bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic alterations (GA) and tumor mutational burden (TMB) in large cell neuroendocrine carcinoma of lung (L-LCNEC) as compared to small cell lung carcinoma (SCLC) as assessed via comprehensive genomic profiling (CGP).
Authors: Chae Young Kwang , Tamragouri Keerthi , Chung Jon , Schrock Alexa Betzig , Kolla Bhaskar , Ganesan Shridar , Suh James , Velcheti Vamsidhar , Bivona Trever Grant , Ross Jeffrey S. , Stephens Phil , Miller Vincent A. , Patel Manish , Giles Francis J. , Ali Siraj Mahamed , Ou Sai-Hong Ignatius , Wang Victoria 
Published: July 2017

8517 Background: SCLC and L-LCNEC are aggressive neoplasms that are both associated with smoking history and are thought to overlap in clinical, histogenetic, and genomic features. We reviewed the genomic profiles of >1187 patients to assess the genomic similarities of these diseases. Methods: Comprehensive genomic profiling (CGP) of tumors from 300 L-LCNEC and 887 SCLC patients in the course of clinical care was performed to suggest pathways to benefit from therapy. Results: Commonly altered genes in both diseases included TP53, RB1, MYC/MYCL1, MLL2, LRP1B and PTEN; alterations in other genes occurred at somewhat differing frequencies (table). For both diseases, RB1 mutation significantly co-occurred with TP53 mutations (p<0.001), but occurred in a mutually exclusive fashion to STK11 and CDKN2A (p<0.001). RB1 was mutually exclusive with KRAS for L-LCNEC but not for SCLC. The interquartile range for SCLC and L-LCNEC TMB is 7.9 and 12.6 with the 75% quartile being 14.4 and 17.1 respectively. Cases of both diseases will be presented with radiographic response to genomically matched targeted therapy and immunotherapy, particularly in cases of high TMB. Conclusions: Given the similar overall genomic profiles and clinical behavior of a subset of these diseases, they could be conceived of as a single disease to be further classified by genomically defined classes such as SCLC-type ( TP53/ RB1mutated) and NSCLC-like (wild type for one or both). By analogy to NSLC and melanoma, benefit from immunotherapy appears most likely for only the upper quartile of cases in TMB. [Table: see text]
Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Dagogo-Jack Ibiayi , Bernicker Eric , Li Tianhong , Wang Victoria , Ross Jeffrey S. , Young Lauren , Stephens Philip J. , Chung Jon , Shaw Alice Tsang , Ali Siraj Mahamed , Miller Vincent A. , Schrock Alexa Betzig , Spigel David R. , Ou Sai-Hong Ignatius 
Published: July 2017

