tbuckley/cabot-search huggingface dataset:
304. Particle Titer Determination and Characterization of rAAV Molecules Using Nanoparticle Tracking Analysis
Authors: Samantha F. Povlich, Jonathan G. Mehtala, Gwendolyn M. Wilmes, Christopher J. Morrison, Samuel C. Wadsworth, K. Reed Clark
Journal: Molecular Therapy (2016)

The development and commercialization of a biological pharmaceutical, such as recombinant adeno associated virus (rAAV), requires rigorous quantitative and qualitative testing. An accurate particle titer measurement is important for the development of purification processes. Current methods for titering rAAV include qPCR, for measuring genome copy titer, and ELISA, for measuring particle titer. Additionally, methods such as dynamic light scattering (DLS) have been considered for assessment of particle size and aggregation but with limited success for rAAV. Here, a novel method is described called Nanoparticle Tracking Analysis (NTA), to provide rAAV titer (concentration) within minutes, as opposed to hours or days required by traditional techniques. NTA characterization was enabled by a gold labeling technique to increase the light scattered from rAAVs. With a purified gold labelled rAAV sample, NTA results indicated a monodisperse size distribution and a measured rAAV particle titer equivalent to the concentration based on genome copies by qPCR. Particle titer determination can also be relevant for assessment of product stability. NTA was used to assess the stability of rAAV over a 3 month thermal stress test. The NTA method enabled the detection of a reduction of the primary rAAV particle peak within 1 month, as well as further reductions over time. These initial results demonstrate the potential uses of NTA for product characterization.
Prolonged Low Dose Therapy with a Pan-Deacetylase Inhibtor, Panobinostat (LBH589), in Patients with Myelofibrosis
Authors: John Mascarenhas, Alice Mercado, Amelyn Rodriguez, Min Lu, Carla Kalvin, Xiaochun Li, Bruce Petersen, Vesna Najfeld, Judith D. Goldberg, Ronald Hoffman
Journal: Blood (2011)
Abstract 2975: Comprehensive analysis of genetic alterations and DNA copy number in Borrmann type IV gastric cancer
Authors: Makiko Yasumoto, Sachiko Ogasawara, Jun Akiba, Hironori Kusano, Akiko Sumi, Taro Isobe, Junya Kizaki, Yoshito Akagi, Takuji Torimura, Etsuko Sakamoto, Hiraku Itadani, Tsutomu Kobayashi, Shinji Mizuarai, Shinji Oie, Hirohisa Yano
Journal: Cancer Research (2015)

Abstract The prognosis of patients with Borrmann type IV gastric cancer (Type IV) is extremely poor. Thus, there is an urgent need to elucidate the molecular mechanisms underlying the oncogenesis of Type IV and to identify new therapeutic targets. Although previous studies using whole-exome and whole-genome sequencing have elucidated genomic alternations in gastric cancer, no reports have focused on the comprehensive genetic analysis in Type IV. To find cancer relevant genes in Type IV, we performed whole exome sequencing and genome-wide copy number analysis on 14 patients of Type IV. The exome sequencing identified a total of 182 somatic mutations which cause amino-acid substitutions or splice-site alterations. Previously reported mutations in gastric cancer were detected, such as ARID1A, CDH1, TP53 and RHOA. Moreover, our study has found novel mutations that have not been reported in gastric cancer and other tumor types. Among the newly identified genetic alterations, a mutation in muscle RAS oncogene homolog (MRAS) was predicted to cause molecular dysfunction. MRAS belongs to the Ras subgroup of small G proteins, including the prototypic RAS oncogene, KRAS, HRAS, and NRAS. The MRAS mutation discovered by whole-exome sequencing was validated by mutation-specific PCR. To investigate the frequency of mutation in MRAS, we performed Sanger sequencing of additional 46 Type IV samples. A total of 9 non-synonymous mutations were discovered with a mutation frequency of 17%, showing that MRAS is recurrently mutated in Type IV. The genome-wide copy number analysis also showed that copy number was aberrant in 41 genes, including Insulin-like growth factor 1 receptor (IGF1R). The samples with IGF1R amplification showed remarkably higher expression levels of mRNA and protein compared with other samples. In conclusion, this is the first research to discover mutation in MRAS among human tumor samples, although introduction of artificially mutated MRAS is known to have oncogenic activity. In addition, these results suggested that MRAS mutation and IGF1R amplification could drive tumorigenesis of Type IV and could be a new therapeutic target for Type IV. Citation Format: Makiko Yasumoto, Sachiko Ogasawara, Jun Akiba, Hironori Kusano, Akiko Sumi, Taro Isobe, Junya Kizaki, Yoshito Akagi, Takuji Torimura, Etsuko Sakamoto, Hiraku Itadani, Tsutomu Kobayashi, Shinji Mizuarai, Shinji Oie, Hirohisa Yano. Comprehensive analysis of genetic alterations and DNA copy number in Borrmann type IV gastric cancer. [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 2975. doi:10.1158/1538-7445.AM2015-2975
The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense
Authors: Luis H. Franco, Vidhya R. Nair, Caitlyn R. Scharn, Ramnik J. Xavier, Jose R. Torrealba, Michael U. Shiloh, Beth Levine
Journal: Cell Host & Microbe (2016)
OC-086 Model for specialist-led “acute gastroenterology service”: development and delivery
Authors: A U Jawhari, S Ryder, M James, T Bowling, C Fraser-Moodie, R Spiller, J Atherton, K Ragunath, G Aithal
Journal: Gut (2010)

