tbuckley/cabot-search huggingface dataset:
Patterns of second-line chemotherapy and its effect on survival in patients treated within the Veterans Health Administration (VHA).
Authors: Rafael Santana-Davila, Danielle M. File, Carlos Eduardo Arce-Lara, Michael J. Kelley, Christina D. Williams, Jeffrey C. Whittle
Journal: Journal of Clinical Oncology (2013)

8090 Background: Second-line chemotherapy (2-L) improves overall survival (OS) in patients with metastatic NSCLC. In 2004, erlotinib and pemetrexed were approved as 2-L agents. In this study we analyze the utilization of anti-cancer agents and survival for patients with NSCLC who received 2-L treatment within the VHA. Methods: We identified from the VA Central Cancer Registry incident cases of metastatic NSCLC diagnosed between 2001 and 2008. We included patients who received their 1st cycle of chemotherapy within 120 days of diagnosis. A chemotherapy regimen included all chemotherapy agents prescribed during the next 28 days. We defined a subsequent line of therapy when a new agent was started after a period of more than the initial 28 days since the last drug. We divided our cohort into two based on whether they were diagnosed or treated before August of 2004 (the date pemetrexed was approved). Results: 5,893 patients fulfilled our eligibility criteria and were included for analysis. 2,200 patients were diagnosed before 2004 and 3,693 after. 2-L was administered in 35% (n=2052) of patients overall. Veterans diagnosed after 2004 were more frequently prescribed 2-L compared to those diagnosed earlier (30.2 vs. 37.6%, p&lt;0.001). The most commonly prescribed agent in the earlier period was docetaxel in 43% (n=226) followed by gemcitabine in 22% (n=115). In contrast for patients treated after 2004 the most common agents were pemetrexed in 28% (n=421) followed by erlotinib in 27% (n=418). In this period docetaxel and gemcitabine was prescribed in 19 and 10% of cases respectively. Time from diagnosis to the start of 2-L was shorter in patients treated before 2004 (median 3.6 months (IQR 2.3-6.9) vs. 4.9 (IQR 2.6-8.2) p&lt;0.001). Third-line chemotherapy was administered more frequently in those patients treated after 2004 (26 vs. 5.9%, p&lt;0.001). There was no difference in survival between the two periods (Median OS 5.8 vs. 5.6 months in patients treated after 2004p=0.73) Conclusions: Since 2004 with the introduction of two new agents, which were widely adopted, patients are more likely to receive 2-L for NSCLC. In the last decade there has been no improvement in OS for patients treated with 2-L.
Abstract 215: The Role of Titin in Cardiac Function: Studies in Two Genetically Engineered Mouse Models With Disparate Titin’s Size
Authors: Mei Methawasin, Kirk R Hutchinson, John E Smith, Henk L Granzier
Journal: Circulation Research (2015)

Titin, a myofilament that acts as a molecular spring in the sarcomere, is considered the main contributor to passive stiffness of cardiomyocytes and is responsible for cardiac diastolic function. Increased titin stiffness is related to diastolic dysfunction and HFpEF (Heart Failure with preserved Ejection Fraction). Alteration in size of titin’s spring region leads to changes in cardiomyocyte and left ventricular (LV) chamber stiffness. We tested the effect of alteration in titin’s size in two genetically engineered mouse models. We investigated the effect of shortening titin’s spring region in a mouse model in which I-band/A-band region of titin’s spring has been deleted (TtnΔIAjxn ), in comparison to the effect of lengthening titin’s spring region in a mouse model deficient in titin splicing factor (Rbm20ΔRRM). Integrative approaches were used from single cardiomyocyte mechanics to pressure-volume analysis and exercise study. Study of skinned LV cardiomyocytes revealed that cellular passive stiffness was inversely related to the size of titin. Cellular passive stiffness was increased in TtnΔIAjxn homozygous (-/-) (~ 110 % higher than wildtype (WT)) and was reduced in a graded manner in Rbm20ΔRRM heterozygous (+/-) and -/- cardiomyocytes (~61% and ~87% less than WT). This effect was carried through at the LV chamber level which could be demonstrated in pressure volume (PV) analysis as an increased end-diastolic pressure-volume relationship (EDPVR) in TtnΔIAjxn -/- (~110% higher than WT’s hearts) and reduced EDPVR in Rbm20ΔRRM +/- and -/- (~57% and ~48% less than WT’s hearts). Free-wheel running studies revealed a running deficiency in TtnΔIAjxn -/- mice but an increase in exercise capacity in Rbm20ΔRRM +/– mice. Conclusions: Functional studies from the cellular to in-vivo LV chamber levels showed that mice with shortening of titin’s spring region had increased LV stiffness, diastolic dysfunction and reduced exercise capacity, while mice with lengthening titin’s spring region had compliant LV and increased exercise capacity. Thus, our work supports titin’s important roles in LV diastolic function and suggests that modification of the size of titin’s spring region could be a potential therapeutic strategy for HFpEF.
Enzymatic properties between the N- and C- terminal halves of overexpressed human hexokinase II
Authors: Keunjae Ahn, Mijin Yun, Jong Doo Lee
Journal: Clinical Cancer Research (2007)

