tbuckley/cabot-search huggingface dataset:
Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL.
Authors: David L. Porter, Noelle V. Frey, Jan J. Melenhorst, Wei-Ting Hwang, Simon F. Lacey, Pamela A Shaw, Anne Chew, Katherine Marcucci, Saar Gill, Alison W. Loren, Anthony R. Mato, Stephen J. Schuster, Lester Lledo, Holly McConville, Joan Gilmore, James Capobianchi, Michael D. Kalos, Stephan A. Grupp, Bruce Levine, Carl H. June
Journal: Journal of Clinical Oncology (2016)

3009 Background: Autologous T cells genetically modified to express a CD19-targeting CAR (CTL019) can mediate potent anti-tumor effects in CLL and other CD19+ malignancies. Since CTL019 are self-replicating, and the optimal dose is unknown, we are performing a randomized phase II study of 2 CTL019 doses in R/R CLL. Methods: Eligible pts had > 2 prior therapies and progressed within 2 yrs of >2nd line therapy. Pts receive lymphodepleting chemotherapy before infusion. Stage 1 pts were randomized to 5x108 (high dose) or 5x107(low dose) CTL019; Stage 2 pts receive the chosen optimal dose. 35 pts median age 62 have been enrolled. 40% had deletion of p53, 23% failed ibrutinib, median prior therapies was 3 and all had active disease. Median follow-up is 9 mo (range 1-34). Results: 28 pts were treated on stage 1 with 24 evaluable for response (11 high dose, 13 low dose). 6/11 responded at the high dose (4 CRs) and 4/13 at the low dose (1 CR) (p=0.11) with similar toxicity. Therefore a dose of 5 x 108CTL019 was chosen as optimal for Stage 2; 21 pts have been treated at this dose with 17 evaluable for response (11 Stage 1, 6 Stage 2). 9 of the 17 responded (6 CR, 3PR). 5 remain in CR with median follow-up 26 mo (range 5-34) and1 progressed with CD19- disease. Response did not correlate with typical prognostic factors including age, prior therapies or mutated P53. In contrast, CAR T expansion correlated with response as robust CTL019 in-vivo expansion was noted in all responding pts with a median peak of 14.7% of CD3+ cells but 0.35% in non-responders. All 35 pts were evaluable for toxicity and 19 had delayed cytokine release syndrome (CRS) (7 gr 3-4) associated with high levels of IL6 and IFN-g. Tocilizumab successfully reversed CRS in 4 pts; 15 did not require intervention. Dose was not associated with CRS development or severity. Conclusions: This study identifies optimal dosing of CTL019 for R/R CLL and confirms that CTL019 undergo robust in vivo expansion with manageable CRS. CTL019 proliferation in vivo is a predictive biomarker of response. Additional biomarker studies to identify pts likely to respond will be presented. CTL019 cells can induce potent and durable responses in R/R CLL. Clinical trial information: NCT01747486.
Structure-activity relationships of new chemical entities based on the anti-tumor and anti-angiogenic agent 2-methoxyestradiol
Authors: Theresa M. Lavallee, Arthur D. Hanson, Glenn Swartz, Kirk Volker, Gregory E. Agoston, Jamshed Shah, Lita Suwandi, William E. Fogler, Victor S. Pribluda, Anthony M. Treston
Journal: Cancer Research (2004)

4085   2-Methoxyestradiol (2ME2) is an endogenous metabolite of estradiol that exhibits potent anti-proliferative activity against a wide range of tumor and non-tumor cell types  in vitro , as well as significant anti-angiogenic and anti-tumor activities  in vivo  with minimal toxicity at pharmacologically active doses. The anti-proliferative activity of 2ME2 is independent of estrogen receptors, and while all mechanistic actions are not fully defined, 2ME2 has been shown to disrupt microtubule polymerization and to inhibit HIF activity. 2ME2 is currently in clinical trials for oncology under the name Panzem®. Pre-clinical studies in murine models and clinical studies in humans demonstrated that, as reported for estradiol, 2ME2 undergoes significant oxidation at the 17-position to form 2-methoxyestrone (2ME1) as well as extensive conjugation at the 3- and 17-positions. To get a better understanding of the structure-activity relationships and metabolism of 2ME2, we have designed and synthesized several series of new chemical entities (NCEs) modified at position 3 on the A-ring, at position 17 on the D-ring or at both positions simultaneously. Hundreds of NCEs have been generated with a range of activities. These NCEs are screened for anti-proliferative activity  in vitro  using tumor and endothelial cell types.  In vitro  estrogenicity is tested by the ability of these NCEs to support the proliferation of an estrogen-dependent cell line. Several NCEs with single or combined substitutions at positions 3 and/or 17 show similar or improved anti-proliferative activities and further reduced estrogenicity as compared to 2ME2. Additionally, many of these molecules demonstrate improved pharmacokinetic (PK) parameters in rodents. Several of the NCEs showing acceptable responses in the  in vitro  screening assays and having a good PK profile after oral administration are being tested for efficacy in animal tumor models. Their mechanism of action is also being investigated.
Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism
Authors: Guang Liang, Lintao Song, Zilu Chen, Yuanyuan Qian, Junjun Xie, Longwei Zhao, Qian Lin, Guanghui Zhu, Yi Tan, Xiaokun Li, Moosa Mohammadi, Zhifeng Huang
Journal: Kidney International (2017)
Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III
Authors: Jessica Finlay-Schultz, Austin E. Gillen, Heather M. Brechbuhl, Joshua J. Ivie, Shawna B. Matthews, Britta M. Jacobsen, David L. Bentley, Peter Kabos, Carol A. Sartorius
Journal: Cancer Research (2017)

Abstract Greater than 50% of estrogen receptor (ER)–positive breast cancers coexpress the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive patient-derived xenograft models of breast cancer, where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens. Probing the genome-wide mechanisms by which this occurs, we documented that chronic progestin treatment blunted ER-mediated gene expression up to 2-fold at the level of mRNA transcripts. Unexpectedly, &amp;lt;25% of all ER DNA binding events were affected by the same treatment. The PR cistrome displayed a bimodal distribution. In one group, &amp;gt;50% of PR binding sites were co-occupied by ER, with a propensity for both receptors to coordinately gain or lose binding in the presence of progesterone. In the second group, PR but not ER was associated with a large fraction of RNA polymerase III–transcribed tRNA genes, independent of hormone treatment. Notably, we discovered that PR physically associated with the Pol III holoenzyme. Select pre-tRNAs and mature tRNAs with PR and POLR3A colocalized at their promoters were relatively decreased in estrogen + progestin–treated tumors. Our results illuminate how PR may indirectly impede ER action by reducing the bioavailability of translational molecules needed for tumor growth. Cancer Res; 77(18); 4934–46. ©2017 AACR.
AB0895 Osteoporosis risk factors in patients with calcium pyrophosphate crystal deposition disease (CPPD)
Authors: S Vladimirov, M Eliseev, O Zhelyabina, A Smirnov, S Glukhova
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Osteoporosis (OP) risk factors (RF) in CPPD patients are not sufficiently studied, although some of these RFs may be more prevalent in CPPD pts than in general population [1] <h3>Objectives</h3> To identify the input of individual RFs into OP development in pts with <i>CPPD</i> <h3>Methods</h3> 64 patients with CPPD (35 males and 29 females), but without OP were included into open prospective study. CPPD was confirmed based on McCarty criteria (detection of calcium pyrophosphate crystals in the synovial fluid using polarized light microscopy and detection of chondrocalcinosis based on joint radiography or US examination). 40 pts of those had acute and/or chronic arthritis, and 24 pts had osteoarthritis with CPP crystal depositions. Mean age was 57.6±10.2 years, mean follow up – 4.85±0.96 years. Bone mass density (BMD) was measured by dual energy X-ray absorptiometry (DXA) at the forearm, lumbar spine and total hip was performed in all pts at baseline. OP was diagnosed by BMD (T-criterion ≤2,5). The following OP risk factors were evaluated in this study: sex, age &gt;55 years for females and &gt;65 years for males, smoking, alcohol, fractures in past medical history, fractures in parents, BMI ≤20 kg/m<sup>2</sup>, BMI ≤25 kg/m<sup>2</sup>, serum levels of calcium, magnesium, vitamin D, hypoparathyroidism (HPT), chronic kidney disease (GFR ≤60 mL/min), intake of diuretics and glucocorticosteroids (GCs), Erythrocyte sedimentation rate (ESR) &gt;20 mm/h, C-reactive protein (CRP) &gt;5,0 mg/L. Odds ratio (OR) (95% confidence interval, CI) was estimated for each risk factor and logistic regression analysis was performed. Statistical analysis was made using SPSS v. 11 package, <i>p</i> values of &lt;0.05 were considered statistically significant. <h3>Results</h3> OP was identified in 22 (34%) out of 64 pts with CPPD (13 males and 9 females) by the end of the study. The following factors were associated with OP: age &gt;55 years in females (odds ratio (OR) 5.0, 95% CI; 1.021–24,49; <i>p</i>=0.047), age &gt;65 years in males (OR 3.9, 95% CI 1.3–11.5; <i>p</i>=0.014), HPT (OR 15.38, 95% CI 1.7–137.9; <i>p</i>=0.015), elevated ESR (OR 3.38, 95% CI 1.14–10.0; <i>p</i> =0.028) and CRP (OR 6.42, 95% CI 2.05–20.05; <i>p</i>=.001) (Fig.1). Only hypoparathyroidism was identified by logistic regression analysis (sensitivity-71%, specificity -82%) as OP-associated risk factor (OR 14.24, 95% CI 1.05–194.05; <i>p</i>=0.046) (Table 1). <h3>Conclusions</h3> Hypoparathyroidism is the key risk factor for OP in CPPD pts. Among other risk factors chronic inflammation (ESR and CRP levels) is of highest importance. <h3>References</h3> Ross P.D. Osteoporosis: frequency, consequences, and risk factors. Archives Internal Med.1996; 156:1399–141. <h3>Disclosure of Interest</h3> None declared
Abstract 068: Age-associated, Vinculin-mediated Remodeling of the Intercalated Disc Results in Localized Myocardial Stiffening but Preserved Mechanical Function
Authors: Gaurav Kaushik, Ayla O Sessions, Alice Spenlehauer, Mayuko Nishimura, Karen Ocorr, Rolf Bodmer, Anthony Cammarato, Adam J Engler
Journal: Circulation Research (2013)

Molecular and ultrastructural remodeling of the intercalated disc occurs with advanced age and onset of cardiomyopathy, yet the precise effect of this remodeling on mechanical function remains unclear. We employed recently-developed biophysical techniques to measure passive and active cardiac mechanics to investigate how intercalated disc remodeling affects structure and mechanical function with age. Nanoindentation of intact, living Drosophila heart reveals that juvenile myocytes are mechanically homogeneous; however, aging induces mechanical heterogeneity, indicated by increased transverse passive stiffness proximal to the intercalated disc (ID). Localized stiffening up to a 111% increase correlates with an 18% age-related decline in diastolic dimension (DD) as well as increased fascia adherens expression. On the other hand, aged specimens with stiffened IDs were found to have preserved systolic function, assessed by measuring shortening velocity under acute hemodynamic load, as compared to their juvenile counterparts. Aged specimens with no change in ID stiffness experienced reduced shortening velocities at all loads. Cardiac-specific vinculin overexpression stiffened IDs and increased shortening velocity and fractional shortening at all hemodynamic loads. Cardiac specific, RNAi-mediated knockdown of vinculin softened the IDs of intact hearts and reduced fractional shortening at all loads. These data indicate that increased expression of vinculin at the ID results in a stiffer cortical cytoskeleton which acts as a more stable anchor against which the myocytes can shorten. These findings have potential implications for geriatric patients with diastolic heart failure, in whom increased vinculin expression at the intercalated disc, concomitant with increased diastolic stiffness but preserved ejection fraction, has been observed.
Assessing HER2 testing quality in breast cancer (BC): Variables that influence HER2-positivity from a large, multicenter, observational study in Germany.
