tbuckley/cabot-search huggingface dataset:
Phase I study of intraperitoneal IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer administered in combination with pegylated liposomal doxorubicin in recurrent or persistent epithelial ovarian, Fallopian tube, or primary peritoneal cancer patients: An NRG/GOG study.
Authors: Premal H. Thaker, William E Brady, William Hampton Bradley, Khursheed Anwer, Ronald David Alvarez
Journal: Journal of Clinical Oncology (2015)

5541 Background: EGEN-001 is an immunotherapeutic agent that comprises a human IL-12 plasmid that encodes for functional IL-12 and a synthetic DNA delivery system polyethyleneglycol-polyethyleneimine-cholesterol that facilitates plasmid delivery into cells. Ip injection of EGEN-001 is associated with increases in IL-12 levels and its downstream cytokines in the tumor environment without a significant increase in systemic circulation. The study’s purpose was to assess safety and efficacy of escalating doses of EGEN-001 with pegylated liposomal doxorubicin (PLD) in recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients. Methods: Patient eligibility criteria: Females age ≥ 18 years with persistent or recurrent EOC. Patients were not required to have measurable disease and could have a biochemical recurrence; must have had one prior platinum-based chemotherapeutic regimen and up to two additional cytotoxic regimens; have adequate organ function. The trial was a standard 3 + 3 phase I dose escalation with patients receiving PLD every 28 days and EGEN-001 ip on days 1, 8, 15, and 22 of a 28 day cycle (table 1). Cycles were repeated every 28 days until disease progression. Results: Sixteen evaluable patients enrolled on trial from 9/2012-7/2012. No DLTs were found during cycle one of each dose level. The adverse side effects were 3 grade 3 anemia; 2 grade 3 abdominal pain; 7 grade 3 neutropenia and 2 grade 4 neutropenia. There were minimal side effects of fever, flu-like symptoms, and infusion or injection site reactions. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of PRs were found at dose level 3 (28.6%) along with SD at 57.1%. The MTD was not achieved. Translational studies are ongoing. Conclusions: EGEN-001 in combination with PLD has clinical benefit in recurrent or persistent EOC and warrants further investigation with escalating doses of EGEN-001. Clinical trial information: NCT#01489371. Dose Level EGEN-001 (mg/m2 ip) PLD (mg/m2 iv) 1 24 40 2 36 40 3 36 50
Analysis of bone mineral density and bone turnover proteins on patients receiving celecoxib anti-aromatase neoadjuvant (CAAN) trial for breast cancer
Authors: Louis Chow, Wings Loo, Adrian Yip, Masakazu Toi
Journal: Clinical Cancer Research (2007)

A27     Background:   Anti-aromatase therapy is important in the treatment of breast cancer in postmenopausal women but they have effects on the bone mineral density (BMD) and osteoporosis. Cyclooxygenase-2 (COX-2) inhibitors have been shown to be effective in chemoprevention in animal and clinical studies. A proof of principle study was performed to investigate the efficacy of combing anti-aromatase therapy (exemestane) and COX-2 inhibitors neoadjuvantly. The long term changes in the BMD and bone turnover protein were analysed and presented here.    Patients and Methods:   82 postmenopausal patients with histologically confirmed invasive hormone-sensitive breast cancers were included for the neoadjuvant therapy. 30 patients received exemestane 25 mg daily and celecoxib 400 mg twice daily (group A), 24 patients received exemestane 25 mg daily (group B) and 28 patients received letrozole 2.5 mg daily (group C). The same assigned treatment was intended to continue for 2 years to study the changes in the bone metabolism. However, the study was suspended since February 2005 when FDA was investigating the toxicity of the long-term use of COX-2 inhibitors. BMD (measured by DEXA scan at 12 and 24 months) of 48 patients were analyzed; 23 belongs to group A, 10 to group B and 15 to group C. The serum bone turnover proteins [bone-specific alkaline phosphatase (bap) and Carboxyterminal crosslinked telopeptide of type I collagen (ictp)] before treatment, 3 months and 15 months after treatment were measured with commercially available test kits.    Results:   BMD at the femur for group A patients did not change after 24 months but it was lowered for group C patients and raised for group B patients. The values for group B patients was significantly greater than group A (p=0.011) and C patients (p=0.003). The BMD at the spine did not have any significant differences between the 3 groups. The changes for bap at 3 months and ictp at 3 and 15 months were not different between the 3 groups. However, the changes of bap at 12 months were higher group B patients than the other groups. The difference between group B and A patients were not of statistical significance but it was significant between group B and C patients (p=0.017).    Conclusion:   The long term use of anti-aromatase therapy may have different impact on BMD and bone turnover proteins. The study suggests that exemestane may have better profiles on the bone metabolism.
Abstract 12755: Heart-specific Overexpression of (pro)renin Receptor Induces Atrial Fibrillation in Mouse
Authors: hong lian, xiaojian wang, ning liu, li zhang, yingdong lu, shengshou hu, lianfeng zhang
Journal: Circulation (2013)

