tbuckley/cabot-search huggingface dataset:
Investigating circulating microRNAs as potential biomarkers of quadriceps weakness in COPD
Authors: Anna Donaldson, Amy Lewis, Samantha Natanek, William Man, Paul Kemp, Michael Polkey
Journal: European Respiratory Journal (2011)

Introduction:  Non-invasive biomarkers of quadriceps phenotype in COPD are needed. MicroRNAs (mirs) are small non-coding RNA that modulate gene expression. They circulate in blood as exosomes and are promising biomarkers. We hypothesised that muscle specific mir-499, which controls slow myosin expression, would be differentially expressed and correlate with physiological parameters.   Methods:  We studied 101 COPD patients and 24 controls. Mir-499 was quantified in stored plasma samples using q-RT PCR 1 . Mir-16 and mir-122 were quantified as negative controls. Results were normalised to a spiked-in control. All subjects had paired quadriceps biopsy samples.   Results:  Characteristics as mean (SD); COPD patients: 66 M: 35 F, age= 66 (8), FEV1% pred= 44 (19), six-minute walk (6MW)= 394 (121). Controls: 14 M: 10 F, age 66 (8), FEV1% pred= 112 (13), 6MW= 616 (83).  Plasma mir-499 was significantly elevated in COPD patients, p= 0.0036. There was no difference in mir-16 and mir-122.  Mir-499 levels negatively correlated with total fibre cross sectional area (P= 0.03 R 2 = 0.04) and in the patients there was a weak positive correlation with 6MW (p=0.047 R 2 = 0.0016). Patients with no quadriceps muscle fibre type shift (defined from the control samples) had higher mir-499 (p= 0.02).   Conclusion:  We have demonstrated a difference in plasma mir-499 levels between COPD patients and controls. Higher mir-499 in patients with no fibre type shift is consistent with its proposed role of maintaining a high endurance skeletal myofibre phenotype. Our results may reflect higher protein turnover in COPD and contribute towards developing a blood-borne biomarker to stratify treatment.   1 Kroh, Methods 50 (2010)298–301
Combined modality therapy for localized aggressive lymphoma: enough or too much?
Authors: D L Longo
Journal: Journal of Clinical Oncology (1989)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1989.7.9.1179 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 2769325 Combined modality therapy for localized aggressive lymphoma: enough or too much? D L LongoxD L LongoSearch for articles by this author https://doi.org/10.1200/JCO.1989.7.9.1179 First Page PDF © 1989 by American Society of Clinical Oncology
Autosomal dominant polycystic kidney disease
Authors: Roslyn J Simms
Journal: BMJ (2016)

#### What you need to know

Polycystic kidney disease (PKD) is an inherited condition defined by the pathological development of fluid-filled cysts throughout the kidneys leading to organ enlargement (fig 1⇓) and chronic kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited kidney disease1 and is the fourth commonest cause of kidney failure worldwide.2 Autosomal recessive PKD is a rare disease usually identified antenatally or during the neonatal period by enlarged echogenic kidneys on ultrasound.3 This review will focus on ADPKD.



Fig 1  Anatomical illustration of a polycystic kidney (right) compared with a normal kidney (left)



#### Sources and selection criteria

I searched PubMed, Clinical Evidence, and the Cochrane Library for primary and review articles available in English until October 2015. Articles included systematic reviews, randomised clinical trials, and observational studies. The following search terms were used in isolation and combination: “ADPKD,” “polycystic kidney disease,” “progression,” “treatment,” “humans,” “complications,” “mutations.” I identified additional references from my personal archive. Where evidence based medicine was not available, published expert opinion was referenced.

ADPKD presents to a variety of doctors and is more prevalent than the combination …
Lysosomal Changes in Lytic and Nonlytic Infections With the Simian Vacuolating Virus (SV40)&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: A. C. Allison, Paul H. Black
Journal: JNCI Journal of the National Cancer Institute (1967)

