tbuckley/cabot-search huggingface dataset:
Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension
Authors: L. Savale, R. Magnier, J. Le Pavec, X. Jais, D. Montani, D. S. O'Callaghan, M. Humbert, J. Dingemanse, G. Simonneau, O. Sitbon
Journal: European Respiratory Journal (2012)

Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial hypertension (PAH)-specific therapies. This study investigated the short- and long-term efficacy/safety of bosentan in these patients, as well as its pharmacokinetics. All 34 consecutive patients with PoPH treated with first-line bosentan (December 2002 to July 2009) were retrospectively evaluated. Assessments included the New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-min walk distance (6MWD) and event-free status. The pharmacokinetics of bosentan in five patients with Child-Pugh (C-P) class B cirrhosis were compared with idiopathic PAH patients. Significant improvements from baseline were observed in NYHA FC, 6 MWD and haemodynamics, and were largely maintained during follow-up. Patients with C-P class B cirrhosis (n=9) had significantly larger haemodynamic improvement after mean ± SD 5 ± 2 months. Mean follow-up time was 43 ± 19 months; four patients died and seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with C-P class B cirrhosis than those observed in idiopathic PAH. These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.
Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells
Authors: Hans-Heinrich Oberg, Matthias Peipp, Christian Kellner, Susanne Sebens, Sarah Krause, Domantas Petrick, Sabine Adam-Klages, Christoph Röcken, Thomas Becker, Ilka Vogel, Dietrich Weisner, Sandra Freitag-Wolf, Martin Gramatzki, Dieter Kabelitz, Daniela Wesch
Journal: Cancer Research (2014)

The ability of human γδ T cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of γδ T-cell-stimulating antigens. In this study, we demonstrate that γδ T cells isolated from patients with PDAC tumor infiltrates lyse pancreatic tumor cells after selective stimulation with phosphorylated antigens. We determined the absolute numbers of γδ T-cell subsets in patient whole blood and applied a real-time cell analyzer to measure their cytotoxic effector function over prolonged time periods. Because phosphorylated antigens did not optimally enhance γδ T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vγ9 on γδ T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced γδ T-cell cytotoxicity with the Her2/Vγ9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of γδ T cells with the Her2/Vγ9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit γδ T cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous γδ T cells for immunotherapy.
Breast Tumor Kinase (Brk/PTK6) Is a Mediator of Hypoxia-Associated Breast Cancer Progression
Authors: Tarah M. Regan Anderson, Danielle L. Peacock, Andrea R. Daniel, Gregory K. Hubbard, Kristopher A. Lofgren, Brian J. Girard, Alexandra Schörg, David Hoogewijs, Roland H. Wenger, Tiffany N. Seagroves, Carol A. Lange
Journal: Cancer Research (2013)

Basal-type triple-negative breast cancers (TNBC) are aggressive and difficult to treat relative to luminal-type breast cancers. TNBC often express abundant Met receptors and are enriched for transcriptional targets regulated by hypoxia-inducible factor-1α (HIF-1α), which independently predict cancer relapse and increased risk of metastasis. Brk/PTK6 is a critical downstream effector of Met signaling and is required for hepatocyte growth factor (HGF)-induced cell migration. Herein, we examined the regulation of Brk by HIFs in TNBC in vitro and in vivo. Brk mRNA and protein levels are upregulated strongly in vitro by hypoxia, low glucose, and reactive oxygen species. In HIF-silenced cells, Brk expression relied upon both HIF-1α and HIF-2α, which we found to regulate BRK transcription directly. HIF-1α/2α silencing in MDA-MB-231 cells diminished xenograft growth and Brk reexpression reversed this effect. These findings were pursued in vivo by crossing WAP-Brk (FVB) transgenic mice into the MET(Mut) knockin (FVB) model. In this setting, Brk expression augmented MET(Mut)-induced mammary tumor formation and metastasis. Unexpectedly, tumors arising in either MET(Mut) or WAP-Brk × MET(Mut) mice expressed abundant levels of Sik, the mouse homolog of Brk, which conferred increased tumor formation and decreased survival. Taken together, our results identify HIF-1α/2α as novel regulators of Brk expression and suggest that Brk is a key mediator of hypoxia-induced breast cancer progression. Targeting Brk expression or activity may provide an effective means to block the progression of aggressive breast cancers.
Cancer-Related Mortality in People With Mental Illness
Authors: Stephen Kisely, Elizabeth Crowe, David Lawrence
Journal: JAMA Psychiatry (2012)

