tbuckley/cabot-search huggingface dataset:
Nature of Long-Range Evolutionary Constraint in Enzymes: Insights from Comparison to Pseudoenzymes with Similar Structures
Authors: Avital Sharir-Ivry, Yu Xia
Journal: Molecular Biology and Evolution (2018)

Enzymes are known to fine-tune their sequences to optimize catalytic function, yet quantitative evolutionary design principles of enzymes remain elusive on the proteomic scale. Recently, it was found that the catalytic site in enzymes induces long-range evolutionary constraint, where even sites distant to the catalytic site are more conserved than expected. Given that protein-fold usage is generally different between enzymes and nonenzymes, it remains an open question to what extent this long-range evolutionary constraint in enzymes is dictated, either directly or indirectly, by the special three-dimensional structure of the enzyme. To investigate this question, we have compared evolutionary properties of enzymes with those of counterpart pseudoenzymes that share the same protein fold but are catalytically inactive. We found that the long-range evolutionary constraint observed in enzymes is significantly reduced in pseudoenzyme counterparts, despite very high structural similarity (∼1.5 Å RMSD on average). Furthermore, this significant reduction in long-range evolutionary constraint is observed even in pseudoenzyme counterparts which retain the ligand-binding ability of enzymes. Finally, the distance between the site that induces the highest gradient of sequence conservation and the pseudocatalytic site in pseudoenzymes is significantly larger than the corresponding distance in enzymes. Taken together, our results suggest that the long-range evolutionary constraint in enzymes is induced mainly by the presence of the catalytic site rather than by the special three-dimensional structure of the enzyme, and that such long-range evolutionary constraint in enzymes depends mainly on the catalytic function of the active site rather than on the ligand-binding ability of the enzyme.
The incidence of germline cancer susceptibility mutations in primary CNS neoplasm patients.
Authors: Katharine Lord, Christina Boman, Gayle Patel, Srivani Thatikonda, Morris D. Groves
Journal: Journal of Clinical Oncology (2018)

1586 Background: Genomic profiling is performed on primary brain (CNS) tumors to identify somatic mutations. Several syndromes, (e.g. Neurofibromatosis) are well known causes of CNS neoplasms but data is limited on other germline cancer susceptibility mutations in CNS tumor patients. After a somatic mutation was unexpectedly found to be germline, we interrogated our database of somatic CNS tumor mutations. Methods: This IRB approved study reviewed patients at our center from May 2013 - November 2017. Tumors from 319 patients underwent next generation sequencing. At least 1 somatic mutation on a gene of interest was found in 208 tumors; 108 patients were deceased prior to study start. Of the remaining 100 patients, 28 were offered germline testing. Results: 26 patients completed germline testing: 12 had germline mutations (12%), 6 had germline variants of uncertain significance (6%) and 8 had negative germline testing (8%). Germline mutations were identified in the following genes: BRCA2 (3 patients), CHEK2 (4 patients), APC (3 patients), ATM (3 patients), MUTYH (2 patients), PMS2 (2 mutations in 1 patient). Of the 12 patients with germline mutations, five (41.6%) did not meet guidelines for hereditary cancer genetic testing. As a result of the germline findings, medical management was altered and additional family members with pathogenic mutations were identified. Conclusions: Based on somatic and germline mutational data from 319 CNS tumor patients, we estimate 5.8% of all CNS tumor patients (without an obvious CNS tumor syndrome) carry a germline cancer susceptibility mutation. Twelve percent of patients whose tumor contains a somatic mutation of possible “germline” interest carry a germline cancer susceptibility mutation. Pathogenic germline variants were identified in the following genes: BRCA2, CHEK2, APC, ATM, MUTYH and PMS2. Five patients (41.6%) did not meet recognized criteria for germline cancer genetic testing, thus without the somatic data, would have been overlooked. Nearly 50% of CNS tumor patients with germline cancer susceptibility mutations are overlooked when using routine testing criteria; tumor genomic profiling is the only means for identifying these undiscovered germline mutations.
NIK signaling axis regulates dendritic cell function in intestinal immunity and homeostasis
Authors: Zuliang Jie, Jin-Young Yang, Meidi Gu, Hui Wang, Xiaoping Xie, Yanchuan Li, Ting Liu, Lele Zhu, Jianhong Shi, Lingyun Zhang, Xiaofei Zhou, Donghyun Joo, Hans D. Brightbill, Yingzi Cong, Daniel Lin, Xuhong Cheng, Shao-Cong Sun
Journal: Nature Immunology (2018)
ALLELE: A consortium for prospective genomics and functional diagnostics to guide patient care and trial analysis in newly-diagnosed glioblastoma.
Authors: Mehdi Touat, Adrian M. Dubuc, David M. Meredith, Sarah C. Gaffey, Jack E. Gedulig, Shakti H. Ramkissoon, John Frederick De Groot, Evanthia Galanis, Mary Roberta Welch, Louis B. Nabors, Isabel Arrillaga, E. Antonio Chiocca, Sandro Santagata, David Schiff, Manmeet Singh Ahluwalia, Howard Colman, Jan Drappatz, Brian M. Alexander, Patrick Y. Wen, Keith L. Ligon
Journal: Journal of Clinical Oncology (2018)

