tbuckley/cabot-search huggingface dataset:
Positron emission tomography-guided conformal fast neutron therapy for glioblastoma multiforme
Authors: Keith J. Stelzer, James G. Douglas, David A. Mankoff, Daniel L. Silbergeld, Kenneth A. Krohn, George E. Laramore, Alexander M. Spence
Journal: Neuro-Oncology (2007)

Glioblastoma multiforme (GBM) continues to be a difficult therapeutic challenge. Our study was conducted to determine whether improved survival and tumor control could be achieved with modern delivery of fast neutron radiation using three-dimensional treatment planning. Ten patients were enrolled. Eligibility criteria included pathologic diagnosis of GBM, age >or=18 years, and KPS >or=60. Patients underwent MRI and (18)F-fluorodeoxyglucose PET (FDG PET) as part of initial three-dimensional treatment planning. Sequential targets were treated with noncoplanar fields to a total dose of 18 Gy in 16 fractions over 4 weeks. Median and 1-year overall survival were 55 weeks and 60%, respectively. One patient remains alive at last follow-up 255 weeks after diagnosis. Median progression-free survival was 16 weeks, and all patients had tumor progression by 39 weeks. Treatment was clinically well tolerated, but evidence of mild to moderate gliosis and microvascular sclerosis consistent with radiation injury was observed at autopsy in specimens taken from regions of contralateral brain that received approximately 6-10 Gy. Fast neutron radiation using modern imaging, treatment planning, and beam delivery was feasible to a total dose of 18 Gy, but tumor control probability was poor in comparison to that predicted from a dose-response model based on older studies. Steep dose-response curves for both tumor control and neurotoxicity continue to present a challenge to establishing a therapeutic window for fast neutron radiation in GBM, even with modern techniques.
Treatment of Metastatic Melanoma Using Interleukin-2 Alone or in Conjunction with Vaccines
Authors: Franz O. Smith, Stephanie G. Downey, Jacob A. Klapper, James C. Yang, Richard M. Sherry, Richard E. Royal, Udai S. Kammula, Marybeth S. Hughes, Nicholas P. Restifo, Catherine L. Levy, Donald E. White, Seth M. Steinberg, Steven A. Rosenberg
Journal: Clinical Cancer Research (2008)

To identify prognostic factors associated with survival beyond 4 years and overall response in patients with metastatic melanoma treated with high-dose bolus i.v. interleukin-2 (IL-2) given either alone or in combination with a variety of melanoma vaccines.684 consecutive patients with metastatic melanoma received high-dose bolus i.v. IL-2 either alone or in conjunction with a variety of melanoma vaccines. Treatments occurred between August 1, 1985 and January 1, 2006.The overall objective response rate was 13% for patients receiving IL-2 alone and 16% for patients who received IL-2 with vaccine. In patients treated with IL-2 alone (n=305) and IL-2 with vaccine (n=379), having an objective response was associated with survival beyond 4 years (P<0.0001). No pretreatment factors could be identified that were strongly associated with increased rate of objective response or long-term survival in patients receiving IL-2 alone. In patients receiving IL-2 with vaccines, there were increased response rates in patients with s.c. or cutaneous disease only and lower response rates with visceral disease only. Patients who received the gp100:209-217(210M) peptide plus IL-2 showed a strong trend to increased objective responses compared with IL-2 alone (22% versus 12.8%; P=0.01) and also compared with patients who received a variety of vaccines that did not include this immunogenic peptide (13.8%; P=0.009).IL-2 can produce a modest response rate in patients with metastatic melanoma including patients with durable complete responses. S.c. or cutaneous disease only and vaccination with gp100:209-217(210M) peptide was associated with significant increase in response rates.
Erythropoietin Protects the Kidney against the Injury and Dysfunction Caused by Ischemia-Reperfusion
Authors: Edward J. Sharples, Nimesh Patel, Paul Brown, Keith Stewart, Helder Mota-Philipe, Michael Sheaff, Julius Kieswich, David Allen, Steven Harwood, Martin Raftery, Christoph Thiemermann, Muhammad M. Yaqoob
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-XL and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
Raising standards in UK TB control: introducing cohort review: Table 1
Authors: Charlotte Anderson, Jacqueline White, Ibrahim Abubakar, Marc Lipman, Surinder Tamne, Sarah R Anderson, Jennifer deKoningh, Susan Dart
Journal: Thorax (2013)