<h3>Context</h3>There is a 30% higher case fatality rate from cancer in psychiatric patients even though their incidence of cancer is no greater than in the general population. The reasons are unclear, but if increased cancer mortality were due to lifestyle only, cancer incidence should be similarly increased. Other hypotheses include delays in presentation, leading to more advanced staging at diagnosis, and difficulties in treatment access following diagnosis.<h3>Objective</h3>To assess why psychiatric patients are no more likely than the general population to develop cancer but are more likely to die of it.<h3>Design, Setting, and Patients</h3>A population-based record-linkage analysis compared psychiatric patients with the Western Australian population, using an inception cohort to calculate rates and hazard ratios. Mental health records were linked with cancer registrations and death records from January 1, 1988, to December 31, 2007, in Western Australia.<h3>Main Outcome Measures</h3>Metastases, incidence, mortality, and access to cancer interventions.<h3>Results</h3>There were 6586 new cancers in psychiatric patients. Cancer incidence was lower in psychiatric patients than in the general population in both males (rate ratio = 0.86; 95% CI, 0.82-0.90) and females (rate ratio = 0.92; 95% CI, 0.88-0.96), although mortality was higher (males: rate ratio = 1.52; 95% CI, 1.45-1.60; females: rate ratio = 1.29; 95% CI, 1.22-1.36). The proportion of cancer with metastases at presentation was significantly higher in psychiatric patients (7.1%; 95% CI, 6.5%-7.8%) than in the general population (6.1%; 95% CI, 6.0%-6.2%). Psychiatric patients had a reduced likelihood of surgery (hazard ratio = 0.81; 95% CI, 0.76-0.86), especially resection of colorectal, breast, and cervical cancers. They also received significantly less radiotherapy for breast, colorectal, and uterine cancers and fewer chemotherapy sessions.<h3>Conclusions</h3>Although incidence is no higher than in the general population, psychiatric patients are more likely to have metastases at diagnosis and less likely to receive specialized interventions. This may explain their greater case fatality and highlights the need for improved cancer screening and detection.
Renal Kallikrein Excretion in Cirrhotics with Ascites: Relationship to Renal Hemodynamics
Authors: Rosa M. Pérez-Ayuso, Vicente Arroyo, Jordi Camps, Antoni Rimola, Josep Costa, Joan Gaya, Francisca Rivera, Joan Rodes
Journal: Hepatology (1984)

To investigate if the renal kallikrein-kinin system may be involved in the homeostasis of renal perfusion in cirrhosis, urinary kallikrein activity was measured in 11 normal subjects, 31 cirrhotics with ascites and preserved rena plasma flow (548.2 ± 32.2 ml per min) and glomerular filtration rate (85.8 ± 3.4 ml per min), and 18 cirrhotics with functional renal failure (renal plasma flow: 229.9 ± 23.4 ml per min; glomerular filtration rate: 34.9 ± 3.3 ml per min). Plasma renin activity, plasma norepinephrine concentration and the urinary excretion of prostaglandin E 2 were also measured in these subjects. Cirrhotics without renal failure showed a significantly higher renin (4.9 ± 1.1 ng per ml per hr), norepinephrine (458.2 ± 50.4 pg per ml), urinary kallikrein (15.4 ± 1.8 pkat per min) and urinary prostaglandin E 2 (0.52 ± 0.08 ng per min) than did normal subjects (1.08 ± 0.1 ng per ml per hr, 218.1 ± 18.2 pg per ml; 8.4 ± 1.4 pkat per min and 0.24 ± 0.02 ng per min, respectively). Cirrhotics with renal failure showed a significantly higher renin (16.1 ± 3.4 ng per ml per hr) and norepinephrine (739.4 ± 79.2 pg per ml), and a significantly lower urinary kallikrein (5.2 ± 0.6 pkat per min) and urinary prostaglandin E 2 (0.15 ± 0.02 ng per min) than did normal subjects and cirrhotics without renal failure. Glomerular filtration rate correlated (p &lt; 0.001) with urinary kallikrein (r = 0.53), urinary prostaglandin E 2 (r = 0.55), plasma renin (r = -0.41) and norepinephrine (r = -0.44). These results suggest that renal kallikrein-kinin system may be involved in maintenance of renal blood flow in cirrhosis with ascites, and that functional renal failure in these patients could be a consequence of impaired renal production of kallikrein and prostaglandins in the setting of activation of the renin-angiotensin and sympathetic nervous systems.
Molecular Clocks in Reptiles: Life History Influences Rate of Molecular Evolution
Authors: Lindell Bromham
Journal: Molecular Biology and Evolution (2002)

