tbuckley/cabot-search huggingface dataset:
Infliximab-induced acne: report of two cases
Authors: E. Bassi, F. Poli, A. Charachon, P. Claudepierre, J. Revuz
Journal: British Journal of Dermatology (2006)

Conflicts of interest: none declared. Sir, Infliximab is a chimeric (mouse–human) monoclonal antibody targeting tumour necrosis factor (TNF)‐α. We report two cases of infliximab‐induced acne. Patient 1, a 32‐year‐old man, had been treated since 2001 for Crohn disease. No past medical history of acne was noted. He had received prednisone between 2001 and November 2005 and azathioprine since 2002, with no clinical improvement. In August 2005, infliximab (5 mg kg−1 monthly) was started. In January 2006, after five monthly perfusions, the patient complained of papulopustules and nodules on the back (Fig. 1) with open and closed comedones. Treatment with doxycycline 100 mg daily together with local adapalene produced some clinical improvement. Patient 2, a 30‐year‐old man, had been treated since 2002 for ankylosing spondylitis using nonsteroidal anti‐inflammatory drugs without clinical improvement. He had no past medical history of acne. Infliximab (5 mg kg−1 every 15 days) was started in September 2005. After the second perfusion, open and closed comedones on the face with few inflammatory lesions were noted. Treatment with lymecycline 300 mg daily together with topical adapalene resulted in clinical improvement.
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival
Authors: Tyler J Curiel, George Coukos, Linhua Zou, Xavier Alvarez, Pui Cheng, Peter Mottram, Melina Evdemon-Hogan, Jose R Conejo-Garcia, Lin Zhang, Matthew Burow, Yun Zhu, Shuang Wei, Ilona Kryczek, Ben Daniel, Alan Gordon, Leann Myers, Andrew Lackner, Mary L Disis, Keith L Knutson, Lieping Chen, Weiping Zou
Journal: Nature Medicine (2004)
Prostate Cancer Diagnosis and Treatment After the Introduction of Prostate-Specific Antigen Screening: 1986-2005
Authors: H. G. Welch, P. C. Albertsen
Journal: JNCI Journal of the National Cancer Institute (2009)

Although there is uncertainty about the effect of prostate-specific antigen (PSA) screening on the rate of prostate cancer death, there is little uncertainty about its effect on the rate of prostate cancer diagnosis. Systematic estimates of the number of men affected, however, to our knowledge, do not exist. We obtained data on age-specific incidence and initial course of therapy from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. We then used age-specific male population estimates from the US Census to determine the excess (or deficit) in the number of men diagnosed and treated in each year after 1986—the year before PSA screening was introduced. Overall incidence of prostate cancer rose rapidly after 1986, peaked in 1992, and then declined, albeit to levels considerably higher than those in 1986. Overall incidence, however, obscured distinct age-specific patterns: The relative incidence rate (2005 relative to 1986) was 0.56 in men aged 80 years and older, 1.09 in men aged 70–79 years, 1.91 in men aged 60–69 years, 3.64 in men aged 50–59 years, and 7.23 in men younger than 50 years. Since 1986, an estimated additional 1 305 600 men were diagnosed with prostate cancer, 1 004 800 of whom were definitively treated for the disease. Using the most optimistic assumption about the benefit of screening—that the entire decline in prostate cancer mortality observed during this period is attributable to this additional diagnosis—we estimated that, for each man who experienced the presumed benefit, more than 20 had to be diagnosed with prostate cancer. The introduction of PSA screening has resulted in more than 1 million additional men being diagnosed and treated for prostate cancer in the United States. The growth is particularly dramatic for younger men. Given the considerable time that has passed since PSA screening began, most of this excess incidence must represent overdiagnosis.
Results of a phase I/II study with monoclonal antibody CG250 in combination with IFN α-2A in metastatic renal cell carcinoma patients
Authors: P. Bevan, C. Mala, M. Kindler, M. Siebels, R. Oberneder, H.-J. Beck
Journal: Journal of Clinical Oncology (2004)

