tbuckley/cabot-search huggingface dataset:
The Desmoplastic Reaction Surrounding Hepatic Colorectal Adenocarcinoma Metastases Aids Tumor Growth and Survival via αv Integrin Ligation
Authors: John A. Conti, Timothy J. Kendall, Adrian Bateman, Thomas A. Armstrong, Andrew Papa-Adams, Qian Xu, Graham Packham, John N. Primrose, R. Christopher Benyon, John P. Iredale
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The treatment of metastatic colorectal carcinoma represents a major clinical challenge. We investigated the hypothesis that the desmoplastic reaction within the liver elicited by metastatic adenocarcinoma, characterized by collagen I deposition and altered collagen IV distribution, promotes the growth and survival of hepatic colorectal carcinoma metastases. Experimental Design: Partial hepatectomy specimens for metastatic colorectal adenocarcinoma were examined immunohistochemically for differential integrin expression. Human colorectal adenocarcinoma cell lines HT-29, KM12SM, and KM12c were grown on wild-type collagen I or IV, or cleavage-resistant r/r collagen I, and assessed for their growth, survival, and resistance to 5-fluorouracil. The effect of αvβ3 and αvβ5 integrin blockade by neutralizing antibodies was examined. Results: Collagen I, in contrast to collagen IV, significantly enhanced the growth, survival, and chemoresistance of colorectal carcinoma cells. Blockade of the αvβ3 and αvβ5 integrins significantly reduced colorectal carcinoma cell proliferation on collagen, especially in the cell line with the most metastatic potential. These in vitro findings correlated with the pattern of integrin expression identified within resected hepatic colorectal carcinoma metastases. Using matrix metalloproteinase-resistant r/r collagen I as a dominant negative ligand for αv integrins, we showed a key role for this integrin-ligand interaction in mediating the survival and proliferation of colorectal carcinoma cells. Conclusions: Desmoplasia has an important role in the development of hepatic colorectal carcinoma metastasis. The interaction between integrin and collagen I is identified as a potential therapeutic target.
A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer
Authors: Chantel Samardzija, Rodney B Luwor, Mila Volchek, Michael A Quinn, Jock K Findlay, Nuzhat Ahmed
Journal: Molecular Cancer (2015)

High grade epithelial ovarian cancer (EOC) is commonly characterised by widespread peritoneal dissemination and ascites. Metastatic EOC tumour cells can attach directly to neighbouring organs or alternatively, maintain long term tumourigenicity and chemoresistance by forming cellular aggregates (spheroids). Cancer stem-like cells are proposed to facilitate this mechanism. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance. To investigate the expression of Oct4A in primary EOC tumours, IHC and qRT-PCR analyses were used. The expression of Oct4A in chemonaive and recurrent EOC patient ascites-derived tumour cells samples was investigated by qRT-PCR. The functional role of Oct4A in EOC was evaluated by generating stable knockdown Oct4A clones in the established EOC cell line HEY using shRNA-mediated silencing technology. Cellular proliferation, spheroid forming ability, migration and chemosensitivty following loss of Oct4A in HEY cells was measured by in vitro functional assays. These observations were further validated in an in vivo mouse model using intraperitoneal (IP) injection of established Oct4A KD clones into Balb/c nu/nu mice. We demonstrate that, compared to normal ovaries Oct4A expression significantly increases with tumour dedifferentiation. Oct4A expression was also significantly high in the ascites-derived tumour cells of recurrent EOC patients compared to chemonaive patients. Silencing of Oct4A in HEY cells resulted in decreased cellular proliferation, migration, spheroid formation and increased chemosensitivity to cisplatin in vitro. IP injection of Oct4A knockdown cells in vivo produced significantly reduced tumour burden, tumour size and invasiveness in mice, which overall resulted in significantly increased mouse survival rates compared to mice injected with control cells. This data highlights a crucial role for Oct4A in the progression and metastasis of EOC. Targeting Oct4A may prove to be an effective strategy in the treatment and management of epithelial ovarian tumours.
Enzyme activity changes in rat heart after chronic alcohol ingestion
Authors: I. EDES, A. ANDO, M. CSANADY, H. MAZAREAN, F. GUBA
Journal: Cardiovascular Research (1983)

