tbuckley/cabot-search huggingface dataset:
A Novel Reduced Immunogenicity Bispecific Targeted Toxin Simultaneously Recognizing Human Epidermal Growth Factor and Interleukin-4 Receptors in a Mouse Model of Metastatic Breast Carcinoma
Authors: Seunguk Oh, Brad J. Stish, Deepali Sachdev, Hua Chen, Arkadiusz Z. Dudek, Daniel A. Vallera
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To develop a targeted biological drug that when systemically injected can penetrate to metastatic breast cancer tumors, one needs a drug of high potency and reduced immunogenicity. Thus, we bioengineered a novel bispecific ligand–directed toxin (BLT) targeted by dual high-affinity cytokines with a PE38KDEL COOH terminus. Our purpose was to reduce toxin immunogenicity using mutagenesis, measure the ability of mutated drug to elicit B-cell antitoxin antibody responses, and show that mutated drug was effective against systemic breast cancer in vivo. Experimental Design: A new BLT was created in which both human epidermal growth factor (EGF) and interleukin 4 cytokines were cloned onto the same single-chain molecule with truncated Pseudomonas exotoxin (PE38). Site-specific mutagenesis was used to mutate amino acids in seven key epitopic toxin regions that dictate B-cell generation of neutralizing antitoxin antibodies. Bioassays were used to determine whether mutation reduced potency, and ELISA studies were done to determine whether antitoxin antibodies were reduced. Finally, a genetically altered luciferase xenograft model was used; this model could be imaged in real time to determine the effect on the systemic malignant human breast cancer MDA-MB-231. Results: EGF4KDEL 7mut was significantly effective against established systemic human breast cancer and prevented metastatic spread. Mutagenesis reduced immunogenicity by ∼90% with no apparent loss in in vitro or in vivo activity. Conclusions: Because EGF4KDEL 7mut was highly effective even when we waited 26 days to begin therapy and because immunogenicity was significantly reduced, we can now give multiple drug treatments for chemotherapy-refractory breast cancer in clinical trials. (Clin Cancer Res 2009;15(19):6137–47)
Collagen breakdown during acute lung injury.
Authors: I Y Adamson, G M King, D H Bowden
Journal: Thorax (1988)

Injury to the capillary endothelium and to alveolar epithelial cells of the lung may result in damage to the underlying collagen of the extracellular matrix. To examine this possibility, whole body irradiation, bleomycin injections, and exposure to hyperoxia were used to induce various types of lung damage in mice. The morphology of the lung and the cellular and protein content of bronchoalveolar lavage fluid were used to assess injury. Collagen breakdown was assessed from the hydroxyproline concentrations in bronchoalveolar lavage fluid. When lung cell injury was observed, protein leaked in to alveoli and hydroxyproline was detected in bronchoalveolar lavage fluid. An increase in hydroxyproline followed endothelial damage by irradiation and was greatly increased when type 1 epithelial cell necrosis also occurred after bleomycin injection or hyperoxia. Maximal concentrations of hydroxyproline occurred in mice showing respiratory distress after six days of hyperoxia. Concentrations returned to zero during the subsequent phases of cell regeneration and fibrosis seen after bleomycin injection and irradiation. There was little change in the cellular components of bronchoalveolar lavage fluid at any time. The results indicate that collagen breakdown occurs during acute lung injury and can be quantified in terms of the hydroxyproline concentration in lavage fluid. Such a change in the extracellular matrix might influence the subsequent division and differentiation of regenerating cells during repair.
Detecting Activation of Ribosomal Protein S6 Kinase by Complementary DNA and Tissue Microarray Analysis
Authors: M. Barlund, F. Forozan, J. Kononen, L. Bubendorf, Y. Chen, M. L. Bittner, J. Torhorst, P. Haas, C. Bucher, G. Sauter, O.-P. Kallioniemi, A. Kallioniemi
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Studies by comparative genomic hybridization (CGH) have shown that chromosomal region 17q23 is amplified in up to 20% of primary breast cancers. We used microarray analyses to measure the expression levels of genes in this region and to explore their prognostic importance. Methods: A microarray that contained 4209 complementary DNA (cDNA) clones was used to identify genes that are overexpressed in the MCF-7 breast cancer cell line as compared with normal mammary tissue. Fluorescence in situ hybridization was used to analyze the copy number of one overexpressed gene, ribosomal protein S6 kinase (S6K), and to localize it to the 17q23 region. Northern and western blot analyses were used to measure S6K gene and protein expression, and an enzymatic assay was used to measure S6K activity. Tumor tissue microarray analysis was used to study amplification of S6K and the HER-2 oncogene, another 17q-linked gene, and the relationship between amplification and prognosis was analyzed. The Kaplan–Meier method was used for data analysis, and the log-rank test was used for statistical analysis. All P values are two-sided. Results: S6K was amplified and highly overexpressed in MCF-7 cells relative to normal mammary epithelium, and protein expression and enzyme activity were increased. S6K was amplified in 59 (8.8%) of 668 primary breast tumors, and a statistically significant association between amplification and poor prognosis (P = .0021) was observed. Amplification of both S6K and HER-2 implied particularly poor survival (P = .0001). Conclusions: The combination of CGH information with cDNA and tissue microarray analyses can be used to identify amplified and overexpressed genes and to evaluate the clinical implications of such genes and genomic rearrangements. S6K is likely to be one of the genes at 17q23 that is amplified during oncogenesis and may adversely affect the prognosis of patients with this amplification.
Cognitive Rehabilitation for Traumatic Brain Injury&lt;SUBTITLE&gt;A Randomized Trial&lt;/SUBTITLE&gt;
Authors: Andres M. Salazar
Journal: JAMA (2000)