4606 Background: cG250 (WX-G250, Renecarex) is a chimeric monoclonal antibody of IgG1 subtype that binds to the cell surface antigen of carboxyanhydrase IX (MN antigen) that is found on 95% of clear cell RCC cells but not on normal kidney tissue. A multi-center, open-label, prospective, single-arm phase I/II trial study has been performed, evaluating the safety and efficacy of repeated doses of WX-G250 in combination with IFN α-2a in a total of 32 patients with metastatic RCC. Methods: Patients with stage IV renal cell carcinoma, nephrectomy for the primary tumor, in progression at study entry and with measurable bidimensionally disease between ≥1 cm and ≤5 cm in diameter were included in the study. WX-G250 was applied once weekly for 3 months at 20 mg by iv infusion (total dose). In addition, patients were treated with IFN α-2a, 3 MIU, 3 times per week subcutaneously. In week 16, in the event of stable disease or tumor response, continuation of treatment with the WX-G250 for 6 more weeks was offered. Results: Of 32 enrolled patients, 31 patients could be analyzed. The safety population patients (n = 31) experienced a total of 183 adverse events (AEs). The AEs which were definitely related to study medication (39/183, 25.8%) were of toxicity grade 1 and 2. They mainly comprised ‘constitutional symptoms’ (22 AEs, 25.8%) and ‘pain’ (13 AEs, 12.9 %), described as typical side effects of the treatment with cytokines. No immunological response (HACA) could be detected during the course of WX-G250 treatment. Tumor assessment was performed by the investigators by computertomography (CT)-evaluation. Preliminary primary efficacy results were determined by tumor assessment in week 16 with 83.3% of the patients (N=26). 11.5% (N=3) of these patients showed PR, 46.2% (N=12) SD and 42.3% (N=11) PD. All results are subject to further evaluation by an independent radiologist. Data collection on TTP and OS are still ongoing. Conclusions: Treatment with WX-G250 is generally safe and well tolerated. Objective tumor responses and disease stabilization can be considered as clinically meaningful and are of clinical benefit for this metastatic patient population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wilex AG Wilex AG
Effect of Ethanol on Serum Cholesterol Concentration in Dog and Man
Authors: FRANCISCO GRANDE, LYLE J. HAY, H. WILLIAM HEUPEL, DONALD S. AMATUZIO
Journal: Circulation Research (1960)

The effect of ethanol on serum cholesterol concentration has been studied in normal male dogs subsisting on diets of low cholesterol content. Daily administration of 1.65 Gm. ethanol/Kg, of body weight produced significant increases of serum cholesterol in dogs when fed either a low-fat diet (4 per cent of fat calories) or a high-fat (40 per cent) diet. The mean cholesterol increase after 2 weeks of ethanol administration was 52 mg./100 ml. (SE, 8.2) for 8 dogs on the low-fat diet, and 75 (SE, 6.6) for 24 dogs on the high-fat (lard) diet. No significant difference was found between the mean increases of serum cholesterol produced by ethanol administration, using either the high-fat diet of saturated fat (lard) or that of unsaturated fat (sunflower oil). Serum cholesterol concentration decreases rapidly after discontinuing the administration of ethanol, reaching the prealcohol levels in 2 to 3 weeks. The higher levels of serum cholesterol are maintained as long as the administration of ethanol continues. Sodium acetate, when given at the same molar quantity as ethanol, failed to produce any change of serum cholesterol concentration in the dog. The effect of ethanol administration on serum cholesterol concentration in man was tested in 2 switchback experiments, comparing the effects of alcohol and those of a supplement of syrup of equal calorie value while the men were eating a normal diet containing 38 per cent of fat calories. When 0.45 Gm. ethanol/ Kg./day were given to 59 normal men for 3 weeks, no significant difference of serum cholesterol concentration was observed between the values on syrup and on alcohol. However, the administration of 1.35 Gm./Kg./ day to 14 men produced a mean increase of serum cholesterol concentration of 18 mg./100 ml. (SE, 5.0) within 1 week. The individual increases of serum cholesterol are correlated with the intrinsic cholesterol levels of the subjects (r = + 0.67, p &gt; 0.01). It is concluded that ethanol increases serum cholesterol concentration in the dog and man. The response in the dog is much greater than that observed in the human subjects.
Cholesterol in health and disease
Authors: Ira Tabas
Journal: Journal of Clinical Investigation (2002)