2003 Background: Multi-dimensional genomic analyses may improve outcome in glioblastoma (GB) but are not widely available as routine clinical care. ALLELE is an ABC2-funded consortium to generate prospective clinical genomics and develop novel biomarkers for use in GB patients. Methods: Multi-center prospective study of tumor genotyping in newly diagnosed GB. Clinical (CLIA) genome-wide tumor whole exome sequencing (WES) and chromosomal microarray (CMA) were performed following surgery. Primary objective: to evaluate the feasibility of genotyping tumors in a time-frame to support real-time use in clinical trials. Comparisons with orthogonal genomic and functional methods were incorporated to inform best practices. Results: As of 1/30/18, 46 patients with GB enrolled among 5 sites. Median age was 60. WES and CMA were completed in 39 patients, with a median time between surgery and biomarker analysis completion of 51 days. Actionable findings, including activating BRAF and FGFR1 mutations were identified in 2 patients, and two tumors were reclassified as non-GB based on genomics. 26 patients with MGMT unmethylated GB were enrolled in INSIGhT, a companion randomized multi-arm trial comparing standard of care versus adjuvant CC-115, neratinib or abemaciclib in newly diagnosed GB (NCT02977780). Pre-defined biomarker groups (EGFR-, PI3K- and CDK-positive) will be evaluated for their ability to predict outcome in each arm. 10 patients received standard of care, and 3 patients enrolled in other clinical trials. In a subset of patients, exploratory functional biomarker assays were generated on live cells from freshly resected tumors and patient-derived GB cell line models were derived. Updated outcomes and results of exploratory biomarker analyses will be presented at the conference. Prospectively generated genomic data will be made publicly available. Conclusions: Molecular profiling with WES and CMA is feasible within a clinically acceptable time frame following surgery for patients with newly diagnosed GB. Genomic analyses conducted in a prospective manner can inform subsequent clinical trial analysis aiming at matching outcome with tumor genotyping.
The effect of donor source on outcomes after second allogeneic hematopoietic cell transplantation for relapsed leukemia.
Authors: Eric Huselton, Michael Slade, Camille N. Abboud, Amanda F. Cashen, John F. DiPersio, Armin Ghobadi, Iskra Pusic, Rizwan Romee, Geoffrey L. Uy, Ravi Vij, Peter Westervelt, Mark A. Schroeder
Journal: Journal of Clinical Oncology (2017)