Lysosomal changes have been observed by histochemical methods in the BSC-1 green monkey kidney cell line and the 3T3 mouse cell line infected with high multiplicities of simian vacuolating virus (SV40) and in 3T3 cells infected with herpes simplex virus. BSC-1 cells infected with SV40 showed marked cytoplasmic vacuolation and lysis. The lysosomes were enlarged and aggregated and there was second-stage activation with release of enzyme into the cytoplasm. Possibly, some product of viral replication in the nucleus is released into the cytoplasm and brings about changes in lysosomes and other cytoplasmic organelles. Lysosomal enzymes probably contribute to the dissolution of cells and release of virus from nuclei. 3T3 cells infected with SV40 under these conditions do not lyse, but a large proportion may become transformed. First-stage activation of lysosomes was seen for at least 6 days. After 6 days these changes disappeared. The possible relationship of lysosomal changes to the events occurring in transformed cells is discussed. The cells infected with herpes simplex virus showed marked cytopathic effects associated with second-stage lysosomal activation.
Reply to Letter Regarding Article, “Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine: Novel Explanation of Cardiovascular Side Effects Associated With Anti-Inflammatory Drugs”
Authors: Blerina Ahmetaj-Shala, Nicholas S. Kirkby, Rebecca Knowles, Malak Al’Yamani, Sara Mazi, Zhen Wang, Arthur T. Tucker, Louise S. Mackenzie, Paul C.J. Armstrong, Rolf M. Nüsing, James A. P. Tomlinson, Timothy D. Warner, James Leiper, Jane A. Mitchell
Journal: Circulation (2015)
Outcome of elderly (≥70 years) non-small cell lung cancer (NSCLC) patients on a multicenter, phase III randomized trial comparing weekly vs. standard schedules of paclitaxel (P) plus carboplatin (C)
Authors: S. Ramalingam, M. C. Perry, R. V. Larocca, D. A. Rinaldi, P. Gable, W. J. Tester, C. P. Belani
Journal: Journal of Clinical Oncology (2005)

7149 Background: Elderly NSCLC patients are at increased risk for myelosuppression with standard chemotherapy. Weekly paclitaxel regimens are associated with a more favorable toxicity profile. We present the analysis of the elderly subgroup (≥70 years) treated with either the weekly or standard regimen of paclitaxel administered in combination with carboplatin from our randomized, Phase III trial (Belani et al, Proc Am Soc Clin Oncol, 23:619, 2004). Methods: Patients with stage IIIB/IV NSCLC (previously untreated) were randomized to one of two treatment arms: Weekly - carboplatin AUC=6 mg/ml.min every 4 weeks, in combination with paclitaxel 100 mg/m2 weekly for 3 out of 4 weeks or Standard - carboplatin AUC= 6 mg/ml.min and paclitaxel 225 mg/m2, both administered every 3 weeks. Results: Of the 444 patients enrolled to this trial, 136 (31%) patients were ≥70 years of age. Efficacy and toxicity results of the initial phase of therapy for patients ≥70 years receiving Weekly or Standard therapy are summarized below (intent-to-treat). Conclusion: For the elderly subgroup, the efficacy of the weekly regimen appears to be higher in terms of response rate, TTP and MST with reduction in neuropathy as compared to the standard regimen of paclitaxel and carboplatin administered every 3 weeks. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol- Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Challenges for retrospective cohort studies: A profile of patients who refuse participation or are lost to follow-up
Authors: R. Patel, S. Kurian, C. Sun, L. Francisco, L. Wong, J. Sharp, S. Armenian, S. Forman, S. Bhatia
Journal: Journal of Clinical Oncology (2009)

6615 Background: As hematopoietic cell transplantation (HCT) has increasingly become a curative option for many diseases, studying long-term complications has assumed critical importance. A major issue in conducting scientifically rigorous long-term follow up studies with large cohorts is the ability to track patients, and obtain informed consents. High participation rates are critical to avoid selection bias and ensure generalizability. Methods: A mass consenting process was implemented to obtain informed consents from 1056 City of Hope HCT patients transplanted during 1976–2006 who were one+ year survivors and alive in June 2007. This process involved mailing consent forms followed by phone calls. Patients were classified as consented, refused, or lost-to-follow-up (LTFU). Sociodemographic and clinical characteristics indicative of higher risks for refusal or LTFU were identified. Results: Study patients comprised 58% males, and 53% Caucasians. Median age at HCT was 34 years (0.6–73); median age at study initiation was 47 years (6–81); and median time from HCT to study initiation was 10 years (1–30). Primary diagnoses included acute/chronic leukemia (43%), Hodgkin/non-Hodgkin lymphoma (36%), multiple myeloma (9%), and other miscellaneous diagnoses (12%). Fifty percent received allogeneic HCT. At the end of the process, 46% consented, 17% refused, and 37% were LTFU. Compared to consented patients, males, Asians, and younger patients were more likely to refuse consent. Patients LTFU were more likely to have lower SES, a longer time since HCT, in addition to being males, Asians and younger at HCT (Table). Conclusions: This study demonstrates the critical need for maintaining up-to-date contact information on patients after HCT in order to obtain valid long-term follow-up data. It also describes the characteristics of the sub-population that are more likely to refuse or be LTFU, information necessary for planning targeted interventions in long-term follow-up initiatives. [Table: see text] No significant financial relationships to disclose.
Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients
Authors: Nada Lallous, Stanislav V. Volik, Shannon Awrey, Eric Leblanc, Ronnie Tse, Josef Murillo, Kriti Singh, Arun A. Azad, Alexander W. Wyatt, Stephane LeBihan, Kim N. Chi, Martin E. Gleave, Paul S. Rennie, Colin C. Collins, Artem Cherkasov
Journal: Genome biology (2016)

