tbuckley/cabot-search huggingface dataset:
Accelerated evolution of developmentally biased genes in the tetraphenic ant <i>Cardiocondyla obscurior</i>
Authors: Lukas Schrader, Heikki Helanterä, Jan Oettler
Journal: Molecular Biology and Evolution (2016)

Plastic gene expression underlies phenotypic plasticity and plastically expressed genes evolve under different selection regimes compared with ubiquitously expressed genes. Social insects are well-suited models to elucidate the evolutionary dynamics of plastic genes for their genetically and environmentally induced discrete polymorphisms. Here, we study the evolution of plastically expressed genes in the ant Cardiocondyla obscurior—a species that produces two discrete male morphs in addition to the typical female polymorphism of workers and queens. Based on individual-level gene expression data from 28 early third instar larvae, we test whether the same evolutionary dynamics that pertain to plastically expressed genes in adults also pertain to genes with plastic expression during development. In order to quantify plasticity of gene expression over multiple contrasts, we develop a novel geometric measure. For genes expressed during development, we show that plasticity of expression is positively correlated with evolutionary rates. We furthermore find a strong correlation between expression plasticity and expression variation within morphs, suggesting a close link between active and passive plasticity of gene expression. Our results support the notion of relaxed selection and neutral processes as important drivers in the evolution of adaptive plasticity.
Prospective validation of the palliative prognostic index in terminally ill Egyptian patients with cancer.
Authors: E. F. Hakim
Journal: Journal of Clinical Oncology (2011)

e19715 Background: Patients with cancer and their care givers frequently wish to know how long they expect to live. Improved prognostication would enable the patients and their carers to be better prepared for their impending death and allow clinicans to make better informed decisions about place of care. The aim of this prospective study is to validate the palliative prognostic index (PPI) in a population of terminally ill cancer patients referred to the palliative care unit (PCU) of Kasr Al-Aini Center of Clinical Oncology and Nuclear Medicine (NEMROCK), in order to determine its applicability in a different setting to that in which it was originally developed. Methods: The PPI is based on the following variables: palliative performance status (PPS), oral intake, oedema, dysopnea at rest and delirium. A numerical score was given to each variable, based on the original value of the PPI score. The individual PPI scores are callculated for 100 incurable cancer patients; the sum of the single scores gives the overall PPI score for each patient and is used to subdivide the study population into three groups Results: Group 1 corresponded to patients of low PPI ≤ 4 with median survival of 107 days, Group 2 of intermediate PPI > 4 and ≤ 6 with median survival of 103.5 days, and Group 3 of high PPI > 6 with median survival of 77 days, compared to 68, 21 and 5 days of corresponding groups respectively as reported by Stone et al. Current study showed that the median survival according to PPI was higher than other studies which could be attributed to relatively earlier referral of Egyptian advanced cancer patients to palliative care without exhausting patients with several lines of palliative chemotherapy or cancer modifying treatment. Conclusions: With this earlier referral the PPI may not be the best prognostic scoring system for palliative care Egyptian advanced cancer patients, so that further studies to evaluate other systems and to develop a suitable model is needed.
The Chlamydia trachomatis Inclusion Membrane Protein CpoS Counteracts STING-Mediated Cellular Surveillance and Suicide Programs
Authors: Barbara S. Sixt, Robert J. Bastidas, Ryan Finethy, Ryan M. Baxter, Victoria K. Carpenter, Guido Kroemer, Jörn Coers, Raphael H. Valdivia
Journal: Cell Host & Microbe (2016)
Incompletely Activated CD4+ T Cells Induce Granzyme B+ Regulatory B Cells In An Interleukin 21-Dependent Manner
Authors: Bernd Jahrsdoerfer, Karen Dahlke, Magdalena Hagn, Kai Sontheimer, Thamara Beyer, Oleg Lunov, Dorit Fabricius, Kyrylo Tron, G. Ulrich Nienhaus, Thomas Simmet
Journal: Blood (2010)
Treatment of Epilepsy
Authors: Samuel Livingston
Journal: JAMA (1977)

