tbuckley/cabot-search huggingface dataset:
Dialysis Initiation and Mortality Among Older Veterans With Kidney Failure Treated in Medicare vs the Department of Veterans Affairs
Authors: Manjula Kurella Tamura, I.-Chun Thomas, Maria E. Montez-Rath, Kristopher Kapphahn, Manisha Desai, Randall C. Gale, Steven M. Asch
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> The benefits of maintenance dialysis for older adults with end-stage renal disease (ESRD) are uncertain. Whether the setting of pre-ESRD nephrology care influences initiation of dialysis and mortality is not known. <h3>Objective</h3> To compare initiation of dialysis and mortality among older veterans with incident kidney failure who received pre-ESRD nephrology care in fee-for-service Medicare vs the Department of Veterans Affairs (VA). <h3>Design, Setting, and Participants</h3> Retrospective cohort study of patients from the US Medicare and VA health care systems evaluated 11 215 veterans aged 67 years or older with incident kidney failure between January 1, 2008, and December 31, 2011. Data analysis was performed March 15, 2016, through September 20, 2017. <h3>Exposures</h3> Pre-ESRD nephrology care in Medicare vs VA health care systems. <h3>Main Outcome and Measures</h3> Dialysis treatment and death within 2 years. <h3>Results</h3> Of the 11 215 patients included in the study, 11 085 (98.8%) were men; mean (SD) age was 79.1 (6.9) years. Within 2 years of incident kidney failure, 7071 (63.0%) of the patients started dialysis and 5280 (47.1%) died. Patients who received pre-ESRD nephrology care in Medicare were more likely to undergo dialysis compared with patients who received pre-ESRD nephrology care in VA (82% vs 53%; adjusted risk difference, 28 percentage points; 95% CI, 26-30 percentage points). Differences in dialysis initiation between Medicare and VA were more pronounced among patients aged 80 years or older and patients with dementia or metastatic cancer, and less pronounced among patients with paralysis (<i>P</i> &lt; .05 for interaction). Two-year mortality was higher for patients who received pre-ESRD care in Medicare compared with VA (53% vs 44%; adjusted risk difference, 5 percentage points; 95% CI, 3-7 percentage points). The findings were similar in a propensity-matched analysis. <h3>Conclusions and Relevance</h3> Veterans who receive pre-ESRD nephrology care in Medicare receive dialysis more often yet are also more likely to die within 2 years compared with those in VA. The VA's integrated health care system and financing appear to favor lower-intensity treatment for kidney failure in older patients without a concomitant increase in mortality.
Biallelic <i>TSC2</i> Mutations in a Patient With Chromophobe Renal Cell Carcinoma Showing Extraordinary Response to Temsirolimus
Authors: Pablo Maroto, Georgia Anguera, Juan Maria Roldan-Romero, Maria Apellániz-Ruiz, Ferran Algaba, Jacqueline Boonman, Mark Nellist, Cristina Montero-Conde, Alberto Cascón, Mercedes Robledo, Cristina Rodríguez-Antona
Journal: Journal of the National Comprehensive Cancer Network (2018)

mTOR inhibitors are used to treat renal cell carcinoma (RCC). Treatment response is variable and appears to correlate with genetic alterations that activate mTOR signaling. Recently, everolimus was suggested to be more effective than sunitinib in chromophobe RCC (chRCC), a tumor with frequent mTOR pathway defects. This report presents the genomic and functional characterization of a metastatic chRCC that showed complete response at metastatic sites and 80% reduction in primary tumor size upon temsirolimus treatment. After surgery, the patient remained disease-free for 8 years after temsirolimus therapy. Whole-exome sequencing (WES) revealed 2 somatic variants in TSC2, a critical negative regulator of mTOR: a splicing defect (c.5069-1G>C) and a novel missense variant [c.3200_3201delinsAA; p.(V1067E)]. In vitro functional assessment demonstrated that the V1067E substitution disrupted TSC2 function. Immunohistochemistry in the tumor tissues revealed increased phosphorylated S6 ribosomal protein, indicating mTOR pathway activation. In conclusion, WES revealed TSC2 inactivation as the likely mechanism for this extraordinary response to temsirolimus. These findings support high efficacy of mTOR inhibitors in a subset of patients with chRCC and propose sequencing of mTOR pathway genes to help guide therapy.
