tbuckley/cabot-search huggingface dataset:
Retrospective comparison of treatment outcome and cost effective analysis of BEP and VIP for poor-prognosis metastatic germ cell tumors in India
Authors: H. K. Dadhich, S. V. Attili, K. S. Saini, U. Batra, L. A. Jacob, G. Anupama, N. Singhal, B. Pp
Journal: Journal of Clinical Oncology (2006)

14638 Purpose: Retrospective comparison of treatment out come and cost effective analysis in two chemotherapeutic regimens (BEP vs. VIP) for poor-prognosis metastatic germ cell tumors in India, a resource poor nation. Methods: All male patients with poor risk germ cell tumors were included in the study between 2001–2003. The patients were stratified into two categories depending on the type of the regimens they received. Results: Finally 36 patients were analyzed with median follow up of 21.8 months. Medical 7.5 for windows was used for the analysis. The baseline characters (age, stage, PS, histology and serum markers) were not different in two treatment arms (P &gt; 0.05). The different treatments (BEP vs. VIP) had no statistically significant influence on the outcome. VIP is less cost effective and more toxic compared to BEP. Conclusion: In view of absence of survival advantage and more toxicities as well as cost of therapy it would be appropriate to still treat the patients of high risk germ cell tumors with the conventional BEP rather than VIP in the Indian setting and keeping the later reserved for the relapse. [Table: see text] No significant financial relationships to disclose.
An open-label pilot study of memantine, an N-methyl-D-aspartate receptor antagonist in chronic cough
Authors: Rayid Abdulqwai, Rachel Dockry, Holt Kimberley, Shilpi Sen, Emma Hilton, Jaclyn Smith
Journal: European Respiratory Journal (2014)

Background: N-Methyl-D-Aspartate Receptor (NMDAR) mediated central sensitisation of the cough reflex may play a role in chronic cough. Memantine, a use-dependent NMDAR antagonist, has been shown to be an effective anti-tussive in animal models. It is well-tolerated in Alzheimer9s disease.  Aim: To explore the efficacy and tolerability of oral memantine in patients with refractory chronic cough.  Methods: 14 subjects (13 women, mean age 58yrs) received escalating doses of memantine; 10mg OD initially, titrated weekly to 40mg OD or maximum tolerated dose. Daytime cough frequency (c/h) (VitaloJAK ™ ) and cough quality of life (Cough Quality of Life Questionnaire, CQLQ) were assessed at baseline and after 4 weeks of maximum tolerated dose, earlier if not tolerated.  Results: Memantine did not significantly improve cough. Geometric mean daytime cough rate was 41.1 c/h (95%CI 22.9–73.8) at baseline vs. 30.9 c/h (95%CI 15.6–61.2) with memantine, p=0.141; median change -17.3% (range -73.6% to +115%), see Figure 1. CQLQ scores remained stable (-2.6, p=0.4).  For the majority of subjects (n=10, 71.4%) 10 mg was the maximum tolerated dose, with 2 subjects (14.3%) on 20 mg and 2 (14.3%) on 30 mg. Main adverse events limiting dose were dizziness (71%), tiredness (43%) and drowsiness (36%).  Conclusions: Memantine is poorly tolerated by chronic cough patients and its efficacy as an anti-tussive disappointing.
Abstract 11922: Adiponectin Limits Monocytic Microparticle-Induced Inflammasome Activation and Endothelial Dysfunction
Authors: Mehroz Ehsan, Fina Lovren, Adrian Quan, Yi Pan, Krishna K Singh, Hwee Teoh, Subodh Verma
Journal: Circulation (2014)