Traumatic brain injury (TBI) is a principal cause of death and disability in young adults. Rehabilitation for TBI has not received the same level of scientific scrutiny for efficacy and cost-efficiency that is expected in other medical fields.To evaluate the efficacy of inpatient cognitive rehabilitation for patients with TBI.Single-center, parallel-group, randomized trial conducted from January 1992 through February 1997 at a US military medical referral center.One hundred twenty active-duty military personnel who had sustained a moderate-to-severe closed head injury, manifested by a Glasgow Coma Scale score of 13 or less, or posttraumatic amnesia lasting at least 24 hours, or focal cerebral contusion or hemorrhage on computed tomography or magnetic resonance imaging.Patients were randomly assigned to an intensive, standardized, 8-week, in-hospital cognitive rehabilitation program (n=67) or a limited home rehabilitation program with weekly telephone support from a psychiatric nurse (n=53).Return to gainful employment and fitness for military duty at 1-year follow-up, compared by intervention group.At 1-year follow-up, there was no significant difference between patients who had received the intensive in-hospital cognitive rehabilitation program vs the limited home rehabilitation program in return to employment (90% vs 94%, respectively; P=.51; difference, 4% [95% confidence interval ¿CI¿, -5% to 14%]) or fitness for duty (73% vs 66%, respectively; P=. 43; difference, 7% [95% CI, -10% to 24%]). There also were no significant differences in cognitive, behavioral, or quality-of-life measures. In a post-hoc subset analysis of patients who were unconscious for more than 1 hour (n = 75) following TBI, the in-hospital group had a greater return-to-duty rate (80% vs 58%; P=. 05).In this study, the overall benefit of in-hospital cognitive rehabilitation for patients with moderate-to-severe TBI was similar to that of home rehabilitation. These findings emphasize the importance of conducting randomized trials to evaluate TBI rehabilitation interventions. JAMA. 2000;283:3075-3081
Tenocyte apoptosis in the torn rotator cuff: a primary or secondary pathological event?
Authors: Kirsten Lundgreen, Øystein Bjerkestrand Lian, Lars Engebretsen, Alex Scott
Journal: British Journal of Sports Medicine (2011)