9025 Background: Tissue biopsy is the gold standard for detection of genomic alterations (GA) and selection of matched targeted therapies in NSCLC, but ctDNA assay provides a possible complementary approach for some pts. Methods: Hybrid-capture based genomic profiling of 62 genes using a ctDNA assay (FoundationACT™) was performed on blood samples from 1,019 consecutive NSCLC pts. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Results: Pt characteristics: Median age 69 years (range 8-94); 54% were female. Histologies included adenocarcinoma (n = 720), NSCLC not otherwise specified (NSCLC NOS; n = 179), squamous cell (n = 57), LC NOS (n = 51), large cell (n = 6), and sarcomatoid (n = 6). ≥1 reportable GA was detected in 71% of all cases and in 83% of cases with evidence of ctDNA in the blood (MSAF > 0). For 22 pts with paired blood and tissue samples collected within 30 days and MSAF > 0, 33/64 (52%) GA detected in tissue were also detected in ctDNA. In 55 pts for whom tissue was insufficient for analysis, ≥1 GA was detected in ctDNA in 43 (78%) cases. For 856 cases with MSAF > 0, an average of 1.8 GA/sample were reported. GA were most frequently detected in TP53 (57%), EGFR (23%) and KRAS (17%). Comparative analysis with the tissue-based FoundationCORE™ database (n = 19,264) showed similar frequencies of GA per gene, although KRAS mutation was more frequent in tissue than ctDNA (27% vs 17%, P < 0.0001), and EGFR T790M was more frequent in ctDNA than tissue (7% vs 2%, P < 0.0001), likely reflecting use of liquid versus tissue biopsy after relapse on targeted therapy .Kinase fusions ( ALK, ROS1, RET, FGFR3, PDGFRA) were identified in 5% (39/856) of cases. Diverse and novel mechanisms of acquired resistance (AR) were detected in ctDNA including MET Y1230C and EGFR amplification post-crizotinib, FGFR3-TACC3 fusion post-EGFR inhibitor, and multiple EGFRAR mutations post-osimertinib. Conclusions: In this series, use of a rigorously validated capture-based assay revealed evidence of ctDNA in the blood in 84% of cases. Our results provide clinical support for use of this assay as a complementary technology to tissue-based genomic testing in a subset of pts with NSCLC.
Landscape of genomic alterations (GA) and tumor mutational burden (TMB) in different metastatic melanoma (MM) subtypes.
Authors: Johnson Douglas Buckner , Carlson J. Andrew , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Daniel Sugganth , Fabrizio David , Frampton Garrett Michael , Ali Siraj Mahamed , Schrock Alexa Betzig , Cho Byoung Chul , Gibney Geoffrey Thomas , Chmielowski Bartosz , Ganesan Shridar , Mehnert Janice M. , Miller Vincent A. , Stephens Phil , Gay Laurie M. , Ross Jeffrey S. 
Published: July 2017

9536 Background: MM is a highly targetable malignancy, with both kinase inhibitors and immunotherapies providing meaningful survival benefit. Different subtypes of mm harbor distinct GA that suggest targeted and immunotherapy options. Methods: Comprehensive genomic profiling was performed in 2,197 MMs for up to 315 cancer-related genes plus introns from 28 genes commonly rearranged in cancer on hybrid-capture, adaptor ligation-based libraries (mean coverage depth > 600X). TMB was calculated from ≥1.11 Mb sequenced DNA. We assessed base substitutions, insertions and deletions (short variants; SV), rearrangements, and copy number changes. Results: We assessed 6 subtypes: routine cutaneous (CT; 90%), desmoplastic (DM: 1%), acral lentiginous (AL; 1%), Spitzoid (SP; 1%), mucosal (MC; 2%) and ocular (OC; 5%). Each group harbored characteristic genomic signatures (Table). BRAFwas mutated in 38% of CT of which 92% were SV GA and 8% were amplifications, fusions or cases with > 1 BRAF GA. High TMB in CT and DM is highly prevalent (42% and 83% with > 20 mut/Mb). BRAFGA were less common in AL (18%), MC (15%), and OC (2%). SP GA were dominated by fusions in BRAF (60%) and other kinases. KIT GA were prominent in MC and AL. TMB for MC and OC mm were very low. Key findings include novel drivers of BRAF inhibitor resistance including BRAFinternal rearrangements and kinase domain duplications. Conclusions: In the largest cohort of mm with NGS to date, genomic profiles and TMB differ across mm subtypes. Highly prevalent BRAF GA (including in the SP variant) and high TMB in CT and DM mm permit effective use of targeted and immunotherapies. Although MC and OC have lower BRAF GA frequency and lower TMB, targetable GA can be present. Novel BRAF inhibitor resistance mechanisms were observed. [Table: see text]
Comprehensive genomic profiling to identify tumor mutational burden (TMB) as an independent predictor of response to immunotherapy in diverse cancers.
Authors: Goodman Aaron , Kato Shumei , Bazhenova Lyudmila , Patel Sandip Pravin , Frampton Garrett Michael , Miller Vincent A. , Stephens Phil , Kurzrock Razelle 
Published: July 2017

