tbuckley/cabot-search huggingface dataset:
Abstract 40: Developmental profile and regulation of the glycolytic enzyme hexokinase 2 and its association with aerobic glycolysis
Authors: Amparo M. Wolf, Sameer Agnihotri, Diana M. Munoz-Gajadhar, Cynthia Hawkins, Abhijit Guha
Journal: Cancer Research (2010)

Abstract Proliferating embryonic and tumor tissues rely on aerobic glycolysis, or the metabolism of glucose to lactate under oxygenated conditions, to assist in the synthesis of biosynthetic precursors necessary for proliferation. The reliance on aerobic glycolysis may be mediated by the expression of specific metabolic enzymes. Mammalian Hexokinases HK1 and HK2 are 100kDa proteins that phosphorylate glucose to glucose-6-phosphate as the first step of the glycolytic pathway. In normal adult tissues, HK1 is ubiquitously expressed but is particularly prominent in the brain and kidney. HK2 is generally expressed at low levels within adipose tissue and skeletal tissue and negligently in normal brain. In this study, we wished to determine the ontogeny of these isoforms within the developing brain and determine how their expression relates to the extent of aerobic glycolysis in Glioblastoma Multiforme (GBM), a highly aggressive malignant brain tumor. Mining of existing published microarray data found strong expression of HK1 in 1, 2, 4 cell stage but a switch to stronger expression of HK2 in the blastocyst stage, previously reported to rely heavily on aerobic glycolysis. We performed HK2 immunohistochemistry in mice from gestational age E12, E16, post natal 1 month and 2 months. Our results demonstrated an age and cell specific HK1 and HK2 immunoreactivity in embryonic brain tissue with decreased expression of HK2 post-natally. Subsequently, we investigated the expression of HK1 and HK2 isoforms in a panel of GBM cell lines with varying levels of dependence on aerobic glycolysis, as measured by lactate levels and O2 consumption. HK2 but not HK1 expression was higher in GBM cells that had low O2 consumption and high extracellular lactate levels, supporting an association of HK2 with aerobic glycolysis. As HK2 expression is nearly silent in adult brain but expressed in fetal tissue and GBM cells, we hypothesized that DNA methylation/demethylation events may be playing important in its regulation. Adult normal human brain and GBM cell lines that had no HK2 expression were found to be methylated at CpG islands within intron 1 by bisulfite sequencing in contrast to fetal tissue and HK2-expressing GBM cells. The degree of methylation correlated with transcript expression in GBM cell lines. Treatment of U343 and A172 cell lines with 5-azacytidine restored HK2 transcript expression, supporting that HK2 maybe epigenetically regulated. Overall, our results demonstrate that the expression of the HK2 isoform, in contrast to HK1, may be particularly important in tissues relying on aerobic glycolysis for proliferation including embryonic tissue and GBMs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 40.
Initial Staging of Locally Advanced Rectal Cancer and Regional Lymph Nodes
Authors: Milena Cerny, Vincent Dunet, John Olivier Prior, Dieter Hahnloser, Anna Dorothea Wagner, Reto Antoine Meuli, Sabine Schmidt
Journal: Clinical Nuclear Medicine (2016)