<h3>To the Editor. —</h3> In the article "Reversible Renal Failure and Myositis Caused by Phenytoin Hypersensitivity" (236:2773-2775, 1976), Michael and Mitch reported the case of a patient taking phenobarbital and phenytoin simultaneously; a skin rash developed followed by a serious constellation of symptoms that they concluded were "presumably caused by phenytoin hypersensitivity." Subsequently, Wilensky (237:2600-2601, 1977) challenged the etiologic role of phenytoin in this case since both phenobarbital and phenytoin have independently provoked similar hypersensitivity syndromes in the past. We agree that it is usually impossible to identify unequivocally the offending agent when a patient has a hypersensitivity reaction while receiving multiple drug therapy; however, based on our experience in the treatment of thousands of patients with phenobarbital and phenytoin, singly and in combination, we believe that the cutaneous eruption and the other hypersensitivity manifestations described by Michael and Mitch were more likely due to phenytoin. The primary purpose of
Obatoclax effects on MCL1 addiction in mesothelioma and activity in vivo.
Authors: N. McTavish, F. McCoy, I. Paul, S. Busacca, D. A. Fennell
Journal: Journal of Clinical Oncology (2011)

e13539 Background: Resistance to apoptosis is a common characteristic of mesothelioma and contributes to multidrug resistance, a particular problem in the clinical setting upon relapse following conventional chemotherapy. Overexpression of the pro-survival BCL-2 family of proteins which include BCL-2, BCL-XL, and MCL-1 contributes to anti-apoptotic signalling, and are highly expressed in mesothelioma. MCL-1 is one of the most commonly amplified genes at 1q21.2 in human cancer and this locus is also amplified in mesothelioma. Methods: All molecular and cell biology techniques used were carried out as described in Crawford et al 2010 or McTavish et al 2007. Results: Across a panel of mesothelioma cell lines several were demonstrated to be primed for death as silencing of Mcl-1 induced apoptosis. This addiction to Mcl-1 was dependent on the intrinsic mitochondrial death pathway as cells that stably expressed shRNA Bax and Bak rescued the addiction due to Mcl-1. Depletion of Bak but not Bax was sufficient to rescue from MCL1 knockdown. In the two Mcl-1 addicted mesothelioma cell lines studied (Ren and MSTO-211H), knockdown of the Noxa also rescued cells from MCL1 silencing induced apoptosis, however depletion of activator BH3 only proteins Bim or Bid only rescued in Ren cells. Amplification of Mcl-1 locus was not essential for addiction. Obatoclax is an inhibitor of MCL1 that is currently in clinical development. On-target activity of obatoclax was demonstrated by BAK/MCL1 co-immunoprecipitation demonstrating dissociation of Bak from Mcl-1 at early timepoints (6-12 hours). Across the panel of mesothelioma cell lines obatoclax exhibited cytotoxicity associated with reduction in cell viability and reduced clonogenic survival in both Mcl-1 addicted and non addicted cell lines. Activity in vivo was evaluated using REN and MSTO-211 xenografts. Obatoclax treatment (8mg/kg) of tumours exhibits significantly reduced tumour growth compared to control tumours. Conclusions: Obatoclax exhibits on target inhibition indicating its activity as a prosurvival BCL-2 antagonist however its activity is not solely dependent on cells being addicted to Mcl-1 for their survival. It is active in both in vitro and in vivo and clinical evaluation mesothelioma is warranted.
Prevalence of alexithymia in patients with psoriasis and its association with disease burden: a multicentre observational study
Authors: F. Sampogna, L. Puig, P. Spuls, G. Girolomoni, M.A. Radtke, B. Kirby, M. Brunori, P. Bergmans, P. Smirnov, J. Rundle, F. Lavie, C. Paul
Journal: British Journal of Dermatology (2016)

Single‐centre studies show that alexithymia, defined as difficulty in recognizing and describing emotions, is more prevalent among patients with psoriasis than in the general population. However, its prevalence and the consequences of the association between alexithymia and psoriasis are unclear. The primary objective of this study was to determine the prevalence of alexithymia, as defined by a score ≥ 61 in the 20‐item Toronto Alexithymia Scale, in a large sample of patients who had plaque psoriasis for ≤ 10 years and were eligible for phototherapy or systemic treatment. The secondary objectives were to investigate the relationship between alexithymia and the clinical and psychological aspects of psoriasis. Data were collected in the framework of an observational, multicentre, international study, the EPidemiological Study In Patients With Recently DiagnosEd PSOriasis (EPIDEPSO), aiming at investigating the prevalence of alexithymia and other psychosocial comorbidities in patients with psoriasis of ≤ 10 years' disease duration. The prevalence of alexithymia within a cohort of 670 patients was 24·8% (95% confidence interval 21·7–28·2). Patients with alexithymia had a higher burden of psoriasis, including significant impairment of quality of life, higher levels of anxiety and depression, a higher risk of alcohol dependency and impairment of work productivity, compared with patients without alexithymia. It is important to identify alexithymic patients with psoriasis in clinical practice as they experience a higher disease burden and have a lower ability to express their feelings.
155. Cancer-Specific Theranosis Using Quantum Dots and siRNA Co-Loaded in Micellar Nanoparticles
Authors: Seong Jae Kang, Hwa Yeon Jeong, Min Woo Kim, In Ho Jeong, Moon Jung Choi, Young Myoung You, Chan Su Im, Yong Serk Park
Journal: Molecular Therapy (2016)