Impact of primary tumor side (TS) on outcomes of once-every-2-weeks (q2w) cetuximab + first-line (1L) FOLFOX or FOLFIRI in patients with <i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 2 APEC trial.
Authors: Timothy Jay Price, Lin Shen, Brigette Ma, Regina Esser, Wen-Feng Chen, Peter Gibbs, Robert S.C. Lim, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2018)

747 Background: In the RAS wt population of APEC, q2w cetuximab combined with 1L FOLFOX or FOLFIRI achieved a best confirmed overall response rate (BORR), median progression-free survival (PFS), and median overall survival (OS) similar to those reported in prior 1L pivotal studies involving weekly (qw) cetuximab. In this hypothesis-generating subgroup analysis, we evaluated the impact of TS in APEC study patients with RAS wt mCRC. Methods: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region, with BORR as the primary endpoint. Patients with KRAS exon 2 wt tumors received q2w cetuximab + investigator’s choice of FOLFOX or FOLFIRI; subsequent analyses considered patients who were RAS wt ( KRAS/ NRAS, exons 2-4). TS was categorized in evaluable patients with RAS wt tumors (left [L]-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right [R]-sided = appendix, cecum, ascending colon, hepatic flexure, and transverse colon). Results: Among 167 patients with RAS wt mCRC, 159 were evaluable for TS; 130 (81.8%) had L-sided and 29 (18.2%) had R-sided mCRC. Baseline characteristics in the TS subgroups reflected the known differences between L- and R-sided mCRC. Efficacy data for the TS subgroups are summarized in the table. Conclusions: Consistent with prior 1L pivotal studies involving qw cetuximab, a prognostic effect of TS in patients receiving 1L q2w cetuximab was confirmed in APEC. BORR remained ≥50% in patients with R-sided mCRC, in line with prior evidence that use of cetuximab may be appropriate when tumor shrinkage/cytoreduction is the goal. These hypothesis-generating data also raise the possibility of synergy between cetuximab and, in particular, irinotecan for PFS and OS in patients with R-sided tumors, although numbers are small. Clinical trial information: NCT00778830. [Table: see text]
Significance of hypoxia inducible factor-1 expression in liver metastasis of colorectal cancer.
Authors: Yuma Wada, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Shuichi Iwahashi, Yu Saito, Hiroki Teraoku, Shogo Ohta, Jun Higashijima, Mitsuo Shimada
Journal: Journal of Clinical Oncology (2018)

464 Background: In colorectal liver metastasis (CRLM), the difference of tumor malignancy between primary and metastatic lesion has been elucidated. Hypoxia inducible factor-1 (HIF-1) represent tumor malignancy including angiogenesis, tumor growth and epithelial mesenchymal transition (EMT). The aim of this study was to investigate the difference of tumor malignancy between metastatic and primary lesion of CRLM and its impact for patient’s prognosis. Methods: In an initial curative hepatectomy of 75 cases in CRLM, HIF-1 expression in primary and metastatic lesion was evaluated by immunostaining method (Sigma-Aldrich, HPA 001275). Staining score was classified as follows, staining intensity (0: negative, 1: low, 2: medium, 3: high) and staining area (0: 0%, 1: -25%, 2: 26-50%, 3: ≥ 51%), and defined more than 4 points as positive expression. We evaluated the clinicopathological features according to HIF-1 expression. Results: Regarding HIF-1 expression of metastatic site, we divided into the positive group (n = 54) and the negative group (n = 21). There was no difference between metastatic HIF-1 expression and clinicopathological factors. Nevertheless, in overall survival, multivariate analysis revealed that HIF-1 positive in metastasis (HR: 2.850, p = 0.042) and poor differentiation type of primary lesion (HR: 20.873, p = 0.001) were independent prognostic factors. HIF-1 positive and negative patients were 3 year survival of 95.2% and 58.6%, respectively. Also, in disease free survival, HIF-1 positive in metastasis (HR: 2.608, p = 0.004), Synchronous (HR: 1.794, p = 0.049), Grade BC (HR: 2.145, p = 0.008), and lymph node metastasis in primary lesion (HR: 2.070, p = 0.016) was identified. Regarding HIF-1 expression of primary site, we divided into 51 cases of positive group and 24 cases of negative group. There was no relationship to clinicopathological factors as well as HIF-1 expression in metastasis, besides HIF-1 expression of prognosis was not associated. Conclusions: In CRLM, HIF-1 expression in the metastatic lesion is not associated with the primary lesion and may be useful as prognostic marker.