A25  The mammalian hexokinase (HK) family includes three closely related 100-kDa isoforms (HKI-III) that are thought to have arisen from a common 50-kDa precursor by gene duplication and tandem ligation. Four different enzymes with different properties and different tissue distribution are responsible for glucose phosphorylation in humans. Previous studies of HK II indicated that both the N- and C-terminal halves of HKII (N-term and C-term, respectively) are catalytically active. In contrast, we now show that the N-terminal half of HKII has a significantly higher catalytic activity than C-terminal half. Furthermore, C-terminal has a significantly higher Km for ATP and Glu than N-terminal. In addition, a truncate form lacking the first 18 amino acids at the N-terminal (Δ18) of HK II and a truncate form of N-term lacking the first 18 amino acids (Δ18N) have higher catalytic activity than other mutants. Therefore, the first 18 N-terminal amino acids influence the specific activity of HK but are unable to affect the kinetic properties investigated. Also, similar results were obtained in PET-scan using F-18-FDG. This suggests that each half of the HKII molecule retains catalytic activity within the 100-kDa protein. Also, this study could explain why cancer cells favor HKII more than other HK subtypes. HK II with catalytic activity in both terminals may be beneficial for cancers to have efficient glycolysis to meet their high metabolic demands.
Abstract 246: Human Induced Pluripotent Stem Cells Reveal Mitophagy as an Essential Process Against Diabetic Cardiomyopathy
Authors: Sang-Ging Ong, Won Hee Lee, Kazuki Kodo, Haodi Wu, Joseph C Wu
Journal: Circulation Research (2015)

Diabetic cardiomyopathy is a common consequence of diabetes and associated with mitochondrial pathology. Using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as an in vitro model of diabetes, we sought to understand the role of mitophagy, a process that selectively degrades mitochondria through the autophagy-lysosome pathway as a crucial quality control pathway against diabetic cardiomyopathy. We first showed that iPSC-CMs exposed to a diabetic milieu demonstrated increased hypertrophy, impaired calcium signaling, and higher oxidative stress. Flow cytometry analysis of iPSC-CMs subjected to diabetic conditions revealed two distinct population of cells (normal and hypertrophied), suggesting a heterogeneous response to hyperglycemia. In these cells, hypertrophied iPSC-CMs were found to have reduced mitophagy compared to normal cells when exposed to hyperglycemia. In addition, we showed that mitochondrial fragmentation was also decreased in the hypertrophied iPSC-CMs compared to normal cells upon exposure to hyperglycemia, demonstrating a link between mitochondrial fragmentation and mitophagy. Surprisingly, pretreatment of iPSC-CMs with a non-selective antioxidant, N-(2-mercaptopropionyl)-glycine, not only failed to limit the deleterious effects of hyperglycemia, but actually led to increased hypertrophy and cell death. We found that mitophagy was significantly reduced in iPSC-CMs following antioxidant treatment, suggesting the need of mild oxidative stress as a trigger for mitophagy. Future studies are warranted to further investigate the association between oxidative stress, mitochondrial fragmentation, and mitochondrial fission as targets against diabetic cardiomyopathy.
Pulmonary sarcomatoid carcinoma: An analysis of the National Cancer Database.
Authors: Conor Ernst Steuer, Madhusmita Behera, Yuan Liu, Chao Fu, Theresa Wicklin Gillespie, Nabil F. Saba, Dong Moon Shin, Rathi Narayana Pillai, Suchita Pakkala, Taofeek Kunle Owonikoko, Fadlo Raja Khuri, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2015)