The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In order to develop an effective CRPC therapy, it is crucial to understand the effects of these mutations on the functionality of the AR and its ability to interact with endogenous steroids and conventional AR inhibitors.
Abstract 19299: PPARγ Plays a Novel, Pivotal Role in DNA Damage Sensing and Repair, That is Perturbed in Pulmonary Arterial Hypertension
Authors: Caiyun G Li, Nathaly Sweeney, Vivek Kantamani, Silin Sa, Jan K Hennigs, Isabel Diebold, Christophe Guignabert, Karlene A Cimprich, Marlene Rabinovitch
Journal: Circulation (2014)

We previously observed that mice with deletion of peroxisome proliferator-activated receptor γ (PPARγ) in endothelial cells (EC) (EC-Pparγ-/-) do not reverse pulmonary hypertension (PH) during recovery in room air after three weeks of chronic hypoxia. Impaired PPARγ interaction with ß-catenin was linked to pulmonary arterial (PA) EC dysfunction in the pathogenesis of PH. To gain further insight into PPARγ function, important in reversing PH, we applied affinity purification-mass spectrometry in HEK293T cells to analyse the PPARγ interactome. Analyses revealed a network highly enriched in DNA damage response (DDR) proteins, including the MRE11, RAD50 and NBN (MRN) heterotrimeric complex. MRN senses damaged DNA and activates the ATM/ATR pathway essential for DNA repair. Using co-immmunoprecipitation in PAECs, we confirmed the PPARγ:MRN interaction via the PPARγ ligand binding domain. To determine the function of this novel interaction, we depleted PPARγ with siRNA and induced DNA damage with doxorubicin (DOX) or hydroxyurea (HU). PPARγ depletion impaired DDR activation after DOX/HU, with reduced levels of pATM and its substrates, pCHK1, pCHK2 and γH2AX. To test whether these abnormalities were related to reduced DNA repair, we assessed damaged DNA 24h after removal of DOX/HU using the COMET assay. PPARγ depleted PAECs showed longer comet tails reflective of unrepaired DNA. To investigate if persistent PH in EC-Pparγ-/- mice after chronic hypoxia correlated with impaired DDR, we evaluated both γH2AX (sensor) and Brca1 (repair) foci formation in the mouse lung tissues using confocal microscopy. Consistent with impaired DNA repair, Brca1 foci formation was significantly increased in ECs of EC-Pparγ-/- mice compared to the wildtype littermates. Moreover, reduced PPARγ previously described in PAECs from PH patients relative to controls was also associated with unrepaired DNA, judged by longer comet tails and by persistent γH2AX foci as assessed by confocal microscopy in tissue sections. In summary we report a novel interaction between PPARγ and the MRN that is necessary in DNA damage sensing and repair. We suggest that persistent DNA damage associated with PPARγ deficiency in PAECs could cause dysfunction or transformation related to the pathology of PH.
Selection of myeloid progenitors lacking BCR/ABL mRNA in chronic myelogenous leukemia patients after in vitro treatment with the tyrosine kinase inhibitor genistein
Authors: C Carlo-Stella, G Dotti, L Mangoni, E Regazzi, D Garau, A Bonati, C Almici, G Sammarelli, B Savoldo, MT Rizzo, V Rizzoli
Journal: Blood (1996)
Pattern of progression and its impact on outcome in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: A retrospective multicenter long-term follow-up study
Authors: J. T. Hartmann, F. Heidel, J. Stoehlmacher, M. Duex, J. R. Izbicki, A. Elsaid, E. Wardelmann, T. Fischer, E. Jaeger, S. Al-Batran
Journal: Journal of Clinical Oncology (2006)