Genomic non-coding regions reveal hidden patterns of mumps virus circulation in Spain, 2005 to 2015
Authors: Ana M Gavilán, Aurora Fernández-García, Angel Rueda, Ana Castellanos, Josefa Masa-Calles, Noemí López-Perea, María V Torres de Mier, Fernando de Ory, Juan E Echevarría
Journal: Eurosurveillance (2018)

Background Since mumps vaccination was introduced in 1981 in Spain, the incidence of the disease has dropped significantly. However, cyclic epidemic waves and outbreaks still occur, despite high vaccination coverage. The World Health Organization (WHO) recommends genotyping to trace the pattern of mumps virus (MuV) circulation. Genotype H was predominant in Spain, but was replaced in 2005 by genotype G which has subsequently remained dominant. Of the small hydrophobic protein gene sequences, 78% are identical and belong to the MuVi/ Sheffield.GBR.1.05/[G]-variant. Aim: Our study aimed to investigate whether the circulation of MuV strains in Spain was continuous after the emergence of genotype G in 2005. Method: We obtained 46 samples from Spanish patients infected with MuVi/Sheffield.GBR.1.05/[G] during two epidemic waves and analysed them using new molecular markers based on genomic non-coding regions (NCRs) that discriminate subvariants of this virus strain. Results: Phylogenetic analyses of the nucleoprotein–phosphoprotein and matrix protein–fusion protein NCR indicated strain replacement after a drop in incidence in 2009, which had not been detectable by SH sequencing. Clustering of sequences from patients epidemiologically linked in the same outbreak suggests a potential use for these NCRs in outbreak characterisation. Conclusion: We suggest to consider their use in conjunction with the SH gene in the future WHO recommendations for MuV epidemiological surveillance.
Assessment of antitumor function of NK cells expanded with exosomes from K562.mb21 cells.
Authors: Jeremiah Oyer, Sarah B. Gitto, Sara Khederzadeh, Kari Shaver, Dean A. Lee, Deborah Altomare, Alicja Copik
Journal: Journal of Clinical Oncology (2017)

132 Background: NK cells can kill malignant cells to provide innate immunity against tumors. Due to their low abundance in blood, a focus is to expand NK cells ex vivo having enhanced anti-tumor cytotoxicity to be used as a treatment. Our group has pioneered a cell-free method using plasma membrane (PM) particles derived from K562 cells expressing 41BBL and membrane-bound IL-21 (K562.mb21) which were developed for NK cell expansion. Compared to feeder cell based methods for NK cell expansion, PM21-particles improve safety and allow for potential wide-spread dissemination, and also allows direct in vivo use. Exosomes, vesicles naturally secreted by cells, may yet be another novel feeder cell free way for NK cell expansion and may have further advantageous therapeutic dimensions. Methods: EX21-exosomes and PM21-particles were prepared from K562.mb21 cells and characterized by Nanosight and Western blot analysis. CD3-depleted PBMCs were cultured with EX21 for 14 days, NK cell amounts were monitored and media changed every 2-3 days. In vitro cytotoxicity against K562 cells were comparatively assessed for EX21-NK cells and PM21-NK cells. In vivo anti-tumor efficacy of EX21- and PM21-NK cells was assessed in NSG mice implanted ip with SKOV3_luc ovarian tumor cells (1 x 10 6 cells seeded