tbuckley/cabot-search huggingface dataset:
Use of a 2-Dose Schedule for Human Papillomavirus Vaccination — Updated Recommendations of the Advisory Committee on Immunization Practices
Authors: Elissa Meites, Allison Kempe, Lauri E. Markowitz
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Vaccination against human papillomavirus (HPV) is recommended to prevent HPV infections and HPV-associated diseases, including cancers. Routine vaccination at age 11 or 12 years has been recommended by the Advisory Committee on Immunization Practices (ACIP) since 2006 for females and since 2011 for males (1,2). This report provides recommendations and guidance regarding use of HPV vaccines and updates ACIP HPV vaccination recommendations previously published in 2014 and 2015 (1,2). This report includes new recommendations for use of a 2-dose schedule for girls and boys who initiate the vaccination series at ages 9 through 14 years. Three doses remain recommended for persons who initiate the vaccination series at ages 15 through 26 years and for immunocompromised persons.
Switching to aromatase inhibitor (AI) after tamoxifen in premenopausal patients with chemotherapy-induced amenorrhea (CIA) after early breast cancer treatment.
Authors: J. A. Perez-Fidalgo, M. J. Miranda, B. Bermejo, V. Pons, S. Rosello, E. Garcia-Garre, C. Guzman, A. Lluch
Journal: Journal of Clinical Oncology (2011)

e11099 Background: AI are contraindicated in women with functioning ovaries as the reduced feedback of estrogen leads to an increased secretion of gonadotropins. Previous data obtained in our center confirms that the incidence of CIA among premenopausal patients is 75.5% - 82.7% depending on the chemotherapy administered. The aim of our study was to analyze outcome in terms of ovarian function recovery in premenopausal patients treated with tamoxifen that switched to AI after long-term CIA (>1 year) and/or estradiol levels < 20 pmol. Methods: 102 patients diagnosed with hormone-sensitive early breast cancer at the Hospital Clinico of Valencia, and clinically premenopausal at diagnosis were included from May 2004 to December 2009. All patients were treated with chemotherapy in the adjuvant or neoadjuvant setting, and adjuvant tamoxifen. Patients had to accomplish criteria of postmenopausal status at the time of switching defined as a period of CIA of more than 1 year and/or levels of estradiol < 20 pmol/L. Results: Median age at switching was 49.8 years, 81 patients were 45 years or older, 19 patients were 40-44 years and 2 treated with high-dose chemotherapy were younger than 40 years. 40% received both anthracyclines and taxanes and 14% high-dose adjuvant chemotherapy. 87 patients were switched after at least 2 years of tamoxifen, and to 15 patients switching was offered earlier due to tamoxifen intolerance. Monitoring of estradiol levels was obtained in 55 patients (53.9%) at the time of switch, of whom 46 presented levels of estradiol < 20 pmol/L. In 9 patients (7.8%) ovarian function returned with renewal of menses and serum estradiol levels > 20 pmol/L. None of the patients younger than 40 returned to normal ovarian function. Conclusions: AI should be used with caution in premenopausal patients after CIA. However, with an appropriate monitoring and follow-up, incidence of recovery of ovarian function occured in only 7.8% of the patients. Switch to an AI in patients younger than 40 with CIA after high dose CT may be a safe procedure.
Abstract 2207: Elucidating mechanisms employed by NFIL3 to impact cancer cell survival
Authors: Megan Keniry, Omar Caballero, Itzel Flores, Andrea Salinas
Journal: Cancer Research (2015)