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia, causing substantial cardiovascular morbidity and mortality. Renin-angiotensin system has been shown to be involved in t...
Abstract P022: Functional and Transcriptomic Recovery of Infarcted Mouse Myocardium Treated with Bone Marrow Mononuclear Cells
Authors: Adriana B Carvalho, Stephan Lachtermacher, Bruno Esporcatte, Nazareth Rocha, Patricia Costa, Dumitru Iacobas, Sanda Iacobas, David C Spray, Regina Goldenberg, Antonio Carlos Campos de Carvalho
Journal: Circulation Research (2011)

Although bone marrow-derived mononuclear cells (BMNC) have been extensively used in cell therapy for cardiac diseases, little mechanistic information is available to support reports of their efficacy. To address this shortcoming, we compared structural and functional recovery and associated global gene expression profiles in post-ischaemic myocardium treated with BMNC transplantation. BMNC suspensions were injected into cardiac scar tissue ten days after experimental myocardial infarction. Six weeks later, mice undergoing BMNC therapy were found to have normalized antibody repertoire and improved cardiac performance measured by ECG, treadmill exercise time and echocardiography. After functional testing, gene expression profiles in cardiac tissue were evaluated using high-density oligonucleotide arrays. Expression of more than 18% of the 11981 quantified unigenes was significantly altered in the infarcted hearts. BMNC therapy restored expression of 2099 (96.2%) of the genes that were altered by infarction but led to altered expression of 286 new genes, considered to be a side effect of the treatment. Transcriptional therapeutic efficacy, a new metric calculated using a formula that incorporates both recovery and side effect of treatment, was 74.5%. In conclusion, our results confirm a beneficial role for bone marrow-derived cell therapy and provide new information on molecular mechanisms operating after BMNC transplantation on post ischemic heart failure in mice.
BMA annual meeting: Doctors who carry out abortions should not face criminal sanctions, says BMA
Authors: Abi Rimmer, Rebecca Coombes
Journal: BMJ (2017)

Abortion should be decriminalised in respect of health professionals administering abortions in clinical practice and for women who procure and administer their own abortion, the BMA has said.

Delegates at the BMA’s annual representative meeting in Bournemouth voted on Tuesday 27 June in favour of a motion that also said that abortion should be regulated in the same way as other medical treatments, such as no longer requiring the agreement of two doctors.

Proposing the motion, GP Coral Jones, said, “Decriminalisation is the removal of abortion from the penal code. Doctors and women will no longer face the threat of imprisonment for procuring or performing abortions.”

She added, “Following the decriminalisation of abortion, providers will be regulated by the General Medical Council’s standards of good medical practice, including consent and confidentiality. Central collection of anonymised abortion data will continue, and health professionals will have a statutory right to conscientious objection.”

Abortion is a crime under the 1861 Offences Against the Person Act. The Abortion Act 1967 creates an exception, making abortion on licensed premises lawful under specific conditions.1

When two doctors agree that continuing the pregnancy is a greater risk than the abortion to the life or health of the mother or any …
Tissue DNA methylation as a tool for clinical decision making after neo-adjuvant treatment in rectal cancer
Authors: Moshe Mishaeli, Liron Berkovich, Baruch Shpitz, Nasreen Hag-Yahiya, Walter Pulverer, Andreas Weinhäusel, Ronen Ghinea, Shmuel Avital
Journal: Annals of Oncology (2017)
Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility
Authors: Martin Valdearcos, John D. Douglass, Megan M. Robblee, Mauricio D. Dorfman, Daniel R. Stifler, Mariko L. Bennett, Irene Gerritse, Rachael Fasnacht, Ben A. Barres, Joshua P. Thaler, Suneil K. Koliwad
Journal: Cell Metabolism (2017)
Cost Benefit Analysis of Laparoscopic Colorectal Surgery in an Irish Population
Authors: E Boyle, PF Ridgway, FB Keane, P Neary
Journal: Endoscopy (2006)