7044 Background: There is no standard treatment for patients with leukemia who relapse after allogeneic stem cell transplant (HCT). A second HCT (HCT2) may be the only possibly curable option; however, this is performed in few patients. We hypothesized that patient and transplant characteristics, such as donor source will affect outcomes. Methods: We retrospectively evaluated adult patients who received a HCT2 for relapsed leukemia or MDS at a single institution between 2000-2016. 85 patients underwent a HCT2 with an unmanipulated graft from a matched related (MRD, n = 21), matched unrelated (MUD, n = 40), or haploidentical (haplo, n = 24) donor, preceded by either a reduced intensity (RIC) or myeloablative conditioning (MAC) regimen. Results: The median age at HCT2 was 50 yrs and the median time between transplants was 448 days. Patients had relapsed AML (n = 62), ALL (n = 12), and MDS (n = 10). The median length of follow up for survivors was 22.3 months (range 3.9-131) with 20 patients alive in June 2016. 65 patients died; 32 from relapse, 21 from infection, 7 from GvHD, and 5 from organ failure. 1-year OS from HCT2 was 38.6%. For patients with MRD, MUD, haplo donors, 1 year OS was 52.3%, 33.3%, and 34.6% (p = 0.72). 1-year DFS in the entire cohort, MRD, MUD, and haplo groups was 26.4%, 14.3%, 34.8%, and 25.3% (p = 0.45). 1-year TRM was 36.2% and not different across these groups (p = 0.80). Univariate analyses of OS, DFS, and TRM based on patient, disease, and transplant characteristics showed an association with RIC and worse OS and DFS (HR 2.0, 95% CI 1.2-3.3; and HR 1.9, 1.2-3.1). Having &gt; 1 year between transplants was associated with lower TRM (HR 0.38, 0.19-0.77). Traditional risk factors like age, presence of active disease at HCT2, shorter time between transplants, and using the same donor from the first HCT were not otherwise significantly associated with OS, DFS, or TRM. Conclusions: Outcomes after HCT2 did not differ based on donor source. MAC is associated with better OS relative to RIC (1yr OS 51% vs 23%, p &lt; 0.01), DFS (1yr DFS 37% vs 12%, p &lt; 0.01), with similar TRM (1yr TRM 30% vs 47%, p = 0.12). Based on these data, serious consideration is necessary before using RIC regimens for HCT2 in patients with relapsed leukemia.
A phase 1 study of the next-generation ALK/ROS1/TRK inhibitor ropotrectinib (TPX-0005) in patients with advanced <i>ALK/ROS1/NTRK+</i> cancers (TRIDENT-1).
Authors: Alexander E. Drilon, Sai-Hong Ignatius Ou, Byoung Chul Cho, Dong-Wan Kim, Jeeyun Lee, Jessica Jiyeong Lin, Viola Weijia Zhu, HyeRyun Kim, Tae Min Kim, Myung-Ju Ahn, D. Ross Camidge, John K.C. Lim, Shanna Stopatschinskaja, Jingrong Jean Cui, David Michael Hyman, Robert Charles Doebele, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2018)

2513 Background: Pts with ALK/ROS1/NTRK fusion-positive cancers can develop on-target TKI resistance [e.g. solvent front mutations (SFMs)] and/or central nervous system (CNS) relapse. Ropotrectinib is a potent next-generation ALK/ROS1/TRK TKI designed to inhibit SFMs in addition to most clinically relevant resistance mutations. Methods: Phase I eligible pts had ALK, ROS1, or NTRK1-3 fusion-positive advanced solid tumors and were TKI-naïve or TKI pre-treated. Pts with treated/untreated asymptomatic brain mets were allowed. Dose escalation followed a 3+3 design. Results: As of Jan 2, 2018, 65 pts (28 ALK+, 29 ROS1+, and 8 NTRK+) received at least 1 dose of ropotrectinib. The most common tumor was NSCLC (83%). The median # of prior chemo- or immune-therapy was 1 (range 0-9). Many pts were TKI pre-treated (86% of ALK+ had ≥ 2 prior TKIs, 66% of ROS1+ and 50% of NTRK+ had ≥ 1 prior TKIs). 23 pts (35%) had baseline CNS metastases, including 52% with untreated CNS disease. Pts were treated over 5 dose levels/schedules (40–240 mg QD & 160 mg BID). The majority of AEs were G1-2. Treatment-related AEs ( > 10% of pts) included: dysgeusia (38%), dizziness (35%), paresthesia (24%), nausea (12%), anemia, constipation, fatigue, and oral numbness (11% each). DLTs occurred in 2 NSCLC pts: G3 dizziness at 240 mg QD (resolved with dose reduction) and G3 dyspnea/hypoxia at 160 mg BID (resolved with drug discontinuation). The MTD has not been reached. Dose escalation is ongoing. Confirmed partial responses (cPR, RECISTv1.1, n = 8) were observed in TKI-naïve or TKI pre-treated ROS1+/NTRK+ pts at all dose levels. These include pts with acquired SFM+ tumors (1 entrectinib-refractory NTRK3 G623E+, 1 crizotinib-refractory ROS1 G2032R+ pt with untreated CNS mets). The median duration on study of cPRs was 6.7 mos (range 2.6-9.9+ mos), and 88% (7/8) of responses are ongoing. Of the 16 ALK+ pts completed 2 cycles of ropo, 4 had confirmed SD (4 cycles) as best response at data cutoff. Conclusions: Ropotrectinib was well-tolerated and exhibited both intra- and extra-cranial clinical activity in TKI-refractory ROS1+ and NTRK+ pts with SFM-containing tumors. Clinical trial information: NCT03093116.
Total neoadjuvant chemotherapy to facilitate delivery and tolerance of systemic chemotherapy and response in locally advanced rectal cancer.
Authors: Andrea Cercek, Campbell SD Roxburgh, Paul Strombom, Jesse Joshua Smith, Larissa K. F. Temple, Garrett Michael Nash, Jose G. Guillem, Philip Paty, Rona Yaeger, Zsofia Kinga Stadler, Neil Howard Segal, Diane Lauren Reidy, Jinru Shia, Efsevia Vakiani, Abraham Jing-Ching Wu, Christopher H Crane, Marc Jeffrey Gollub, Julio Garcia-Aguilar, Leonard Saltz, Martin R. Weiser
Journal: Journal of Clinical Oncology (2017)