Introduction:  Monocytic microparticles (mono-MPs) play a fundamental role in the atherothrombotic process. Alterations in monocyte-endothelial cell (EC) interaction mediate immune activation and propagate inflammation. Adiponectin primes monocyte differentiation into anti-inflammatory M2 vs. pro-inflammatory M1 macrophages and inhibits EC activation.   Hypothesis:  We hypothesized that mono-MPs trigger NLRP3 inflammasome-dependent EC activation and adiponectin inhibits this phenomenon, in part, through limiting mono-MP production and activation.   Methods:  Mono-MPs were characterized using electron microscopy, flow cytometry and NanoSight microscopy. Exosomes were excluded based on size and absence of the exosome-specific markers. Studies were conducted with THP-1 monocytes and peritoneal monocytes from adiponectin knockout (Adipoq-/-) mice. We evaluated the effects of lipopolysaccharide (LPS; 5 μg/ml, 24 h) and recombinant adiponectin (10 μg/ml) on mono-MP production, expression of the NLRP3 inflammasome and its components, and key downstream inflammatory factors. We also studied how MPs alter the expression of critical adhesion molecules and inflammatory transcription factors in HUVEC cultures. Inflammasome activation was examined in mono-MPs derived from THP-1 cells.   Results:  Adiponectin suppressed LPS-induced MP generation by THP-1 monocytes. LPS-treated mono-MPs exhibited a marked upregulation in NLRP3 inflammasomes and NLRP3 components (ASC, caspase-1, pro-IL1β and IL1β). Adiponectin attenuated these changes. Adiponectin inhibited the significant increases in ICAM-1, VCAM-1, p-IkB, p-NFkB and p-ERK-1 noted in mono-MP-HUVEC co-cultures. Compared to monocytes from Adipoq+/+ mice, those from Adipoq-/- littermates showed a ~6-fold greater production of MPs following LPS stimulation.   Conclusions:  We report a novel mechanism through which mono-MPs sustain NLRP3 inflammasome activation and endothelial dysfunction. These data reveal a previously unknown atheroprotective mechanism for adiponectin that may account for the inverse relationship between circulating adiponectin levels and the risk of diabetes and obesity.
A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers.
Authors: B Ardalan, G Singh, H Silberman
Journal: Journal of Clinical Oncology (1988)

Fifty-two patients with advanced gastrointestinal (GI) malignancies who had not received previous chemotherapy or radiation therapy were randomized to be treated either with 24-hour infusion of weekly fluorouracil (5-FU) or the same plus N-(phosphonacetyl)-L-aspartic acid (PALA). Forty-seven patients were evaluable for the assessment of toxicity and antitumor activity. PALA was administered as an intravenous (IV) bolus over 15 minutes at a fixed dose, 250 mg/m2. The latter agent was administered 24 hours before the start of 5-FU infusion. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 3,400 mg/m2. In both arms of the randomized study, the courses were repeated every week. In both arms of the study, ataxia and myelosuppression were the dose-limiting toxic effects. At 5-FU dose of 3,400 mg/m2, one patient in each arm developed grade 3 hematologic toxicity. Other reversible side effects included grade 2 skin changes, nausea, and vomiting. During the administration of 2,600 mg/m2 of 5-FU over 24 hours, the steady state plasma 5-FU concentration was approximately 20 mumol/L. The maximum tolerated dose (MTD) for 5-FU for protracted treatment is 2,600 mg/m2 in either arm of the study. Therapeutic response was predominantly seen in the combination arm: there were two patients with complete response (CR) and 11 patients with partial response (PR) of 28 patients in the study. In the 5-FU alone arm there were four PR and 19 patients in the study.
THE INFLUENCE OF THE INTERVAL BETWEEN BEATS ON MYOCARDIAL CONTRACTILITY
Authors: JAN KOCH-WESER, JOHN R. BLINKS
Journal: Pharmacological Reviews (1963)

The last few years have seen significant progress toward an understanding of the interval-strength relationship of heart muscle, particularly in regard to the relation of the various constituent phenomena to one another. It has become clear that interval-dependent changes in myocardial contractility result both from changes in the duration of the active state and from changes in the degree of activation of the muscle; the changes in the degree of activation can be analyzed in terms of the interaction of three factors.

Unfortunately, knowledge about the interval-strength relationship is restricted almost entirely to the level of a descriptive analysis. The nature of the underlying processes in the myocardium remains unknown, though some hypotheses about them can now be rejected with certainty, and some promising clues have been uncovered. Interval-dependent changes in the duration of the active state appear to be related to changes in the duration of the action potential; those in the degree of activation fall in the broad category of changes in excitation-contraction coupling. The study of the cardiac action potential and that of excitation-contraction coupling in striated muscle are both fields of widespread interest and activity, and it can be anticipated that as more is learned about these subjects, the nature of the processes underlying the interval-strength relationship will become clearer. Light may be shed on the character of these processes by studies of the influence of various physical and chemical factors on the interval-strength relationship. It is not enough to determine the effect of such agents on the strength of contraction at various frequencies, however, or to examine the effect of an intervention on a special case of the interval-strength relationship, such as post-extrasystolic oil post-stimulation potentiation. Experiments must be designed in such a way that it can be determined which of the interval-dependent determinants of the strength of contraction are involved in any changes observed. Just as studies of the actions of drugs on the interval-strength relationship are likely to prove helpful in the effort to learn its basic nature, they also may lead to a better understanding of the mechanisms through which drugs alter myocardial contractility.
Neurocognitive outcomes in adult survivors of childhood Hodgkin lymphoma.
Authors: N. Jain, K. R. Krull, D. K. Srivastava, E. B. Morris, M. Metzger, K. Helton, L. L. Robison, M. M. Hudson
Journal: Journal of Clinical Oncology (2010)

