tbuckley/cabot-search huggingface dataset:
Clinical, socio‐demographic and psychological characteristics in individuals with persistent psychotic experiences with and without a “need for care”
Authors: Emmanuelle Peters, Thomas Ward, Mike Jackson, Craig Morgan, Monica Charalambides, Philip McGuire, Peter Woodruff, Pamela Jacobsen, Paul Chadwick, Philippa A. Garety
Journal: World Psychiatry (2016)

Individuals reporting persistent psychotic experiences (PEs) in the general population, but without a “need for care”, are a unique group of particular importance in identifying risk and protective factors for psychosis. We compared people with persistent PEs and no “need for care” (non‐clinical, N=92) with patients diagnosed with a psychotic disorder (clinical, N=84) and controls without PEs (N=83), in terms of their phenomenological, socio‐demographic and psychological features. The 259 participants were recruited from one urban and one rural area in the UK, as part of the UNIQUE (Unusual Experiences Enquiry) study. Results showed that the non‐clinical group experienced hallucinations in all modalities as well as first‐rank symptoms, with an earlier age of onset than in the clinical group. Somatic/tactile hallucinations were more frequent than in the clinical group, while commenting and conversing voices were rare. Participants in the non‐clinical group were differentiated from their clinical counterparts by being less paranoid and deluded, apart from ideas of reference, and having fewer cognitive difficulties and negative symptoms. Unlike the clinical group, they were characterized neither by low psychosocial functioning nor by social adversity. However, childhood trauma featured in both groups. They were similar to the controls in psychological characteristics: they did not report current emotional problems, had intact self‐esteem, displayed healthy schemas about the self and others, showed high life satisfaction and well‐being, and high mindfulness. These findings support biopsychosocial models postulating that environmental and psychological factors interact with biological processes in the aetiology of psychosis. While some PEs may be more malign than others, lower levels of social and environmental adversity, combined with protective factors such as intact IQ, spirituality, and psychological and emotional well‐being, may reduce the likelihood of persistent PEs leading to pathological outcomes. Future research should focus on protective factors and determinants of well‐being in the context of PEs, rather than exclusively on risk factors and biomarkers of disease states.
Practitioners need input from behavioural medicine specialists
Authors: Chris Bundy
Journal: BMJ (2015)

McCartney is right,1 nagging doesn’t work: it assumes deliberate non-compliance, undermining patients’ autonomy and intelligence. Some people need nudges (as I do to complete the review that has been sitting on my desk for 10 days) and others support (as I do to clear more urgent work to find time for that review), but few respond …
Incidence, clinical manifestations and prognosis of cardiac sarcoidosis in patients with pulmonary sarcoidosis
Authors: Tomoe Abe, Takahiro Sato, Ichizo Tsujino, Hiroshi Ohira, Keiichiro Yoshinaga, Noriko Oyama-Manabe, Takeshi Hattori, Satoshi Konno, Masaharu Nishimura, Tomoe Karino
Journal: European Respiratory Journal (2013)

Background Early diagnosis of cardiac sarcoidosis (CS) is vitally important in the management of patients with pulmonary sarcoidosis (PS), because of the risk of sudden cardiac death. Some patients with PS develop CS during follow-up, but few studies have addressed its incidence and clinical course.

Aim To investigate the incidence, initial manifestations, and prognosis of CS in patients with PS.

Methods Participants comprised 215 subjects who had been pathologically diagnosed with PS since January 2002. The incidence of CS was evaluated using the diagnostic guidelines for CS of the Japan Society of Sarcoidosis. 18F-fluoro-2-deoxyglucose positron emission tomography and cardiac magnetic resonance imaging were included in the diagnostic work-up unless contraindicated. Initial manifestations and prognosis of CS were also reviewed.

Results Twenty (9.5%) of the 215 PS patients developed CS during follow-up (median, 2.5 years; range, 0.8-4.5 years). Annual incidence rate of CS was 3.8%. Initial manifestations of CS were abnormal findings on screening electrocardiogram (n=12), chest symptoms such as palpitation (n=6), and others (n=2). During the follow-up of CS (median, 2.6 years; range, 0.4-4.6 years), three died (lung cancer, n=2; sudden cardiac death, n=1) and four were implanted with a permanent pacemaker or implantable cardioverter-defibrillator.