Little information exists on the contribution of apoptosis to pathological tendon changes in rotator cuff tendinopathy. The purpose of this study was to quantitate the rate of tenocyte apoptosis in torn supraspinatus tendons and in the matched intact subscapularis and to examine the potential relation between apoptotic index (AI) and tendon pathology. In addition, the authors examined tenocyte density, proliferation rate and p53 gene expression patterns to gain further insight into relevant pathological mechanisms in the torn suprapinatus. 15 torn supraspinatus tendons with matched intact subscapularis tendon samples and 10 reference subscapularis samples were collected. Immunohistochemistry was used to define the AI (F7-26), proliferation rate (Ki67) and presence of p53 (M7001). Tendon degeneration was evaluated according to the Bonar scale. Expression of p53 and relevant genes (n=84) was examined on a subset of samples using microfluidic arrays. The AI was significantly increased in torn supraspinatus tendon and matched subscapularis tendon (R 2 =0.5742; p=0.0005). Cell density and proliferation rate were also elevated in torn supraspinatus compared with reference subscapularis tendons (p&lt;0.05). A significant increase in p53 occurred specifically in torn supraspinatus tendon (p&lt;0.05), and several genes encoding p53-inhibiting proteins were downregulated in association, including HDAC1 (p&lt;0.05), MDM4 (p&lt;0.001) and PPM1D (p&lt;0.05). Our results suggest that tenocyte apoptosis results from more than one mechanism in the injured rotator cuff, including both intrinsic factors related specifically to the torn supraspinatus tendon, as well as a more generalised effect on the adjacent subscapularis tendon.
Lipoprotein Management in Patients With Cardiometabolic Risk
Authors: John D. Brunzell, Michael Davidson, Curt D. Furberg, Ronald B. Goldberg, Barbara V. Howard, James H. Stein, Joseph L. Witztum
Journal: Diabetes Care (2008)

Risk factors for type 2 diabetes and cardiovascular disease (CVD) often cluster, including obesity (particularly central), insulin resistance, hyperglycemia, dyslipoproteinemia, and hypertension. These conditions can also occur in isolation, and they are exaggerated by physical inactivity and smoking. Since each of these factors increases risk of CVD, the concept of global cardiometabolic risk (CMR) (Fig. 1) is of value (1). Lipoprotein abnormalities, including elevated triglycerides, low HDL cholesterol, and increased numbers of small dense LDL particles, are common findings in patients with CMR. Clinical entities with increased CMR include type 2 diabetes, familial combined hyperlipidemia, familial hypoalphalipoproteinemia, and polycystic ovary syndrome (2). These disorders often share the CMR characteristics of central obesity, insulin resistance, dyslipoproteinemia, and hypertension.

There are stringent lipid treatment goals for patients with type 2 diabetes or CVD; however, guidelines for treatment of dyslipoproteinemia in high-risk subjects without diabetes or CVD are less intense and are based primarily on LDL cholesterol concentrations, with non-HDL concentrations a secondary consideration in some subjects. Numerous trials have demonstrated that therapies (primarily statins) directed at LDL cholesterol lowering clearly reduce risk of CVD events in patients with diabetes and in those without diabetes but with other CVD risk factors; yet, a number of questions remain. Even with adequate LDL cholesterol lowering, many patients on statin therapy have significant residual CVD risk. It is unclear whether lipoprotein parameters other than LDL or non-HDL cholesterol provide clinically significant additional prognostic information regarding CVD risk, yield more information about the effectiveness of therapy, or indicate more appropriate treatment targets. Many patients with CMR or diabetes have relatively normal levels of LDL cholesterol but increased numbers of small dense LDL particles and other atherogenic lipoproteins. Some have advocated that assessment of other lipoprotein parameters might be more helpful than assessment limited to LDL or non-HDL …
Sputum microRNA Biomarkers for Identifying Lung Cancer in Indeterminate Solitary Pulmonary Nodules
Authors: Lingxiao Xing, Jian Su, Maria A. Guarnera, Howard Zhang, Ling Cai, Rixin Zhou, Sanford A. Stass, Feng Jiang
Journal: Clinical Cancer Research (2015)

