tbuckley/cabot-search huggingface dataset:
Trastuzumab Has Preferential Activity against Breast Cancers Driven by HER2 Homodimers
Authors: Ritwik Ghosh, Archana Narasanna, Shizhen Emily Wang, Shuying Liu, Anindita Chakrabarty, Justin M. Balko, Ana María González-Angulo, Gordon B. Mills, Elicia Penuel, John Winslow, Jeff Sperinde, Rajiv Dua, Sailaja Pidaparthi, Ali Mukherjee, Kim Leitzel, Wolfgang J. Kostler, Allan Lipton, Michael Bates, Carlos L. Arteaga
Journal: Cancer Research (2011)

In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers, and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2(+) breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. Trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, the HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with HER2-overexpressing breast cancer. Together, our findings confirm the notion that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K (phosphoinositide 3-kinase)/AKT pathway. A clinical implication of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab.
Neurocognitive Outcomes Decades After Treatment for Childhood Acute Lymphoblastic Leukemia: A Report From the St Jude Lifetime Cohort Study
Authors: Kevin R. Krull, Tara M. Brinkman, Chenghong Li, Gregory T. Armstrong, Kirsten K. Ness, Deo Kumar Srivastava, James G. Gurney, Cara Kimberg, Matthew J. Krasin, Ching-Hon Pui, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2013)

To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL).Survivors of childhood ALL treated at St Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion.Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk [RR], 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment.This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.
High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses
Authors: De Yang, Yuri V. Postnikov, Yana Li, Poonam Tewary, Gonzalo de la Rosa, Feng Wei, Dennis Klinman, Theresa Gioannini, Jerrold P. Weiss, Takashi Furusawa, Michael Bustin, Joost J. Oppenheim
Journal: The Journal of Experimental Medicine (2011)

Alarmins are endogenous mediators capable of promoting the recruitment and activation of antigen-presenting cells (APCs), including dendritic cells (DCs), that can potentially alert host defense against danger signals. However, the relevance of alarmins to the induction of adaptive immune responses remains to be demonstrated. In this study, we report the identification of HMGN1 (high-mobility group nucleosome-binding protein 1) as a novel alarmin and demonstrate that it contributes to the induction of antigen-specific immune responses. HMGN1 induced DC maturation via TLR4 (Toll-like receptor 4), recruitment of APCs at sites of injection, and activation of NF-κB and multiple mitogen-activated protein kinases in DCs. HMGN1 promoted antigen-specific immune response upon co-administration with antigens, and Hmgn1−/− mice developed greatly reduced antigen-specific antibody and T cell responses when immunized with antigens in the presence of lipopolysaccharide (LPS). The impaired ability of Hmgn1−/− mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment at sites of immunization and reduced production of inflammatory cytokines. Bone marrow chimera experiments revealed that HMGN1 derived from nonleukocytes was critical for the induction of antigen-specific antibody and T cell responses. Thus, extracellular HMGN1 acts as a novel alarmin critical for LPS-induced development of innate and adaptive immune responses.
Mechanisms of dyspnoea relief following radiation treatment in a patient with severe COPD
Authors: P. O'Meara, J.A. Guenette, N. Raghavan, N. Amornputtisathaporn, C.E. deMetz, R.L. Nolan, D.E. O’Donnell
Journal: European Respiratory Journal (2011)

To the Editors:

Chronic obstructive pulmonary disease (COPD) and lung cancer coexist in many smokers. In those with more advanced COPD in whom surgical resection is contraindicated, palliative or curative radiotherapy may be considered. The effects of radiation treatment on respiratory physiology and functional status in patients with background COPD are highly variable and difficult to predict [1]. Radiation-associated inflammatory injury to airways, lung parenchyma and the pulmonary vasculature can lead to further respiratory impairment, including disruption of pulmonary gas exchange with consequent clinical deterioration. The decision to proceed with radiotherapy must be carefully weighed and based on individualised risk–benefit analysis, especially in those patients with severe COPD. Contrary to expectation, there are anecdotal reports of patients with COPD who experience symptomatic improvement following radiation treatment, but the mechanisms remain unknown [2].