3519 Background: The most common therapy for locally advanced (T3/4 or N+) rectal cancer (LARC) consists of preoperative chemoradiotherapy (chemoRT) followed by surgery and adjuvant chemotherapy. Recently, use of total neoadjuvant therapy (TNT) with preoperative chemotherapy in addition to chemoRT prior to resection has been accepted as an alternative. Methods: Of 811 consecutive patients (pts) who presented with LARC at our cancer center in 2009-2015, 320 received chemoRT with planned adjuvant chemotherapy, and 308 received TNT (induction FOLFOX/CAPOX chemotherapy followed by chemoRT). Treatment and outcome data for those two cohorts were compared. Results: Pts in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort (p &lt; 0·005 and p &lt; 0·001, respectively). The complete response (CR) rate, which includes pathological CR (pCR) and clinical CR (cCR) at 6 months post-treatment, was 21% in the chemoRT with planned adjuvant chemotherapy cohort and 36% in the TNT cohort. The median follow-up was 40 months in the chemoRT with planned adjuvant chemotherapy cohort and 23 months in the TNT cohort. Fewer distant recurrences were seen in patients who had T downstaging (p &lt; 0·001), N downstaging (p &lt; 0·005), a cCR (p = 0·005), or a pCR (p &lt; 0·005). There was no statistically significant difference in distant-recurrence-free survival between the two cohorts. Conclusions: Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines for rectal cancer treatment, which categorizes TNT as a viable treatment strategy that facilitates superior compliance and delivery of systemic therapy. Given its high CR rate, TNT may be beneficial as part of a nonoperative treatment strategy aimed at organ preservation.
Integrative analysis of sarcomatoid clear-cell renal cell carcinomas reveals an immune subgroup.
Authors: Gabriel G. Malouf, Ronan Flippot, Roger Mouawad, Hui Yao, Eva Comperat, Morgan Roupret, David Khayat, Jean-Philippe Spano, Xiaoping Su, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2017)

4571 Background: Integrative analysis of clear-cell renal cell carcinomas (ccRCC) has revealed four transcriptomic subgroups associated with distinct patients outcomes. Integrative analysis of sarcomatoid ccRCC which represent the most agressive forms of ccRCC remains unknown. Methods: We performed integrative analysis of sarcomatoid (n = 28) and Fuhrman grade IV ccRCC (n = 9) using whole-exome sequencing (n = 37), RNA-sequencing (n = 32), and DNA methylation profiling by Infinium 450K arrays (n = 31). Correlation with clinico-pathlogical tumor features and patients outcomes were performed. Results: The most frequent somatic mutations in sarcomatoid ccRCC were VHL (71%), PBRM1 (50%), SETD2 (21%), BAP1 (11%), and TP53 (11%). Hierarchical unsupervised clustering of gene expression revealed two transcriptomic subgroups C1 and C2 which do not differ in term of clinical features, presence of sarcomatoid dedifferentiation and patients outcomes. Furthermore, these clusters do not differ according to their genomic features ( VHL, PBRM1 and SETD2 mutations) or their mutational loads. Strikingly, C1 cluster was highly enriched for genes related to T cell receptor signaling pathway (p = 2.6x10 -6 ) and adapative immunity (p = 8.5x10 -5 ); in addition, the C1 « immune » subgroup was characterized by up-regulation of genes related to cell cycle. Conversely, C2 cluster revealed down-regulation of metabolic pathways (p = 7. 5x10 -5 ). At the epigenetic level, methylome clustering revealed two distinct epi-clusters, epi-C1 (n = 10) and epi-C2 (n = 21); patients with tumors belonging to C2 epi-cluster displayed 9p loss and harbored inferior progression-free survival as compared to those in C1 epi-cluster (11 months versus NR ; P = 0.02); of note, this was independent of clinico-pathological tumor features and transcriptomic classification. Conclusions: Our data suggest that genetic and epigenetic landscapes of sarcomatoid ccRCC might not differ from grade IV ccRCC. In addition, we discovered an immune sarcomatoid ccRCC cluster. This finding provides a rationale for use of immune checkpoint inhibitors in sarcomatoid ccRCC.
Cetuximab plus platinum-based chemotherapy in patients with malignant pleural mesothelioma: A single arm phase II trial.
Authors: Annelies De Paepe, Karim Y Vermaelen, Robin Cornelissen, Paul Richard Germonpre, Annelies Janssens, Marc Lambrechts, Gerben Bootsma, Jan P. Van Meerbeeck, Veerle Surmont
Journal: Journal of Clinical Oncology (2017)