The aim of the study was to compare diffusion-weighted MRI (DW-MRI) parameters with 18F-FDG PET/CT in primary locally advanced rectal cancer (LARC).From October 2012 to September 2014, 24 patients with histologically confirmed and untreated LARC (T3-T4) prospectively underwent a pelvic 1.5-T DW-MRI (b = 0 s/mm, b = 600 s/mm2) and a whole-body 18F-FDG PET/CT, before neoadjuvant therapy. The 2 examinations were performed on the same day. Two readers measured 18F-FDG SUVmax and SUVmean of the rectal tumor and of the pathological regional lymph nodes on PET/CT and compared these with minimum and mean values of the ADC (ADCmin and ADCmean) on maps generated from DW-MRI. The diagnostic performance of ADC values in identifying pathological lymph nodes was also assessed.Regarding tumors (n = 24), we found a significant negative correlation between SUVmean and corresponding ADCmean values (ρ = -0.61, P = 0.0017) and between ADCmin and SUVmax (ρ = -0.66, P = 0.0005). Regarding the lymph nodes (n = 63), there was a significant negative correlation between ADCmean and SUVmean values (ρ = -0.38, P = 0.0021), but not between ADCmin and SUVmax values (ρ = -0.11, P = 0.41). Neither ADCmean nor ADCmin values helped distinguish pathological from benign lymph nodes (AUC of 0.24 [confidence interval, 0.10-0.38] and 0.41 [confidence interval, 0.22-0.60], respectively).The correlations between ADCmean and SUVmean suggest an association between tumor cellularity and metabolic activity in untreated LARC and in regional lymph nodes. However, compared with 18F-FDG PET/CT, ADC values are not reliable for identifying pathological lymph nodes.
Protective Effect of the Bispiperazinedione ICRF-187 against Doxorubicin-Induced Cardiac Toxicity in Women with Advanced Breast Cancer
Authors: James L. Speyer, Michael D. Green, Elissa Kramer, Mariano Rey, Joseph Sanger, Cynthia Ward, Neil Dubin, Victor Ferrans, Peter Stecy, Anne Zeleniuch-Jacquotte, James Wernz, Frederick Feit, William Slater, Ronald Blum, Franco Muggia
Journal: New England Journal of Medicine (1988)

Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC+ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC+ICRF-187 group (no significant difference). Eleven patients on the FDC+ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC+ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC+ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC+ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions. (N Engl J Med 1988; 319:745–52.)
Submucosal lesions / extrinsic compression of the upper digestive tract: Is it worthwhile to do endoscopic ultrasonography? Is it so in all cases?
Authors: P Lago, F Castro-Poças, T Moreira, J Areias
Journal: Endoscopy (2006)

Introduction: finding of localised protrusions in digestive tract wall, submucosal lesions (SL) or extrinsic compression (EC), during ultrasound is not unusual and is one indications for carrying out endoscopic ultrasonography (EUS). However, as this exam is not available in the majority of centres and is not without additional costs and risks, the ration of costs to benefits must be examined.
Abstract P6-11-12: Nanoparticle-enhanced chemotherapeutics delivery in drug-resistant triple-negative breast cancer
Authors: AL van de Ven, MD Landis, LA Paskett, A Meyn, HB Frieboes, JC Chang, M Ferrari
Journal: Cancer Research (2012)

Abstract Chemotherapeutics delivery is generally poor in tumors characterized by rapid perfusion and low blood volume fraction. Systemically administered nanoparticles can be engineered to overcome abnormal flow conditions to act as intravascular drug depots for the localized delivery of high concentrations of chemotherapeutics. The feasibility of this approach was first demonstrated using melanoma, and is now being further investigated using well-characterized human triple-negative breast cancer biopsies implanted into mice. Intravital microscopy studies of human cancer-in-mice selected for differing vascular morphologies have yielded intriguing preliminary data regarding the role of tumor vascularity in drug and particle delivery. The first-pass perfusion of a 40kDa dextran tracer revealed that BCM-2665 tumors are perfused ∼6x more rapidly than BCM-4195 tumors (11.3 ± 2.3s vs. 67.6 ± 11.0) and contain ∼30% lower volume fraction of blood (0.046 ± 0.011 vs. 0.062 ± 0.015). Interestingly, flow parameters that adversely impact drug accumulation appear to favor plateloid particle accumulation. BCM-2665 xenografts receiving an i.v. injection of 1000×400 nm particles show ∼10x more particle accumulation than BCM-4195 tumors (24.8 ± 3.2 × 103/mm3 vs. 3.5 ± 0.4 × 103/mm3). The ability of these therapeutic particles to reach tumors appears to be primarily driven by flow-related parameters, which we characterize using a combination of intravital microscopy, computed tomography, and mathematical modeling. The total number of particles accumulated within a given tumor appears to be largely driven by the number of particles entering the tumor, since ∼65–70% of entering plateloid particles are retained by the tumor vasculature. This suggests that cytotoxic intravascular drug depots may be a promising strategy for increasing the efficiency of chemotherapeutics delivery to drug-resistant tumors and is the premise of ongoing therapeutic response studies. Clearly if more drugs can be delivered to the tumors, better outcomes can be expected for the patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-12.
Industry and drug regulators disagree on which data should remain confidential
Authors: N. Hawkes
Journal: BMJ (2013)