Conclusions CS developed in PS patients at an annual incidence rate of 3.8%, with electrocardiogram changes and chest symptoms being the most prevalent initial manifestations. Of the 20 CS patients, 25% encountered CS-related death or were forced to be treated by device implantation during the follow-up.
Multiple biomarker expression in circulating tumor cells (CTCs) from locally advanced/inflammatory (LA/IBC) and metastatic breast cancer (MBC) patients (pts)
Authors: R. H. Bruce, H. B. Hseih, D. N. Curry, R. T. Krivacic, N. Lazarus, P. Frankel, S. Lau, G. Somlo
Journal: Journal of Clinical Oncology (2009)

1092 Background: Numeration of CTCs from MBC pts is predictive of outcome. Quantitative changes in CTC-s are currently tested for their potential to monitor therapy (Rx). Biomarker characterization of CTCs may be a useful adjunctive guide for Rx selection. Methods: At the COHCC between May 1, 2008 and December 31, 2008, consecutively treated pts with LABC/IBC, or with newly diagnosed/progressing MBC were accrued. Blood samples (20–30 mL) were procured prior to initiating neoadjuvant (neo)Rx (LABC and IBC patients) or systemic Rx (MBC), and were sent to PARC for analysis. A novel high-speed scanning instrument located CTCs from cytokeratin (CK) labeling enabling high resolution images to be selectively acquired using digital microscopy. From these images, CTCs were identified by CK, DAPI (nuclear marker) and CD45, and protein expression levels were determined for HER-2, estrogen receptor (ER), Excision repair cross-complementation group 1 (ERCC1), and EGFR. Cell lines with expression of each marker were used for normalization of the cell intensities, and a scoring system was used to account for relative number and expression levels of markers on the CTCs. Results: Twenty-seven pts with LABC, 4 pts with IBC, and 11 pts with MBC were enrolled. We have observed CTCs prior to initiating neoRx in all pts with IBC relative to 39% of all LABC/IBC cases, and in 57% of pts (n:14) with HER-2+ primary BC versus 24% (n = 17) with HER-2- BC . ER status, size, or grade did not predict for CTC detection. Numeration of CTCs was seen in 45% of pts with MBC. Expression of EGFR and ERCC1 was detected in 3 of 4, and 2 of 4 tested CTC samples from MBC cases. Expression of HER-2 and ER was observed on 1 of 3 and 3 of 4 CTC samples; there was discrepancy between the CTC expression profile and HER-2 and ER status of the primary BC in one case each. Conclusions: Detecting multiple markers in CTCs from pts with MBC is feasible, and similar testing in LABC/IBC patients is needed. Such multiplex testing may allow for more personalized Rx for pts with LABC/IBC and MBC. No significant financial relationships to disclose.
Why they want to be treated in clinical trial -fundamental reasons of patient's decision
Authors: A. I. Jagiello-Gruszfeld, M. Czerniawska, E. Wachula, A. Kazarnowicz, S. Szablowska-Siwik
Journal: Journal of Clinical Oncology (2004)

6147 Background: Today, in oncological treatment most of patients are treating with new agents in clinical trials. For every one making decision of taking part in that study is not so easy. In new Regional Cancer Center in Poland (Olsztyn) we provided a questionnaire study to evaluate the most important factors which influent in patient's decision of take part in clinical trials. Methods: We made a questionnaire for two groups of patients.The questionnaire consisted of one 4 multiple-choice questions.The first group (group A) was the 41 patients with advanced breast or lung cancer, who already participated, in clinical trials. The second group (group B) consisted of 39 patients who were treated with conventional methods, but declared what, treatment in clinical trials was for them interesting option. In study patients were choosing the most important things which help them in consent to take part in clinical trial. Results: Twenty eight patients (68%) of group A and twenty one (54%) of group B regarded that discussion with physician and physician's opinions are more important. Nine patients (22%) of group A and eleven (28%) of group B thought that the most important is them family opinion. Other patients regarded that the information from press and internet and hope for better treatment results is the factor which making them sure in taking part in clinical trial. Conclusions: For most of cancer patients very helpful in making decision of taking part in clinical trial is discussion with them physician. The opinion of physician is the fundamental for both, patients who already participated in trials and who don't take part in that trial yet. No significant financial relationships to disclose.
Analysis of interleukin-8, alpha1-antitrypsin, and tumor necrosis factor-alpha as biomarkers of breast cancer in women of northeastern Mexico.
Authors: Miguel Angel Reyes-Lopez, Alberto Onofre Sanchez-Meza, Virgilio Bocanegra-Garcia, Hugo Alberto Barrera-Saldana, Maria de Lourdes Garza-Rodriguez, Celia Nohemi Sanchez-Dominguez
Journal: Journal of Clinical Oncology (2012)