Theranostics is a proposed process of diagnostic therapy for an individual patient. It has been considered a powerful tool of personalized medicine. In this study, we have prepared lipid micellar nanoparticles encapsulating quantum dots (QDs) as a diagnostic agent and incorporating cholesterol-siRNA (Cho-siRNA) as a therapeutic agent. Furthermore, for targeted delivery of QDs and Cho-siRNA, anti-EGFR antibodies or aptamers were conjugated to the surface of the nanoparticles. First of all, for stable nanostructure of lipid micelles, we determined an optimal molar ratio of lipids, QDs, and Cho-siRNA as 350:1:0.35. The size of QD micelles was approximately 50 nm that is suitable for efficient localization in tumors via enhanced permeability and retention (EPR) effect. Their serum stability and pH stability suggest that the QD micelle structure is stable enough to be applied under biological conditions. The RNase protection assay showed that Cho-siRNA molecules in the QD micelles were effectively protected by steric shielding of hydrophilic polyethylene glycol molecules. The analyses with a flow cytometry and a confocal microscope showed that the nanoparticles can effectively deliver Cho-siRNA to the target cells, followed by effective residing of siRNA molecules in the cytoplasm. A further systematic evaluation of the micellar nanoparticles established in this study would verify their value as a theranostic vehicle.
Host Immunogenetic Single Nucleotide Polymorphisms (SNPs) Predict Overall Survival in Small Lymphocytic Lymphoma.
Authors: Carrie A. Thompson, Sophia Wang, Matthew J. Maurer, Thomas M. Habermann, Richard K. Severson, Nathaniel Rothman, Charles F. Lynch, Scott Davis, Lindsay M. Morton, Wendy Cozen, Patricia Hartge, Susan M. Geyer, Stephen Chanock, James R. Cerhan
Journal: Blood (2006)
Abstract 3497: Mechanism-based scheduling of triple therapy gemcitabine/CHK1i/WEE1i in pancreatic cancer at submaximal yet synergistic concentrations
Authors: Siang-Boon Koh, Frances M. Richards, Esther Rodriguez, Scott K. Lyons, Duncan I. Jodrell
Journal: Cancer Research (2015)

Abstract Sensitization of cancer cells to gemcitabine has been shown with checkpoint kinase CHK1 and WEE1 inhibitors. To rationalize and optimize the concomitant use of these three agents, we first performed growth inhibition assays on MIA PaCa-2 pancreatic cancer cells using gemcitabine in combination with either CHIR-124 (CHK1 inhibitor) or MK-1775 (WEE1 inhibitor). In silico analysis with three mathematical models (Bliss Independence, Loewe and Highest Single Agent) identified synergistic growth inhibition at submaximal (i.e. &amp;lt;GI50) concentrations of the single agents (10nM gemcitabine, 20nM CHIR-124, 300nM MK-1775) in MIA PaCa-2 cells. At these concentrations of gemcitabine+CHIR-124, quantitative image-based cytometry demonstrated S-phase redistribution, with 31% of &amp;gt;8000 individual cells undergoing extensive fork collapse (compared to 0-1% with single agents) as evidenced by co-staining of yH2AX and hyper-phosphorylated RPA32. Conversely, submaximal gemcitabine+MK-1775 induced clear reduction of inhibitory CDK1 Y15 level compared to single agents. Consistent with this G2/M abrogation, in a Fucci-based CDT1/geminin-expressing MIA PaCa-2 stable cell line, gemcitabine+MK-1775 partially reversed the accumulation of the geminin-expressing (S/G2) population induced by gemcitabine alone. This was accompanied by an increase in the CDT1-expressing (G1) population, alongside aberrant mitotic cells with features of perturbed kinetochore-microtubule integrity. Based on these findings, we performed a series of long-term, kinetic live-cell imaging assays to determine the optimal scheduling for gemcitabine/CHK1i/WEE1i as a triplet at synergistic concentrations. In contrast to the widely proposed scheduling regimen, we found that delayed administration of CHK1i (at 24 hours), relative to gemcitabine, did not lead to synergy. However, concurrent administration yielded durable growth inhibition, even when the two agents were removed after 24 hours. This inhibition was further enhanced with the subsequent addition of WEE1i at 24 hours, but not continuation of a CHK1i. Together, our results illustrate differential mechanistic effects of CHK1 and WEE1 inhibitors with gemcitabine, when combined at sub-GI50 concentrations, and propose a novel triple agent schedule that will be evaluated in vivo. Citation Format: Siang-Boon Koh, Frances M. Richards, Esther Rodriguez, Scott K. Lyons, Duncan I. Jodrell. Mechanism-based scheduling of triple therapy gemcitabine/CHK1i/WEE1i in pancreatic cancer at submaximal yet synergistic concentrations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3497. doi:10.1158/1538-7445.AM2015-3497
265. Polysialic Acid as a Novel Regulator of AAV Tropism in the Developing Brain
Authors: Giridhar Murlidharan, Aravind Asokan
Journal: Molecular Therapy (2015)

Recombinant AAV vectors are currently being exploited in a number of clinical trials that aim to correct neurological diseases. In many cases, it is important that therapeutic intervention occurs in the infantile stage of life. Thus, it is important to understand how AAV vectors interact with the constantly changing environment in the brain during neurodevelopment. Recombinant AAV is thought to spread through the central nervous system (CNS) by exploiting cerebrospinal fluid (CSF) flux and hijacking axonal transport pathways. The role of host receptors that mediate these processes in the developing brain are not well understood. In the current study, we utilized AAV serotype 4 as a model to evaluate whether ubiquitously expressed 2,3-linked sialic acid and the developmentally regulated marker, 2,8-linked polysialic acid (PSA) regulate viral transport and tropism in the neonatal brain. Modulation of the levels of SA and PSA in cell culture studies using specific neuraminidases revealed possibly opposing roles of the two glycans on AAV4 transduction. Interestingly, upon intracranial injection into lateral ventricles of the neonatal mouse brain, a low affinity AAV4 mutant displayed a striking shift in cellular tropism from 2,3-linked SA+ ependymal lining to 2,8-linked PSA+ migrating progenitors in the rostral migratory stream and olfactory bulb. In addition, this gain-of-function phenotype correlated with robust CNS spread of the mutant through paravascular transport pathways. Consistent with these observations, altering glycan dynamics within the brain by co-administering SA and PSA specific neuraminidases resulted in striking changes to the cellular tropisms and transduction efficiencies of both parental and mutant vectors. We postulate that glycan signatures associated with host development can be exploited to redirect novel AAV vectors to specific cell types in the brain.
310. Analysis of AAV5 Biodistribution and Viral Shedding in the Presence or Absence of Neutralizing Antibodies
Authors: David Salas, Anna Majowicz, Nerea Zabaleta, Estefania Rodríguez-Garcia, Harald Petry, Valerie Ferreira, Gloria Gonzalez Aseguinolaza
Journal: Molecular Therapy (2016)

Neutralizing antibodies (NAbs) are the main obstacle that must be overcome to achieve a successful delivery of a viral vector to the target organ. NAbs acquisition can be induced naturally after infection with wild type AAV or after the first administration of AAV vector in the course of gene therapy treatment. Therefore, the objective of this project was to evaluate the efficacy and presence of the vector in the organism, as well as the response and vector elimination in the presence and absence of NAbs. We analyzed the presence of the reporter transgene (hFIX), humoral and cellular immune responses against the vector, viral shedding and biodistribution. The administration of AAV2/5 was successful in absence of NAbs. In contrast, vector administration in presence of specific NAbs was unsuccessful, probably due to the vector being completely depleted by anti-AAV2/5 NAbs. Our data demonstrate that while in the absence of antibodies the vector can be detected in serum and in other body fluids for 70 days after vector administration, the presence of antibodies immediately clears the vector from the organism. 24 hours after the AAV-hFIX administration 1X1008 gc/mL are detected in the serum in the absence of NAbs but in the presence of NAbs the concentration is reduced 1000-fold. In both groups the presence of NAbs increased upon infection without a cellular immune response against the vector. Finally, the biodistribution studies showed remarkable differences between the two groups: in the absence of NAbs vector genomes are detected mainly in liver, heart, spleen and inguinal LN, while in the presence of NAbs vector genomes are almost undetectable in all tissues analyzed.
Association of excision repair cross-complementation group 1 (ERCC1) gene expression (GE) with outcome in stage II-III esophageal adenocarcinoma (EA) patients treated with preoperative platinum-based chemoradiation (CRT) in a phase II cooperative study (SWOG 0356).
Authors: P. O. Bohanes, B. H. Goldman, J. Benedetti, C. D. Blanke, L. P. Leichman, S. Iqbal, C. R. Thomas, C. L. Corless, P. J. Gold, H. Lenz
Journal: Journal of Clinical Oncology (2011)