The effect of a chronic intake of dietary alcohol upon myocardial enzymes was studied in rats. Alcohol, comprising more than 40% of the dietary calorie content, was administered to rats for 6 or 12 weeks. To assess the metabolic changes in the myocardium, the following enzymes were measured: lactate dehydrogenase (LDH), malate dehydrogenase (MDH), aldolase (ALD), isocitrate dehydrogenase (ICDH), creatine kinase (CK) and glutamate-pyruvate transaminase (GPT). The activity of CK was decreased (4.79 +/- 0.99 U X mg-1 protein) after 6 weeks on alcohol and was significantly different from that of the controls (5.98 +/- 1.44 U X mg-1 protein). After 12 weeks the CK activity of alcoholic rats had recovered to 5.99 +/- 1.08 U X mg protein-1 and approached the value found in the normal myocardium. A pronounced decrease was found in the activity of MDH: 8.26 +/- 0.69 U X mg protein-1 in the controls, and 6.78 +/- 1.07 U X mg protein-1 and 5.79 +/- 0.85 U X mg protein-1 in the alcoholic rats after 6 and 12 weeks, respectively. The LDH activity decreased to a lesser extent, but significantly: 2.45 +/- 0.18 U X mg protein-1 in the controls, and 2.11 +/- 0.07 U X mg protein-1 and 2.06 +/- 0.29 U X mg protein-1 after 6 and 12 weeks on test. Only slight, not significant, changes were observed for the other enzymes investigated (ICDH, ALD, GPT).(ABSTRACT TRUNCATED AT 250 WORDS)
Postpartum Depression: Current Status and Future Directions
Authors: Michael W. O'Hara, Jennifer E. McCabe
Journal: Annual Review of Clinical Psychology (2013)

Postpartum depression (PPD) is a common and serious mental health problem that is associated with maternal suffering and numerous negative consequences for offspring. The first six months after delivery may represent a high-risk time for depression. Estimates of prevalence range from 13% to 19%. Risk factors mirror those typically found with major depression, with the exception of postpartum-specific factors such as sensitivity to hormone changes. Controlled trials of psychological interventions have validated a variety of individual and group interventions. Medication often leads to depression improvement, but in controlled trials there are often no significant differences in outcomes between patients in the medication condition and those in placebo or active control conditions. Reviews converge on recommendations for particular antidepressant medications for use while breastfeeding. Prevention of PPD appears to be feasible and effective. Finally, there is a growing movement to integrate mental health screening into routine primary care for pregnant and postpartum women and to follow up this screening with treatment or referral and with follow-up care. Research and clinical recommendations are made throughout this review.
Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer
Authors: John J Kavanagh, Charles F Levenback, Pedro T Ramirez, Judith L Wolf, Carla L Moore, Marsha R Jones, Lisa Meng, Gail L Brown, Robert C Bast
Journal: Journal of Hematology & Oncology (2010)

Abstract Background Canfosfamide is a novel glutathione analog activated by glutathione S-transferase P1-1. This study evaluated the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum resistant ovarian cancer. Patients with platinum resistant ovarian carcinoma and measurable disease received canfosfamide at 960 mg/m 2 in combination with PLD at 50 mg/m 2 , intravenously day 1 in every 28 day cycles until tumor progression or unacceptable toxicities. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Results Canfosfamide plus PLD combination therapy was administered at 960/50 mg/m 2 , respectively. Thirty-nine patients received a median number of 4 cycles (range 1.0-18.0). The ORR was 27.8% (95% CI, 14.2-45.2) with a disease stabilization rate of 80.6% (95% CI, 64.0-91.8) in the evaluable population. The CA-125 marker responses correlated with the radiological findings of complete response or partial response. The median PFS was 6.0 months (95% CI, 4.2-7.9) and median survival was 17.8 months. The combination was well tolerated. Myelosuppression was managed with dose reductions and growth factor support. Grade 3 febrile neutropenia was observed in 2 patients (5.1%). Non-hematologic adverse events occurred at the expected frequency and grade for each drug alone, with no unexpected or cumulative toxicities. Conclusions Canfosfamide in combination with PLD is well tolerated and active in platinum and paclitaxel refractory or resistant ovarian cancer. A randomized phase 3 study was conducted based on this supportive phase 2 study. Trial Registration This study was registered at www.clinicaltrials.gov: NCT00052065.
An Anti-Wnt-2 Monoclonal Antibody Induces Apoptosis in Malignant Melanoma Cells and Inhibits Tumor Growth
Authors: Liang You, Biao He, Zhidong Xu, Kazutsugu Uematsu, Julien Mazieres, Naoaki Fujii, Iwao Mikami, Noemi Reguart, Joe K. McIntosh, Mohammed Kashani-Sabet, Frank McCormick, David M. Jablons
Journal: Cancer Research (2004)