Abstract NFIL3 was recently identified as a novel modulator of FOXO1 output on the PI3K pathway. NFIL3 bound to DNA to physically block FOXO1 recruitment to genes that induce apoptosis. The diminishment in NFIL3 expression via RNA interference led to FOXO recruitment to cell death genes, an increase in Histone H3 acetylation on these genes, and increased expression of these genes. However, a number of observations suggest that FOXO1 is not the main target of NFIL3 in these cells. First, the NFIL3 and FOXO1 DNA consensus sites have almost no similarity. Second, the loss of FOXO1 or all three FOXO factors failed to suppress the cell death phenotype upon the diminishment of NFIL3 in MEFs. The goal of this project is to identify the factor(s) that NFIL3 directly blocks from DNA recruitment to promote cellular survival. In previous work, the NFIL3 and FOXO1 sites were mapped as being adjacent on the DNA. The mapped NFIL3 site was required for NFIL3 to associate with the DNA in biochemical experiments and for NFIL3 to regulate the promoter sequence in reporter assays. The mapped NFIL3 site is a perfect match for the bZIP transcription factor CCAAT/enhancer binding protein beta (CEBPB) consensus sequence. NFIL3 has been shown to block the ability of CEBPB to activate transcription by competing for access to the same DNA consensus site in numerous contexts including neuronal regeneration, PKA pathway transcriptional programs and the regulation of hepatitis C viral genes. Aside from DBP in circadian rhythm, CEBPB is the most commonly antagonized factor by NFIL3 in the literature. We are investigating if NFIL3 hinders FOXO1 recruitment to cell death genes by directly antagonizing CEBPB recruitment to these genes using cell biological and bioinformatics approaches. We have found that CEBPB is required for efficient induction of a subset of NFIL3 repressed genes. Citation Format: Megan Keniry, Omar Caballero, Itzel Flores, Andrea Salinas. Elucidating mechanisms employed by NFIL3 to impact cancer cell survival. [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 2207. doi:10.1158/1538-7445.AM2015-2207
ATCT-35QUALITY OF LIFE, COGNITIVE FUNCTION AND FUNCTIONAL STATUS IN THE EF-14 TRIAL: A PROSPECTIVE, MULTI-CENTER TRIAL OF TTFIELDS WITH TEMOZOLOMIDE COMPARED TO TEMOZOLOMIDE ALONE IN PATIENTS WITH NEWLY DIAGNOSED GBM
Authors: Jay-Jiguang Zhu, Susan Pannullo, Maximilian Mehdorn, Franz Payer, Nicholas Avgeropoulos, Andrea Salmaggi, Antonio Silvani, Alessandro Olivi, Samuel Goldlust, Carlos David, Alexandra Benouaich-Amiel, Eilon Kirson, Zvi Ram, Roger Stupp
Journal: Neuro-Oncology (2015)

BACKGROUND: Tumor Treating Fields (TTFields) are an anti-mitotic, electric-physical treatment modality. An interim analysis of the phase 3 trial comparing TTFields with maintenance temozolomide (TTFields/TMZ) showed superior progression free and overall survival compared to temozolomide alone (TMZ alone) in patients with newly diagnosed GBM. METHODS: After completion of radiotherapy with concomitant temozolomide, patients were randomized (2:1) to TTFields/TMZ or TMZ alone. The main trial endpoints were progression-free survival (PFS) and overall survival (OS). Here we report the quality of life (EORTC QLQ C-30 / BN20), Karnofsky performance scores (KPS) and minimental status exam (MMSE) results in the interim analysis of the first 315 patients randomized, with a median follow-up of 38 months (range 18-60). RESULTS (intent-to-treat): 210 patients were randomized to TTFields/TMZ and 105 patients to TMZ alone. Patient characteristics were balanced. Median PFS was 7.1 and 4.0 months [Hazard ratio (HR) 0.62, p = 0.001], respectively and OS from randomization was 19.6 and 16.6 months (HR 0.74, p = 0.034), respectively, both favoring TTFields/TMZ. Global health status improved in patients treated with TTFields/TMZ (change from baseline to 3 months [CFB3] = +24% and change from baseline to 6 months [CFB6] = +13%), whereas a decrease was seen in patients treated with TMZ alone (CFB3 = -7% and CFB6 = - 17%). A full analysis of all domains of the QLQ C-30/BN-20 will be presented. No differences in KPS or MMSE was seen between treatment groups over time. CONCLUSIONS: Maintenance TTFields/TMZ provides a clinically and statistically significant improvement in progression-free and overall survival in newly diagnosed GBM. Quality of life was not adversely affected by the continuous use of TTFields and may be improved in some domains of the EORTC QLQ C-30 and BN20. Cognitive and functional capabilities were not impeded by the addition of TTFields to TMZ therapy.
Prevalence of Risk Factors for VTE In Hospitalized Medical and Surgical Patients. Data From the Comparison of Methods for Thromboembolic Risk Assessment with Clinical Perceptions and AwareneSS In Real Life Surgical and Medical Patients (COMPASS) Study
Authors: Grigoris T Gerotziafas, Miltos Chrysanthidis, Reda Isaad, Hela Baccouche, Chrysoula Papageorgiou, Brigitte Thiolier, Alex C Spyropoulos, Vassiliki Galea, Asterios Katsamouris, Dimitris Kiskinis, Ismail Elalamy
Journal: Blood (2010)
Abstract 2452: Deorphanizing TLX: Implications for treatment of glioblastomas
Authors: Cindy C. Benod, Rosa Villagomez, Paul Webb
Journal: Cancer Research (2015)