18 Background: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease and variations of protein values in plasma. Interleukin (IL)-8, alpha 1-antitrypsin (AAT) and tumor necrosis factor-alpha (TNF alpha) have been related to carcinogenesis in breast tissue. Whether polymorphisms of the genes and protein values also influence breast cancer risk is unclear. The objective was to analyze the levels and polymorphisms of biomarkers in breast cancer patients for diagnostic purposes. Methods: In this cases-controls study a total of 30 patients with breast cancer confirmed by histopathology and 21 healthy individuals were studied, both groups were of three generations born in the Northeast of Mexico. Two polymorphisms of the AAT gene (Alleles Z and S), a polymorphism of IL-8 (-251 A/T polymorphism of the IL-8 promoter), and the polymorphism of TNF-alpha [-308 G/A (TNF1/TNF2) polymorphism of the TNF-alpha promoter gene] were analyzed using PCR-RFLP. Additionally, the plasma protein values of the biomarkers were measured by ELISA. Results: The IL-8 (-251T) and TNF-alpha (-308G) polymorphisms were significantly associated with breast cancer. Odds ratios for women with one high-risk allele versus women homozygous for the low-risk allele were 4.06 for -308G TNF-alpha (95% confidence interval, 1.298-13.678; P = 0.006) and 2.44 for -251T IL-8 (95% confidence interval, 1.277-4.7; P = 0.003). Significant differences between protein values of patients and controls were observed (ATT U=63, Z=4.81, p (2) &lt;0.0001; IL-8 U=112.5, Z=3.87 p (2) =0.0001; TNF-α U=135.5, Z=3.43, p (2) =0.0006), AAT and IL-8 were over-expressed in patients with breast cancer. The presence of the polymorphism does not influence the protein values (TNF r s =0.1203, IL-8 r s =0.2246), apparently. No association between presences of the polymorphism. Conclusions: In this study, the presence of the IL-8 (-251T) and TNF-alpha (-308G) alleles may increase the risk of breast cancer in these Mexican women. Over-expression of IL-8 and AAT may directly correlate to the pathogenesis of breast cancer. Both biomarkers may be combined with other markers for presumptive diagnosis.
Impaired Na(+)-H+ exchanger activity of hepatocytes in chronic renal failure.
Authors: M Michnowska, M Smogorzewski, S G Massry
Journal: Journal of the American Society of Nephrology (1997)

Available data indicate that cation transport is impaired in many cells in chronic renal failure (CRF). The information on the activity of the Na(+)-H+ exchanger in CRF is variable, and both increased and reduced activity have been reported. The mechanisms through which CRF may exert an effect on the Na(+)-H+ transport are not known. Data exist indicating that PTH inhibits the Na(+)-H+ exchange in kidney and liver, and this action of hormone is most likely due to its ability to raise cytosolic calcium ([Ca2+]i). Therefore, it is possible that excess PTH in CRF may adversely affect the activity of the Na(+)-H+ antiport. This study examines the activity of Na(+)-H+ antiport, intracellular pH (pHi), and buffering capacity of hepatocytes obtained from rats after 6 wk of CRF, from CRF parathyroidectomized animals, and from CRF rats and normal rats treated with verapamil. The pHi and the buffering capacity of hepatocytes were not different in all groups of animals. The activity of the Na(+)-H+ antiport of hepatocytes from CRF animals was significantly (P < 0.01) lower than in hepatocytes from normal rats, CRF parathyroidectomized rats, CRF rats treated with verapamil, and normal rats treated with verapamil, and the values in the latter four groups of animals were not different. This impaired activity of Na(+)-H+ antiport in CRF was observed in all external concentrations of sodium (25, 50, 75, 100, 125, and 150 mM). Thus, CRF altered the kinetics of the transporter in that its Vmax decreased and its K(m) increased. The data show that: (1) CRF is associated with reduction in the activity of Na(+)-H+ antiport in hepatocytes; (2) this defect is due to the state of secondary hyperparathyroidism of CRF; and (3) excess PTH mediates its effect by elevating [Ca2+]i of hepatocytes because treatment of CRF animals with verapamil, which blocks the PTH-induced rise in [Ca2+]i of these cells, prevented the impairment in the activity of the Na(+)-H+ antiport.
Type II diabetes and breast cancer.
Authors: K. D. Erickson, J. P. Pierce, R. E. Patterson, T. R. Reid, L. Natarajan, S. Flatt, B. A. Parker, D. Heath
Journal: Journal of Clinical Oncology (2010)