Life history has been implicated as a determinant of variation in rate of molecular evolution amongst vertebrate species because of a negative correlation between body size and substitution rate for many molecular data sets. Both the generality and the cause of the negative body size trend have been debated, and the validity of key studies has been questioned (particularly concerning the failure to account for phylogenetic bias). In this study, a comparative method has been used to test for an association between a range of life-history variables-such as body size, age at maturity, and clutch size-and DNA substitution rate for three genes (NADH4, cytochrome b, and c-mos). A negative relationship between body size and rate of molecular evolution was found for phylogenetically independent pairs of reptile species spanning turtles, lizards, snakes, crocodile, and tuatara. Although this study was limited by the number of comparisons for which both sequence and life-history data were available, the results suggest that a negative body size trend in rate of molecular evolution may be a general feature of reptile molecular evolution, consistent with similar studies of mammals and birds. This observation has important implications for uncovering the mechanisms of molecular evolution and warns against assuming that related lineages will share the same substitution rate (a local molecular clock) in order to date evolutionary divergences from DNA sequences.
Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model
Authors: Burcu Bestas, Pedro M.D. Moreno, K. Emelie M. Blomberg, Dara K. Mohammad, Amer F. Saleh, Tolga Sutlu, Joel Z. Nordin, Peter Guterstam, Manuela O. Gustafsson, Shabnam Kharazi, Barbara Piątosa, Thomas C. Roberts, Mark A. Behlke, Matthew J.A. Wood, Michael J. Gait, Karin E. Lundin, Samir El Andaloussi, Robert Månsson, Anna Berglöf, Jesper Wengel, C.I. Edvard Smith
Journal: Journal of Clinical Investigation (2014)

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2′-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro–B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
When will the <i>News of the World</i> moment arrive for medical journals?
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2011)

What does the demise of Britain's most famous Sunday tabloid mean for medical journals? Probably nothing much except reminding us that any publication, like any employee, is dispensable. Some editors describe bigger medical journals as tankers that just keep steaming ahead regardless of what they publish and whether or not anybody bothers to read them. But the Titanic sank and so have super-tankers, reminder enough that even the most famous journals should never become complacent.

The world of scientific publishing tends to look down at the lowly ethics of tabloids, and recent events might serve to reinforce that view. Equally, you might argue that medical journals have plenty to learn from tabloids. Sydney Bolam, editor of the Daily Mirror in the 1940s, believed that tabloids fulfilled a ‘necessary and valuable public service.’ Instead of distorting the truth, Bolam argued that a tabloid's mission was ‘the vivid and dramatic presentation of events so as to give them a forceful impact on the reader. It means big headlines, vigorous writing, simplification into familiar everyday writing.’

Tabloids might have deviated from Bolam's guidance in important ways but they have refined their ability to impact on their readers. The tabloid agenda has only thrived because the public has encouraged it; tabloids give readers what they want. The News of the World failed to remember, however, that there are limits to the public's tolerance of intrusion and law-breaking in pursuit of the next sensational headline.

In many ways, medical journals have pursued an agenda diametrically opposed to that of the tabloid press by virtually ignoring what readers want. Medical journals have preferred to pander to the whims of their editors and an unwritten code of scientific publishing that values the inscrutable as well as the obscure. The number of journals that primarily attempt to satisfy the needs of their readers is small.

Indeed, the challenge for medical journals is more complex since the needs of authors tend to dominate. But falling subscriptions and the Internet information revolution have forced more foresighted publishers into thinking hard about their publication portfolios. Medical publishing has been a cash cow, it remains so but the cow is struggling to refill its udders. As a consequence, those journals and even publishers who fail to adapt to the challenges of the modern world, and properly balance the needs of authors and readers, might best serve a necessary and valuable public service by following the News of the World out of existence.
Phase II Study of Cetuximab in Combination with Cisplatin and Radiation in Unresectable, Locally Advanced Head and Neck Squamous Cell Carcinoma: Eastern Cooperative Oncology Group Trial E3303
Authors: Ann Marie Egloff, Ju-Whei Lee, Corey J. Langer, Harry Quon, Alec Vaezi, Jennifer R. Grandis, Raja R. Seethala, Lin Wang, Dong M. Shin, Athanassios Argiris, Donghua Yang, Ranee Mehra, John Andrew Ridge, Urjeet A. Patel, Barbara A. Burtness, Arlene A. Forastiere
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination. Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m2) followed by 250 mg/m2/week and cisplatin 75 mg/m2 q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival. Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%–61%]. Two-year overall survival (OS) was 66% (95% CI, 53%–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively). Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. Clin Cancer Res; 20(19); 5041–51. ©2014 AACR.
Note on a Hitherto Undescribed Appearance of the Retina, or "Shot-Silk" Retina
Authors: W. S. Watson
Journal: BMJ (1884)