Our patient was a 70 yr-old female with a 50-pack-yr smoking history who had documented progressive respiratory deterioration despite maximal medical therapy and pulmonary rehabilitation. Pulmonary function tests (PFTs) prior to treatment indicated very severe airway obstruction (forced expiratory volume in 1 s (FEV1) 34% predicted) and lung hyperinflation (total lung capacity (TLC) 155% pred), and diffuse centrilobular emphysema was evident on computed tomography (CT) scan, although diffusing capacity of the lung for carbon monoxide ( D L,CO) was relatively preserved (13.6 mL·min−1·mmHg−1, 73% pred). CT scanning fortuitously identified a suspicious spiculated nodule (10.5×11 mm) in the patient’s right middle lobe, which increased in size by 2 mm over 11 months with no evidence of airway obstruction or atelectasis. Subsequent positron emission tomography demonstrated that she probably had primary lung cancer in stage Ia (T1aN0M0). Tissue diagnosis was not attempted given the location of the nodule, her fragile respiratory status and the high risk of pneumothorax. Our patient had …
Growth Velocity Predicts Recurrence of Sleep-disordered Breathing 1 Year after Adenotonsillectomy
Authors: Raouf Amin, Leonard Anthony, Virend Somers, Matthew Fenchel, Keith McConnell, Jenny Jefferies, Paul Willging, Maninder Kalra, Stephen Daniels
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Adenotonsillectomy, the first line of treatment of sleep-disordered breathing (SDB), is the most commonly performed pediatric surgery. Predictors of the recurrence of SDB after adenotonsillectomy and its impact on cardiovascular risk factors have not been identified.Demonstrate that gain velocity in body mass index (BMI) defined as unit increase in BMI/year confers an independent risk for the recurrence of SDB 1 year after adenotonsillectomy.Children with SDB and hypertrophy of the tonsils and a comparison group of healthy children were followed prospectively for 1 year.Serial polysomnographies, BMI, and blood pressure were obtained before adenotonsillectomy and 6 weeks, 6 months, and 1 year postoperatively. Gain velocity in BMI, BMI and being African American (odds ratios, 4-6/unit change/yr; 1.4/unit and 15, respectively) provided equal amounts of predictive power to the risk of recurrence of SDB. In the group that experienced recurrence, systolic blood pressure at 1 year was higher than at baseline and higher than in children who did not experience recurrence.Three clinical parameters confer independent increased risk for high recurrence of SDB after adenotonsillectomy: gain velocity in BMI, obesity, and being African American. A long-term follow-up of children with SDB and monitoring of gain velocity in BMI are essential to identifying children at risk for recurrence of SDB and in turn at risk for hypertension.
Female Estrogen-Related Factors and Incidence of Basal Cell Carcinoma in a Nationwide US Cohort
Authors: Elizabeth K. Cahoon, Cari M. Kitahara, Estelle Ntowe, Emily M. Bowen, Michele M. Doody, Bruce H. Alexander, Terrence Lee, Mark P. Little, Martha S. Linet, D. Michal Freedman
Journal: Journal of Clinical Oncology (2015)

UV radiation exposure is the primary risk factor for basal cell carcinoma (BCC), the most common human malignancy. Although the photosensitizing properties of estrogens have been recognized for decades, few studies have examined the relationship between reproductive factors or exogenous estrogen use and BCC.Using data from the US Radiologic Technologists Study, a large, nationwide, prospective cohort, we assessed the relationship between reproductive factors, exogenous estrogen use, and first primary BCC while accounting for sun exposure, personal sun sensitivity, and lifestyle factors for geographically dispersed women exposed to a wide range of ambient UV radiation.Elevated risk of BCC was associated with late age at natural menopause (hazard ratio [HR] for ≥ 55 years v 50 to 54 years, 1.50; 95% CI, 1.04 to 2.17) and any use of menopausal hormone therapy (MHT; HR, 1.16; 95% CI, 1.03 to 1.30; P for trend for duration = .001). BCC risk was most increased among women reporting natural menopause who used MHT for 10 or more years versus women who never used MHT (HR, 1.97; 95% CI, 1.35 to 2.87). Risk of BCC was not associated with age at menarche, parity, age at first birth, infertility, use of diethylstilbestrol by participant's mother, age at hysterectomy, or use of oral contraceptives.These analyses confirm a previous finding of increased risk of BCC associated with MHT. Novel findings of increased BCC risk associated with MHT in women experiencing natural menopause and for late age at natural menopause warrant further investigation. Users of MHT may constitute an additional high-risk group in need of more frequent skin cancer screening.
A 6-Week Randomized, Placebo-Controlled Trial of CP-316,311 (a Selective CRH <sub>1</sub> Antagonist) in the Treatment of Major Depression
Authors: Brendon Binneman, Douglas Feltner, Sheela Kolluri, Yuanjun Shi, Ruolun Qiu, Thomas Stiger
Journal: American Journal of Psychiatry (2008)