Abstract Nuclear receptors (NRs) are important ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of so- called “orphan” NRs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and emerging evidence indicates that it is an excellent target to treat Neural Stem Cell (NSC) derived brain tumors and glioblastomas. Indeed, several groups hypothesized that small molecules de-repressing TLX activity in glioblastoma cells should slow tumor progression and invasiveness by inducing the cyclin-dependent kinase inhibitor p21 and the tumor suppressor pten. Until recently, no chemical probes to modulate TLX activity to test this hypothesis were available, and it was not clear whether TLX was druggable. Our homology models of the TLX ligand binding domain (LBD) suggest that TLX belongs to an emerging class of NRs that lack two LBD helices and fold into an auto-repressed conformation. While our models suggests that TLX could harbor a ligand binding pocket, the consequences of its unusual organization for small molecule development were unknown. We used a medium throughput screening strategy to assess TLX ligand binding capacity. We investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity. As a result, we reported three compounds that bind to TLX with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. Based on this study, we could conclude that TLX is druggable. We are now investigating how to de-repress TLX transcriptional activity using derivatives of these small molecules. We are imaging the mode of binding of the three identified ligands and discovering surfaces which bind coregulators of TLX in glioblastomas. This knowledge will allow us to devise strategies to chemically modify novel TLX ligands to disrupt coregulator interactions and to obtain the desirable biological activities. A first generation of novel analogues is currently being tested. In this presentation we will describe ongoing Structure-Activity Relationship studies to identify new specific TLX ligands able to de-repress TLX transcriptional activity. Citation Format: Cindy C. Benod, Rosa Villagomez, Paul Webb. Deorphanizing TLX: Implications for treatment of glioblastomas. [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 2452. doi:10.1158/1538-7445.AM2015-2452
A case of unusual extra-medullary hematopoiesis
Authors: S. S. Eapen, R. Narayan, A. Khan
Journal: Journal of Clinical Oncology (2004)

6698 Background: Extramedullary hematopoiesis is defined as growth of hematopoietic tissue outside the bone marrow. Usual sites are liver, spleen and spine. It is extremely rare in the uterus, cervix and ovaries. Methods: Case Report. Results: A 43 year-old African American female who presented to the emergency room with one day history of left lower quadrant pain that radiated to the back and down her left thigh. She was afebrile, but tachycardic on presentation. Her abdominal exam was significant for a large palpable spleen that was tender. The patient had mild abdominal distention, tenderness over the lower abdomen, rebound tenderness,and guarding on examination. The pelvic examination revealed exquisite cervical motion tenderness and a diffuse pelvic mass. Her initial CBC revealed a White Cell Count of 261,000, Hemoglobin of 10.0, Hematocrit of 32.0, and Platelets of 477,000. The differential count was significant for 14 bands, 4 lymphocytes, 2 monocytes, 2 eosinophils, 1 basophil, 3 metamyelocytes, 19 myelocytes, 5 promyelocytes, 5 myeloblasts and 1 nucleated RBC. Bone Marrow biopsy was consistent with Chronic Myeloid Leukemia. An abdominal CT scan revealed complex tubular structures in both adnexal regions which are highly suspicious for pyosalpinges or tubo-ovarian abscesses. Patient was started on broad-spectrum antibiotics and hydroxyurea. Pt had mild improvement with antibiotics, and after 48 hours of treatment underwent exploratory laparotomy. She was noted to have bilateral tubo-ovarian masses intraoperatively. A total abdominal hysterectomy and bilateral salphingooopherectomy was performed. Histopathologic examination revealed extramedullary hematopoiesis in the right ovary, endometrial stroma and cervical polyp. Patient was discharged home on Imatinib and will follow up with oncology. Conclusions: We report a case of unusual extramedullary hematopoiesis causing abdominal pain as a presenting feature of CML. No significant financial relationships to disclose.
Mitotic Arrest Deficiency 2 (Mad2) Is Required for Proliferative Synergy of GM-CSF Plus SCF in Hematopoietic Progenitors Via Effects on Apoptosis and Is Mediated by Ligand-Dependent Association of Mad2 with SCF and GM-CSF Receptors.
Authors: Shigeki Ito, Charlie Mantel, Yoji Ishida, Hal E. Broxmeyer
Journal: Blood (2006)
370. Reconstruction of the Nigrostriatal Pathway in Parkinsonian Macaques
Authors: Diego Pignataro, Diego Sucunza, Alberto J. Rico, Iria G. Dopeso-Reyes, Elvira Roda, Africa Vales, Gloria Gonzalez-Aseguinolaza, Nick Kholodilov, Robert E. Burke, José L. Lanciego
Journal: Molecular Therapy (2016)