Nitrofurantoin is a synthetic derivative of imidazolinedione, used to treat uncomplicated urinary tract infections. It acts by inhibiting bacterial DNA, RNA and cell wall protein synthesis. It is used prophylactically as a urinary anti-infective agent against most gram-positive organism and for long-term suppression of infections. Nitrofurantoin-associated pulmonary injuries occur in 1% of patients, presenting with dyspnoea and dry cough, and it can mimic interstitial lung disease. We present a case of an 81-year-old woman with shortness of breath and cough 3 days after initiation of nitrofurantoin. CT of the chest revealed bilateral pleural effusion and extensive pulmonary interstitial prominence, suggesting pulmonary fibrosis. According to the Naranjo Adverse Drug Reaction Probability Scale score of 6, it was determined that nitrofurantoin was the probable cause, and immediate cessation of the medication showed a marked clinical improvement and resolution after 10 days.
Gynaecologist is struck off for dishonesty and intention to cause distress
Authors: Clare Dyer
Journal: BMJ (2016)

A consultant gynaecologist who treated a neighbouring couple out of apparent friendship, then tried to bill them when the relationship turned sour, has been struck off after a fractious hearing at a medical practitioners’ tribunal in Manchester.

Joseph Loze Onwude was also found to have worked for eight months without professional indemnity cover, acted as a GP in prescribing drugs for his neighbours despite lacking general practice qualifications, and failed to keep proper records of this treatment or to inform their actual GPs.

Onwude, who qualified in Nigeria in 1981, trained at Dublin and Leeds before becoming a fellow of the Royal College of Obstetricians …
Tetrahydrobiopterin (6R-BH4): Novel Therapy for Endothelial Dysfunction in Sickle Cell Disease
Authors: Lewis Hsu, Kenneth I Ataga, Victor R. Gordeuk, Paul S. Swerdlow, Abdullah Kutlar, Wally Smith, J. Martin Johnston, Ian A Chen, Anne Greist, Frances Flug, Susumu Inoue, Olise M. Nwose, Saba Sile, Emil Kakkis
Journal: Blood (2008)
Abstract 1589: Investigation of circulating tumor cells from head and neck cancer patients undergoing radiation therapy: A pilot study
Authors: Michael J. Eblan, Ja Hye Myung, Joseph M. Caster, Bhishamjit S. Chera, Seungpyo Hong, Andrew Z. Wang
Journal: Cancer Research (2015)