9541 Background: To investigate the clinical impact of the different types of disease progression (focal v extensive) in patients (pts) with metastatic gastrointestinal stromal tumors (GIST) after initial response to imatinib. Methods: Pts who received imatinib for metastatic GIST at three Cancer Centers and who have been followed up for at least 2.5 years were eligible for the study. Disease progression was classified as focal or extensive as defined by protocol. Responses were evaluated according to WHO criteria. Progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meier-method. In three pts with focal progressions, serial biopsies were obtained for mutation analysis. Results: Thirty-eight patients (21 men; mean age 58.4 years; range, 37–73 years) were included in the analysis. After a median follow-up of 31.8 mos, 25 of 38 (65.8%) patients had progressed. Nine of 25 progressions were classified as focal and 16 as extensive. Salvage therapies included dose escalation of imatinib with or without surgical resection. Median and 6- and 12-mos PFS were 11.3 mos, 89%, and 40% in pts with focal progression, and 2.5 mos, 39%, and 32%, in patients with extensive progression, respectively. The median OS was 22.8 mos in pts with extensive progression, and was not reached in pts with focal progression. Two subsequent focal progressions in one pt were associated with 2 different secondary KIT-mutations, whereas non-progressive disease harbored the original KIT-mutation alone. Conclusions: Imatinib resistance seems to be partial in a subset of progressing GIST pts. These pts may benefit from local treatment and imatinib continuation and further investigation of imatinib combinations with other compounds appears warranted. Extensive progression is associated with a dismal survival. No significant financial relationships to disclose.
Early-stage breast cancer: Do 70 to 79-year-old women in NYC receive different treatment than younger women?
Authors: F. Lepar, J. J. Wang, N. A. Bickell
Journal: Journal of Clinical Oncology (2005)

8135 Background: Older women with early-stage breast cancer (ESBC) have been shown to be less likely than younger women to receive care recommended by consensus statements and may have worse survival as a result. Women 70–79 years old are an important group that may benefit more from effective breast cancer treatment than women over 80. Methods: Cases of stage I or II breast cancer surgically treated from 1999–2000 were identified through pathology reports at 6 NYC hospitals. Starting with the surgeon’s chart, in- and outpatient records were abstracted. 187 physician offices provided treatment data. Results: 680 women with ESBC were identified. Of these, 129 were 70 to 79 years old. Women 70 to 79 did not differ from those under 70 in disease stage or hormone receptor (HR) status (84% \(\frac{108}{129}\) HR+ vs 78% \(\frac{388}{495}\), p=0.18). They were less likely to have 0 comorbidities (73% \(\frac{94}{129}\) vs 83% \(\frac{415}{495}\), p=0.004). Women 70 to 79 were as likely as younger women to: undergo axillary evaluation (88% \(\frac{114}{129}\) vs 93% \(\frac{458}{495}\), p=0.13), have breast-conserving surgery (BCS) (63% \(\frac{81}{129}\) vs 57% \(\frac{284}{495}\), p=0.27), receive radiation (RT) following BCS (83% \(\frac{67}{81}\) vs 89% \(\frac{247}{279}\), p=0.17), and to receive tamoxifen for HR+ disease > 1cm (79% \(\frac{63}{80}\) vs 77% \(\frac{230}{297}\), p=0.80). The 70–79 year olds were, however, less likely to: receive chemotherapy for HR- disease > 1 cm (63% \(\frac{12}{19}\) vs 85% \(\frac{85}{100}\), p=0.02), get an anthracycline if they received chemotherapy (43% \(\frac{12}{28}\) vs 76% \(\frac{198}{260}\), p=0.0002), and be referred to a medical oncologist for a tumor >1 cm (75% \(\frac{74}{99}\) vs 92% \(\frac{371}{405}\), p<0.0001). Multivariable logistic regression models controlling for race, stage or tumor size, comorbidities, HR, insurance, nursing home residence, and hospital confirmed these results. Conclusions: Women in NYC aged 70 to 79 with ESBC were as likely as younger women to receive axillary evaluation, BCS, RT after BCS, and tamoxifen for HR+ disease but less likely to have chemotherapy for HR- disease, receive an anthracycline, and be referred to a medical oncologist. When analysis is confined to women aged 70 to 79, disparities in care for older women cannot be demonstrated for several therapies, but the lower rate of oncology referral is still of concern. No significant financial relationships to disclose.
NHS future in doubt without extra funding as trusts record “staggering” deficit
Authors: Gareth Iacobucci
Journal: BMJ (2015)

NHS hospital trusts in England recorded a combined deficit of almost a billion pounds in the first three months of this year, higher than the deficit for the whole of the previous financial year.