1532 Background: Adult survivors of childhood Hodgkin lymphoma (HL) are at increased risk for cardiac morbidity as a consequence of previous treatment. Cardiovascular morbidity in non-cancer populations is associated with increased rates of neurocognitive deficits. Methods: Forty-eight adult survivors of childhood HL were randomly selected from a large cohort of childhood cancer survivors (≥ 18 yrs of age and >10 yrs post-diagnosis) recruited for participation in the St. Jude Lifetime Cohort Study. Treatment included high-dose chest radiation (≥ 30 Gy) in Cohort 1 (n = 24) and anthracycline chemotherapy and chest radiation (any dose) in Cohort 2 (n = 24). All survivors completed standardized neurocognitive, cardiac, and brain magnetic resonance imaging examinations. The data were evaluated with one-sample t-tests, independent samples t-tests, and point- biserial correlations. Results: Cohorts 1 and 2 were similar in mean age and time since diagnosis (Cohort 1: age = 43.5 yrs., range 37.4- 52.4, time since diagnosis = 29.1 yrs., range 21.8-27.3; Cohort 2: age = 40.1 yrs., range 37-46.7, time since diagnosis = 23.8 yrs., range 18.4-33.8). Compared to age-adjusted national normative values, significant differences in performance were seen on measures of verbal IQ (p < 0.01), cognitive processing speed (p < 0.01), verbal memory (p < 0.05), sustained attention (p < 0.01), and fine motor speed (p < 0.01). Between groups comparisons revealed significantly lower performance in Cohort 1 on measures of focused attention, sustained attention, cognitive processing speed, and fine motor speed, and lower performance in Cohort 2 on measures of short and long-term verbal memory (all comparisons p < 0.05). Approximately 54% of the sample demonstrated evidence of cardiac complications. Neuroimaging abnormalities (e.g., cerebral volume loss and white matter leukoencephalopathy) were significantly associated with measures of processing speed (p < 0.01) and fine motor speed (p < 0.01). Conclusions: HL survivors demonstrate increased rates of brain impairment, reflected through neurocognitive assessment and neuroimaging studies. Given the sample size, these findings should be interpreted with caution, but do support the need for larger studies in this population. No significant financial relationships to disclose.
Abatacept in B7-1–Positive Proteinuric Kidney Disease
Authors: Ariela Benigni, Elena Gagliardini, Giuseppe Remuzzi
Journal: New England Journal of Medicine (2014)

Abatacept (cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin fusion protein [CTLA-4-Ig]) is a costimulatory inhibitor that targets B7-1 (CD80).The present report describes five patients who had focal segmental glomerulosclerosis (FSGS) (four with recurrent FSGS after transplantation and one with primary FSGS) and proteinuria with B7-1 immunostaining of podocytes in kidney-biopsy specimens.Abatacept induced partial or complete remissions of proteinuria in these patients, suggesting that B7-1 may be a useful biomarker for the treatment of some glomerulopathies.Our data indicate that abatacept may stabilize β1-integrin activation in podocytes and reduce proteinuria in patients with B7-1-positive glomerular disease.
Abstract 92: Sirtuin 2 mediated-deacetylation regulates cellular iron homeostasis
Authors: Xiaoyan Yang, Athanassios Vassilopoulos, Seong-Hoon Park, David Gius, Hossein Ardehali
Journal: Circulation Research (2014)