Activation of the Wnt/beta-catenin signaling pathway has been associated with human cancers. To test whether Wnt-2 signal is a survival factor in human melanoma cells and thus represents a potential therapeutic target, we investigated the effects of inhibition of Wnt-2 signaling in human melanoma cell lines. We have developed a novel monoclonal antibody against the NH(2) terminus of the human Wnt-2 ligand that induces apoptosis in human melanoma cells overexpressing Wnt-2. Whereas incubation of this antibody with normal cells lacking Wnt-2 expression does not induce apoptosis, Wnt-2 signaling blockade by the ligand-binding antibody is confirmed by down-regulation of Dishevelled and beta-catenin. Wnt-2 small interfering RNA treatment in these cells yielded similar apoptotic effects and downstream changes. Down-regulation of an inhibitor of apoptosis family protein, survivin, was observed in both the Wnt-2 antibody-treated and small interfering RNA-treated melanoma cell lines, suggesting that the antibody induces apoptosis by inactivating survivin. In an in vivo study, this monoclonal anti-Wnt-2 antibody suppresses tumor growth in a xenograft model. These findings suggest that the anti-Wnt-2 monoclonal antibody may be useful for the treatment of patients with malignant melanoma.
ABNORMAL STATES OF CONSCIOUSNESS AND MUSCLE TONE IN INFANTS BORN TO SCHIZOPHRENIC MOTHERS
Authors: BARBARA FISH, MURRAY ALPERT
Journal: American Journal of Psychiatry (1962)