1552 Background: Type II diabetes mellitus (T2DM) has been related to poorer health outcomes from breast cancer in a growing number of studies. It's estimated that 16 to 20% of breast cancer patients are diabetic and up to 30% are undiagnosed. The current report uses the HbA1c assay as a diagnostic measure of diabetes and glycemic control in a large cohort of breast cancer survivors to identify the robustness of reported relationships between diabetes and prognosis. Methods: Participants included 3,003 women with a history of early stage breast cancer enrolled in a large prospective dietary intervention trial designed to assess risk of recurrent and new primary breast cancer and all-cause mortality. Median follow-up was 7 years. HbA1c was analyzed using high-performance liquid chromatography [Bio-Rad; normal range 4.5-6.5%] on stored red blood cells collected at baseline. HbA1c categorical cut points were determined according to clinical interpretation with HbA1c levels of 7.0% and above identifying T2DM, HbA1c% levels of 6.5% to 6.9% identifying high-risk for diabetes, and HbA1c levels of 6.4% and below serving as the reference category. Results: HbA1c levels of 6.5% and greater were more likely to be associated with certain sociodemographic (less educated, older age, non-white ethnicity) and prognostic (more advanced breast cancer at diagnosis, obesity) factors. Obese women accounted for 70% of T2DM. HbA1c was significantly associated with overall survival (p for trend < 0.0001). After adjusting for confounders, the risk of all-cause mortality was twice as high in women with T2DM compared to women with HbA1c levels of 6.4% or less (HR 2.39, 95% CI: 1.59,3.59). Although the relationship between T2DM and disease-free survival did not reach statistical significance (HR 1.30, 95% CI: 0.79, 2.05), Kaplan-Meier estimates showed similar trends to that of overall survival (p for trend = 0.11), suggestive of worsening prognosis with increasing HbA1c levels. Conclusions: There is significant under-reporting of T2DM particularly in obese breast cancer survivors. This comorbidity is significantly associated with poorer overall survival and suggestive of worse disease free survival. Further study of T2DM and its relationship to breast cancer outcomes is warranted. No significant financial relationships to disclose.
Preliminary definitions of ‘flare’ in axial spondyloarthritis, based on pain, BASDAI and ASDAS-CRP: an ASAS initiative
Authors: Laure Gossec, Agnès Portier, Robert Landewé, Adrien Etcheto, Victoria Navarro-Compán, Féline Kroon, Désirée van der Heijde, Maxime Dougados
Journal: Annals of the Rheumatic Diseases (2016)

Introduction Flares may be used as outcomes in axial spondyloarthritis (axSpA) trials or observational studies. The objective was to develop a definition for ‘flare’ (or worsening) in axSpA, based on validated composite indices, to be used in the context of clinical trial design. Methods (1) Systematic literature review of definitions of ‘flare’ in published randomised controlled trials in axSpA. (2) Vignette exercise: 140 scenarios were constructed for a typical patient with axSpA seen at two consecutive visits. Each scenario included a change in one of the following outcomes: pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI plus C-reactive protein (CRP) or Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP. Each Assessment of Spondyloarthritis (ASAS) expert determined if every scenario from a random sample of 46 scenarios was considered a flare (yes/no). Receiver-operating characteristic (ROC) analyses were applied to derive optimal cut-off values. (3) ASAS consensus was reached. Results (1) The literature review yielded 38 studies using some definition of ‘flare’, with 27 different definitions indicating important heterogeneity. The most frequent definitions were based on BASDAI changes or pain changes. (2) 121 ASAS experts completed 4999 flare assessments. The areas under the ROC curves were high (range: 0.88–0.89). Preliminary cut-offs for pain (N=3), BASDAI (N=5) and ASDAS-CRP (N=4) were chosen, with a range of sensitivity 0.60–0.99 and range of specificity 0.40–0.94 against the expert's opinions. Conclusions This data-driven ASAS consensus process has led to 12 preliminary draft definitions of ‘flare’ in axSpA, based on widely used indices. These preliminary definitions will need validation in real patient data.
Molecular mechanisms underlying disease relapse on treatment with selective BRAF inhibitor vemurafenib (PLX4032).
Authors: F. Su, H. Yang, B. Higgins, K. D. Kolinsky, K. Packman, M. Kim, B. J. Lestini, G. Bollag, D. C. Heimbrook
Journal: Journal of Clinical Oncology (2011)