Cohort review has been used internationally to support tuberculosis (TB) control. We describe its first use in the UK by a London TB service. Improvements were noted in case management and contact tracing, weaknesses identified and important service changes put in place. Key areas of impact were directly observed therapy (DOT) provision (a greater proportion of cases offered DOT, and in response to low uptake resources diverted to create posts responsible for patient-centred DOT delivery), and contact tracing (more contacts per case screened and assessed). Cohort review enables whole system review and improvement. It has subsequently been adopted across the UK.
PTEN Protein Loss by Immunostaining: Analytic Validation and Prognostic Indicator for a High Risk Surgical Cohort of Prostate Cancer Patients
Authors: Tamara L. Lotan, Bora Gurel, Siobhan Sutcliffe, David Esopi, Wennuan Liu, Jianfeng Xu, Jessica L. Hicks, Ben H. Park, Elizabeth Humphreys, Alan W. Partin, Misop Han, George J. Netto, William B. Isaacs, Angelo M. De Marzo
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Analytically validated assays to interrogate biomarker status in clinical samples are crucial for personalized medicine. PTEN is a tumor suppressor commonly inactivated in prostate cancer that has been mechanistically linked to disease aggressiveness. Though deletion of PTEN, as detected by cumbersome FISH spot counting assays, is associated with poor prognosis, few studies have validated immunohistochemistry (IHC) assays to determine whether loss of PTEN protein is associated with unfavorable disease. Experimental Design: PTEN IHC was validated by employing formalin fixed and paraffin-embedded isogenic human cell lines containing or lacking intact PTEN alleles. PTEN IHC was 100% sensitive and 97.8% specific for detecting genomic alterations in 58 additional cell lines. PTEN protein loss was then assessed on 376 prostate tumor samples, and PTEN FISH or high resolution single nucleotide polymorphism microarray analysis was done on a subset of these cases. Results: PTEN protein loss, as assessed as a dichotomous IHC variable, was highly reproducible, correlated strongly with adverse pathologic features (e.g., Gleason score and pathologic stage), detected between 75% and 86% of cases with PTEN genomic loss, and was found at times in the absence of apparent genomic loss. In a cohort of 217 high risk surgically treated patients, PTEN protein loss was associated with decreased time to metastasis. Conclusion: These studies validate a simple method to interrogate PTEN status in clinical specimens and support the utility of this test in future multicenter studies, clinical trials, and ultimately perhaps for routine clinical care. Clin Cancer Res; 17(20); 6563–73. ©2011 AACR.
A single blood test to rule out myocardial infarction?
Authors: A. Timmis
Journal: BMJ (2015)

High sensitivity troponin assays could get us there, if combined with clinical judgment

The release into the circulation of troponin I and T signals irreversible injury to cardiac myocytes and is central to the diagnosis of myocardial infarction.1 Conventional (non-high sensitivity) troponin assays are optimally sensitive 10-12 hours after the onset of symptoms, and in patients presenting with cardiac chest pain a rise or fall in troponin levels during this period—with at least one value exceeding the upper reference limit—is diagnostic of myocardial infarction.

In practice, troponin plays a bystander role in the diagnosis of ST segment elevation myocardial infarction (STEMI), the electrocardiogram (ECG) providing sufficient diagnostic certainty for emergency intervention. But in non-ST segment elevation myocardial infarction (NSTEMI) the ECG is non-diagnostic, and serial troponin testing is required to confirm the diagnosis. Because most patients attending emergency departments with chest pain do not have NSTEMI and can often be discharged safely, strategies that can rule out NSTEMI reliably and quickly to accelerate care pathways and relieve pressure on beds are urgently needed.2 The two linked papers (doi:10.1136/bmj.h15, doi:10.1136/bmj.g7873) are therefore timely in reporting the use of high sensitivity troponin assays to rule out myocardial infarction early, in …
Implementing and evaluating shared decision making in oncology practice
Authors: Heather L. Kane, Michael T. Halpern, Linda B. Squiers, Katherine A. Treiman, Lauren A. McCormack
Journal: CA A Cancer Journal for Clinicians (2014)