e20030 Background: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Previous studies suggested that cetuximab enhances chemotherapy activity in the presence of EGFR overexpression, which is present in a majority of MPM specimens. We investigated the activity and safety of the combination of platinum-based chemotherapy and cetuximab in EGFR immunohistochemical positive (IHC+) MPM patients (pts). Methods: This is an open, single arm multicenter phase II study according to a Simon 2-step design with progression-free survival (PFS) rate at 18 weeks as primary endpoint. PFS rate at 18 weeks in MPM pts with cisplatin-pemetrexed is 0.67. We hypothesized that the combination of cetuximab and chemotherapy would increase the PFS rate with 30% to 0.87 (alpha = 0.05, power 90%). 18 chemotherapy-naïve pts with epithelioid MPM and PS 0-1, EGFR IHC+ (assessed by DAKO kit with at least 1% of cells showing staining), were included in step 1 of in the study. If ≥14 were alive and free of progression at 18 weeks, sample size was to be increased to 43 pts. Treatment consisted of cisplatin (75 mg/m², day 1 of each 3-week cycle) or carboplatin AUC 5 (day 1 of each 3-week cycle) and pemetrexed (500mg/m2, day 1 of each 3-week cycle) and cetuximab (loading dose of 400 mg/m² followed by 250 mg/m² weekly) during chemotherapy until disease progression. Chemotherapy was given up to 6 cycles. Secondary end points were overall survival (OS), toxicity and response rate. Results: We enrolled 18 eligible pts between June 2010 and June 2013; 89% males, median age 68 years (range 57-80), 83% PS 1. Median number of cycles was 4 (range 2-6). Median number of weekly administrations of cetuximab was 25 (range 8-51). 13 pts were alive and without progression at 18 weeks, median PFS was 24 weeks (95% CI 18.5-29.5), median OS 49 weeks (95% CI 38.6-59.4). 44% (8/18) of patients obtained a partial response. The treatment was well tolerated; the most common adverse event was skin rash (89%), mainly grade 1-2. Conclusions: As platinum-based chemotherapy in combination with cetuximab in pts with epithelioid MPM did not reach the predefined threshold, the study was not continued. No new safety signal was observed. Clinical trial information: NCT00996567.
Real-world data on treatment patterns and survival among ALK+ NSCLC patients in Japan.
Authors: Kaname Nosaki, Ryo Toyozawa, Kenichi Taguchi, Makoto Edagawa, Shin-ichiro Shimamatsu, Goji Toyokawa, Fumihiko Hirai, Masafumi Yamaguchi, Yoko Takeda, Takashi Seto, Mitsuhiro Takenoyama, Yukito Ichinose
Journal: Journal of Clinical Oncology (2017)

e20505 Background: Three ALK inhibitors (ALKi) are approved in Japan for treatment of patients with ALK-positive (ALK+) advanced or metastatic non-small cell lung cancer (NSCLC). However, the optimal sequence of therapy with ALKi is unclear. The objective of this study was to provide real-world data on the treatment patterns and survival among ALK+ NSCLC patients. Methods: ALK+ patients treated with ALKi in our institute were included in this retrospective analysis. Data on the treatment patterns and outcomes were collected from medical records. Results: In total, 60 patients were included. The median age at the diagnosis was 52.5 years, with 60% female and 65% non-smokers. The first treatment was chemotherapy in 67% and ALKi in 33%. The median overall survival (OS) was 186 weeks. We found differences in the OS for Crizotinib use at any line (118 weeks; presence vs. NR; absence) and first-line use of an ALKi (127 weeks; Crizotinib vs. 416 weeks; Alecitinib or Ceritinib, p = 0.0048). Conclusions: The role of Crizotinib in the treatment of ALK+ NSCLC is decreasing. Alectinib followed by Ceritinib seems to be promising. Treatment decision-making based on a re-biopsy is immature at present. The development of sequential therapy with ALKi based on resistance mechanisms is urgently needed. [Table: see text]