e14508 Background: Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. Methods: We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Results: Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = <0.0001); median OS, not reached vs. 16.3 months (P = 0.0036) (Table). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P < 0.0001). Comparable data was observed when patients with melanoma (N = 52) and NSCLC (N = 36) were excluded (N = 63 patients; 19 tumor types). Interestingly, anti-CTLA4/anti-PD-1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Conclusions: Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. [Table: see text]
Frequency of genetic homologous recombination (HR) alterations in metastatic cutaneous melanoma.
Authors: Kim Kevin , Leong Stanley P. L. , Singer Mark I. , Parrett Brian M , Moretto John , Minor David R. , Vosoughi Elham , Millis Sherri Z. , Ross Jeffrey S. , Kashani-Sabet Mohammed 
Published: July 2017

e21033 Background: In various cancer types, cells with “BRCA-like” or HR mutations/alterations have been shown to be sensitive to PARP inhibitors in preclinical studies. In ovarian cancer, PARP inhibitors have shown improved response rate and progression-free survival in clinical studies. We investigated the frequency of HR mutations/alterations in melanoma. Methods: Comprehensive genomic profiling, (next-generation sequencing [NGS]) that included the entire coding sequence of 315 cancer-related genes was performed on formalin-fixed, paraffin-embedded tumor samples. The patient and tumor characteristics were obtained from electronic health records. Results: At our institution (CPMC), 59 patients underwent NGS analysis of melanoma specimens. Eighteen (30.5%) harbored a mutation in at least 1 of the HR genes in their tumor. The patient characteristics are: median age 69, male (83%), primary head and neck melanoma (61%), absence of ulceration at the primary site (86%) and mitotic rate >1 mm/m2 (86%). Tumor mutation burden was high in 12 (67%) patients and low in 1 (6%) patient. The most commonly altered gene was ARID2 (11.9%), followed by ARID1A, FANCA, ATM, BRCA1 (3.4% each). Three patients had multiple HR alterations: one with mutations in ARID1A, BRCA1 and MRE11A, one with mutations in ARID2 and ATM, and one with mutations in ARID2 and CHEK2. Among the 18 patients with HR mutation(s), concurrent NF1, NRAS, BRAF (V600), and KIT mutations were found in 7 (39%), 6 (33%), 5 (28%) and 1 (6%) patients, respectively. A larger dataset analyzed by Foundation Medicine (FM) (n=1,986) showed a similar pattern: The most common mutations/alterations were ARID2, followed by ARID1A, ATM, ATRX, BRCA2, ATR, BRCA1, BRIP1 and FANCA (Table). Conclusions: HR mutations / alterations are frequently observed in metastatic melanoma. Melanomas with these alterations may represent a unique subset of patients who could potentially benefit from PARP inhibitors. [Table: see text]
Measurement of Pro-Islet Amyloid Polypeptide (1–48) in Diabetes and Islet Transplants
Authors: Courtade Jaques A. , Klimek-Abercrombie Agnieszka M. , Chen Yi-Chun , Patel Nirja , Lu Phoebe Y. T. , Speake Cate , Orban Paul C. , Najafian Behzad , Meneilly Graydon , Greenbaum Carla J. , Warnock Garth L. , Panagiotopoulos Constadina , Verchere C. Bruce 
Published: July 2017

Abstract

Context:
Islet amyloid is a feature of β-cell failure in type 2 diabetes (T2D) and type 1 diabetes (T1D) recipients of islet transplants. Islet amyloid contains islet amyloid polypeptide (IAPP; amylin), a circulating peptide that is produced in β cells by processing of its precursor, proIAPP1-67, via an intermediate form, proIAPP1-48. Elevated proinsulin to C-peptide ratios in the plasma of persons with diabetes suggest defects in β-cell prohormone processing.

Objective:
Determine whether plasma levels of precursor forms of IAPP are elevated in diabetes.

Design, Setting, and Patients:
We developed an immunoassay to detect proIAPP1-48 in human plasma, and we determined the ratio of proIAPP1-48 to mature IAPP in subjects with T1D, T2D, recipients of islet transplants, and healthy controls.