Authors: Josef Ruschoff, Annette Lebeau, Hans Heinrich Kreipe, Hans-Peter Sinn, Claus Dieter Gerharz, Winfried Koch, Johannes Ammann, Michael Untch
Journal: Journal of Clinical Oncology (2015)

11062 Background: Despite > 10 years of routine HER2 testing in BC, quality is still an issue. It is often assumed that inter- and intra-laboratory variations in testing quality can be assessed by HER2-positivity rates. However, the extent to which patient- or tumor-related factors influence HER2-positivity rates has not been systematically studied. Methods: This observational, prospective study in Germany monitored routine HER2 testing to identify patient- or tumor-related factors that influence HER2-positivity rates, and to identify centers with HER2-positivity rates that could not be explained by these factors. Data collected from eligible BC specimens included test result, patient- and tumor-related factors, sample source, and method of retrieval. Factors influencing HER2-positivity rates were identified by multiple logistic regression (MLR) analysis. Center effects were assessed in an extended MLR model by their statistical significance after adjusting for the combined effect of covariates and multiple testing. Results: From Jan 2013 to Aug 2014, data were collected from 16,528 BC specimens and 57 centers. Final analyses included 15,332 invasive BC specimens. Tumor grade showed the highest correlation with HER2-positivity, followed by hormone receptor status, carcinoma subtype, age, and nodal status (all P< .0001). No significant correlation was found for specimen source. Overall HER2-positivity rate across centers was 14.4%. Adjusting for patient- or tumor-related covariates and multiple testing, a statistically significant center effect on HER2-positivity rate was identified for three centers and a significant trend toward center effect for a further three. Conclusions: This study is the first of its kind, reporting on the multifactorial parameters that can impact on routine HER2-positivity rates. Results highlight that assessing HER2 testing quality by comparing positivity rates only, as recommended, may be insufficient, and that patient characteristics should be considered to assess HER2 testing quality effectively. As therapy options for HER2-positive BC continue to evolve, identifying the right patients is key.
Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC.
Authors: Luis A. Diaz, Aurelien Marabelle, Jean-Pierre Delord, Ronnie Shapira-Frommer, Ravit Geva, Nir Peled, Tae Won Kim, Thierry Andre, Eric Van Cutsem, Rosine Guimbaud, Dirk Jaeger, Elena Elez, Takayuki Yoshino, Andrew K. Joe, Baohoang Lam, Christine K. Gause, Scott Knowles Pruitt, S. Peter Kang, Dung T Le
Journal: Journal of Clinical Oncology (2017)

3071 Background: Mismatch repair deficient cancers harbor high levels of microsatellite instability and somatic mutations. Treatment with anti-PD-1 antibodies has resulted in durable objective responses in MSI-H cancer. As part of the ongoing, global, multicenter phase 2 studies KEYNOTE(KN)164 and KN158, we assessed the efficacy of pembrolizumab in patients (pts) with MSI-H tumors. Methods: Both studies enrolled pts with MSI-H status determined locally by IHC or PCR. KN164 enrolled pts with MSI-H CRC and ≥2 prior therapies, whereas the multicohortKN158 study included pts with MSI-H non-CRC and ≥1 prior therapy. Eligible pts in both studies received pembrolizumab 200 mg Q3W until progression, unacceptable toxicity, or pt/investigator decision. Tumor response was assessed every 9 wk by independent review per RECIST v1.1. Primary endpoint was ORR. Secondary endpoints included DOR, PFS, OS, and safety. Analyses were performed in pts from KN164 and KN158 who had ≥27 wk of follow-up as of Aug 3, 2016 and Oct 19, 2016, respectively. Results: KN164 enrolled 61 pts with MSI-H CRC (90% with ≥2 prior therapies) whereas KN158 included 21 pts with MSI-H non-CRC (42% with ≥2 prior therapies). In KN158 the most common tumor types were endometrial and small intestinal cancer (n = 4 each), cholangiocarcinoma (n = 3), and gastric and pancreatic cancer (n = 2 each). Median follow-up was 7.4 mo for MSI-H CRC and 4.5 mo for MSI-H non-CRC. ORR for MSI-H CRC was 26.2% (95% CI, 15.8%-39.1%), with 15 confirmed responses and 1 unconfirmed response, and ORR for MSI-H non-CRC was 42.9% (21.8%-66.0%), with 8 confirmed responses and 1 unconfirmed response. DCR was 50.8% (n = 31; 37.7%-63.9%) for MSI-H CRC and 66.7% (n = 14; 38.4%-83.7%) for MSI-H non-CRC. Median duration of response was not reached for either MSI-H CRC or non-CRC, and 100% of responses were ongoing. Survival and safety analyses are ongoing. Conclusions: Early results from KN164 and KN158 confirm the robust antitumor activity of pembrolizumab in heavily pretreated pts with MSI-H cancers. Clinical trial information: NCT02628067; NCT02460198.