Background: Sirtuins (SIRTs) are NAD+-dependent deacetylases, which regulate energy metabolism and response to oxidative stress in the heart. Iron is essential for these processes but is toxic when present in excess. However, whether SIRTs are involved in maintaining cellular iron homeostasis is not known. SIRT2 is among the least characterized SIRTs and is mainly present in the cytoplasm. We hypothesized that SIRT2 is required for cellular iron homeostasis. Methods and Results: Iron content was significantly lower in SIRT2-/- mouse embryonic fibroblasts (MEFs) compared to SIRT2+/+ MEFs (non-heme iron: 0.073 vs. 0.060 nmol/μg protein, p=0.02), andlevels of ferroportin-1 (FPN1), the major cellular iron exporter, was significantly increased in SIRT2-/- MEFs. Similarly, silencing SIRT2 in HepG2 cells decreased cellular iron levels and increased FPN1 expression, indicating that enhanced FPN1 with SIRT2 downregulation drove iron export and caused a reduction in cellular iron levels. Furthermore, iron export assays showed that iron export was increased in HepG2 cells with SIRT2 knockdown. To investigate the underlying mechanism, we focused our studies on nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a known regulator of FPN1. Our results demonstrated that Nrf2 is upregulated and translocates into the nucleus in SIRT2-/- MEFs and knocking down Nrf2 in SIRT2-/- MEFs reverses iron deficiency. Furthermore, Nrf2 is acetylated by P300/CBP and can be deacetylated by SIRT2. Finally, to confirm the role of SIRT2 in iron regulation, cellular heme and non-heme iron in the heart (major iron-consuming organ) and liver (major iron-storage organ) were measured in wild type (WT) and SIRT2-/- mice. Heme and non-heme iron content were significantly decreased in SIRT2-/- mouse livers compared to WT livers (heme: 2.25 vs. 1.65 nmol/mg protein, p=0.002; non-heme iron: 0.073 vs. 0.064 nmol/μg protein, p=0.03). Furthermore, heme levels were also significant decreased in the heart, while non-heme iron was not significantly altered. Conclusions: Our results suggest that SIRT2 regulates cellular iron homeostasis by deacetylating NRF2 and altering iron export through FPN1.
Effect of human neutrophil proteases on ex vivo small airway function
Authors: Natasha J. Madge, Duncan F. Rogers, Louise E. Donnelly
Journal: European Respiratory Journal (2013)

Small airways are the main site of airflow obstruction in COPD. Neutrophils are implicated in COPD pathophysiology via the activity of their released products, including proteases, which damage airway tissue.

We studied the effects of activated neutrophil supernatants on small airway function in rat precision-cut lung slices (PCLS) using videomicroscopy. PCLS were incubated overnight in fMLP-stimulated neutrophil supernatants from non-smokers (NS), smokers (S) and COPD patients (C), and contraction to carbachol (CCh) assessed. Supernatant levels of MMP-8, -9, neutrophil elastase (NE) and myeloperoxidase (MPO) were measured.

Compared with untreated (UT) airways, airway maximal contraction (at 10µM CCh) was significantly reduced after incubation in supernatants (UT 80±4; NS 56±10; S 40±11; C 52±7%, n=6-10, p<0.01). Airway reopening after CCh washout was significantly augmented in airways incubated in neutrophil supernatants, compared with UT airways (UT 18±8; NS 157±25; S 186±68; C 171±79% difference in contraction (10µM CCh vs. post-washout), n=4, p<0.05). There was a significant decrease in baseline airway patency after incubation in COPD neutrophil supernatants, compared with UT airways (10±5 vs . 40±7% decrease in patency, n=8-10, p<0.01). Maximal contraction correlated with supernatant \[NE\] (r=-0.5, n=46, p<0.001) and \[active MMP-9\] (r=-0.6, n=27, p<0.001), whilst airway reopening correlated with \[NE\] (r=0.6, n=11).

Hence, activated neutrophil supernatants reduce maximal contraction, augment reopening, and decrease baseline patency of small airways, possibly due to proteolytic action. Thus, increased numbers of neutrophils in COPD may contribute to the airway dysfunction characteristic of the disease.
Colorectal cancer (CRC) cohort analysis of patients treated with buparlisib in a distinctive tissue-agnostic trial model for molecularly preselected tumors.
Authors: Sarina Anne Piha-Paul, James A. Knost, Petros Nikolinakos, Lee Steven Schwartzberg, Denise A. Yardley, Eric Daniel Slosberg, Barinder Kang, Theresa White, Claudia Lebedinsky
Journal: Journal of Clinical Oncology (2015)