Aims: International randomised trials have endorsed the routine use of laparoscopic techniques in colorectal surgery. The authors prospectively establish the cost benefit analysis of delivering laparoscopic colorectal resection to an Irish population.
The role of quantitative TFPI2 methylation as a novel serum diagnostic and prognostic marker in hepatopancreaticobiliary cancers
Authors: Neslihan Erdem, Elmas Kasap, Seda Örenay Boyacıoğlu, Tahir Buran, Emre Gerçeker, Hakan Yüceyar Münip, Ceren Ekti Uludogan Burcu, Gokcen Tufan Ayse, Mehmet Korkmaz
Journal: Annals of Oncology (2017)
A phase 1 trial of NBTXR3 nanoparticles activated by intensity-modulated radiation therapy (IMRT) in the treatment of advanced-stage head and neck squamous cell carcinoma (HNSCC).
Authors: Christophe Le Tourneau, Valentin Calugaru, Thomas Jouffroy, Jose Rodriguez, Caroline Hoffmann, Bernard Dodger, Victor Moreno, Emiliano Calvo
Journal: Journal of Clinical Oncology (2017)

6080 Background: Functionalized hafnium oxide nanoparticles (NBTXR3) have been developed as selective radioenhancers, which may represent a breakthrough approach for the local treatment of solid tumors. The high electron density of the nanoparticles, when exposed to radiotherapy (RT), allow the absorption/deposition of a high radiation dose within the tumor cells, to physically kill the cells and possibly improve outcome. A phase I trial was implemented for the treatment of locally advanced HNSCC in patients (pts) older than 65 years who cannot receive cisplatin. Methods: Pts received a single intratumor (IT) injection of NBTXR3, volume dose levels escalated at 5%, 10%, 15% and 22% of baseline tumor volume, followed by RT (IMRT, 70Gy/ 35 fractions / 7 weeks). Primary endpoints included feasibility of the IT implantation and safety. Secondary endpoints included IT residency of NBTXR3 using CT scan and RECIST 1.1 response. Results: Enrollment was completed for volume 5%, 10%, and 15% (11 pts) and 1 patient at volume dose level 22%. Feasibility of the IT injection was confirmed. The treatment was easily administered, was safe with no SAE, or early DLT, which allowed the pts for completion of the planned RT schedule. Adverse events related to the injection procedure included grade 1-2 injection pain (1 pt), and tumor hemorrhage (1 pt). Results demonstrated that a single injection of NBTXR3 provides adequate bioavailability of NBTXR3 IT over seven weeks of RT. No leakage of NBTXR3 to the adjoining healthy tissues was observed. Preliminary results of antitumor activity according to RECIST 1.1 are presented below: 11 evaluable pts, 10 showed complete or partial response (RECIST 1.1) including, 1/5 complete response at dose levels ≤ 10% and 3/6 complete responses at dose levels &gt; 10% Follow up results with duration of response and tolerance will be disclosed. Conclusions: Injection of NBTXR3 was safe and well tolerated. All pts received the planned RT. Clinical trial information: NCT01946867.
MAGNIFY: Phase IIIb Randomized Study of Lenalidomide Plus Rituximab (R2) Followed By Lenalidomide Vs. Rituximab Maintenance in Subjects with Relapsed/Refractory Follicular, Marginal Zone, or Mantle Cell Lymphoma
Authors: David J. Andorsky, Abdulraheem Yacoub, Jacob D. Bitran, Jason Melear, Heather D. Brooks, Kenneth A. Foon, Syed Rizvi, Mary Llorente, Jiahui Li, Jeff P. Sharman
Journal: Blood (2016)
A novel risk-predictive metric to uncover differences in cell cycling kinetics among racially-distinct breast tumors.
Authors: Nikita Wright, Sergey Klimov, Guilherme Henrique Cantuaria, Padmashree C.G. Rida, Ritu Aneja
Journal: Journal of Clinical Oncology (2016)