Abstract Answer questions and earn CME/CNE Engaging individuals with cancer in decision making about their treatments has received increased attention; shared decision making (SDM) has become a hallmark of patient‐centered care. Although physicians indicate substantial interest in SDM, implementing SDM in cancer care is often complex; high levels of uncertainty may exist, and health care providers must help patients understand the potential risks versus benefits of different treatment options. However, patients who are more engaged in their health care decision making are more likely to experience confidence in and satisfaction with treatment decisions and increased trust in their providers. To implement SDM in oncology practice, physicians and other health care providers need to understand the components of SDM and the approaches to supporting and facilitating this process as part of cancer care. This review summarizes recent information regarding patient and physician factors that influence SDM for cancer care, outcomes resulting from successful SDM, and strategies for implementing SDM in oncology practice. We present a conceptual model illustrating the components of SDM in cancer care and provide recommendations for facilitating SDM in oncology practice. CA Cancer J Clin 2014;64:377–388. © 2014 American Cancer Society .
Multidrug-resistant tuberculosis in Czech Republic during the period of recent 5 years (2007-2012)
Authors: Veronika Polcová, Emília Kopecká, Martina Vasáková
Journal: European Respiratory Journal (2013)

BACKGROUND:  Multidrug-resistant tuberculosis (MDR-TB) is defined as a resistance of Mycobacterium tuberculosis complex (MTB) to isoniazid and rifampicin at least.  METHODS AND RESULTS:  The aim of this retrospective study was to evaluate and compare a cohort of 37 patients with MDR-TB hospitalized in our specialized Unit for a treatment of MDR patients of the Czech Republic located in Prague in the years 2007 – 2012. We have evaluated the group of patients according to a birthplace, resistance type, clinical outcome, social profile, length of bacteriological positivity of sputum and length of hospitalization.  14 of the patients (38%) were born in the Czech Republic (group A) and 23 (62%) were immigrants to the Czech Republic (group B). In cohort of 37 patients were 27 males (mean age 39 years) and 10 females (mean age 35 years). Primary resistance was present in 24 (65%) cases and in 13 (35%) cases secondary resistance. From social point of view there were 17 (46%) manual workers, 8 (21,6%) pensioners, 8 (21,6) unemployed, 4 (10,8%) refugees.  There were 26 (70%) cured patients, ten (27%) remained on treatment, treatment faulire was noticed in 2 patients (5,4%), discontinuation of treatment in 1 patient (2,7%), and no patients died. The mean length of bacteriological positivity of sputum samples was 3,8 months and the mean length of hospitalization was 9,8 months.  CONCLUSIONS:  Prevalence of MDR TB cases in the Czech Republic has remained on the same level for several previous years compared to gradual increase in the world. If the number of immigrants from countries with high prevalence of tuberculosis to the Czech Republic will increase, the control of TB can be negatively influenced.
Psychological Aspects of Peptic Ulcer Disease in Childhood
Authors: Jacqueline Sagala Vaillant
Journal: Psychotherapy and Psychosomatics (1985)

The purpose of this paper is to review the psychological aspects of primary peptic ulcer disease in childhood and to illustrate their integration in the evaluation, treatment and follow-up of 2 cases. The data suggest that certain psychological stresses may play a significant role in the pathogenesis of peptic ulcer in genetically predisposed children. They also highlight the importance of a psychiatric intervention in these cases as well as the need for controlled outcome studies.
Expression of an idiotype (Id-460) during in vivo anti-dinitrophenyl antibody responses. II. Transient idiotypic dominance.
Authors: E A Dzierzak, R W Rosenstein, C A Janeway
Journal: The Journal of Experimental Medicine (1981)

After immunization of mice with 2,4-dinitrophenyl-ovalbumin (DNP-OVA), it was shown previously that strains having Igh-Va genes and able to express light chains of the Vk1 group produce high levels of anti-DNP antibody bearing an idiotype (Id-460) associated with the combining site of the BALB/c DNP-binding myeloma protein MOPC 460. Expression of Id-460 in serum is transient; Id-460 levels peak early in the response and are regulated independently of total anti-DNP antibody. In this paper, the transient dominance of Id-460 expression has been confirmed at the cellular level by inhibition of splenic anti-DNP plaque-forming cells (PFC) with rabbit anti-Id-460 antiserum. Id-460+ PFC can account for 52-91% of anti-DNP PFC early after secondary challenge with DNP-OVA. Furthermore, Id-460 is represented at these high levels in IgM, IgG, and IgG1, and IgG2a, the three isotypes tested in the PFC assay, as well as in IgE, as tested by passive cutaneous anaphylaxis. Thus, there is no preferential association of Id-460 with a given isotype. We conclude from these studies that Id-460 is a dominant idiotype in the anti-DNP antibody response of BALB/c mice to DNP-OVA. This dominance is expressed transiently and is independent of isotype. A further conclusion from these studies is that regulation of isotype expression is independent of the regulation of idiotype expression in this system. We would suggest that regulation of Id-460 expression involves Ig-dependent helper T cells specific for Id-460 that induce Id-460+ B cells and also activate suppressor T cells, both events occurring via idiotype-anti-idiotype interactions.
THE LIFE SPAN OF IgA PLASMA CELLS FROM THE MOUSE INTESTINE
Authors: Carlos A. Mattioli, Thomas B. Tomasi
Journal: The Journal of Experimental Medicine (1973)