2 Background: Preoperative platinum-based CRT for operable esophageal cancer has improved overall survival (OS) compared to surgery alone. The phase II SWOG 0356 trial designed to test oxaliplatin (OXP) plus infusion 5-fluorouracil (5-FU) and external beam radiation prior to surgery for potentially curable EA has produced promising centrally confirmed complete pathologic response (pCR) rate (28.3%). After surgery patients were given a second cycle of OXP and 5FU. 2-year OS was 54.2%. However, treatment efficacy may be significantly compromised as a result of interindividual variations. We tested whether intratumoral GE levels in drug metabolism (DPD, GSTPi, TS and TP) and DNA repair (ERCC1 and XPD) predicted clinical outcome (CO). We also tested whether specific pattern of 12 polymorphisms in 8 genes (drug metabolism (GSTP, MTHFR and TS) and DNA repair (ERCC1, RAD51, XPD, XRCC1 and XRCC3)) predicted CO. Methods: A total of 90 patients from the SWOG 0356 study were eligible for the molecular correlative study. mRNA was extracted from laser-capture-microdissected tumor tissue. After cDNA was prepared by reverse transcription, quantitation of the candidate genes and an internal reference gene (ß-actin) was performed using a fluorescence-based real-time detection method (TaqMan). Established GE cutoffs were tested (ERCC1 &lt;1.7 x 10 -3 ; TS &lt;4.0 x 10 -3 ). DNA was extracted from blood and genotyped using PCR-RFLP techniques. Results: In univariate analysis, we found ERCC1 GE levels to be significantly associated with progression-free survival (PFS) and OS. Patients with high ERCC1 GE levels had worse 2-year PFS (17 vs 67%, p=0.004) and 2-year OS (37 vs 72%, p=0.04) compared to low GE levels. ERCC1 GE levels were not associated with pCR. All the other GE levels tested did not show significant association with CO. None of the tested polymorphisms showed any association with CO. Conclusions: Our data suggest that GE levels of ERCC1 may help to identify patients with stage II-III EA likely to experience longer survival when treated with preoperative OXP-based CRT. No significant financial relationships to disclose.
Coincidence of retinoblastoma and leiomyosarcoma in father and daughter - a rare case report
Authors: D. Schoeler, T. Lindner, S. Schulenburg, None Von der, D. Pink, P. Reichardt
Journal: Journal of Clinical Oncology (2004)

9059 Retinoblastoma is the most common primary ocular malignancy of childhood, which results from sporadic or heritable mutations in the retinoblastoma gene, RB1. It is well recognized to occur in two patterns: a sporadic, non-heritable form and a genetic, heritable form presenting with uni- or bilateral disease, which is assaociated with a germline defect and greatly elevated risk of developing a second malignancy. We here report a very rare case of familial retinoblastoma and leiomyosarcoma in a father and his daughter. Father: The 54-years old male was diagnosed with unilateral retinoblastoma of his right eye in 1950 and underwent enucleation in the age of 1, he was not treated by chemotherapy or radiation in the childhood. In 2000 a leiomyosarcoma of his right lower leg with pulmonary metastases was diagnosed. He was treated by polychemotherapy, radiotherapy and surgery of lung and soft tissue metastases. At the moment the patient is treated by a fourth line chemotherapy with ET-743. Daughter: The 31-years old female was diagnosed with bilateral retinoblastoma in 1973. Both eyes were enucleated in the age of 2, followed by radiochemotherapy. In 1980 retinoblastoma recurred in the left orbita, she was treated by surgery and radiotherapy. 17 years later she was diagnosed with a frontobasal leiomyosarcoma with local involvement of the left orbita. She was treated by radical surgery. Only 4 month later she recurred locally. She underwent a chemotherapy with epirubicin/ifosfamide followed by surgery. The second local recurrence of leiomyosarcoma in 2000 was treated by stereotactic radiotherapy. In 2002 she underwent R2 resection of the 3rd local recurrence. Since that time the situation remains stable. Conclusions: The propensity for survivors of heritable retinoblastoma to develop second nonocular malignancies is well known, they can occur within the field of irradiation (case of the daughter) or fail previous radiation or chemotherapy (case of the father). In the presented family the grandchild is also affected by retinoblastoma, fortunately it is under local control by laser therapy. With this familial history systematic screening for tumor symptoms should be performed. No significant financial relationships to disclose.