Sharp differences of opinion have emerged over how much clinical trial data some drug companies are willing to release as the clock ticks down to the transparency deadline of 1 January 2014 set by the European Medicines Agency (EMA).

A meeting in Brussels late last month showed that the industry itself is split, despite the publication of a draft policy by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) which outlined the principles their members should follow.1

At the meeting one drug company representative, Neal Parker, of the US company AbbVie, broke ranks by asserting that some data on adverse drug reactions should be treated as commercially confidential.

AbbVie, a research based biopharmaceutical company which split off from Abbott at the beginning of this year, has already taken action in the courts to prevent the European Medicines Agency from releasing to …
MIBG Activity in the Gallbladder
Authors: Xia Bai, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2016)

Whole-body I-MIBG images were acquired in a 12-year-old girl who had metastatic malignant paraganglioma to assess the extent of the metastases. Image quality was suboptimal because of diffusely increased muscle activity, which was related to the labetalol the patient took to control her blood pressure. Despite the suboptimal images, a subtle activity in the lower border of the liver was noted, along with known lesions in the sacrum and upper chest. Further SPECT/CT images localized this activity in the gallbladder.
Aberrent hedgehog signaling is an early event in breast cancer development.
Authors: S O'Toole, A Swarbrick, E Millar, D McLeod, C McNeil, M Qiu, E Lopez-Knowles, E Caldon, S Oakes, C Ormandy, A Morey, E Musgrove, S Henshall, R Sutherland
Journal: Cancer Research (2009)

Abstract Abstract #24 Background: The Hedgehog (Hh) signaling pathway is a highly conserved system which regulates development and cell fate. It also contributes to the pathogenesis of a number of human malignancies, including basal cell, prostate and pancreatic carcinoma as well as medulloblastoma. There is emerging evidence that Hh may play an important role in breast cancer.&amp;#x2028; Methods: We examined the immunohistochemical expression of key Hh proteins, sonic hedgehog (Shh), Patched (Ptch) and Gli1 in 3 cohorts of patients; 2 independent cohorts of the histological progression model of breast cancer and a cohort of 292 patients with a median follow up of 5.5 years. We also investigated expression of Shh in the C3/SV40T mouse model of mammary carcinogenesis. We then investigated the effects of recombinant Shh in the MCF10A in vitro model of early breast cancer development. Finally, a mammary reconstitution graft model was employed where donor mammary epithelial cells were briefly cultured and transduced with a retroviral construct carrying a Shh-GFP construct, then transplanted into the cleared mammary fat pad of a recipient mouse.&amp;#x2028; Results: Overexpression of Shh was an early event in human premalignant lesions, with progressive increases (p&amp;lt;0.05) with the development of hyperplasia, atypia and malignancy in both test and validation progression cohorts. Similar results were observed in the mammary gland lesions of the C3/SV40T mouse. In human breast cancer, overexpression of Shh was associated with a poor prognosis (recurrence HR=2.0, p=0.003 and breast cancer specific death (HR=2.4, p=0.002) and also associated with a poor prognosis in chemotherapy (HR=2.4, p=0.03) and endocrine therapy (HR 3.5, p=0.03) treated patients. There was a highly significant (p=0.004) association by chi squared analysis with the basal-like subtype of breast cancer. Based on these data, we investigated the effects of Shh in 2 experimental systems – Shh caused disorganization of MCF-10A acini and was associated with the development of an unusual discohesive phenotype. In the mammary graft model, expression of Shh was associated with ductal epithelial hyperplasia in 58% of ducts, compared to 5% of controls.&amp;#x2028; Conclusion: These experimental data suggest that excessive Shh may cause hyperplasia and dysplasia of normal human and murine mammary gland epithelium. Together with our observations in human breast preinvasive and malignant lesions, these results support a role for aberrant Hh signaling in breast carcinogenesis. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 24.
Canine atrial and ventricular muscle mechanics studied as a function of age.
Authors: F Urthaler, A A Walker, K Kawamura, L L Hefner, T N James
Journal: Circulation Research (1978)