Figures published by national regulators Monitor1 and the NHS Trust Development Authority2 showed that the NHS trust and foundation trust sectors recorded a combined deficit of £930m (€1260m; $1420m) in the first quarter of 2015-16, compared with £822m for the whole of 2014-15.3

The disclosure lays bare the rapidly deteriorating financial position at most NHS hospitals and indicates that the £2bn end of year deficit previously forecasted for NHS trusts finances is likely to be exceeded.

Monitor’s figures showed that 118 of England’s 151 foundation trusts (78%) ended the period in deficit with …
Cetuximab-related hypersensitivity reactions associated with pre-existing cetuximab-specific IgE antibody
Authors: C. H. Chung, E. Chan, J. Berlin, J. Gilbert, W. Yarbrough, S. Satinover, B. Murphy, R. J. Slebos, T. Hatley, T. Platts- Mills
Journal: Journal of Clinical Oncology (2007)

9097 Background: Cetuximab is a chimeric (mouse/human) IgG 1 monoclonal antibody against the epidermal growth factor receptor and is approved for use in patients (pts) with colorectal cancer and head and neck squamous cell carcinoma. Hypersensitivity reactions caused by cetuximab (C-HSR) have been reported; however, the mechanism underlying these reactions is unknown. We hypothesize that C-HSR are mediated by pre-existing cetuximab-specific IgE antibodies (C-IgE). Methods: A total of 140 serum samples were obtained under IRB approved protocols and retrospectively analyzed across 2 cohorts: 1) 71 pretreatment sera from cetuximab-treated pts collected from multiple centers (47 pts with no HSR and 24 pts with any grade HSR; samples were biased for HSR pts), and 2) 69 sera from healthy volunteers in the Nashville TN area. The samples were analyzed for total-, cetuximab-specific and mouse-specific IgE levels using a modified ImmunoCAP assay (Phadia US Inc.). Severe HSR was defined as grade 3/4 reactions during the first infusion by NCI CTC version 3.0 Allergic reaction/hypersensitivity criteria by a reviewer blinded to the immunoCAP assay results. Results: Of the 71 cetuximab-treated pts from cohort 1, 21 experienced severe HSR by retrospective evaluation. All C-IgE(+) pts (15/15) experienced severe HSR and were immediately discontinued from therapy. Of the remaining 6 severe HSR pts with C-IgE(-), 4 pts were re-challenged and completed their cetuximab infusion without any further reaction, suggestive of a non-IgE mediated mechanism, while 2 pts were not re-challenged. Also, the C- IgE(+) pts tended to have higher levels of total IgE compared to the C-IgE(-) pts. All 47 non-HSR pts were C-IgE(-). Mouse-specific IgE was not detected in any sera from the pts. Analysis of sera from healthy volunteers from the cohort 2 revealed that 15/69 (21.7%) were C-IgE(+), suggestive of pre-existing C-IgE; however, the association with C-HSR could not be made. Conclusion: Our data suggest that C-IgE antibodies are present prior to treatment and appears highly predictive of severe HSR during the first infusion; however, IgE-mediated reactions may not account for all cases of HSR. Prospective validation of the association between C-IgE and cetuximab-induced HSR is warranted. [Table: see text]
Zika virus and microcephaly: why is this situation a PHEIC?
Authors: David L Heymann, Abraham Hodgson, Amadou Alpha Sall, David O Freedman, J Erin Staples, Fernando Althabe, Kalpana Baruah, Ghazala Mahmud, Nyoman Kandun, Pedro F C Vasconcelos, Silvia Bino, K U Menon
Journal: The Lancet (2016)
Abstract 10286: Benefit of High-Dose Atorvastatin in Patients With Acute Coronary Syndromes After Recent Influenza-like Illness: Results From the PROVE IT-TIMI 22 Trial
Authors: Jacob A Udell, Deepak L Bhatt, Elaine B Hoffman, Christopher P Cannon
Journal: Circulation (2013)

Background: Patients with recent influenza-like illness (ILI) may have subclinical systemic inflammation that contributes to atherosclerotic plaque rupture and acute coronary syndrome (ACS). Whethe...