8517 Background: Vemurafenib (V) has demonstrated extraordinary results in clinical evaluation, with confirmed response rates of >50%. However, most patients progress eventually, indicating that acquired resistance may impact long-term clinical activity. This study was to elucidate mechanisms of acquired resistance to V in BRAFV600 mutated melanoma in vitro and in vivo. Methods: Six A375 BRAFV600E melanoma clones resistant to V were established by culturing the sensitive cells under continuous V selection to model disease relapse associated with V treatment in melanoma patients. This model system was used in vitro and in vivo to identify potential molecular mechanisms and combination therapies to prevent or mitigate emergence of disease progression. Results: These clones were approximately 100-fold resistant to V in proliferation assays compared to the parental cells, despite retention of the V600E mutation and absence of additional BRAF mutations. High levels of ERK phosphorylation were observed, suggesting that ERK signaling is re-activated in the resistant cells. CRAF protein was upregulated in resistant cells, and knock-down of CRAF restored V-sensitivity in the resistant cells, while overexpression of CRAF in the parental cells conferred resistance to V. Resistance also correlated with increased levels of RAS-GTP, and sequencing of RAS genes revealed an activating mutation in KRAS. High levels of AKT phosphorylation were observed, implicating upregulation of alternative pathways. The combination of V with a MEK inhibitor, but not either compound alone, was able to effectively block ERK activation in resistant cells and to abrogate tumor growth in xenografts, suggesting that ongoing BRAF inhibition is required to block ERK signaling when combined with MEK inhibition. Likewise, V showed strong in vitro synergism with an AKT inhibitor. Conclusions: These data implicate reactivation of the RAS/RAF pathway and activation of an alternative pathway as key mechanisms of disease relapse on V treatment, and support further clinical studies in which a MEK or an AKT inhibitor is added to V treatment to combat resistance.
Abstract 122: Increasing Short-term Cardiomyocyte Progenitor Cell Survival By Necrostatin-1 Does Not Further Preserve Cardiac Function
Authors: Dries Feyen, Roberto Gaetani, Jia Liu, Willy Noort, Anton Martens, Krista den Ouden, Pieter Doevendans, Joost Sluijter
Journal: Circulation Research (2013)

Aim: One of the main limitations for an effective cell therapy for the heart is the poor cell engraftment after implantation, which is partly due to a large percentage of cell death in the hostile myocardium. In the present study, we investigated the utilization of Necrostatin-1 (Nec-1) as a possible attenuator of cell death in Sca-1+ cardiac progenitor cells (CPCs). Methods and Results: Under oxidative stress conditions in vitro, Nec-1 pretreatment reduced necrotic cell death in Sca-1+ CPCs. In a mouse model of myocardial infarction, survival of CPCs 3 days after intra-myocardial injection was 39% higher (BLI signal, 71,665 ± 11,165 vs 117,138 ± 18,567 ph/s/cm2/sr) in cells pretreated with the Nec-1 compound. However, the increase in cell number did not translate into improved cardiac function at one month follow-up (EF %, 20.6±2.1 vs 21.4±2.5 for vehicle and Nec-1 treated CPC, respectively). We extensively investigated, but did not find, alternative effects to the pro-survival properties of the compound on the CPCs. Furthermore, CPCs rescued by Nec-1 remained functionally competent. Conclusion: A pharmacological pretreatment approach to solely enhance cell survival on the short-term does not seem to be effective strategy to improve cardiac cell therapy with Sca-1+ CPCs. Since the initial cell retention directly after injection is low (~10%), survival strategies could conceivably be more useful in a tissue engineering setting, in which they can exert their effects on larger number of cells.
A Synthetic Peptide Derived From Human Immunodeficiency Virus Type 1 gp120 Downregulates the Expression and Function of Chemokine Receptors CCR5 and CXCR4 in Monocytes by Activating the 7-Transmembrane G-Protein–Coupled Receptor FPRL1/LXA4R
Authors: Xiyun Deng, Hirotsugu Ueda, Shao Bo Su, Wanghua Gong, Nancy M. Dunlop, Ji-Liang Gao, Philip M. Murphy, Ji Ming Wang
Journal: Blood (1999)