Age-dependent differences in mechanical performance and morphometric and electron microscopic characteristics of atrial and ventricular trabeculae are described.At 3 months, atrial and ventricular trabeculae develop the same amount of force.At 9 months, the ventricular muscle develops twice as much force as its atrial counterpart, although shortening is almost identical in both muscles.At any age, velocity of shortening of atrial trabeculae is at least twice that of the ventricular muscles.StereologicaJ data indicate that atrial and ventricular working myocytes maintain fixed volume fractions of myofibrils (70%) and mitochondria (25%) between 3 and 9 months of age.A broad frequency distribution of sarcomere lengths was measured at Lmax in muscles of the younger age groups.More than 80% of sarcomeres of adult atrial and ventricular myocytes clustered around 2.05 to 2.25 /im; only 30% of sarcomeres of younger atrial myocytes and 45% of sarcomeres of younger ventricular myocytes were within that length bracket.About 45% of sarcomeres in younger atrial muscles had lengths in excess of 2.35 pm; less than 3% of sarcomeres were longer than 2.35 fun in adult atrial muscles.Sarcomere lengths cluster more and more around the mean with increasing age, suggesting that with maturation there is a more homogeneous recruitment of sarcomeres.At both ages, there is a marked difference between atrial and ventricular myocytes whether examined in terms of morphological development or functional performance.We conclude that any work correlating myocardial structure and function must account for two things: the site from which the muscle was excised and the age of the donor heart.AGE-RELATED changes in developed tension, 1 passive elastic stiffness, 2 or maximum velocity of shortening' 1 are as well established as age-related differences in the sensitivity to digitalis. 4It also is well known that the heart is not made of a homogeneous population of working myocytes and that the differences in structure 5 '" and function 7 -a between atria and ventricles are quite marked.Age-related changes in ventricular contractility have been studied in some detail in lambs and sheep 1 and in cats, 9 " 11 but little or no attention has been given to the effects of maturation on atrial contractile performance in any species. 1-9 In this study we describe age-dependent differences in the mechanical performance of isolated canine atrial and ventricular trabeculae.Presentation of the physiological observations is combined with morphometric and electron microscopic data from atrial and ventricular trabeculae previously studied in the myograph. MethodsThirty-six mongrel dogs of either sex were anesthetized with sodium pentobarbital, 30 mg/kg, iv.Two age groups were studied: one group was (n = 18) 13 ± 4 weeks old (3 months) and the second group (n = 18) 35 ± 5 weeks old (9 months).The entire heart was rapidly removed and
Abnormal Cortical Metabolism in Acute Disseminated Encephalomyelitis
Authors: TOM XL. TAN, DIMITRIOS G. SPIGOS, CHARLES F. MUELLER
Journal: Clinical Nuclear Medicine (1998)

A 20-year-old right-handed man awoke with a severe headache and confusion and rapidly developed blurred vision, slurred speech, and right-sided hemiparesis. Initial MRI demonstrated a large demyelinating lesion involving white matter of the left parieto-occipital region with normal cortex and spinal cord. After stereotactic brain biopsy yielded a nondiagnostic specimen, FDG PET scan was performed and showed marked hypometabolism of the left parieto-occipital lobe with diaschisis of the contralateral cerebellum. Acute disseminated encephalomyelitis (ADME) was confirmed by means of a lumbar puncture showing elevated myelin basic protein in the cerebrospinal fluid. A follow-up MRI showed no new white matter lesions after 6 months, and he responded to steroid treatment. The patient recovered completely.
INTENCIÓN DE TRATAR POR DSE Y CONVERSIÓN A RMEF: ¿QUÉ FACTORES DIFICULTAN NUESTROS INTENTOS DE RESECCIÓN EN BLOQUE? ANÁLISIS MULTIVARIANTE
Authors: JC Marín-Gabriel, J Díaz-Tasende, P Cancelas-Navía, S Rodríguez-Muñoz, AJ Del Pozo-García, M Alonso-Riaño, M Pérez-Carreras, F Colina-Ruizdelgado, G Castellano-Tortajada
Journal: Endoscopy (2014)

Introducción: Al inicio del aprendizaje en DSE, puede precisarse una resección mucosa fragmentada (RMEf) para finalizar la exéresis de la lesión.
Shortage of health workers is set to double, says WHO
Authors: A. Gulland
Journal: BMJ (2013)

The world could be short of nearly 13 million health workers by 2035 because of an ageing workforce, a shortage of trainees, and workers leaving for better paid jobs, says a report by the World Health Organization.1

It says that currently the world is short of 7.2 million doctors, nurses, and midwives but that this number will rise to 12.9 million by 2035 if the shortages are not tackled.

The report found that of 186 countries with available data 83 fell below the basic threshold of 22.8 skilled health professionals for …
SP0089 Necrotising myopathy - the new kid on the block that the old kids need to recognise
Authors: O. Boyer, L. Drouot, C. Bloch-Queyrat, G. Butler-Browne, O. Benveniste
Journal: Annals of the Rheumatic Diseases (2013)

Necrotizing autoimmune myopathy (NAM) is a newly recognized group of idiopathic inflammatory myopathies, characterized by pathological features of prominent myofiber necrosis without significant inflammation nor HLA re-expression. Although their precise pathogenesis remains unknown, different forms of NAM may be associated to anti-signal recognition particle (SRP) auto- antibodies (Abs), statin therapy with auto-Abs against 3-hydroxy-3-methylglutaryl-coenzyme A reductase, or cancer. Patients with NAM generally present with severe symmetrical proximal deficiency, associated with high blood creatine kinase (CK) levels. Alternatively, NAM with anti-SRP auto-Abs can be very slowly progressive, with clinical and pathological features masquerading limb-girdle muscular dystrophies. NAM generally responds to immunosuppressive therapy but may require more intense treatment than polymyositis or dermatomyositis. SRP is a ubiquitous protein complex which mediates the transport of newly synthesized proteins to the endoplasmic reticulum (ER). We previously showed that serum titres of anti-SRP Abs closely correlate with CK level and muscle weakness in patients. We are currently investigating a possible direct pathogenic role of anti-SRP Abs. Incubation of muscle sections with different sources of anti-SRP Abs revealed a punctuated intracellular staining within the endomysium with reinforcement at myocyte membranes which disappeared upon preincubation with excess recombinant SRP54. Immunogold staining followed by electron-microscopy revealed immunoreactivity located in the ER. When cultured with purified anti-SRP Abs, myotubes showed a dramatic decrease of their diameter as compared to those cultured with control polyclonal IgG. In vivo injection of anti-SRP positive serum (as compared to normal serum) to mice resulted in weight loss and significant decrease in muscle strength as attested by rotarod and grip tests. Hence, while the mechanisms of how anti-SRP Abs may penetrate into and destroy myofibers remains elusive, these results provide the first experimental evidence that anti-SRP Abs might play a direct role in NAM pathogenesis. <h3>Disclosure of Interest</h3> None Declared