7537 Background: Pulmonary sarcomatoid carcinomas (SC) are a grouping of five rare non-small cell lung cancer (NSCLC) subtypes. Small case series suggest that these patients have a poor prognosis. We sought to better define the clinical characteristics and outcomes of SC utilizing the National Cancer Database (NCDB), an oncology outcomes database administered by the American College of Surgeons and the American Cancer Society. Methods: The NCDB lung cancer database was queried from 1998 to 2011 for SC using ICD-O-3 codes. Data were extracted on patient demographics, tumor pathology, treatments, and outcomes. Overall survival (OS) data were available for patients diagnosed from 1998-2006 and co-morbitity data from 2003-2011. The univariate association with covariates between SC and other forms of NSCLC was assessed using Chi-square test or ANOVA, where appropriate. The univariate (UV) and multivariable analysis (MV) with OS were conducted by Cox proportional hazards model and/or log-rank tests. All statistical analyses were conducted using SAS Version 9.3. Results: Of the 1,547,531 NSCLC patients in the NCDB, 7965 were diagnosed with SC (0.7%). SC patients had a median age of 70, 59% were male, 89% were Caucasian, and 61% had a Charlson/Deyo co-morbidity status of 0. At presentation, the median primary tumor size was 5 cm and 18% of SC patients were AJCC stage I, 10% stage II, 24 % stage III, and 48% stage IV. Patients were treated with surgical resection (38.5%), radiation (38.2%), and chemotherapy (38.6%). The median OS for stage I-II SC was 16.9 months (m), 5.8 m for stage III, and 5.4 m for stage IV. The 1-year and 5-year survival rates for metastatic SC were 30% and 14%. When compared to other forms of NSCLC in MV analysis, SC patients had a higher risk of death (hazard ratio (HR) 1.34 (95% CI 1.20-1.48) p < .001). A propensity scored matched analysis performed for SC vs. other NSCLC confirmed our findings with worse outcomes in the SC group (HR 1.34 (CI 1.15-1.56) p < .001). Conclusions: SC represents a rare histologic subtype of NSCLC accounting for 0.7% of all lung cancers. It is associated with aggressive clinical characteristics and an inferior outcome relative to other histological subtypes of NSCLC.
Questioning Our APHINITY for More
Authors: Kathy D. Miller
Journal: New England Journal of Medicine (2017)

The initial report of the effect of human epidermal growth factor receptor 2 (HER2) amplification on the risk of relapse and death from breast cancer1 ushered in the modern world of “targeted” therapy, and research moved quickly from target identification to therapeutic exploitation. Trastuzumab, the first HER2-targeted monoclonal antibody, improved overall survival when added to chemotherapy for patients with HER2-positive metastatic disease.2 Adjuvant trials followed, with similarly impressive reductions in the risk of recurrence and death.3-5 Given the importance of HER2 as a therapeutic target, it is no surprise that other HER2-targeted agents soon followed. Pertuzumab has limited activity as . . .
Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter?
Authors: Jules L. Derks, Robert Jan van Suylen, Erik Thunnissen, Michael A. den Bakker, Harry J. Groen, Egbert F. Smit, Ronald A. Damhuis, Esther C. van den Broek, Ernst-Jan M. Speel, Anne-Marie C. Dingemans
Journal: European Respiratory Journal (2017)

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC.The Netherlands Cancer Registry and Netherlands Pathology Registry (PALGA) were searched for patients with stage IV chemotherapy-treated LCNEC (2003-2012). For 207 patients, histology slides were available for pathology panel review. First-line platinum-based combined chemotherapy was clustered as "NSCLC-t", comprising gemcitabine, docetaxel, paclitaxel or vinorelbine; "NSCLC-pt", with pemetrexed treatment only; and "SCLC-t", consisting of etoposide chemotherapy.A panel review diagnosis of LCNEC was established in 128 out of 207 patients. NSCLC-t chemotherapy was administered in 46% (n=60), NSCLC-pt in 16% (n
Evaluation of a novel line probe assay to detect resistance to pyrazinamide, a key drug used for tuberculosis treatment
Authors: M. Driesen, Y. Kondo, B.C. de Jong, G. Torrea, S. Asnong, C. Desmaretz, K.S.M. Mostofa, S. Tahseen, M.G. Whitfield, D.M. Cirillo, P. Miotto, A.M. Cabibbe, L. Rigouts
Journal: Clinical Microbiology and Infection (2017)