The evaluation of the changing pattern of consciousness can be used as a measure of the growing integrative capacity of the central nervous system in infancy. In the first months of life, at least two skills develop which are necessary for the maintenance of the quiet, open-eyed alert state. There is an increased general level of arousal(17) sufficient to permit responses to minimal visual and auditory stimuli. There is also a gradual modulation of spontaneous excitability and an increase in the toleration of proprioceptive stimuli. This permits a continuing stable state of awareness and prolonged, focused attention. These abilities are essential prerequisites for the well-integrated development of specffic alerting responses(17), which involve differentiated attentiveness, perceptual discrimination, patterns of accommodation, and the more complex functions which modify the accessibility of the CNS to different stimuli. The organization of a stable, sustained state of alertness by 8 weeks of age, as measured in a standard sample of timed behavior, precedes the organization of consolidated waking-sleeping patterns in 24-hour behavior samples(12, 16, 18). It also antedates the qualitative increase in organization noted in infants's EEGs at 3 months of age(3, 4). As part of an ongoing study into abnormal development and early schizophrenia, consciousness and sensory responsiveness were studied in infants of schizophrenic mothers. Four infants showed marked deviations in the direction of excessive apathy or irritability. At 2 years of age, only the most irritable infant has shown grossly maladaptive behavior. The quiet infants had attentuated motor impulses, minimal response to proprioceptive stimuli, and in the most extreme case, flaccid muscle tone and irregular postural development. This quiet state clinically resembles the "adynamia" which Hess produced in cats by electrical stimulation of the lateral anterior hypothalamus (15). These deviations in the state of consciousness, motility and muscle tonus as early as the first day of life, and continuing into the early months of infancy, provide additional evidence of some early disturbance of functioning of the nervous system in this population, which was genetically loaded for schizophrenia. It is postulated that these dysfunctions are related to the disturbances of motility, excitability and perception which are seen in older schizophrenic children (1, 8).
Factor Analysis of the DSM-III-R Borderline Personality Disorder Criteria in Psychiatric Inpatients
Authors: Charles A. Sanislow, Carlos M. Grilo, Thomas H. McGlashan
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The goal of this study was to examine the factor structure of the DSM-III-R criteria for borderline personality disorder in young adult psychiatric inpatients. METHOD: The authors assessed 141 acutely ill inpatients with the Personality Disorder Examination, a semistructured diagnostic interview for DSM-III-R personality disorders. They used correlational analyses to examine the associations among the different criteria for borderline personality disorder and performed an exploratory factor analysis. RESULTS: Cronbach's coefficient alpha for the borderline personality disorder criteria was 0.69. A principal components factor analysis with a varimax rotation accounted for 57.2% of the variance and revealed three homogeneous factors. These factors were disturbed relatedness (unstable relationships, identity disturbance, and chronic emptiness); behavioral dysregulation (impulsivity and suicidal/self-mutilative behavior); and affective dysregulation (affective instability, inappropriate anger, and efforts to avoid abandonment). CONCLUSIONS: Exploratory factor analysis revealed three homogeneous components of borderline personality disorder that may represent personality, behavioral, and affective features central to the disorder. Recognition of these components may inform treatment plans.
Ethnicity Modifies the Relationships of Insulin Resistance, Inflammation, and Adiponectin With Obesity in a Multiethnic Asian Population
Authors: Chin Meng Khoo, Sarina Sairazi, Siska Taslim, Daphne Gardner, Yi Wu, Jeannette Lee, Rob M. van Dam, E. Shyong Tai
Journal: Diabetes Care (2011)

OBJECTIVE The development of obesity-related metabolic disorders varies with ethnicity. We examined whether ethnicity modifies the relationship between BMI and three metabolic pathways (insulin resistance, inflammation, and adiponectin) that are involved in the pathogenesis of diabetes and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS We analyzed data from 4,804 Chinese, Malay, and Asian-Indian residents of Singapore with complete data on insulin resistance (IR), C-reactive protein (CRP), and total adiponectin levels. Linear regression models with an interaction term ethnicity*BMI were used to evaluate whether ethnicity modifies the association between BMI and IR, CRP, and adiponectin. RESULTS In both uni- and multivariate analyses, BMI was directly associated with IR and CRP and inversely with adiponectin across all ethnic groups. When compared with Chinese and Malays, Asian-Indians had higher IR and CRP and lower adiponectin levels. The associations between BMI and its metabolic pathways were significantly stronger in Chinese than in other ethnic groups. The increase in IR and CRP and the decrease in adiponectin for each unit increase in BMI were greater in Chinese than in other ethnic groups. The findings were similar when waist circumference was used in the analyses instead of BMI. CONCLUSIONS The impact of BMI on IR, CRP, and adiponectin appears greater in Chinese as compared with other major Asian ethnic groups. This may partly explain the rapid increase in the prevalence of diabetes and CVD in Chinese populations and highlights the importance of weight management in Asian ethnic groups despite the apparently low levels of obesity.
AIDS vaccine is a long way off
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

“We don't have a protective vaccine available today, and we don't expect to have a protective vaccine available in the foreseeable future,” Dr David Ho, director of the Aaron Diamond AIDS Research Center, told a symposium on HIV-1 vaccines sponsored by the New York Academy of Sciences and the AIDS Vaccine Advocacy Coalition.

Dr Ho, a professor at the Rockefeller University in New York, said that the outlook was poor despite the fact that some products in clinical trials showed promise against animal models of HIV. “Coming up with a vaccine against this virus is going to be tough,” Dr Ho said.