Imagine if an excess amount of a critical, life-sustaining molecule like ATP were, by a perverse series of events involving the lifestyle of modern humans, causally related to a major human disease.The thought of "ATP" being synonymous with poor health and poor living in the minds of the lay public and press, even of health care providers, would be difficult for any selfrespecting scientist to accept.So one might view the biomedical history of cholesterol -indeed, this history might be seen as even stranger than the hypothetical ATP scenario, given that evolution has devoted close to 100 genes to the synthesis, transport, metabolism, and regulation of cholesterol.This structurally fascinating lipid is utterly essential to the proper functioning of cells and organisms.Cholesterol, cholesterol metabolites, and immediate biosynthetic precursors of cholesterol play essential roles in cellular membrane physiology, dietary nutrient absorption, reproductive biology, stress responses, salt and water balance, and calcium metabolism.Indeed, many of the articles in this Perspective series are devoted to the normal physiology of cholesterol.Still, there is little doubt that the disease process responsible for the leading cause of death in the industrialized world -atherosclerosis -is a disorder in which an excess of cholesterol is a major culprit.How did evolution come up with a molecule that is critical for so many aspects of normal physiology, and what went "wrong"? Cholesterol in health and disease
Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity
Authors: Wyndham H Wilson, Owen A O'Connor, Myron S Czuczman, Ann S LaCasce, John F Gerecitano, John P Leonard, Anil Tulpule, Kieron Dunleavy, Hao Xiong, Yi-Lin Chiu, Yue Cui, Todd Busman, Steven W Elmore, Saul H Rosenberg, Andrew P Krivoshik, Sari H Enschede, Rod A Humerickhouse
Journal: The Lancet Oncology (2010)
A Novel Migration Pathway for Rat Dendritic Cells from the Blood: Hepatic Sinusoids–Lymph Translocation
Authors: Shunsuke Kudo, Kenjiro Matsuno, Taichi Ezaki, Michio Ogawa
Journal: The Journal of Experimental Medicine (1997)

The migration pathways for dendritic cells (DC) from the blood are not yet completely resolved. In our previous study, a selective recruitment of DC progenitors from the blood to the liver was suggested. To clarify the role of the hepatic sinusoids in the migration of blood DC, relatively immature DC and mature DC were isolated from hepatic and intestinal lymph, and intravenously transferred to allogeneic hosts. It was then possible to detect small numbers of DC within secondary lymphoid tissues either by immunostaining for donor type major histocompatibility complex class I antigen or, at much higher sensitivity, for bromodeoxyuridine incorporated by proliferating cells (mainly T lymphocytes), which responded to the alloantigen presented by the administered DC. The intravenously injected DC accumulated in the paracortex of regional lymph nodes of the liver via a lymph-borne pathway. Intravenously injected fluorochrome-labeled syngeneic DC behaved similarly. In contrast, very few DC were found in spleen sections and were hardly detectable in other lymph nodes or in other tissues. An in situ cell binding assay revealed a significant and selective binding of DC to Kupffer cells in liver cryosections. It is concluded that rat DC can undergo a blood-lymph translocation via the hepatic sinusoids, but not via the high endothelial venules of lymph nodes. Hence the hepatic sinusoids may act as a biological concentrator of blood DC into the regional hepatic nodes. Kupffer cells may play an important role in this mechanism.
Measurements of interrupter resistance: reference values for children 3-13 yrs of age
Authors: P.J.F.M. Merkus, H.G.M. Arets, T. Joosten, A. Siero, M. Brouha, J.Y. Mijnsbergen, J.C. de Jongste, C.K. van der Ent
Journal: European Respiratory Journal (2002)

The interrupter technique is a convenient and sensitive technique for studying airway function in subjects who cannot actively participate in (forced) ventilatory function tests. Reference values for preschool children exist but are lacking for children >7 yrs. Reference values were obtained for expiratory interrupter resistance (R(int,e)) in 208 healthy Dutch Caucasian children 3-13 yrs of age. A curvilinear relationship between R(int,e) and height was observed, similar to published airways resistance data measured by plethysmography. No significant differences in cross-sectional trend or level of R(int,e) were observed according to sex. It was found that Z-scores could be used to express individual R(int,e) values and to describe intra- and interindividual differences based on the reference equation: 10logR(int,e)=0.645-0.00668x standing height (cm) kPa x L(-1) x s(-1) and residual SD (0.093 kPa x L(-1) x s(-1)). Expiratory interrupter resistance provides a tool for clinical and epidemiological assessment of airway function in a large age range.
Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation.
Authors: R R Pauly, A Passaniti, C Bilato, R Monticone, L Cheng, N Papadopoulos, Y A Gluzband, L Smith, C Weinstein, E G Lakatta
Journal: Circulation Research (1994)