Tritiated thymidine was injected during the neonatal period into conventional CBA mice. The disappearance rate of tritium-labeled IgA plasma cells was followed by a technique combining immunofluorescence with autoradiography which permitted the identification of the immunoglobulin class of plasma cells with labeled nuclei. In this way, it was possible to calculate that the major population of intestinal IgA plasma cells have a half-life of 4.7 days under physiological conditions of stimulation. It was also found that the maximum life span of both intestinal IgA plasma cells and the IgA, IgG, and IgM plasma cells from the spleen is of the order of 7-8 wk.
KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy
Authors: Ankit Garg, Jason O’Rourke, Chengzu Long, Jonathan Doering, Gianina Ravenscroft, Svetlana Bezprozvannaya, Benjamin R. Nelson, Nadine Beetz, Lin Li, She Chen, Nigel G. Laing, Robert W. Grange, Rhonda Bassel-Duby, Eric N. Olson
Journal: Journal of Clinical Investigation (2014)

Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klhl40–/– mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients.
Phase I/II Trial of Metronomic Chemotherapy With Daily Dalteparin and Cyclophosphamide, Twice-Weekly Methotrexate, and Daily Prednisone As Therapy for Metastatic Breast Cancer Using Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor Levels As Markers of Response
Authors: Nan Soon Wong, Robert A. Buckman, Mark Clemons, Shailendra Verma, Susan Dent, Maureen E. Trudeau, Kathie Roche, John Ebos, Robert Kerbel, Gerrit E. DeBoer, Donald J.A. Sutherland, Urban Emmenegger, Joyce Slingerland, Sandra Gardner, Kathleen I. Pritchard
Journal: Journal of Clinical Oncology (2009)

PURPOSE Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). PATIENTS AND METHODS Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for > or = 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. CONCLUSION Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.
Transpecific Polymorphisms in an Inversion Linked Esterase Locus in Drosophila buzzatii
Authors: Gloria A Gómez, Esteban Hasson
Journal: Molecular Biology and Evolution (2003)

Nucleotide variation was studied in a 1.1 kb section of the coding region of an Esterase gene (Est-A) that maps in the center of the segments rearranged by polymorphic inversions in the cactophilic Drosophila buzzatii. We examine 30 homozygous second-chromosome lines differing in gene arrangement and three D. koepferae isofemale lines as outgroups. Our data show that Est-A is a highly polymorphic gene at both synonymous and replacement sites. Significant departures from homogeneity in the distribution of the ratio of silent polymorphism to divergence predicted by the neutral theory reveals a local excess of silent polymorphism. This is consistent with the presence of two apparent narrow peaks of elevated silent polymorphism surrounding nonconservative amino acid substitutions. These polymorphisms as well as others at synonymous and nonsynonymous sites are shared with D. koepferae. We suggest that the presence of shared nucleotide polymorphisms is probably due to interspecific gene flow and/or balancing selection acting on replacement variants and/or to a decreased probability of loss of ancestral polymorphisms caused by linkage to an adaptive inversion polymorphism. Recurrent mutation and persistence of neutral ancestral polymorphisms cannot, however, be ruled out. The analysis of the distribution of nucleotide variation among the three chromosomal arrangements sampled reveals that derived arrangements (J and JZ(3)) are less polymorphic than the ancestral ST, and that the widely distributed ST and J arrangements are genetically differentiated. However, a significant number of polymorphisms are shared between arrangements, suggesting frequent exchange either from gene conversion or from double crossovers in heterokaryotypes. Finally, our present results in combination with data of sequence variation at the breakpoints of inversion J suggest that this old gene arrangement has risen in frequency in relatively recent times.