Results:
The proIAPP1-48 immunoassay had a limit of detection of 0.18 ± 0.06 pM and cross-reactivity with intact proIAPP1-67 &lt;15%. Healthy individuals had plasma concentrations of proIAPP1-48 immunoreactivity of 1.5 ± 0.2 pM and a proIAPP1-48 to total IAPP ratio of 0.28 ± 0.03. Plasma concentrations of proIAPP1-48 immunoreactivity were not significantly different in subjects with T2D but were markedly increased in T1D recipients of islet transplants. Children and adults with T1D had reduced mature IAPP levels relative to age-matched controls but an elevated ratio of proIAPP1-48 to total IAPP.

Conclusion:
The β cells in T1D and islet transplants have impaired processing of the proIAPP1-48 intermediate. The ratio of proIAPP1-48-to-IAPP immunoreactivity may have value as a biomarker of β-cell stress and dysfunction.
Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer
Authors: Enomoto Keisuke , Zhu Xuguang , Park Sunmi , Zhao Li , Zhu Yuelin J. , Willingham Mark C. , Qi Jun , Copland John A. , Meltzer Paul , Cheng Sheue-yann 
Published: July 2017

Abstract

Context:
Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated.

Objective:
To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models.

Design:
We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells.

Results:
JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling.

Conclusions:
These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.
An Analysis of Substandard Propofol Detected in Use in Zambian Anesthesia
Authors: Mumphansha Hazel , Nickerson Jason W. , Attaran Amir , Overton Sean , Curtis Sharon , Mayer Paul , Bould M. Dylan 
Published: July 2017

BACKGROUND:
In early 2015, clinicians throughout Zambia noted a range of unpredictable adverse events after the administration of propofol, including urticaria, bronchospasm, profound hypotension, and most predictably an inadequate depth of anesthesia. Suspecting that the propofol itself may have been substandard, samples were procured and sent for testing.

METHODS:
Three vials from 2 different batches were analyzed using gas chromatography-mass spectrometry methods at the John L. Holmes Mass Spectrometry Facility.

RESULTS:
Laboratory gas chromatography-mass spectrometry analysis determined that, although all vials contained propofol, its concentration differed between samples and in all cases was well below the stated quantity. Two vials from 1 batch contained only 44% ± 11% and 54% ± 12% of the stated quantity, whereas the third vial from a second batch contained only 57% ± 9%. The analysis found that there were no hexane-soluble impurities in the samples.

CONCLUSIONS:
None of the analyzed vials contained the stated amount of propofol; however, our analysis did not detect additional contaminants that would explain the adverse events reported by clinicians. Our results confirm the presence of substandard propofol in Zambia; however, anecdotal accounts of substandard anesthetic medicines in other countries abound and warrant further investigation to provide estimates of the prevalence and scope of this global problem.
Skeletal Muscle Metabolic Dysfunction in Patients With Malignant Hyperthermia Susceptibility
Authors: Thompson Sara J. , Riazi Sheila , Kraeva Natalia , Noseworthy Michael D. , Rayner Tammy E. , Schneiderman Jane E. , Cifra Barbara , Wells Greg D. 
Published: July 2017

BACKGROUND:Malignant hyperthermia (MH), a pharmacogenetic disorder of skeletal muscle, presents with a potentially lethal hypermetabolic reaction to certain anesthetics. However, some MH-susceptible patients experience muscle weakness, fatigue, and exercise intolerance in the absence of anesthetic triggers. The objective of this exploratory study was to elucidate the pathophysiology of exercise intolerance in patients tested positive for MH with the caffeine-halothane contracture test. To this end, we used phosphorus magnetic resonance spectroscopy, blood oxygen level–dependent functional magnetic resonance imaging (MRI), and traditional exercise testing to compare skeletal muscle metabolism in MH-positive patients and healthy controls.METHODS:Skeletal muscle metabolism was assessed using phosphorus magnetic resonance spectroscopy and blood oxygen level–dependent functional MRI in 29 MH-positive patients and 20 healthy controls. Traditional measures of physical capacity were employed to measure aerobic capacity, anaerobic capacity, and muscle strength.RESULTS:During 30- and 60-second exercise, MH-positive patients had significantly lower ATP production via the oxidative pathway compared to healthy controls. MH-positive patients also had a longer recovery time with blood oxygen level–dependent functional MRI compared to healthy controls. Exercise testing revealed lower aerobic and anaerobic capacity in MH-positive patients compared to healthy controls.CONCLUSIONS:Results of this exploratory study suggest that MH-positive patients have impaired aerobic metabolism compared to healthy individuals. This could explain the exercise intolerance exhibited in MH-susceptible patient population.
Spectraplakin family proteins – cytoskeletal crosslinkers with versatile roles
Authors: Zhang Jamie , Yue Jiping , Wu Xiaoyang 
Published: July 2017