e13052 Background: Breast tumors in African-Americans (AAs) exhibit higher recurrence rates and faster kinetic progression to metastasis than those in European-Americans (EAs). This results in a stark ethnic disparity in breast cancer outcomes. Analysis of cell cycle kinetics in breast tumors may provide insights into racial differences in metastatic propensities. Current proliferation-related biomarkers in breast carcinomas include Mitotic Index (MI) and Ki67 index (KI). However, as autonomous prognosticators measured on vastly distinct scales, MI and KI do not convey information about the cycling kinetics of the proliferative cell population, thus undermining their prognostic value. Methods: We performed a three-color immunofluorescence staining on formalin-fixed paraffin-embedded AA (n = 83) and EA (n = 151) breast tumor specimens from Northside Hospital, Atlanta to extract proportion of mitotic cells (labelled by mitotic marker phosphohistone H3) amongst proliferative (Ki67-positive) cells. Stained samples were examined by confocal microscopy to ascertain frequency of mitotic cells among cycling cells to yield a Mitosis: Proliferation (M:P) Ratio. Results: We observed higher M:P Ratio in AA compared to grade-matched and stage-matched EA tumor tissue specimens. Early stage (Stage I-IIA) tumors in AAs displayed significantly higher M:P Ratio than in EAs (p = 0.015). Furthermore, among the clinicopathological parameters of age, race, grade, stage, and receptor status, a multivariate analysis revealed that race was the only variable that exhibited a significant confounding influence on M:P ratio (p = 0.042). Conclusions: A higher M:P Ratio likely reflects an increased risk of developing intratumoral heterogeneity and producing aggressive clones; thus, a higher M:P ratio provides a plausible explanation for the observed greater metastatic propensity exhibited in AA compared to EA patients. Thus, our novel metric provides new insights into the KI-MI relationship in tumors, exposes previously unrecognized differences in cycling kinetics among early stage AA and EA breast tumors, and proffers additional metastatic risk predictive information currently unavailable in the clinic.
Oncologist use and perception of large panel next-generation tumor sequencing
Authors: A.M. Schram, D. Reales, J. Galle, R. Cambria, R. Durany, D. Feldman, E. Sherman, J. Rosenberg, G. D’Andrea, S. Baxi, Y. Janjigian, W. Tap, M. Dickler, J. Baselga, B.S. Taylor, D. Chakravarty, J. Gao, N. Schultz, D.B. Solit, M.F. Berger, D.M. Hyman
Journal: Annals of Oncology (2017)
Abstract 170: Protein Kinase C regulates alternative splicing transitions during heart development
Authors: Sunil K Verma, Vaibhav Deshmukh, Muge N Kuyumcu-Martinez
Journal: Circulation Research (2013)

Introduction: Highly conserved genetic and molecular pathways coordinate gene expression during heart development. Alternative splicing (AS) regulates gene expression by generating distinct spliced isoforms of proteins such that embryonic variants are expressed only in fetus but not in adult. Importantly, mutations that affect splicing of embryonic genes such as Nkx2.5 and GATA4 can lead to congenital heart defect. Although AS is critical for proper gene expression in developing heart, the signals that regulate AS are not well known. We have previously shown that Protein Kinase C α/β (PKCα/β) phosphorylates splicing regulator CELF1 that controls AS in heart, suggesting that PKC signaling could be responsible for AS regulation during heart development. Hypothesis: PKCα/β contributes to embryonic gene expression by regulating AS. Methods: We used H9c2 rat embryonic cell differentiation into cardiomyocyte-like cells and rat heart tissues at different stages of development to determine whether PKC is responsible for AS transitions. The localization and levels of proteins were assessed by western blot and immunohistochemistry. Quantitative RT-PCR was performed to determine the splicing pattern of nine developmentally regulated genes using specific primers. Results: The results indicate that AS of developmentally important genes transitioned during rat heart development and H9c2 differentiation. PKCα/β regulated embryonic to neonatal AS transitions by phosphorylating splicing regulators CELF1 and Rbfox2. Blocking PKCα/β activity by bisindolylmaleimide IX reduced both the phosphorylation and protein levels of CELF1 and Rbfox2 with concurrent changes in AS transitions. Depletion of PKCα was sufficient to alter a subset of AS events by down-regulating CELF1 and Rbfox2 proteins. Finally, our data suggest that nuclear localization of PKCα/β at embryonic stages could be the mechanism for AS transitions and increased steady state levels of splicing regulators. Conclusions: Our results show that PKCα/β regulate splicing regulators and AS during heart development. Changes in PKCα/β subcellular localization is one of the determinants for embryonic to neonatal AS transitions in developing rat heart and during cardiomyocyte differentiation.
A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with CLDN10 Mutations
Authors: Ernie M.H.F. Bongers, Luke M. Shelton, Susanne Milatz, Sjoerd Verkaart, Anneke P. Bech, Jeroen Schoots, Elisabeth A.M. Cornelissen, Markus Bleich, Joost G.J. Hoenderop, Jack F.M. Wetzels, Dorien Lugtenberg, Tom Nijenhuis
Journal: Journal of the American Society of Nephrology (2017)