The field of Gene Therapy in the CNS has recently witnessed a number of major conceptual changes. At present, ongoing strategies are focused on using vectors carrying genes to further modify brain circuits of interest. It is expected that these approaches will result in a great therapeutic potential being sustained by the induced changes in brain circuitry. Indeed, for the first time these advances will allow the implementation of "disease-modifying" therapies, e.g., trying to arrest or even revert the natural course of Parkinson's disease. Here we are using hRheb(S16H)-carrying Adeno-associated virus (AAV) vectors in parkinsonian macaques, in an attempt to reconstruct the damaged nigrostriatal pathway. Preliminary results reported here stand on the intracerebral delivery of h-Rheb-carrying AAV serotype 5 in the substantia nigra of two MPTP-treated macaques showing a severe parkinsonian syndrome. After a follow-up of six months, both macaques showed a lack of motor improvement, together with no changes on the conducted microPET neuroimage scans. However, the histopathological analysis revealed a moderate degree of axonal reinnervation in the putamen nucleus following a viral infection limited to 10-12 dopaminergic neurons per animal. These results, so far insufficient to elicit any motor/neuroimage improvements, are very appealing and indeed represent the first evidence that a damaged dopaminergic circuit can be reconstructed in adult parkinsonian macaques. A number of ongoing strategies are currently under development in an attempt to improve the amount of neurons being infected with the hRheb gene, therefore leading to a more complete reconstruction of the nigrostriatal pathway.
Abstract 1945: Self-phosphorylation primes JNK2 for activation by MKK4 in glioblastoma and non-small cell lung carcinoma
Authors: Tamer S. Kaoud, Kevin N. Dalby
Journal: Cancer Research (2015)

Abstract JNKs (c-Jun N-terminal kinases) are members of the mitogen-activated protein kinase (MAPK) family, known primarily for their response to cell stress. JNK activation is mediated cooperatively by both MKK4 and MKK7. Uniquely, c-Jun N-terminal kinase 2 (JNK2) isoform has been reported to be constitutively activated (without MKK4/7). Recent studies in glioblastoma and lung carcinoma have identified important roles for JNK2 constitutive activation (but not JNK1). Using phospho-specific antibodies, recombinant activated (MKK4 &amp; MKK7), inactivated (JNK1 &amp; JNK2) and phos-tag PAGE, we have identified that JNK2 self-phosphorylation results in the production of active JNK2 (phosphorylated on both Thr-183 and Tyr-185) and a form of mono-phosphorylated JNK2 (phosphorylated only on Thr-183) whose activation is MKK4-dependent (phosphorylates Tyr-185), but MKK7-independent. The effect of MKK4 on JNK2 constitutive activation has been further investigated in mouse embryonic stem cells that have MKK4 and/or MKK7 knocked out. MKK4 but not MKK7 existence in these cell lines enhanced JNK2 autoactivation. Interestingly, knockdown of MKK4 or JNK2 in U78MG glioblastoma cell line, A549 non-small cell lung carcinoma cell line and HEK293 cells dramatically decreased JNK2 constitutive activation and inhibited A549 cellular growth and anchorage-independent growth that have been reported to be regulated by JNK2 constitutive activity. As a conclusion, our data demonstrates for the first time that JNK2 autophosphorylation primes its activation by MKK4. This phenomenon can allow JNK2 activity to be further regulated by discrete cellular signals. Citation Format: Tamer S. Kaoud, Kevin N. Dalby. Self-phosphorylation primes JNK2 for activation by MKK4 in glioblastoma and non-small cell lung carcinoma. [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 1945. doi:10.1158/1538-7445.AM2015-1945
365. Increased Tissue Temperature Improves Electro-Transfer Mediated Gene Delivery to Skin
Authors: Anna Bulysheva, Amy Donate, Chelsea Edelblute, Derrick Jung, Malik Muhammad, Shoenbach Karl, Heller Richard
Journal: Molecular Therapy (2015)