The migration of vascular smooth muscle cells (VSMCs) from the tunica media to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence of mechanical injury to the blood vessel. In vivo, VSMCs are surrounded by and embedded in a variety of extracellular matrices (ECMs) that must be traversed during migration. One of the principal barriers to cell movement in the intact vessel is the basement membrane (BM) that surrounds each VSMC and separates the VSMC-containing medial cell layer from the endothelium. We have used a Boyden chamber to monitor the ability of VSMCs to degrade a BM barrier as they migrate toward a chemoattractant and to define the role of extracellular proteases in this process. We show that cultured VSMCs can migrate across a BM barrier and that this ability was dependent on the phenotypic state of the cell. VSMCs maintained in a proliferating or "synthetic" state readily migrated across a BM toward a chemoattractant, whereas the migration of serum-starved/differentiated VSMCs was suppressed by &gt; 80% (P &lt; .001). By use of a number of peptides that inhibit matrix metalloproteinase (MMP) activity, the migration of proliferating VSMCs across the BM barrier was inhibited by &gt; 80% (P &lt; .0001), whereas migration that occurred in the absence of the barrier was unaffected. Northern blotting and zymographic analyses indicated that 72-kD type IV collagenase (MMP2) was the principal MMP expressed and secreted by these cells. Accordingly, antisera capable of selectively neutralizing MMP2 activity also inhibited VSMC migration across the barrier without significantly affecting the migration of VSMCs in the absence of the barrier. Finally, MMP2 activity was also regulated by the phenotypic state of the cells in that MMP2 activity expressed by serum-starved/differentiated VSMCs was &lt; 5% of that measured in proliferating VSMCs. Extrapolating to the in vivo situation in which VSMCs reside in an ECM composed of various BM barriers, these results suggest that VSMC migration in vivo may be dependent on MMP2 activity. That activity, in turn, could be regulated by the phenotypic state of VSMCs and increase as these cells undergo the transition from a quiescent and differentiated state to that of a dedifferentiated, proliferating, and motile phenotype after injury to the vessel.
Protein Kinase A Type I and Type II Define Distinct Intracellular Signaling Compartments
Authors: Giulietta Di Benedetto, Anna Zoccarato, Valentina Lissandron, Anna Terrin, Xiang Li, Miles D. Houslay, George S. Baillie, Manuela Zaccolo
Journal: Circulation Research (2008)

Protein kinase A (PKA) is a key regulatory enzyme that, on activation by cAMP, modulates a wide variety of cellular functions. PKA isoforms type I and type II possess different structural features and biochemical characteristics, resulting in nonredundant function. However, how different PKA isoforms expressed in the same cell manage to perform distinct functions on activation by the same soluble intracellular messenger, cAMP, remains to be established. Here, we provide a mechanism for the different function of PKA isoforms subsets in cardiac myocytes and demonstrate that PKA-RI and PKA-RII, by binding to AKAPs (A kinase anchoring proteins), are tethered to different subcellular locales, thus defining distinct intracellular signaling compartments. Within such compartments, PKA-RI and PKA-RII respond to distinct, spatially restricted cAMP signals generated in response to specific G protein-coupled receptor agonists and regulated by unique subsets of the cAMP degrading phosphodiesterases. The selective activation of individual PKA isoforms thus leads to phosphorylation of unique subsets of downstream targets.
Selective Constraint Dominates the Evolution of Genes Expressed in a Novel Reproductive Gland
Authors: Findley R. Finseth, Eliana Bondra, Richard G. Harrison
Journal: Molecular Biology and Evolution (2014)