There were several difficulties in developing …
A Pollen Extract (Cernilton) in Patients with Inflammatory Chronic Prostatitis–Chronic Pelvic Pain Syndrome: A Multicentre, Randomised, Prospective, Double-Blind, Placebo-Controlled Phase 3 Study
Authors: Florian M.E. Wagenlehner, Henning Schneider, Martin Ludwig, Jörg Schnitker, Elmar Brähler, Wolfgang Weidner
Journal: European Urology (2009)
Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1
Authors: Ian A. Parish, Heather D. Marshall, Matthew M. Staron, Philipp A. Lang, Anne Brüstle, Jonathan H. Chen, Weiguo Cui, Yao-Chen Tsui, Curtis Perry, Brian J. Laidlaw, Pamela S. Ohashi, Casey T. Weaver, Susan M. Kaech
Journal: Journal of Clinical Investigation (2014)

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.
Association of Postoperative Hyperglycemia With Outcomes Among Patients With Complex Ventral Hernia Repair
Authors: Eugene J. Won, Erik B. Lehman, Abby K. Geletzke, Matthew R. Tangel, Kazuhide Matsushima, Deborah Brunke-Reese, Ariana R. Pichardo-Lowden, Eric M. Pauli, David I. Soybel
Journal: JAMA Surgery (2015)

Patients with medically complex conditions undergoing repair of large or recurrent hernia of the abdominal wall are at risk for early postoperative hyperglycemia, which may serve as an early warning for delays in recovery and for adverse outcomes.To evaluate postoperative serum glucose level as a predictor of outcome after open ventral hernia repair in patients with major medical comorbidities.We performed a retrospective medical record review of 172 consecutive patients who underwent open ventral hernia repair at Penn State Milton S. Hershey Medical Center, an academic tertiary referral center, from May 1, 2011, through November 30, 2013. We initially identified patients by medical complexity and repair requiring a length of stay of longer than 1 day.Postoperative recovery variables, including time to the first solid meal, length of stay, total costs of hospitalization, and surgical site occurrence.Postoperative serum glucose values were available for 136 patients (79.1%), with 130 (95.6%) obtained within 48 hours of surgery. Among these patients, Ventral Hernia Working Group grade distributions included 8 patients with grade 1, 79 with grade 2, 41 with grade 3, and 8 with grade 4. Fifty-four patients (39.7%) had a postoperative glucose level of at least 140 mg/dL, and 69 patients (50.7%) required insulin administration. Both outcomes were associated with delays in the interval to the first solid meal (glucose level, ≥140 vs <140 mg/dL: mean [SD] delay, 6.4 [5.3] vs 5.6 [8.2] days; P = .01; ≥2 insulin events vs <2: 6.5 [5.5] vs 5.4 [8.4] days; P = .02); increased length of stay (glucose level, ≥140 vs <140 mg/dL: mean [SD], 8.0 [6.0] vs 6.9 [8.2] days; P = .008; ≥2 insulin events vs <2: 8.3 [6.1] vs 6.5 [8.4] days; P < .001); increased costs of hospitalization (glucose level, ≥140 vs <140 mg/dL: mean [SD], $31 307 [$20 875] vs $22 508 [$22 531]; P < .001; ≥2 insulin events vs <2: $31 943 [$22 224] vs $20 651 [$20 917]; P < .001); and possibly increased likelihood of surgical site occurrence (glucose level, ≥140 vs <140 mg/dL: 37.5% [21 of 56 patients] vs 22.5% [18 of 80 patients]; P = .06; ≥2 insulin events vs <2: 36.4% [24 of 66 patients] vs 21.4% [15 of 70 patients]; P = .06). Not all patients with diabetes mellitus developed postoperative hyperglycemia or needed more intense insulin therapy; however, 46.4% of the patients who developed postoperative hyperglycemia were not previously known to have diabetes mellitus, although most had at least 1 clinical risk factor for a prediabetic condition.Postoperative hyperglycemia was associated with outcomes in patients in this study who underwent complex ventral hernia repair and may serve as a suitable target for screening, benchmarking, and intervention in patient groups with major comorbidities.