The early detection of lung cancer in heavy smokers by low-dose CT (LDCT) can reduce the mortality. However, LDCT screening increases the number of indeterminate solitary pulmonary nodules (SPN) in asymptomatic individuals, leading to overdiagnosis. Making a definitive preoperative diagnosis of malignant SPNs has been a clinical challenge. We have demonstrated that sputum miRNAs could provide potential biomarkers for lung cancer. Here, we aimed to develop sputum miRNA biomarkers for diagnosis of malignant SPNs.Using quantitative RT-PCR, we evaluated expressions of 13 sputum miRNAs, previously identified sputum miRNA signatures of lung cancer, in a training set of 122 patients with either malignant (n = 60) or benign SPNs (n = 62) to define a panel of biomarkers. We then validated the biomarker panel in an internal testing set of 136 patients with either malignant (n = 67) or benign SPNs (n = 69), and an external testing cohort of 155 patients with either malignant (n = 76) or benign SPNs (n = 79).In the training set, a panel of three miRNA biomarkers (miRs21, 31, and 210) was developed, producing 82.93% sensitivity and 87.84% specificity for identifying malignant SPNs. The sensitivity and specificity of the biomarkers in the two independent testing cohorts were 82.09% and 88.41%, 80.52% and 86.08%, respectively, confirming the diagnostic value.Sputum miRNA biomarkers may improve LDCT screening for lung cancer in heavy smokers by preoperatively diagnosing malignant SPNs. Nevertheless, a prospective study in a large population to validate the biomarkers is needed.
Psychiatric Characteristics of Homicide Defendants
Authors: Christine A. Martone, Edward P. Mulvey, Suzanne Yang, Andrei Nemoianu, Ryan Shugarman, Layla Soliman
Journal: American Journal of Psychiatry (2013)

The authors examined the rate of mental disorders in an unselected sample of homicide defendants in a U.S. jurisdiction, seeking to identify psychiatric factors associated with offense characteristics and court outcomes.Defendants charged with homicide in a U.S. urban county between 2001 and 2005 received a psychiatric evaluation after arrest. Demographic, historical, and psychiatric variables as well as offense characteristics and legal outcomes were described. Bivariate analyses examined differences by age group and by race, and logistic models examined predictors of multiple victims, firearm use, guilty plea, and guilty verdict.Fifty-eight percent of the sample had at least one axis I or II diagnosis, most often a substance use disorder (47%). Axis I or II diagnoses were more common (78%) among defendants over age 40. Although 37% of the sample had prior psychiatric treatment, only 8% of the defendants with diagnosed axis I disorders had outpatient treatment during the 3 months preceding the homicide; African Americans were less likely than non-African Americans to be in treatment. African American males were more likely to use a firearm and to have a male victim. In exploratory analyses, psychiatric factors did not predict multiple victims, firearm use in the crime, or a guilty verdict.Rates of axis I disorders were lower than reported in previous studies. Few homicide defendants were in psychiatric treatment at the time of the crime, suggesting limited opportunities for prevention by mental health providers.
Retinal Vascular Geometry Predicts Incident Renal Dysfunction in Young People With Type 1 Diabetes
Authors: Paul Z. Benitez-Aguirre, Muhammad Bayu Sasongko, Maria E. Craig, Alicia J. Jenkins, Janine Cusumano, Ning Cheung, Tien Yin Wong, Kim C. Donaghue
Journal: Diabetes Care (2012)

OBJECTIVE To examine the relationship between retinal vascular geometry parameters and development of incident renal dysfunction in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS This was a prospective cohort study of 511 adolescents with type 1 diabetes of at least 2 years duration, with normal albumin excretion rate (AER) and no retinopathy at baseline while attending an Australian tertiary-care hospital. AER was quantified using three overnight, timed urine specimen collections and early renal dysfunction was defined as AER &amp;gt;7.5 μg/min. Retinal vascular geometry (including length-to-diameter ratio [LDR] and simple tortuosity [ST]) was quantified from baseline retinal photographs. Generalized estimating equations were used to examine the relationship between incident renal dysfunction and baseline venular LDR and ST, adjusting for age, diabetes duration, glycated hemoglobin (A1C), blood pressure (BP), BMI, and cholesterol. RESULTS Diabetes duration at baseline was 4.8 (IQR 3.3–7.5) years. After a median 3.7 (2.3–5.7) years follow-up, 34% of participants developed incident renal dysfunction. In multivariate analysis, higher retinal venular LDR (odds ratio 1.7, 95% CI 1.2–2.4; quartile 4 vs. 1–3) and lower venular ST (1.6, 1.1–2.2; quartile 1 vs. 2–4) predicted incident renal dysfunction. CONCLUSIONS Retinal venular geometry independently predicted incident renal dysfunction in young people with type 1 diabetes. These noninvasive retinal measures may help to elucidate early mechanistic pathways for microvascular complications. Retinal venular geometry may be a useful tool to identify individuals at high risk of renal disease early in the course of diabetes.
Fungal Levels in the Home and Allergic Rhinitis by 5 Years of Age
Authors: Paul C. Stark, Juan C. Celedón, Ginger L. Chew, Louise M. Ryan, Harriet A. Burge, Michael L. Muilenberg, Diane R. Gold
Journal: Environmental Health Perspectives (2005)