Mice lacking distal tubular expression of CLDN10 , the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remains undetermined. We identified and characterized CLDN10 mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) &gt;30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants [c.446C&gt;G (p.Pro149Arg) and c.465–1G&gt;A (p.Glu157_Tyr192del)]. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants [c.446C&gt;G (p.(Pro149Arg) and c.217G&gt;A (p.Asp73Asn)]. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype. These data suggest that pathogenic CLDN10 mutations affect TAL paracellular ion transport and cause a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype.
A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma
Authors: Gilbert J Rahme, Bryan W Luikart, Chao Cheng, Mark A Israel
Journal: Neuro-Oncology (2017)

Mouse models of glioblastoma (GBM), the most aggressive primary brain tumor, are critical for understanding GBM pathology and can contribute to the preclinical evaluation of therapeutic agents. Platelet-derived growth factor (PDGF) signaling has been implicated in the development and pathogenesis of GBM, specifically the proneural subtype. Although multiple mouse models of PDGF-driven glioma have been described, they require transgenic mice engineered to activate PDGF signaling and/or impair tumor suppressor genes and typically represent lower-grade glioma.We designed recombinant lentiviruses expressing both PDGFB and a short hairpin RNA targeting Cdkn2a to induce gliomagenesis following stereotactic injection into the dentate gyrus of adult immunocompetent mice. We engineered these viruses to coexpress CreERT2 with PDGFB, allowing for deletion of floxed genes specifically in transduced cells, and designed another version of this recombinant lentivirus in which enhanced green fluorescent protein was coexpressed with PDGFB and CreERT2 to visualize transduced cells.The dentate gyrus of injected mice showed hypercellularity one week post-injection and subsequently developed bona fide tumors with the pathologic hallmarks of GBM leading to a median survival of 77 days post-injection. Transcriptomic analysis of these tumors revealed a proneural gene expression signature.Informed by the genetic alterations observed in human GBM, we engineered a novel mouse model of proneural GBM. While reflecting many of the advantages of transgenic mice, this model allows for the facile in vivo testing of gene function in tumor cells and makes possible the rapid production of large numbers of immunocompetent tumor-bearing mice for preclinical testing of therapeutics.
Routine Cross Matching of Blood for Major Upper GI Resectoins: Do we Need to Change the Current Practice?
Authors: PC Munipalle, JL Clements, BR Gopinath, PA Davis, YKS Viswanath
Journal: Endoscopy (2006)

Aims: The guidelines from the British Society of Gastroenterology1 state that 4 units of blood should be routinely cross-matched for both oesophagectomy and gastrectomy but there is currently no local data on the usage of blood during these procedures. We have reviewed our current practice with a view to minimise the wastage of valuable resources.
Examining the Clinical Features and Underlying Cardiovascular Risk Among Patients with Polycythemia Vera in the REVEAL Study
Authors: Brady L. Stein, Ahmad Naim, Michael R. Grunwald, Alison R. Moliterno, Stephen T. Oh, Dilan Paranagama, Joseph A. Cordaro, Hao Sun, Shreekant Parasuraman, Ralph V. Boccia, Ruben Mesa
Journal: Blood (2016)