Introduction: Developing an optimal gene electro-transfer system for delivery of plasmid DNA to the skin in vivo has been challenging with expression often confined in the epithelium requiring high voltage electric fields, which can cause cellular and tissue damage. Minimizing such damage, while optimizing gene expression profiles, are highly desirable for therapeutic applications of gene delivery to the skin. Cell membrane fluidity is temperature dependent, thus moderate temperature elevation can increase membrane fluidity. Utilizing this concept, we developed a novel gene electro-transfer electrode for in vivo applications with ability to heat tissue with a laser integrated into a four pin multi-electrode array, to improve gene delivery efficiency. Methods: We tested a range of gene electro-transfer conditions in vivo in guinea pigs with and without elevating skin temperature to 43°C immediately prior to application of electric pulses. Firefly luciferase encoding plasmid DNA was delivered and expression levels were measured by luminescence (IVIS Spectrum) for quantifying expression profiles in photons/second. Green florescence protein (GFP) encoding plasmid DNA was also delivered for assessing gene expression location. Results Our results indicated that increasing the temperature resulted in significantly higher gene expression compared to controls without applied heat in luciferase groups. GFP immunohistochemistry showed gene expression was localized in the epidermal layers of the skin. Significance: It is therefore possible to use lower applied electric fields and achieve comparable gene expression to higher electric fields if the tissue temperature is slightly elevated above normal body temperature. Lower applied electric fields, result in reduced cellular and tissue damage compared to higher applied electric field, thus such conditions are more efficient for therapeutic applications. In summary, we developed a safer and a more efficient delivery system for in vivo gene transfer to the skin by moderately elevating tissue temperature during gene-electro transfer.
Stapled Peptides: Leveraging the BH3 α-Helix to Create a New Class of Drugs to Treat Hematological Malignancies
Authors: Rosana Kapeller, Jiawen Han, Kaiming Sun, Pranoti Gangurde, Nori Kawahata, Matt Iadanza, Vincent Guerlevais, Jim Horstick, Justin Noehre, Allen Annis, Larry Licklider, Huw M. Nash, Andrew Kung, Tomi K. Sawyer
Journal: Blood (2008)
84. Pharmacology/Toxicology Studies for Gene-Modified Hematopoietic Stem Cell Transplantation for Cystinosis
Authors: Tatiana Lobry, Sarah Ur, Athena Lau, Jay Sharma, Celine J. Rocca, Donald B. Kohn, Denise Carbonaro, Betty Cabrera, Stephanie Cherqui
Journal: Molecular Therapy (2015)

Cystinosis is an autosomal metabolic disease belonging to the family of lysosomal storage disorders. Mutations in the CTNS gene, encoding a lysosomal cystine transporter, lead to cystine accumulation and multi-organ failure such as blindness, myopathy, diabetes and central nervous system defects. Affected individuals also develop proximal tubulopathy and eventually progress to end stage renal failure. Treatment is available with the drug cysteamine to reduce intracellular cystine content. However, cysteamine only delays the progression of the disease. In April 2012, the first clinical trial using stem cells for cystinosis was approved as an allogeneic Hematopoietic Stem and Progenitor Cell (HSPC) transplant to be conducted at University of California, Los Angeles. This trial was based on our preclinical studies in the mouse model of cystinosis, Ctns-/- mice, which showed that transplantation of HSPCs expressing a functional Ctns gene led to the abundant tissue integration of bone marrow-derived cells, a significant decrease of cystine accumulation and kidney preservation. In order to avoid the high mortality and morbidity associated with allogeneic transplants, however, we have developed an autologous transplantation strategy of HSPCs genetically modified ex vivo to express a functional CTNS gene as a treatment for cystinosis. Preclinical studies using a SIN-lentivirus vector containing CTNS to transduce Ctns-/- HSPCs and transplanted in Ctns-/- mice were promising leading to cystine reduction in all tissues and kidney function improvement. We are currently performing pharmacological and toxicological studies using a batch of pCCL-CTNS lentiviral vector preparation produced under comparable Good Manufacturing Practice, the results of which will be included in an IND for a phase 1 clinical trial for cystinosis. We have now completed the in vitro studies, establishing the optimal conditions to transduce human CD34+ hematopoietic stem cells with our lentiviral vector to obtain a Vector Copy Number (VCN) included between 1 and 3. We performed Colony Forming Unit (CFU) assays using human CD34+ PBSC isolated from five healthy donors and four cystinotic patients and neither showed aberrant proliferation or differentiation potential with the lentivirus compared to negative controls. Additionally, the In Vitro Immortalization (IVIM) assay, a genotoxicity test, did not produce immortalized clones, thus demonstrating an excellent safety profile. Lastly, we have in progress in vivo serial transplantation experiments of transduced murine Ctns-/- HSPCs to assess the safety of this strategy in vivo by comprehensive molecular, clinical and histological analyses. This work represents the first stem cell and gene therapy treatment strategy for cystinosis. If successful, this treatment could be a proof of concept for other degenerative multi-systemic disorders.