The development of rapid molecular diagnostic assays for pyrazinamide (PZA) resistance is considered technically challenging as mutations are highly diverse, scattered along the full length of the pncA gene and not all are associated with PZA resistance. We evaluated the performance of the novel Genoscholar PZA-TB II line probe assay (PZA-LPA2; NIPRO Corporation, Japan).To evaluate the applicability of the PZA-LPA2 in clinical settings, we compared the performance of the PZA-LPA2 to a composite reference standard pncA Sanger and Illumina sequencing plus phenotypic susceptibility testing on a panel of 87 Mycobacterium tuberculosis isolates from World Health Organization (WHO) drug resistance surveys, harbouring mutations previously classified as associated or not associated with resistance according to data from peer-reviewed literature. In addition, the PZA-LPA2 was challenged against a selection of isolates with lineage-specific and non-resistance-associated mutations, for which the frequency among clinical isolates is unknown, and tested directly on 59 sputum extracts.For the survey isolates, the PZA-LPA2 reached an overall agreement with the composite reference of 97.6% (80/82) or 94.3% (82/87) excluding or including heteroresistance, respectively. The PZA-LPA2 failed on 8.5% (5/59) of clinical samples; among valid results, 100% (14/14) sensitivity and 100% (7/7) specificity was reached relative to pncA Sanger sequencing.The PZA-LPA2 represents a valid and rapid alternative for indirect PZA susceptibility testing. Preliminary findings on clinical samples show promise for direct testing. Further studies are needed to assess the clinical risk of missing heteroresistance and falsely detecting lineage-specific, silent and nonassociated mutations.
Coelenterate Sting
Authors: Steven L. Oscherwitz
Journal: Annals of Internal Medicine (1994)

Letters15 December 1994Coelenterate StingSteven L. OscherwitzSteven L. OscherwitzSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-121-12-199412150-00018 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Could there be other causes for the clinical problems noted in the patient in the report by Garcia and colleagues [1]? Although they report no blood culture results, it would seem that infection with Vibrio or other marine organisms might be possible. The ulcerations pictured in Garcia and colleagues' Figure 1 certainly appear similar to those I have seen in patients with V. vulnificus sepsis. Addition of dexamethasone to a regimen of antibiotics that does not cover Vibrio organisms raises the question of multiorgan failure as a result of disseminated bacterial infection from sea water. Previous dives ...REFERENCE1. Garcia PJ, Schein RM, Burnett JW. Fulminant hepatic failure from sea anemone sting. Ann Intern Med. 1994; 120:665-6. Google Scholar Author, Article, and Disclosure InformationAuthors: Steven L. Oscherwitz PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byEnvenomation by Cnidarians and Renal InjuriesCnidarians and human skin 15 December 1994Volume 121, Issue 12Page: 985-986KeywordsAntibioticsArmed forcesBloodSepsisUlcersVibrio ePublished: 15 August 2000 Issue Published: 15 December 1994 Copyright & PermissionsCopyright © 1994 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Generation of Models of Human Hematologic Malignancies Using CRISPR Genome Engineering
Authors: Zuzana Tothova, John M Krill-Burger, Katerina D Popova, Quinlan Sievers, David Yudovich, Roger Belizaire, Jon C. Aster, Elizabeth A. Morgan, Aviad Tsherniak, Benjamin L Ebert
Journal: Blood (2016)
Abstract 422: Activation of the p38 Branch of Mitogen Activated Protein Kinase Pathway Stimulates Proteasome Proteolytic Function
Authors: Xuejun Wang, Changhua Wang, Erin J Terpstra, Yibin Wang, Xuejun “XJ” Wang
Journal: Circulation Research (2015)