for 4 days). SKOV3-bearing mice were treated with vehicle, or two doses of EX21-NK cells or PM21-NK cells (1 x 10 7 , in 5 day intervals), and with or without in vivo administration of EX21 (10 µg, 3x/week) or PM21-particles (600 µg, 3x/week). All groups were injected ip with IL-2 (10 KU, 3x/week). Survival analysis was performed with a Log-rank (Mantel-Cox) test. Results: NK cells cultured with EX21 expanded 530 fold (344-710) over 14 days compared to 735 fold (667-802) in presence of PM21-particles. Treatment of SKOV3 engrafted NSG mice with NK cells, expanded with either EX21 or with PM21, allowed significant ( &lt; 0.0001) increase in survival compared to untreated animals (41-44 vs 29 days post treatment). Ip delivery of EX21 to SKOV3 bearing mice had no effect on survival in either untreated control or EX21-NK cell treated groups. Conclusions: EX21 efficiently expands NK cells and EX21-NK cells have equal anti-tumor effect as PM21-NK cells, both in vitro and in vivo.
Combination of TLR9 agonists EnanDIM with checkpoint inhibitors for cancer immunotherapy.
Authors: Manuel Schmidt, Kerstin Kapp, Detlef Oswald, Burghardt Wittig, Barbara Volz
Journal: Journal of Clinical Oncology (2017)

134 Background: TLR9 agonists have shown anti-tumor effects by modulating the innate and adaptive immune system. Ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. The new family of TLR9 agonists, EnanDIM, consists of linear single-stranded ODN synthesized using L-deoxyribonucleotides (natural enantiomers of D-deoxyribonucleotides) at their 3’-ends to prevent degradation. Therefore, EnanDIM does not own the off-target effects of PTO-modified CpG-ODN. Methods: EnanDIM with varying nucleotid sequences were compared for IFN-alpha response from human peripheral blood mononuclear cells and those molecules inducing the stronges response were selected. A maximum feasible dose (MFD) approach was employed to evaluate their acute toxicity and immunomodulatory properties. In addition, a combinatory approach with aPD-1 was evaluated in an syngeneic colon carcinoma CT26 mouse tumor model. Results: EnanDIM581 and EnanDIM532 were selected due to their pronounced activation of the IFN-alpha pathway in vitro. Safety assessments throughout and a gross necropsy at the end of the study revealed no signs of toxicity despite extremely high doses (300 - 1700 mg/kg). Dose-dependent increase of IP-10 levels in serum was observed between 6 and 24 hours after injection. In the colon carcinoma CT26 model subcutaneous injection of EnanDIM532 and intraperitoneal injection of aPD-1 had a moderate effect on the tumor growth when used in monotherapy (28.3% and 57.0% tumor growth inhibition, TGI). Notably, a combination of EnanDIM532 and aPD-1 further reduced tumor growth (74.7% TGI) and thus prolonged survival of the mice. Conclusions: In conclusion, EnanDIM, a new family of TLR9 agonists and immune surveillance reactivators (ISR), broadly activates the immune system, shows no toxicity in an MFD study and enhances the anti-tumor effects of the aPD-1 checkpoint inhibitor in a pilot study of a murine colon carcinoma tumor model. These data show the promising potential of EnanDIM not only for monotherapeutic but also combinatory approaches.
The role of stereotactic body radiation therapy using the CyberKnife system in limited hepatic metastases.
Authors: Eman ElAlfy, Jerome Doyen, Pierre-Yves Bondiau
Journal: Journal of Clinical Oncology (2018)

481 Background: CyberKnife has shown increasing evidence supporting its use for liver metastases with high rates of local control (LC) and low toxicity. we aim to investigate its safety and efficacy for patients with limited hepatic metastases. Methods: 48 patients (pts) with 63 metastatic liver lesions were treated with Cyberknife between March 2007 and November 2012. Most of pts were aged more than 65 years (ys) (n = 25) and males (n = 25). ECOG Performance status was 2 in 20 pts and 1 in 17 pts. Primary tumors were from GIT (n = 34), breast (6), ovary (2), choroidal melanoma (2), lung (1), kidney (1), thyroid (1) and CUP (1). Number of lesions treated per pt was 1 in 36, 2 in 9 and 3 in 3. GTV volume ranged from 0.81 to 164.07 cm³ (median = 22.53). Median volume of PTV was 23.73 cm³ and mean was 44.11 cm³ (range 2.03 - 215.40). We do not use margin (CTV = GTV). Dose per fraction ranged from 5 Gy to 15 Gy, median total dose was 43.5 Gy (range 25 - 45) in 3 fractions (3-5) and 143 beams prescribed to 80 % isodose line. The delivered median min GTV dose was 39.01 Gy and the prescribed median min PTV dose was 35.55 Gy. Results: Treatment was well tolerated with minimal grade 1 toxicity. 2 acute toxicities as nausea, asthenia and moderate colics. No Grade 3 or higher toxicity. Median follow-up was 11.9 months, overall survival (OS) was 83.6% and 57% at 1 and 2 yrs respectively, disease free survival (DFS) was 69.5% and 46.1% at 1 and 2 yrs and LC was 76.3% and 57.9% at 1 and 2 yrs. OS influenced by; Age &lt; 65 years (P = 0.033), Males (P = 0.050), PTV volume &lt; 50 cm 3 (P = 0.002), Coverage &gt; 95% for GTV (P = 0.041). Factors affected DFS were ; Age &lt; 65 years (P = 0.034), Males (P = 0.017), Total dose of 45 Gy (P = 0.001), Dose per fraction equal to 15 Gy (P = 0.001), P.S = 2 (P = 0.024), Max dose &gt; 55 Gy for GTV (P = 0.000), CTV (P = 0.000), PTV (P = 0.000), coverage &gt; 95% for GTV (P = 0.048), CTV (P = 0.031), PTV (P = 0.001), min dose &gt; 35 Gy for GTV (P = 0.032), CTV (p = 0.013), LC affected by; Females (P = 0.013). min dose &gt; 35 Gy for PTV (P = 0.05). Conclusions: Cyberknife is an effective modality with good LC and minimal side effects for limited hepatic metastases. We recommend further studies to define the role of combined modality treatment, clarify treatment parameters and illustrate the related quality of life.
Abstract 12207: NEDD9 Cysteinyl Thiol Oxidation Impairs NEDD9 Binding by Smad3 to Increase Pulmonary Endothelial Matrix Metalloproteinase-2 Proteolytic Activity
Authors: Thomas E Stephens, Andriy Samokhin, Elena Arons, Vadim N Gladyshev, Stefano M Marino, Joseph Loscalzo, Jane A Lepold, Bradley A Maron
Journal: Circulation (2016)

In pulmonary arterial hypertension (PAH), endothelial dysfunction due to increased oxidant stress induces adverse vascular remodeling. In cancers that share overlap with PAH pathobiology, the CAS-L protein NEDD9 upregulates the remodeling enzyme MMP-2. Clearance of NEDD9 requires Smad3 binding to its protein-docking site, which includes Cys18. We hypothesized that NEDD9 Cys18 oxidation impairs NEDD9-Smad3 binding to increase NEDD9 and MMP-2 activity in pulmonary artery endothelial cells (PAECs). To test this hypothesis, cells were treated with hydrogen peroxide (H 2 O 2 ) (250 μM) for 2.5, 5.0, and 7.5 min and NEDD9 levels were assessed by immunoblot. Compared to time 0, H 2 O 2 increased NEDD9 levels by 2.4-, 2.5-, and 3.1-fold, respectively (P&lt;0.05). Next, structural homology to NEDD9 was modeled after 1wyx, 2181, and 3t6g, and the pKa and accessible surface area (ASA) of 10 putative Cys sulfur atoms was analyzed. By this approach, Cys18 (pKa=6.65; ASA=17.5 Å 2 ) was predicted