wards the left side, and steadily increased until the time I saw her.She had then the appearance of a woman in the sixth month of pregnancy, with a rounded, firm, elastic, but indistinctly fluctuating tumour, occupying the hypogastric region, and extending as high as the umbilicus.The cervix and os uteri were normal; the uterine cavity measured three inches.The uterus was somewhat fixed, espe- cially on the right side, where there was a greater sense of resistance than on the left, but no decided tumour could be made out.The flanks were clear on percussion.There was an entire absence of any sympathetic signs of pregnancy.It appeared to me that we had to deal with an extra-uterine pregnancy almost certainly; but the question then arose: What else was there?What had caused the recent increase in size?The possibility of normal pregnancy at first caused me to hesitate about passing a sound, and this was done only because it was essential to confirm the diagnosis.At the worst, only a miscarriage would occur.Then an adherent ovarian tumour seemed probable, or a fibro-cystic enlargement of the uterus, or per- haps suppuration occurring in a mass of pelvic cellulitis, or in the interior of the sac of an extra-uterine fcetus.It was clearly one of those cases in which an abdominal section was the proper course.This was done on May 14th, 1883, under ether.An incision, about four inches in length, into the peritoneal cavity, exposed what seemed to be a universally adherent omentum, cover- ing a large tumour occupying the uterine region.The adhesion to the abdominal wall on the whole of the right side was so intimate, that the hand could not be passed at all in that direction.The slightest attempt to do so caused free bleeding.On the left side a dark, purplish, smooth portion of tumour could be seen and felt, firm, tense, and apparently semi-solid, and continuous with the uterus.On handling this carefully I felt some crepitus, which de- eided its character.The cyst was opened, and found to contain a large quantity of fmetid, dark, purulent fluid, and a macerated foetus.The bones show that it was almost, if not quite, mature.The con- tents were carefully removed, care being taken to prevent any escape into the peritoneal cavity, and the edges of the cyst were secured to the centre of.the abdominal wound by silk sutures.The cyst- wall was thick, and muscular; it was firmly adherent over the whole of the right side and posteriorly for some inches to the colon, at which point it had thinned, and was very soft and friable.An India-rubber drainage-tube was left in the cavity, and a glass one in the pelvis, through the lower portion of the wound.Gauze dress- ings were used.Slight sickness followed the operation, and the next day she appeared little the worse for it.Temperature 100.40Fahr.
Is the association between irritable bowel syndrome and abuse explained by neuroticism? A population based study
Authors: N J Talley, P M Boyce, M Jones
Journal: Gut (1998)

In outpatients and the community, an association between abuse (particularly sexual abuse) and irritable bowel syndrome (IBS) has been observed, but whether there is a causal link continues to be disputed.To test the hypothesis that psychological factors explain the apparent association between abuse and IBS.A sample of residents of Penrith (a Sydney suburb sociodemographically similar to the Australian population) selected randomly from the electoral rolls (that by law include the entire population of age 18 years and above) was mailed a validated self report questionnaire. Measured were gastrointestinal (GI) symptoms including the Rome criteria for IBS, abuse (including the standardised Drossman questions), neuroticism (Eysenck Personality Questionnaire), and psychological morbidity (General Health Questionnaire).The response rate was 64% (n = 730); 12% fulfilled the Rome criteria for IBS. Overall abuse in childhood (odds ratio (OR) = 2.02, 95% confidence interval (CI) 1.29 to 3.15) but not adulthood (OR = 1.39, 95% CI 0.88 to 2.19) was associated with IBS univariately. Neuroticism and psychological morbidity were also univariately associated with abuse in childhood, abuse in adulthood and IBS, respectively. However, by logistic regression, abuse in childhood was not associated with IBS after controlling for age, gender, and psychological factors (OR = 1.34, 95% CI 0.83 to 2.17). The results were not altered by restricting the analyses to more severe forms of abuse, and were not explained by interactions between abuse and psychological variables.There is an association between abuse and IBS in the community, but this may be explained in part by other psychological factors. Based on a path analysis, we postulate that abuse may induce the expression of neuroticism that in turn leads to IBS.
Chronic Effusive Pericarditis
Authors: S. CONTRO, G. DE GIULI, F. RAGAZZINI
Journal: Circulation (1955)

An unusual case of chronic pericarditis with effusion, lasting at least four years, in an asymptomatic child, is presented. The literature on the subject is reviewed. Attention is drawn to the fact that such cases exist, and should be considered when one is confronted with a case of cardiac enlargement of obscure etiology.