Abstract 314: Infarct Size Reduction by Statins Requires Parkin and Mitophagy
Authors: Allen M Andres, Pamela Lee, Genaro Hernandez, Chengqun Huang, Eric P Ratliff, Christine A Thornton, Roberta A Gottlieb
Journal: Circulation Research (2012)

The cardioprotective effects of statins are well known yet the mechanism is unclear. Previously we showed that autophagy is required for cardioprotection from ischemia/reperfusion injury. More recently, we reported that ischemic preconditioning involves Parkin-mediated mitophagy. We hypothesized that the molecular basis of statin-mediated cardioprotection may involve mitochondrial quality control through mitophagy. HL-1 cardiomyocytes treated with simvastatin for 24hr exhibited diminished Akt/mTOR signaling, increased activation of ULK1, and upregulation of autophagy (n=3, p&lt;0.05). Similar findings were obtained in cardiac tissue in mice 4hr after i.p. administration of simvastatin. Mevalonate addition abolished statin’s effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of HMG-CoA reductase. Statin treatment in HL-1 cells triggered mitochondrial fragmentation, translocation of Parkin and p62/SQSTM1 to the mitochondria followed by mitophagy. To establish the requirement for statin-mediated mitophagy in cardioprotection, we investigated the ability of statins to reduce infarct size in Parkin knockout (KO) mice. While statin treatment reduced infarct size from 55% of area at risk to 30% in wild type mice, it had no protective benefit in Parkin KO mice (n=4-6, p&lt;0.05). These findings indicate that cardioprotection by HMG-CoA reductase inhibitors involves suppression of mTOR signaling and induction of Parkin-dependent mitophagy. Figure: Statin-induced cardioprotection against I/R injury: solid bars/diamonds = wild-type; open bars/diamonds = Parkin knockout mice.
Factors Associated With Achieving a Body Mass Index of Less Than 30 After Bariatric Surgery
Authors: Oliver A. Varban, Ruth B. Cassidy, Aaron Bonham, Arthur M. Carlin, Amir Ghaferi, Jonathan F. Finks
Journal: JAMA Surgery (2017)

Achieving a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of less than 30 is an important goal of bariatric surgery, given the increased risk for weight-related morbidity and mortality with a BMI above this threshold.To identify predictors for achieving a BMI of less than 30 after bariatric surgery.This retrospective study used data from the Michigan Bariatric Surgery Collaborative, a statewide quality improvement collaborative that uses a prospectively gathered clinical data registry. A total of 27 320 adults undergoing primary bariatric surgery between June 2006 and May 2015 at teaching and nonteaching hospitals in Michigan were included.Bariatric surgery.Logistic regression was used to identify predictors for achieving a BMI of less than 30 at 1 year after surgery. Secondary outcome measures included 30-day postoperative complications and 1-year self-reported comorbidity remission.A total of 9713 patients (36%; mean [SD] age, 46.9 [11.3] years; 16.6% male) achieved a BMI of less than 30 at 1 year after bariatric surgery. A significant predictor for achieving this goal was a preoperative BMI of less than 40 (odds ratio [OR], 12.88; 95% CI, 11.71-14.16; P < .001). Patients who had a sleeve gastrectomy, gastric bypass, or duodenal switch were more likely to achieve a BMI of less than 30 compared with those who underwent adjustable gastric banding (OR, 8.37 [95% CI, 7.44-9.43]; OR, 21.43 [95% CI, 18.98-24.19]; and OR, 82.93 [95% CI, 59.78-115.03], respectively; P < .001). Only 8.5% of patients with a BMI greater than 50 achieved a BMI of less than 30 after bariatric surgery. Patients who achieved a BMI of less than 30 had significantly higher reported rates of medication discontinuation for hyperlipidemia (60.7% vs 43.2%, P < .001), diabetes (insulin: 67.7% vs 50.0%, P < .001; oral medications: 78.5% vs 64.3%, P < .001), and hypertension (54.7% vs 34.6%, P < .001), as well as a significantly higher rate of sleep apnea remission (72.5% vs 49.3%, P < .001) and higher satisfaction rate (92.8% vs 78.0%, P < .001) compared with patients who did not.Patients with a preoperative BMI of less than 40 are more likely to achieve a BMI of less than 30 after bariatric surgery and are more likely to experience comorbidity remission. Policies and practice patterns that delay bariatric surgery until the BMI is 50 or greater can result in significantly inferior outcomes.