Abstract Background: Circulating tumor cell (CTC) enumeration provides prognostic information in patients with metastatic breast, prostate, colorectal and lung cancer. However, the effect of radiation therapy (RT) on CTCs in patients with primary head and neck malignancies has not been explored. The purpose of this exploratory study is to examine how CTCs, as measured by a novel cell capture technique, respond to RT in patients with head and neck cancer. Methods: A total of a 16 patients undergoing definitive radiation for primary, non-metastatic head and neck cancer were enrolled in this pilot study. Peripheral blood was collected at 5 time points, including at baseline prior to starting RT, at the first week, mid-point and final week during treatment, and at least 4 weeks after completion of RT. Quantification of CTCs was performed with a novel device that used a biomimetic combination of three cancer cell-specific antibodies (aEpCAM, aHer-2, and aEGFR) immobilized through poly(amidoamine) dendrimers and E-selectin, which respectively induce concurrent stationary binding and dynamic cell rolling of the tumor cells. Results: CTCs were successfully detected in all patients before the start of radiation (100%), including patients with HPV/p16 positive or negative tumors. The novel CTC device yielded up to a 4-fold enhancement in capture efficiency relative to the aEpCAM-functionalized surface. The average CTC count in patients before RT was 386 CTCs per mL (range, 18 to 1134 CTCs per mL), significantly higher than the average CTC count of 90 CTCs per mL after the completion of radiation (range, 5 to 393 CTCs per mL). All but one patient demonstrated a decrease in measured CTCs at sequential time points during the course of RT. The patient with an elevation in CTCs during RT had residual metastatic carcinoma detected after left level II selective cervical neck dissection, which was performed 12 weeks post-RT due to persistent radiographic lymph nodal abnormality. At a median follow-up of 1.5 months, no patient has had a local or distant failure. Conclusions: We have demonstrated that our novel technology can affectively capture CTCs in head and neck cancer patients. Importantly, our pilot data shows CTCs decrease over the course of RT, suggesting CTCs can be a predicative biomarker for radiotherapy response. Further study will investigate associations between CTC kinetics and clinical outcomes. Citation Format: Michael J. Eblan, Ja Hye Myung, Joseph M. Caster, Bhishamjit S. Chera, Seungpyo Hong, Andrew Z. Wang. Investigation of circulating tumor cells from head and neck cancer patients undergoing radiation therapy: A pilot study. [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 1589. doi:10.1158/1538-7445.AM2015-1589
A triple approach strategy for patients with locally advanced pancreatic adenocarcinoma.
Authors: M. Cantore, R. Girelli, A. Mambrini, I. Frigerio, G. Boz, E. Simoncini, A. Lusenti, M. Orlandi, C. Bassi
Journal: Journal of Clinical Oncology (2011)