ABSTRACT
The different cytoskeletal networks in a cell are responsible for many fundamental cellular processes. Current studies have shown that spectraplakins, cytoskeletal crosslinkers that combine features of both the spectrin and plakin families of crosslinkers, have a critical role in integrating these different cytoskeletal networks. Spectraplakin genes give rise to a variety of isoforms that have distinct functions. Importantly, all spectraplakin isoforms are uniquely able to associate with all three elements of the cytoskeleton, namely, F-actin, microtubules and intermediate filaments. In this Review, we will highlight recent studies that have unraveled their function in a wide range of different processes, from regulating cell adhesion in skin keratinocytes to neuronal cell migration. Taken together, this work has revealed a diverse and indispensable role for orchestrating the function of different cytoskeletal elements in vivo.
Review of Hayden White's, Λογοτεχνική θεωρία και ιστορική συγγραφή [Literary theory and historical writing]
Authors: Lianeri Alexandra 
Published: July 2017

Hayden White. Λογοτεχνική θεωρία και ιστορική συγγραφή [Literary theory and historical writing]. Trans. Yorgos Pinakoulas. Athens: Epekeina, 2015. 320 pp.
Review of Dimitris Plantzos', Αρχαιολογίες του Κλασικού: Αναθεωρώντας τον εμπειρικό κανόνα [Archaeologies of the Classical: Reconsidering the empirical rule]
Authors: Vavouranakis Giorgos 
Published: July 2017

Review of Dimitris Plantzos, Οι αρχαιολογίες του κλασικού. Αναθεωρώντας τον εμπειρικό κανόνα [Archaeologies of the Classical: Reconsidering the empirical rule]. Athens: Ekdoseis tou 21ou, 2014. 376 pp.
The effects of centralisation of vascular surgical services in the Bath, Bristol and Weston area on the carotid endarterectomy pathway
Authors: Partridge E , Brooks M , Curd C , Davis V , Oates C , McGeeney D 
Published: July 2017

Introduction Patients who experience a transient ischaemic attack are at the highest risk of having a subsequent stroke immediately after their symptoms. A carotid endarterectomy should be performed on symptomatic, surgically suitable patients who present with a greater than 50% North American Symptomatic Carotid Endarterectomy Trial stenosis of the internal carotid artery within 2 weeks of their symptoms. This study aimed to determine whether the effectiveness of the carotid endarterectomy pathway has been impacted by the centralisation of vascular surgical services in the Bath, Bristol and Weston area. Materials and Methods From October 2013 to October 2015, critical steps in the patient carotid endarterectomy pathway that vascular surgeons from the Royal United Hospital Bath, Bristol Royal Infirmary and North Bristol NHS Trust input into the Royal College of Surgeons National Vascular Registry were collected. The dates of patient’s symptoms, referral, first scan, surgical team review and surgery were analysed. Results Carotid endarterectomy data was collected for 261 patients. Overall, no significant difference in median time (days) from symptom to surgery from precentralisation data compared with post-centralisation data was seen (P = .175), with 65% patients meeting the national target of symptom to surgery in less than 14days. Discussion and Conclusion Centralisation has not significantly impacted the overall efficiency of the carotid endarterectomy pathway. This study highlights areas where improvement across the vascular network is required. This includes addressing the 35% patients that are not currently meeting the 14-day target and standardising the provision of care to outlying communities. Further follow-up is required to assess the longer term effects of centralisation.