as the most reactive cysteinyl thiol. Mass spectrometry performed on in-gel trypsin digested samples of immunoprecipitated NEDD9 from PAECs treated with H 2 O 2 (500 μM) for 20 min confirmed Cys18 oxidation to cysteinyl sulfonic acid. To determine if Cys18 oxidation was associated with changes in NEDD9-Smad3 binding, PAECs were treated with vehicle (V) control, the pro-oxidant hormone aldosterone (ALDO) (10 -7 mol/L) for 24 hr, or H 2 O 2 (500 μM) for 20 min and immunoprecipitated using an antibody to the Cys18 region of NEDD9. Anti-cysteine sulfenic acid (R-SOH) immunoblotting showed that compared to V-treated cells, ALDO and H 2 O 2 increased NEDD9-SOH levels by 54% and 73%, respectively (P&lt;0.04). In turn, increased NEDD9-SOH induced by ALDO or H 2 O 2 decreased NEDD9-Smad3 binding by 64% (P=0.08) and 87% (P&lt;0.01), respectively. Compared to V-treated cells, ALDO also increased MMP-2 proteolysis by zymography (184 ± 4.9 vs. 248 ± 11 a.u., P&lt;0.01), which was inhibited by 38% (P&lt;0.05) in ALDO-treated cells transfected with si-NEDD9. Oxidative modification of NEDD9 Cys18 is a novel molecular mechanism regulating NEDD9 in PAECs in vitro. Identifying NEDD9 Cys18 as a novel target to inhibit endothelial remodeling proteins may have important therapeutic implications for patients with PAH.
Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues
Authors: Dan Zhou, Bonnie M. Alver, Shuang Li, Ryan A. Hlady, Joyce J. Thompson, Mark A. Schroeder, Jeong-Heon Lee, Jingxin Qiu, Philip H. Schwartz, Jann N. Sarkaria, Keith D. Robertson
Journal: Genome biology (2018)

Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Therapeutically targeting the GSC population may improve patient survival, but unique vulnerabilities need to be identified. We isolate GSCs from well-characterized GBM patient-derived xenografts (PDX), characterize their stemness properties using immunofluorescence staining, profile their epigenome including 5mC, 5hmC, 5fC/5caC, and two enhancer marks, and define their transcriptome. Fetal brain-derived neural stem/progenitor cells are used as a comparison to define potential unique and common molecular features between these different brain-derived cells with stem properties. Our integrative study reveals that abnormal expression of ten-eleven-translocation (TET) family members correlates with global levels of 5mC and 5fC/5caC and may be responsible for the distinct levels of these marks between glioma and neural stem cells. Heterogenous transcriptome and epigenome signatures among GSCs converge on several genes and pathways, including DNA damage response and cell proliferation, which are highly correlated with TET expression. Distinct enhancer landscapes are also strongly associated with differential gene regulation between glioma and neural stem cells; they exhibit unique co-localization patterns with DNA epigenetic mark switching events. Upon differentiation, glioma and neural stem cells exhibit distinct responses with regard to TET expression and DNA mark changes in the genome and GSCs fail to properly remodel their epigenome. Our integrative epigenomic and transcriptomic characterization reveals fundamentally distinct yet potentially targetable biologic features of GSCs that result from their distinct epigenomic landscapes.
Ontology is the problem
Authors: John
Journal: Behavioral and Brain Sciences (2002)

Andrews et al. claim that Gould and Lewontin's critique of adaptationism is largely epistemological rather than ontological. In this commentary I argue that, on the contrary, the deepest part of their critique is ontological, raising concerns about the existence of the traits that are the subjects of adaptationist theorising. Andrews et al.'s failure to address this problem undermines their defence of adaptationism.