The corticotropin-releasing hormone (CRH) system is implicated in the pathogenesis of several psychiatric disorders, including major depressive disorder. This study was designed to evaluate the safety and efficacy of CP-316,311, a selective nonpeptide antagonist of corticotropin-releasing hormone type 1 (CRH(1)) receptors, in the treatment of recurrent major depressive disorder.Of a total of 167 patients with recurrent major depression who were screened, 123 were randomly assigned to receive 400 mg of CP-316,311 twice daily, or 100 mg of sertraline daily, or placebo in a 6-week fixed-dose, double-blind, double-dummy, parallel-group, placebo- and sertraline-controlled trial. The primary efficacy analysis compared the change in score from baseline to endpoint on the 17-item Hamilton Depression Rating Scale (HAM-D) between the CP-316,311 and placebo groups. A group sequential design was used to support early trial termination based on efficacy or futility at a planned interim analysis.The evaluable data set for the interim analysis included 28 patients in the CP-316,311 group, 31 patients in the placebo group, and 30 patients in the sertraline group. In the interim analysis, the change from baseline in the HAM-D score at the final visit was not significantly different between the CP-316,311 and placebo groups, while change from baseline between the sertraline and placebo groups was significantly different. Given these results, futility was declared for CP-316,311 and the trial was terminated.Although CP-316,311 was safe and well tolerated in this study population, it failed to demonstrate efficacy in the treatment of major depression.
Emerging Role of Mast Cells and Macrophages in Cardiovascular and Metabolic Diseases
Authors: Jia-Ming Xu, Guo-Ping Shi
Journal: Endocrine Reviews (2012)

Mast cells are essential in allergic immune responses. Recent discoveries have revealed their direct participation in cardiovascular diseases and metabolic disorders. Although more sophisticated mechanisms are still unknown, data from animal studies suggest that mast cells act similarly to macrophages and other inflammatory cells and contribute to human diseases through cell–cell interactions and the release of proinflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. Reduced cardiovascular complications and improved metabolic symptoms in animals receiving over-the-counter antiallergy medications that stabilize mast cells open another era of mast cell biology and bring new hope to human patients suffering from these conditions.
Effects of Post-Session Administration of Methylene Blue on Fear Extinction and Contextual Memory in Adults With Claustrophobia
Authors: Michael J. Telch, Aleksandra K. Bruchey, David Rosenfield, Adam R. Cobb, Jasper Smits, Sandra Pahl, F. Gonzalez-Lima
Journal: American Journal of Psychiatry (2014)

Preclinical studies have shown that low-dose methylene blue increases mitochondrial cytochrome oxidase activity in the brain and improves memory retention after learning tasks, including fear extinction. The authors report on the first controlled experiment to examine the memory-enhancing effects of posttraining methylene blue administration on retention of fear extinction and contextual memory following fear extinction training.Adult participants displaying marked claustrophobic fear were randomly assigned to double-blind administration of 260 mg of methylene blue (N=23) or administration of placebo (N=19) immediately following six 5-minute extinction trials in an enclosed chamber. Retesting occurred 1 month later to assess fear renewal as indexed by peak fear during exposure to a nontraining chamber, with the prediction that the effects of methylene blue would vary as a function of fear reduction achieved during extinction training. Incidental contextual memory was assessed 1 and 30 days after training to assess the cognitive-enhancing effects of methylene blue independent of its effects on fear attenuation.Consistent with predictions, participants displaying low end fear posttraining showed significantly less fear at the 1-month follow-up if they received methylene blue posttraining compared with placebo. In contrast, participants displaying moderate to high levels of posttraining fear tended to fare worse at the follow-up if they received methylene blue posttraining. Methylene blue's enhancement of contextual memory was unrelated to initial or posttraining claustrophobic fear.Methylene blue enhances memory and the retention of fear extinction when administered after a successful exposure session but may have a deleterious effect on extinction when administered after an unsuccessful exposure session.
The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo
Authors: Dmitriy N. Atochin, Annie Wang, Victor W.T. Liu, Jeffrey D. Critchlow, Ana Paula V. Dantas, Robin Looft-Wilson, Takahisa Murata, Salvatore Salomone, Hwa Kyoung Shin, Cenk Ayata, Michael A. Moskowitz, Thomas Michel, William C. Sessa, Paul L. Huang
Journal: Journal of Clinical Investigation (2007)

NO plays critical roles in vascular function. We show that modulation of the eNOS serine 1179 (S1179) phosphorylation site affects vascular reactivity and determines stroke size in vivo. Transgenic mice expressing only a phosphomimetic (S1179D) form of eNOS show greater vascular reactivity, develop less severe strokes, and have improved cerebral blood flow in a middle cerebral artery occlusion model than mice expressing an unphosphorylatable (S1179A) form. These results provide a molecular mechanism by which multiple diverse cardiovascular risks, such as diabetes and obesity, may be centrally integrated by eNOS phosphorylation in vivo to influence blood flow and cardiovascular disease. They also demonstrate the in vivo relevance of posttranslational modification of eNOS in vascular function.
Alteration of clonal profile. III. T15 ontogenetic advantages are not sufficient for establishing idiotypic dominance in adoptive transfer.
Authors: Z S Quan, J Quintáns
Journal: The Journal of Experimental Medicine (1981)