Studies have repeatedly demonstrated that sensitization to fungi, such as Alternaria, is strongly associated with allergic rhinitis and asthma in children. However, the role of exposure to fungi in the development of childhood allergic rhinitis is poorly understood. In a prospective birth cohort of 405 children of asthmatic/allergic parents from metropolitan Boston, Massachusetts, we examined in-home high fungal concentrations (&gt; 90th percentile) measured once within the first 3 months of life as predictors of doctor-diagnosed allergic rhinitis in the first 5 years of life. In multivariate Cox regression analyses, predictors of allergic rhinitis included high levels of dust-borne Aspergillus [hazard ratio (HR) = 3.27; 95% confidence interval (CI), 1.50–7.14], Aureobasidium (HR = 3.04; 95% CI, 1.33–6.93), and yeasts (HR = 2.67; 95% CI, 1.26–5.66). The factors controlled for in these analyses included water damage or mild or mildew in the building during the first year of the child’s life, any lower respiratory tract infection in the first year, male sex, African-American race, fall date of birth, and maternal IgE to Alternaria &gt; 0.35 U/mL. Dust-borne Alternaria and non-sporulating and total fungi were also predictors of allergic rhinitis in models excluding other fungi but adjusting for all of the potential confounders listed above. High measured fungal concentrations and reports of water damage, mold, or mildew in homes may predispose children with a family history of asthma or allergy to the development of allergic rhinitis.
Studies on gastric mucosal microcirculation. 1. The nature of regional variations induced by ethanol injury.
Authors: N Kalia, N J Brown, S Jacob, M W Reed, K D Bardhan
Journal: Gut (1997)

The focal nature of gastric ulcers raises the possibility of underlying regional disturbances in gastric mucosal microcirculation. This study employed fluorescent in vivo microscopy with the aim of directly investigating the response of several areas of the gastric mucosa to 60% ethanol.Changes in macromolecular leakage of fluorescein labelled albumin, vessel diameter, and acridine red labelled leucocyte adhesion and rolling were assessed over a period of two hours. A total of 0.5 ml 60% ethanol was topically applied for five minutes to the exteriorised gastric mucosa of anaesthetised rats. RATS: Three distinct patterns of response were found. Areas of lesion formation were small and occurred within five minutes. These areas showed persistent blood flow stasis throughout the course of the experiment, increased leakage (p < 0.02), and no leucocyte adhesion. Peripheral to the lesion, sustained leakage (p < 0.02) was found with adherence of leucocytes (p < 0.01) after lesion formation. Sites more remote to any lesion showed transient leakage and significant numbers of 'rolling' leucocytes (p < 0.01) were observed again after the lesion had formed.Despite widespread exposure of the entire gastric mucosa to 60% ethanol the resultant mucosal injury was limited. Widespread vascular damage was found reflected by macromolecular leakage, the pattern of which showed regional variation.
PTEN Positively Regulates UVB-Induced DNA Damage Repair
Authors: Mei Ming, Li Feng, Christopher R. Shea, Keyoumars Soltani, Baozhong Zhao, Weinong Han, Robert C. Smart, Carol S. Trempus, Yu-Ying He
Journal: Cancer Research (2011)

Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared with skin lacking these lesions. Likewise, there was a reduction in PTEN levels in human premalignant actinic keratosis and malignant SCCs, supporting a key role for PTEN in human skin cancer formation and progression. PTEN downregulation impaired the capacity of global genomic nucleotide excision repair (GG-NER), a critical mechanism for removing UVB-induced mutagenic DNA lesions. In contrast to the response to ionizing radiation, PTEN downregulation prolonged UVB-induced growth arrest and increased the activation of the Chk1 DNA damage pathway in an AKT-independent manner, likely due to reduced DNA repair. PTEN loss also suppressed expression of the key GG-NER protein xeroderma pigmentosum C (XPC) through the AKT/p38 signaling axis. Reconstitution of XPC levels in PTEN-inhibited cells restored GG-NER capacity. Taken together, our findings define PTEN as an essential genomic gatekeeper in the skin through its ability to positively regulate XPC-dependent GG-NER following DNA damage.