One striking pattern in molecular evolution is that genes encoding proteins involved in reproduction tend to evolve rapidly. Seminal fluid proteins frequently exhibit this pattern and directly affect multiple reproductive processes including enhancing sperm performance and mediating postmating sexual selection. Here, we investigate molecular evolutionary patterns of genes expressed in the foam gland of Japanese quail (Coturnix japonica), a novel reproductive phenotype. Foam provides an interesting contrast to seminal fluid because it plays a similar functional role, yet is produced, stored, and transferred to females independent of semen. We combined RNA-Seq and comparative genomics to examine evolutionary rates of genes with enriched expression in the foam gland of Japanese quail and those that exhibit enriched expression in two other tissues (testis and liver) and with broadly expressed genes. Overall, we found pronounced heterogeneity in evolutionary rates. Foam gland genes evolved under strong evolutionary constraint, whereas testis genes evolved rapidly and sometimes adaptively. These striking differences were robust to variation in gene expression. Genes with enriched expression in the foam gland did not show major shifts in selective pressure after the quail and chicken lineages split; in contrast, testis-expressed genes experienced a burst of accelerated evolution specifically along the Coturnix lineage. Our work demonstrates that, as a class, genes expressed in the novel foam gland experience different selection regimes than genes expressed in many other tissues producing seminal fluid proteins. Our results also highlight the importance of selective constraint in shaping the evolution of male reproductive genes.
Aberrant promoter methylation of CDH13 and MGMT genes is associated with clinicopathological characteristics of primary non small cell lung carcinoma
Authors: Milica Kontic, Jelena Stojsic, Dragana Jovanovic, Simona Ognjanovic, Heather Nelson, Susan Puumala
Journal: European Respiratory Journal (2012)

Introduction: Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. We investigate the relationship between gene methylation in lung tumors relative to normal lung tissue, and whether DNA methylation changes can be detected in paired blood samples.  Material and methods: 65 patients were enrolled in a surgical case series of non-small cell lung cancer (NSCLC) at a single institution. Using bisulfite pyrosequencing, CpG methylation was quantified at five genes (RASSF1A, CDH13, MGMT, ESR1 and DAPK) in lung tumor, pathologically normal lung tissue, and circulating blood from enrolled cases.  Results: The analyses of methylation in tumors compared to normal lung identified higher methylation of CDH13, RASSF1A and DAPK, while ESR1 and MGMT methylation did not differ significantly between these tissue types. We examined whether the three aberrantly methylated genes could be detected in blood. The difference in methylation observed in tumors was not reflected in methylation status of matching blood samples, indicating a low feasibility of detecting lung cancer by analyzing these genes in a blood-based test. Lastly we probed whether tumor methylation was associatied with clinical and demographic characteristics. Histology and gender were associated with methylation at the CDH13, while stage was associated with methylation at MGMT.  Conclusion: Our results show higher methylation of RASSF1A, CDH13 and DAPK genes in lung tumors compared to normal lung. The lack of reflection of these methylation changes in blood samples from patients with NSCLC indicate their poorly suitability for a screening test.
A Noninvasive Method for Assessing Impaired Diastolic Suction in Patients With Dilated Cardiomyopathy
Authors: Raquel Yotti, Javier Bermejo, J. Carlos Antoranz, M. Mar Desco, Cristina Cortina, José Luis Rojo-Álvarez, Carmen Allué, Laura Martín, Mar Moreno, José A. Serrano, Roberto Muñoz, Miguel A. García-Fernández
Journal: Circulation (2005)

Diastolic suction is a major determinant of early left ventricular filling in animal experiments. However, suction remains incompletely characterized in the clinical setting.First, we validated a method for measuring the spatio-temporal distributions of diastolic intraventricular pressure gradients and differences (DIVPDs) by digital processing color Doppler M-mode recordings. In 4 pigs, the error of peak DIVPD was 0.0+/-0.2 mm Hg (intraclass correlation coefficient, 0.95) compared with micromanometry. Forty patients with dilated cardiomyopathy (DCM) and 20 healthy volunteers were studied at baseline and during dobutamine infusion. A positive DIVPD (toward the apex) originated during isovolumic relaxation, reaching its peak shortly after mitral valve opening. Peak DIVPD was less than half in patients with DCM than in control subjects (1.2+/-0.6 versus 2.5+/-0.8 mm Hg, P<0.001). Dobutamine increased DIVPD in control subjects by 44% (P<0.001) but only by 23% in patients with DCM (P=NS). DIVPDs were the consequence of 2 opposite forces: a driving force caused by local acceleration, and a reversed (opposed to filling) convective force that lowered the total DIVPD by more than one third. In turn, local acceleration correlated with E-wave velocity and ejection fraction, whereas convective deceleration correlated with E-wave velocity and ventriculo:annular disproportion. Convective deceleration was highest among patients showing a restrictive filling pattern.Patients with DCM show an abnormally low diastolic suction and a blunted capacity to recruit suction with stress. By raising the ventriculo:annular disproportion, chamber remodeling proportionally increases convective deceleration and adversely affects left ventricular filling. These previously unreported mechanisms of diastolic dysfunction can be studied by using Doppler echocardiography.