We have examined the ontogeny of BALB/c plaque-forming cell (PFC) responses to phosphorylcholine (PC) from fetal and neonatal liver by using the (CBA/N x BALB/c)F1 transplantation model. In this system, thymus-dependent (PC-keyhole limpet hemocyanin) and thymus-independent class 1 (PC-Brucella abortus, PC-lipopolysaccharide) PC antigens stimulate B cell subpopulations, which functionally emerge early after transfer. Responsiveness to a thymus-independent class 2 antigen, C-polysaccharide extract of a Streptococcus pneumoniae mutant, is acquired later. The response to PC antigens tested initially exhibited T15 dominance. Non-T15 clones, which are not expressed to a great degree in normal BALB/c mice, are inherently slow in their rate of maturation; in adoptive transfer, however, they eventually comprise much of the transplanted anti-PC PFC response. Obviously, the advantages the T15 subset has in ontogeny do not result in idiotypic dominance once the immature cells are removed from the intact BALB/c environment. We discuss possible regulatory mechanisms involved in the alteration of the T15+:T15- ratio.
Phase II Study of Capecitabine and Oxaliplatin for Advanced Adenocarcinoma of the Small Bowel and Ampulla of Vater
Authors: Michael J. Overman, Gauri R. Varadhachary, Scott Kopetz, Rosni Adinin, E. Lin, Jeffrey S. Morris, Cathy Eng, James L. Abbruzzese, Robert A. Wolff
Journal: Journal of Clinical Oncology (2009)

Adenocarcinomas of the small bowel and ampulla of Vater represent rare cancers that have limited data regarding first-line therapy. We conducted a phase II trial to evaluate the benefit of capecitabine in combination with oxaliplatin (CAPOX) in patients with advanced adenocarcinoma of small bowel or ampullary origin.Eligible patients with metastatic or unresectable tumors and no prior systemic chemotherapy for advanced disease participated in this phase II trial. CAPOX was administered as a 21-day cycle with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 750 mg/m(2) twice a day on days 1 through 14. The primary end point was overall response rate as assessed by Response Evaluation Criteria in Solid Tumors.Thirty-one patients were enrolled onto the study, and 30 patients received study treatment. The confirmed overall response rate was 50%; three patients with metastatic disease achieved complete responses. The median time to progression (TTP) was 11.3 months, and the median overall survival (OS) was 20.4 months. Subset analysis of patients with metastatic disease only (n = 25) revealed a median TTP of 9.4 months and median OS of 15.5 months. The most common grades 3 or 4 toxicities included fatigue (30%), peripheral neuropathy (10%), vomiting (10%), diarrhea (10%), and neutropenia (10%).When administered to patients with good performance status, CAPOX is well tolerated and produces a superior response rate and longer OS compared with other regimens in the literature. CAPOX should be considered a new standard regimen for advanced small bowel and ampullary adenocarcinomas.
A Tandem Gene Duplication Followed by Recruitment of a Retrotransposon Created the Paralogous Bucentaur Gene (bcntp97) in the Ancestral Ruminant
Authors: Shintaro Iwashita, Sadao Ueno, Kentaro Nakashima, Si-Young Song, Kenshiro Ohshima, Kazuaki Tanaka, Hideki Endo, Junpei Kimura, Masamichi Kurohmaru, Katsuhiro Fukuta, Lior David, Naoki Osada
Journal: Molecular Biology and Evolution (2005)

Retrotransposable element-1 (RTE-1) is a class of long interspersed nucleotide elements that contain in its open reading frame an apurinic/apyrimidinic endonuclease domain (AP-END) and a reverse transcriptase domain. Ruminants have a clade-specific RTE-1 (BovB/RTE). The bovine bcnt gene (bucentaur or craniofacial developmental protein 1) has a duplicated paralog (bcntp97) in tandem that recruited an AP-END of BovB/RTE as a coding exon (RTE exon). We obtained sequence of the bcnt region from several animals and showed that other ruminants also have the bcntp97 with a conserved RTE exon while camels and pigs do not. Genomic Southern analysis showed that camels and pigs have multiple bcnt-related sequences but not BovB/RTE which bovines and lesser mouse deer have abundantly. These results indicate that the bcnt gene duplication followed by the creation of bcntp97 including recruitment of the RTE exon occurred in the ancestral ruminant about 55 MYA. The indication of time frame is supported by a phylogenetic analysis. Taken together with a result of differential tissue expression of the two bcnt paralogs, we conclude that bcntp97 was created concurrently with the early radiation of BovB/RTE in an ancestral ruminant and then acquired a novel function.