticaria control test UCT – were found to correlate i.e. their scores were similar. Omalizumab was effective in two-thirds of patients as measured by the UAS7 score, and in three-quarters by the UCT score. These results were not influenced by whether the patients had angioedema. Quality of life scores improved markedly. Mean levels of a blood protein called D-dimer were increased at the beginning of the study and fell with treatment, but there was no correlation with the improvement in UAS7 or UCT scores. Eight of nine patients with very high D-dimer levels responded to treatment, so measuring D-dimer might predict response to omalizumab. Apart from this, the main conclusions were that omalizumab works for CSU and has few side-effects, and that the UCT is reliable.