Ubiquitin-proteasome system (UPS) dysfunction is associated with development of most heart diseases. Proteasomal functional insufficiency has been experimentally demonstrated to play an important role in cardiac pathogenesis. Hence, enhancing proteasome function is potentially a powerful new strategy for therapeutic exploration but this research area is hindered critically by poor understanding of the regulation of cellular proteasomes. Here, we sought to determine whether and how the p38 branch of mitogen activated protein kinase (MAPK) regulates the UPS. GFPu is a rationally modified green fluorescence protein (GFP) proven to be a UPS-specific substrate. In both an HEK293-GFPu/RFP stable cell line and cultured neonatal rat ventricular myocytes (NRVMs), serum withdrawal activated p38 and decreased GFPu/RFP protein ratios. The decrease was abolished by p38 inhibitor (SB230580). Similar effects were also observed when p38 was activated by anisomycin. Cycloheximide (CHX) chase assays showed that p38 activation by either anisomycin treatment or MKK3 overexpression significantly shortened the half-life of GFPu proteins. These compelling data demonstrate for the first time that p38 stimulates UPS performance. To pinpoint the step of the UPS pathway which p38 acts on, we examined the level of total ubiquitin conjugates and proteasomal peptidase activity. Activation of p38 via various means failed to increase the level of total ubiquitin conjugates but was able to increase significantly proteasomal chymotrypsin-like activity in cultured NRVMs and this increase was remarkably blunted by SB230580. The altered proteasome activity was not associated with discernible changes in the protein abundance of representative subunits of the 19S (Rpt6, Rpn2) and 20S proteasomes (α5, β5, β7); however, 2-dimensional PAGE followed by immunoblot showed that the isoelectric point (pI) of a fraction of β5, but not α2, subunits of the 20S proteasome was shifted to the acidic side, consistent with increased phosphorylation, by MKK3 overexpression in cultured NRVMs. It is thus demonstrated for the first time that p38 MAPK stimulates proteasome proteolytic function and it achieves such effect likely through post-translational modifications of the proteasome.
Which are the best conservative interventions for lymphoedema after breast cancer surgery?
Authors: Martijn M Stuiver, Marieke R ten Tusscher, Margaret L McNeely
Journal: BMJ (2017)

#### What you need to know

Lymphoedema is a common complication of breast cancer surgery with or without adjuvant cancer treatments.1 Fluid accumulates because of damage to the lymphatic system, most commonly after axillary lymph node dissection. Box 1 shows factors associated with lymphoedema. Swelling is commonly in the arm but can involve the chest or back; it can result in pain, dysfunction, and disturbance of body image.3

#### Box 1: Risk factors for breast cancer related lymphoedema with reported ranges of odds ratios (OR)1

##### Factors related to disease and treatment

##### Other factors

Nearly 1 in 5 women who survive breast cancer develops lymphoedema within two years of diagnosis or surgery, with the incidence increasing with time.13 In recent years, sentinel lymph node biopsy has been implemented as standard care and has greatly reduced the incidence of lymphoedema. This means that women with clinically positive lymph nodes undergo the higher risk axillary lymph node dissection, but others can avoid the procedure.

Lymphoedema cannot be completely cured, although it can be managed and perhaps prevented. Box 2 and figure 1 outline non-surgical strategies …
Preconditioning Neutropenia Is a Key Prognostic Factor in Allogeneic Hematopoietic Cell Transplantation for High Risk Acute Myeloid Leukemia
Authors: Philippa J Rohman, Richard M Szydlo, Emily Hobbs, Renuka Palanicawandar, Belen Sevillano, Silvia Monsalvo, Andrew Innes, Edward J Kanfer, Dragana Milojkovic, Ian H Gabriel, Christian Jakob, Donald Macdonald, Aristeidis Chaidos, Anastasios Karadimitris, Jane F Apperley, Eduardo Olavarria, Jiří Pavlů
Journal: Blood (2016)
Smad7 positively regulates keratinocyte proliferation in psoriasis
Authors: D. Di Fusco, F. Laudisi, V. Dinallo, I. Monteleone, A. Di Grazia, I. Marafini, E. Troncone, A. Colantoni, A. Ortenzi, C. Stolfi, M. Picardo, G. Monteleone
Journal: British Journal of Dermatology (2017)

Transforming growth factor (TGF)-β1 exerts inhibitory effects on keratinocyte proliferation.To examine whether Smad7, a known inhibitor of TGF-β1 signalling, is involved in psoriasis-associated keratinocyte hyperproliferation.Smad7 was evaluated in skin sections of patients with psoriasis and healthy controls and in mice with Aldara-induced skin pathology by real-time polymerase chain reaction and immunohistochemistry. To assess whether Smad7 positively regulates in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K)6 and K16, cell-cycle-associated factors, cell-cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS.Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in the S-phase of the cell cycle. Smad7-deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through the S-phase, and hyperphosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT cells was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara-treated mice reduced epidermal thickness.Our data show that Smad7 is overexpressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation.