tbuckley/cabot-search huggingface dataset:
Chromosomal instability and cancer: not just one CINgle mechanism
Authors: C R. Boland, N. L Komarova, A. Goel
Journal: Gut (2009)

One of the most impressive undertakings in the life of a somatic cell occurs when it divides into two daughter cells. Nearly 3 billion base pairs of nucleotides packed into 23 pairs of chromosomes are duplicated, line up on a mitotic plate, and are pulled away from their identical sisters, tethered to mitotic spindles. This almost always results in a perfectly symmetrical division of the duplicated genome. Anyone who has dealt with fishing line along the shore of a stream knows how daunting it can be to keep a few metres of monofilament from becoming lethally tangled. Yet, the cell does this nearly every time with ineffable ease and, moreover, detects when the process is misbehaving, and halts progress. When a cell undergoes an unbalanced mitosis, this leads to the creation of aneuploid cells. In spite of the number of mitoses that occur each day, one is hard-pressed to find aneuploid cells in normal tissues.

Cancer cells have survival advantages over their normal progenitors, but they tolerate some degree of malfunction in mitotic homeostasis, and are frequently aneuploid. Perhaps even more surprising, the more aneuploidy one finds in a colorectal cancer (CRC) the more deadly the tumour.1 One might anticipate from first principles that a derangement in orderly cell division would be difficult to tolerate, would confer a deficit in fitness, and that mitotic instability would lead to its own demise. However, this is not the case, and understanding this paradox might provide some insight into how cancers develop, and how we might find its Achilles heel.

The conceptual challenge for understanding aneuploidy …
Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup
Authors: Robert L Souhami, Alan W Craft, Jan W Van der Eijken, Marianne Nooij, David Spooner, Vivien HC Bramwell, Rafal Wierzbicki, Archibald J Malcolm, Anne Kirkpatrick, Barbara M Uscinska, Martine Van Glabbeke, David Machin
Journal: The Lancet (1997)
Potent inhibition of DOT1L as treatment of MLL-fusion leukemia
Authors: Scott R. Daigle, Edward J. Olhava, Carly A. Therkelsen, Aravind Basavapathruni, Lei Jin, P. Ann Boriack-Sjodin, Christina J. Allain, Christine R. Klaus, Alejandra Raimondi, Margaret Porter Scott, Nigel J. Waters, Richard Chesworth, Mikel P. Moyer, Robert A. Copeland, Victoria M. Richon, Roy M. Pollock
Journal: Blood (2013)
RESPONSE: Re: Randomized Trial of High-Dose Chemotherapy and Blood Cell Autografts for High-Risk Primary Breast Carcinoma
Authors: G. N. Hortobagyi, A. U. Buzdar
Journal: JNCI Journal of the National Cancer Institute (2000)

In the February 2 issue of the Journal, Hortobagyi et al. (1) reported on a randomized trial of high-dose chemotherapy (HDCT) and stem-cell support versus conventional chemotherapy in high-risk patients with breast cancer, who showed no clinically or statistically significant difference in relapse-free or overall survival.This trial was based on
A novel and universal method for microRNA RT-qPCR data normalization
Authors: Pieter Mestdagh, Pieter Van Vlierberghe, An De Weer, Daniel Muth, Frank Westermann, Frank Speleman, Jo Vandesompele
Journal: Genome biology (2009)

Abstract Gene expression analysis of microRNA molecules is becoming increasingly important. In this study we assess the use of the mean expression value of all expressed microRNAs in a given sample as a normalization factor for microRNA real-time quantitative PCR data and compare its performance to the currently adopted approach. We demonstrate that the mean expression value outperforms the current normalization strategy in terms of better reduction of technical variation and more accurate appreciation of biological changes.
Interstitial Fluid Pressure and Associated Lymph Node Metastasis Revealed in Tumors by Dynamic Contrast-Enhanced MRI
Authors: Tord Hompland, Christine Ellingsen, Kirsti Marie Øvrebø, Einar K. Rofstad
Journal: Cancer Research (2012)

Abstract Elevated interstitial fluid pressure (IFP) in tumors can cause metastatic dissemination and treatment resistance, but its study poses a challenge because of a paucity of noninvasive imaging strategies. In this study, we address this issue by reporting the development of a noninvasive tool to assess tumor IFP and interstitial hypertension-induced lymph node metastasis. Using mouse xenograft models of several types of human cancer, we used gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) as a contrast agent for dynamic contrast-enhanced MRI (DCE-MRI). Immediately after Gd-DTPA administration, a high-signal-intensity rim was observed in the tumor periphery, which moved outward with time. Assuming the velocity of Gd-DTPA to be equal to the fluid flow velocity, we used a simple model of peritumoral interstitial fluid flow to calculate the fluid flow velocity at the tumor surface (v0) based on the rim movement. Significant positive correlations were found between v0 and IFP in all tumor xenografts. Moreover, the primary tumors of metastasis-positive mice displayed higher IFP and v0 than the primary tumors of metastasis-negative mice. Findings were confirmed in cervical cancer patients with pelvic lymph node metastases, where we found v0 to be higher compared with patients without lymph node involvement (P &amp;lt; 0.00001). Together, these findings establish that Gd-DTPA-based DCE-MRI can noninvasively visualize tumor IFP, and they reveal the potential for v0 determined by this method to serve as a novel general biomarker of tumor aggressiveness. Cancer Res; 72(19); 4899–908. ©2012 AACR.
Neurologic Manifestations and Outcome of West Nile Virus Infection
Authors: James J. Sejvar
Journal: JAMA (2003)

ContextThe neurologic manifestations, laboratory findings, and outcome of patients with West Nile virus (WNV) infection have not been prospectively characterized.ObjectiveTo describe prospectively the clinical and laboratory features and long-term outcome of patients with neurologic manifestations of WNV infection.Design, Setting, and ParticipantsFrom August 1 to September 2, 2002, a community-based, prospective case series was conducted in St Tammany Parish, La. Standardized clinical data were collected on patients with suspected WNV infection. Confirmed WNV-seropositive patients were reassessed at 8 months.Main Outcome MeasuresClinical, neurologic, and laboratory features at initial presentation, and long-term neurologic outcome.ResultsSixteen (37%) of 39 suspected cases had antibodies against WNV; 5 had meningitis, 8 had encephalitis, and 3 had poliomyelitis-like acute flaccid paralysis. Movement disorders, including tremor (15 [94%]), myoclonus (5 [31%]), and parkinsonism (11 [69%]), were common among WNV-seropositive patients. One patient died. At 8-month follow-up, fatigue, headache, and myalgias were persistent symptoms; gait and movement disorders persisted in 6 patients. Patients with WNV meningitis or encephalitis had favorable outcomes, although patients with acute flaccid paralysis did not recover limb strength.ConclusionsMovement disorders, including tremor, myoclonus, and parkinsonism, may be present during acute illness with WNV infection. Some patients with WNV infection and meningitis or encephalitis ultimately may have good long-term outcome, although an irreversible poliomyelitis-like syndrome may result.
Shouldering the burden: a case of pain in the middle-aged female athlete
Authors: Kathryn Darras, Gordon Andrews, Bruce B Forster
Journal: British Journal of Sports Medicine (2013)

A 56-year-old previously well left-handed woman presents to her family physician with a 2-year history of pain and stiffness in her left shoulder. She describes a constant ‘ache’ that became ‘sharp’ when playing tennis or golf. Over the last 2 months, the pain has become increasingly worse and she has had to reduce her tennis matches from four times per week to only once.

On examination, there was a soft tissue swelling over the left shoulder with no bruising or muscle wasting. Her pain reproduced with active abduction of the left shoulder while the passive range of motion was full. There was reduced power with abduction and flexion of the shoulder. Sensation was intact in the upper extremity.

Plain films and an ultrasound examination were performed (figures 1 and 2).



Figure 1 
Anteroposterior radiograph of the patient's left shoulder demonstrating a focus of calcification within a tendon of the rotator cuff, superior to the humeral head (arrow). Calcium deposition can be localised to the rotator cuff by anteroposterior radiographs in internal and external rotation as well as the axillary lateral radiograph.





Figure 2 
Sonographic image of the shoulder demonstrating a supraspinatus calcium deposit appearing as a well-circumscribed, anechoic focus with posterior acoustic shadowing (arrow).



What is the most likely diagnosis?

For answer see page 1135 



Shoulder pain is a frequent complaint among patients and diagnosing the cause can be challenging, often requiring imaging studies. As the first-line modality, plain radiography should be ordered for all patients with pain persisting beyond 6 weeks.1 The differential diagnosis for this middle-aged female patient with atraumatic shoulder pain includes arthritis and rotator cuff pathology. However, before considering these more common causes, it is important to exclude infection and malignancy.

Septic arthritis is …
Adeno-Associated Virus–Mediated CTLA4Ig Gene Transfer Protects MHC-Mismatched Renal Allografts from Chronic Rejection
Authors: Ariela Benigni, Susanna Tomasoni, Laurence A. Turka, Lorena Longaretti, Lorena Zentilin, Marilena Mister, Anna Pezzotta, Nadia Azzollini, Marina Noris, Sara Conti, Mauro Abbate, Mauro Giacca, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2006)

Short-term results of renal transplantation have improved considerably in the past 20 yr; however, similar improvements in long-term outcome have not been achieved. The primary cause of late graft loss is chronic rejection that might be treated by gene therapeutic approaches. Ideally, one would like to impair locally the contact between transplant antigen and the host immune system without compromising the generalized immune competence of the recipient. This can be achieved by local expression of the therapeutic protein in the site of interest using gene therapy. Here it is shown that chronic allograft rejection can be prevented effectively by local delivery of recombinant adeno-associated virus (AAV) vectors that encode the CTLA4Ig immunosuppressant protein to the donor kidney in a fully MHC-mismatched rat strain combination. AAV CTLA4Ig prevented progressive proteinuria and protected transplant kidneys from renal structural injury. A population of anergic T cells with regulatory activity, which eventually were responsible for the induction of tolerance, were found in recipient lymph nodes and in the graft as long as 120 d after transplantation. These data indicate that AAV-mediated CTLA4Ig gene transfer to donor graft represents a promising tool to prevent the onset of chronic rejection and circumvent the unwanted systemic adverse effects of the administration of immunomodulatory protein.
Autosomal monoallelic expression in the mouse
Authors: Lillian M Zwemer, Alexander Zak, Benjamin R Thompson, Andrew Kirby, Mark J Daly, Andrew Chess, Alexander A Gimelbrant
Journal: Genome biology (2012)

Random monoallelic expression defines an unusual class of genes displaying random choice for expression between the maternal and paternal alleles. Once established, the allele-specific expression pattern is stably maintained and mitotically inherited. Examples of random monoallelic genes include those found on the X-chromosome and a subset of autosomal genes, which have been most extensively studied in humans. Here, we report a genome-wide analysis of random monoallelic expression in the mouse. We used high density mouse genome polymorphism mapping arrays to assess allele-specific expression in clonal cell lines derived from heterozygous mouse strains.Over 1,300 autosomal genes were assessed for allele-specific expression, and greater than 10% of them showed random monoallelic expression. When comparing mouse and human, the number of autosomal orthologs demonstrating random monoallelic expression in both organisms was greater than would be expected by chance. Random monoallelic expression on the mouse autosomes is broadly similar to that in human cells: it is widespread throughout the genome, lacks chromosome-wide coordination, and varies between cell types. However, for some mouse genes, there appears to be skewing, in some ways resembling skewed X-inactivation, wherein one allele is more frequently active.These data suggest that autosomal random monoallelic expression was present at least as far back as the last common ancestor of rodents and primates. Random monoallelic expression can lead to phenotypic variation beyond the phenotypic variation dictated by genotypic variation. Thus, it is important to take into account random monoallelic expression when examining genotype-phenotype correlation.
Identification of Regulatory T Cells in Tolerated Allografts
Authors: Luis Graca, Stephen P. Cobbold, Herman Waldmann
Journal: The Journal of Experimental Medicine (2002)

Induction of transplantation tolerance with certain therapeutic nondepleting monoclonal antibodies can lead to a robust state of peripheral “dominant” tolerance. Regulatory CD4+ T cells, which mediate this form of “dominant” tolerance, can be isolated from spleens of tolerant animals. To determine whether there were any extra-lymphoid sites that might harbor regulatory T cells we sought their presence in tolerated skin allografts and in normal skin. When tolerated skin grafts are retransplanted onto T cell–depleted hosts, graft-infiltrating T cells exit the graft and recolonize the new host. These colonizing T cells can be shown to contain members with regulatory function, as they can prevent nontolerant lymphocytes from rejecting fresh skin allografts, without hindrance of rejection of third party skin. Our results suggest that T cell suppression of graft rejection is an active process that operates beyond secondary lymphoid tissue, and involves the persistent presence of regulatory T cells at the site of the tolerated transplant.
Effectiveness of Management Strategies for Renal Artery Stenosis: A Systematic Review
Authors: Ethan Balk, Gowri Raman, Mei Chung, Stanley Ip, Athina Tatsioni, Alvaro Alonso, Priscilla Chew, Scott J. Gilbert, Joseph Lau
Journal: Annals of Internal Medicine (2006)

Background: Atherosclerotic renal artery stenosis is increasingly common in an aging population. Therapeutic options include medical treatment only or revascularization procedures. Purpose: To compare the effects of medical treatment and revascularization on clinically important outcomes in adults with atherosclerotic renal artery stenosis. Data Sources: The MEDLINE database (inception to 6 September 2005) and selected reference lists were searched for English-language articles. Study Selection: The authors selected prospective studies of renal artery revascularization or medical treatment of patients with atherosclerotic renal artery stenosis that reported mortality rates, kidney function, blood pressure, cardiovascular events, or adverse events at 6 months or later after study entry. Data Extraction: A standardized protocol with predefined criteria was used to extract details on study design, interventions, outcomes, study quality, and applicability. The overall body of evidence was then graded as robust, acceptable, or weak. Data Synthesis: No study directly compared aggressive medical therapy with angioplasty and stent placement. Two randomized trials compared angioplasty without stent and medical treatments. Eight other comparative studies and 46 cohort studies met criteria for analysis. Studies generally had poor methodologic quality and limited applicability to current practice. Overall, there was no robust evidence. Weak evidence suggested no large differences in mortality rates or cardiovascular events between medical and revascularization treatments. Acceptable evidence suggested similar kidney-related outcomes but better blood pressure outcomes with angioplasty, particularly in patients with bilateral disease. Improvements in kidney function and cure of hypertension were reported among some patients only in cohort studies of angioplasty. Available evidence did not adequately assess adverse events or baseline characteristics that could predict which intervention would result in better outcomes. Limitations: The evidence from direct comparisons of interventions is sparse and inadequate to draw robust conclusions. Conclusions: Available evidence does not clearly support one treatment approach over another for atherosclerotic renal artery stenosis.
Papillary Ependymomas Produced in &lt;italic&gt;Rattus (Masfomys) Natalensis&lt;/italic&gt; inoculated With Vacuolating Virus (SV40)
Authors: Alan S. Rabson, Gregory T. O'Conor, Ruth L. Kirschstein, William J. Branigan
Journal: JNCI Journal of the National Cancer Institute (1962)

Subcutaneous inoculation of newborn Mastomys with simian vacuolating virus (SV40) has resulted in production of brain tumors with histopathologic characteristics of papillary ependymomas. The tumors have been found in 8 of 10 animals that survived the inoculation trauma and have become evident after latent periods of 111 to 225 days. Although the oncogenic properties of preparations of SV40 have been previously demonstrated in Syrian hamsters, the present report indicates that the oncogenic activity is not limited to the Syrian hamster. The finding that subcutaneous inoculation of an oncogenic virus can produce brain tumors without subcutaneous or visceral tumors has not been previously reported. It suggests that some ependymomas in humans may result from subcutaneous inoculation of an oncogenic virus or a carcinogenic substance.
Investigator-initiated trials of targeted oncology agents: why independent research is at risk?
Authors: L. Bergmann, B. Berns, A.G. Dalgleish, M. von Euler, T.T. Hecht, G.L. Lappin, N. Reed, S. Palmeri, J. Smyth, S. Embacher-Aichorn, H. Zwierzina
Journal: Annals of Oncology (2010)
A Multicenter Trial of Prolonged Prone Ventilation in Severe Acute Respiratory Distress Syndrome
Authors: Jordi Mancebo, Rafael Fernández, Lluis Blanch, Gemma Rialp, Federico Gordo, Miquel Ferrer, Fernando Rodríguez, Pau Garro, Pilar Ricart, Immaculada Vallverdú, Ignasi Gich, José Castaño, Pilar Saura, Guillermo Domínguez, Alfons Bonet, Richard K. Albert
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Ventilation in the prone position for about 7 h/d in patients with acute respiratory distress syndrome (ARDS), acute lung injury, or acute respiratory failure does not decrease mortality. Whether it is beneficial to administer prone ventilation early, and for longer periods of time, is unknown.We enrolled 136 patients within 48 h of tracheal intubation for severe ARDS, 60 randomized to supine and 76 to prone ventilation. Guidelines were established for ventilator settings and weaning. The prone group was targeted to receive continuous prone ventilation treatment for 20 h/d.The intensive care unit mortality was 58% (35/60) in the patients ventilated supine and 43% (33/76) in the patients ventilated prone (p = 0.12). The latter had a higher simplified acute physiology score II at inclusion. Multivariate analysis showed that simplified acute physiology score II at inclusion (odds ratio [OR], 1.07; p < 0.001), number of days elapsed between ARDS diagnosis and inclusion (OR, 2.83; p < 0.001), and randomization to supine position (OR, 2.53; p = 0.03) were independent risk factors for mortality. A total of 718 turning procedures were done, and prone position was applied for a mean of 17 h/d for a mean of 10 d. A total of 28 complications were reported, and most were rapidly reversible.Prone ventilation is feasible and safe, and may reduce mortality in patients with severe ARDS when it is initiated early and applied for most of the day.
Enhanced gastric mucosal haemostasis after upper gastrointestinal haemorrhage.
Authors: M C Allison, G M Fullarton, I L Brown, G P Crean, K E McColl
Journal: Gut (1991)

An endoscopic technique for the measurement of gastric mucosal bleeding time has been developed to study gastric haemostasis in patients with acute upper gastrointestinal haemorrhage. The relation of gastric mucosal bleeding time to skin bleeding time and nonsterodial anti-inflammatory drug usage was examined in 61 control patients and in 47 patients presenting with bleeding peptic ulcers or erosions. Gastric mucosal bleeding time was shorter in patients with haemorrhage (median 2 minutes, range 0-5 minutes) than in the control group (median 4 minutes, range 2-8 minutes) (p less than 0.001). Skin bleeding times were similar in the two groups (medians 4 minutes in patients with haemorrhage and 4.5 minutes in controls). In 21 patients with haemorrhage who were taking non-steroidal anti-inflammatory drugs, the median gastric mucosal bleeding time (2.5 minutes, range 1.0-5.0 minutes) was similar to that in 26 patients with haemorrhage not associated with these drugs (2.0 minutes, range 0.0-5.0 minutes). These results show that gastric mucosal haemostasis is accelerated in response to haemorrhage in the upper gastrointestinal tract, even in patients taking nonsteroidal anti-inflammatory drugs. This enhanced gastric haemostasis probably reflects a local protective response to minimise blood loss from the bleeding lesion.
Dopamine: A Prolactin-Inhibiting Hormone*
Authors: NIRA BEN-JONATHAN
Journal: Endocrine Reviews (1985)

DOPAMINE (DA) is an interesting and versatile compound. In the central nervous system (CNS) it is involved with the control of fine movements and mental processes. Its association with disorders such as Parkinsonism and schizophrenia is well recognized. In the hypothalamo-hypophysial axis, DA is the primary physiological inhibitor of PRL secretion. Currently, this catecholamine represents the only nonpeptidergic hypothalamic agent with a well defined hypophysiotropic function. By virtue of its dual role as a neurotransmitter and a hormone, DA provides perhaps the best example of neuroendocrine interactions. It also possesses a more universal property. In all hormonal systems studied thus far, whether at the hypothalamic, posterior pituitary, or anterior pituitary level, DA functions as an inhibitor. Perhaps the common denominator to these diverse cells is the presence of D2 DA receptors, which are negatively linked to the adenylate cyclase system.
Impact of Nonadherence to Antihypertensive Therapy
Authors: Aram V. Chobanian
Journal: Circulation (2009)

T he benefits of antihypertensive therapy in reducing car- diovascular complications have been impressive.Several clinical trials in hypertension have shown that reduction of blood pressure is associated with significant decreases in the incidence of stroke, ischemic heart disease, congestive heart failure, and renal failure, irrespective of age, gender, race or ethnicity, type of antihypertensive used, or severity of hypertension. 1 Nevertheless, control of hypertension remains unsatisfactory in the United States and throughout the world.Recent data from the National Health and Nutrition Examination Survey indicate that approximately 40% of hypertensive individuals are untreated, and 65% do not have their hypertension controlled to a blood pressure level of Ͻ140/ 90 mm Hg. 2 Although control rates have improved in the past several years, the total number of patients with uncontrolled hypertension has actually increased because of the rise in hypertension prevalence during this period (Figure).