644 Background: This is a CRC cohort analysis from the novel Novartis “Signature” program of tissue-agnostic, genetic alteration specific signal-finding protocols. Potential patients are identified via standard-of-care profiling; we bring the ‘Protocol to the Patient’, with rapid start-up process. Buparlisib (BKM120) is an oral pan-PI3K inhibitor evaluated in this program. Methods: Patients had progressive/relapsed CRC harboring PI3K pathway activated tumors, measurable disease, ECOG PS ≤1, and adequate organ function. A local CLIA-certified test is sufficient for eligibility. Central post hoc broad tumor molecular profiling of genetic alteration is performed. BKM120 was given orally (100 mg) qd. The primary objective is to assess clinical benefit (SD or better at 16 weeks). Statistical design adaptively clusters patients into cohorts for independent analysis for early futility or efficacy. Results: 18 CRC patients were dosed: 10 females, 15 Caucasian, median age 58 years (40-80), all had ECOG PS ≤1. Median prior therapies: 4 (1-13). Actionable alterations present at baseline (local): 10 (55.6%) PIK3CA mutation, 4 (22.2%) PTEN loss (IHC), 3 (16.7%) each PTEN mutated and PIK3R1 mutated. Median time on study was 5.1 weeks (1-16). Frequently observed AEs: nausea (67%), fatigue (39%), vomiting (33%), diarrhea (33%), anxiety (28%) and decreased appetite (28%). Three patients discontinued due to AEs. At week 16: 13 patients did not meet clinical benefit criteria and 5 patients were non-evaluable. Two patients had SD at week 8. Central genomic profiling: DNA from 14 patients was assessed covering a panel of 288 cancer genes. All patients had a mutation in APC, 10 (71%) also had KRAS mutations and 11 (79%) had mutations in TP53. Three patients with the lowest PFS exhibited mutations in ERBB2 and ERBB4. Concordance between local and central lab results was 73%. Conclusions: This program facilitated the enrollment of molecularly profiled CRC patients with PI3K pathway alterations. In this cohort, BKM120 had a manageable safety profile with negligible activity as single agent. Further evaluation can determine the effect of BKM120 in combination with other agents. NCT01833169 Clinical trial information: NCT01833169.
Lymphomas and multiple myeloma in rural Kenya: A cross-sectional survey
Authors: J. R. Aluoch
Journal: Journal of Clinical Oncology (2006)

17558 Background: Prevalence of lymphomas and multiple myeloma in rural referral centers and far isolated district hospitals in Kenya was unknown apart from the teaching hospital, the Kenyatta National Hospital in Nairobi. Methods: A questionnaire on which disease code according to the WHO international diagnostic index (IDIC) numbers was used for data collection for a ten year period from 1991 to 2000. Care was taken to avoid double entry of patients who might have been seen in more than one center. Disease codes were entered for Burkit Lymphoma (BL), Hodgkin’s Lymphoma (HL), Non-Hodgkin’s Lymphoma (NHL), Unclassified Lymphomas and Other Lymphomas (OL) and Multiple Myeloma (MM). Seven rural referral centers, known as Provincial Hospitals (PGH), namely Coast, Nyanza, Western, Central, Eastern, North Eastern and Rift Valley were used for data collection. Results: There were no data from the semi-arid North Eastern province. A total of 1,027 lymphomas were recorded from the six remaining centers. 40.7% were BL, 36% NHL, 12.6% HL and 10.7% UL. There were 133 cases of MM. 87% of BL were from oceano-lacustrine centers. The same applied to 61% of NHL. 43.4% of HL were from Rift Valley, the rest being spread over the other five centers. The same applied to 69% of UL. 81.2% of MM cases were from the high altitude areas of Rift Valley and the mountain region. Conclusions: Although predominance of BL in oceano-lacustrince regions is accouneted for in association with malaria endemicity, we cannot so far account for high prevalence of MM in high altitude regions of Kenya. We also cannot fully account for the absence of any case from the semi-arid North Eastern Province. [Table: see text]
Evaluation of quality of life in patients with primary and metastatic lung cancer following radiofrequency ablation
Authors: Julia Beeson, Sunny Kaul, Winston Banya, Paras Dalal
Journal: European Respiratory Journal (2012)

Objective:  Radiofrequency ablation (RFA) is an increasingly utilised treatment option for high risk patients with primary lung cancer and metastatic lung disease. We assessed quality of life in patients undergoing RFA for primary and secondary lung cancers at this institution in patients deemed unfit for surgical intervention.   Materials and Methods:  55 patients, (42 primary lung cancer and 13 metastatic lung tumours) were entered into the study. One standard instrument was used to measure quality of life, the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30). An integrated system for assessing health-related quality of life of cancer patients. All procedures were performed by a single operator. All patients were clinically and radiologically followed-up in a standardised way, all questionnaires were collected by a single associate pre treatment and one year post ablation. Data was analysed using the Stata version 10 software.   Results:  The EORTC scores were converted to physical function, respiratory function, emotional functioning and global health scales, mean value for each scale was calculated pre and post ablation. There was a reported improvement in all four scales after ablation. The paired t test was used to assess statistical significance of the results. This revealed statistically significant improvement in emotional function (p =0.023) and the global health scales (p = 0.008).   Conclusion:  This retrospective study demonstrates that patients undergoing ablation therapy for primary and secondary lung cancer describe overall improved function with statistically significant improvement in emotional and global health scales.