e14607 Background: Patients with locally advanced pancreatic cancer (LAPC) have an expected median survival ranging from 10 to 13 months. No new chemotherapic drug or targeted therapy have significantly changed natural history of this disease. New strategies are needed. Radiofrequency ablation (RFA) is an emerging and feasible procedure to treat patients with LAPC, radiochemotherapy (RCT) seems to increase local control and intra-arterial/systemic chemotherapy (IASC) can reduce liver progression. Methods: At our Institutions, patients with LAPC were treated with RFA; RCT (twice-weekly gemcitabine 40 mg/m2 administered concurrently with external beam radiation therapy at a dose of 54.0-59.4 Gy) and IASC (epirubicin 35 mg/m2 and cisplatin 42 mg/m2 on day 1 every 4 weeks, combined with systemic gemcitabine 1,000 mg/m2 on day 2, and capecitabine 650 mg/m2/bid over 14 days) were combined with RFA, in a triple approach strategy (TAS). Results: Between February 2007 and June 2010, 107 patients with LAPC were treated with RFA. RCT was performed in 88 patients; IASC in 35; combination of RFA plus RCT plus IASC (TAS) in 32. After a median follow-up of 25.7 months, median overall survival (OS) was 25.6 months, with 1-year and 2-year survival of 76% and 52%, respectively. Patients submitted to TAS had an OS of 34.0 months (1- and 2-year survival of 97% and 80%). In univariate analysis, performance status (0 vs 1, OS 39.9 vs 18.4 months) RCT (yes vs no, OS 31.5 vs 14.2 months), IASC (yes vs no, OS 35.1 vs 16.5 months) and TAS (yes vs no, OS 34.0 vs 18.4 months) were significant predictors of survival. Among patients treated with TAS, 3 were submitted to laparotomy (10%) and showed a patological complete response. Multivariate analysis revealed three independent significant variables: performance status, RCT and IASC. Conclusions: Observed survival of 25.6 months from diagnosis appears unexpected in a group of 107 consecutive patients with LAPC. Multimodality approach identify a sub-group of 32 patients submitted to TAS with an impressive survival of 34 months. It urgely needs further evaluations to confirm these results.
Core I97L mutation in conjunction with P79Q is associated with persistent low HBV DNA and HBs antigen clearance in patients with chronic hepatitis B
Authors: T. Honda, M. Ishigami, Y. Ishizu, T. Kuzuya, K. Hayashi, T. Ishikawa, Y. Murakami, M. Iwadate, H. Umeyama, H. Toyoda, T. Kumada, Y. Katano, H. Goto, Y. Hirooka
Journal: Clinical Microbiology and Infection (2016)
High Serum Level of Placental Growth Factor (PlGF) Predicts Adverse Overall Survival in Patients with Acute Myeloid Leukemia Treated with Standard Chemotherapy
Authors: Agnieszka Wierzbowska, Anna Krawczynska, Ewa Wawrzyniak, Agnieszka Pluta, Anna Wolska, Agnieszka Janus, Anna Szmigielska, Tadeusz Robak
Journal: Blood (2008)
Abstract 18460: A Comparison of Complexity of Extraction Between Sprint Fidelis and Other Right Ventricular Leads
Authors: Madhu Y Reddy, Ajay Vallakati, Kirill Lipatov, Pramod Janga, Gopi C Ponnaganti, Vivek Yarlagadda, Ramchandur Bakhtiani, Donita Atkins, Sudharani Bommana, Namratha Reddy, Rhea Pimentel, Martin Emert, Raghuveer Dendi, Luigi DiBiase, Andrea Natale, Buddhadeb Dawn, Dhanunjaya Lakkireddy, Loren Berenbom
Journal: Circulation (2013)

Introduction: There is no data comparing the relative difficulty of extraction between Sprint Fidelis and other right ventricular (RV) leads. Methods: We performed a retrospective analysis of all consecutive RV lead extractions in a single large referral center performed between 2005 and 2011. RV leads were grouped into Fidelis, non-Fidelis ICD and pacemaker leads. Indications, baseline characteristics, procedural variables and outcomes were compared between the different RV leads. Results: A total of 475 patients were included in the study of which Fidelis, non-Fidelis ICD and pacemaker lead was extracted in 198 (42%), 128 (27%) and 149 (31%) of the patients with a mean lead age of 47, 42 and 71months respectively (p=0.002). Mean age of the population was 64years with no difference across the groups. The indications for extraction were prophylaxis (32%), infection (25%) and malfunction (18%) with Fidelis lead much more likely to be extracted for prophylaxis and malfunction than for infection when compared to the other 2 groups (p&lt;0.001). Extraction support (ES) was needed in 302 (64%) (laser in 57% and mechanical device only in 43%) of the leads. Many more leads needed ES in the Fidelis group (77%) when compared to either the non-Fidelis ICD (56%) or the pacemaker group (52%) (p&lt;0.001). Analysis of leads &gt;24months old revealed that for a given lead age, Fidelis lead was much more likely to require ES when compared to both non-Fidelis ICD lead and the pacemaker lead (p=0.001). Complications occurred in 16%, 15% and 6% of the patients with Fidelis, non-Fidelis ICD and pacemaker leads respectively (p = 0.003 between ICD and pacemaker patients). One major complication occurred each in Fidelis and pacemaker group patients. Conclusion: Extraction of Sprint Fidelis lead appears to be more difficult than other RV ICD or pacemaker leads with similar major complication rate.
Abstract 3548: Oncolytic adenovirus Ad5dlE1b replication efficiency is dependent on p53 mutation type in cancer cells
Authors: Moemen Abdalla, Basma M. Abbas, Yousef Haj-Ahmad
Journal: Cancer Research (2015)

Abstract Adenoviruses are the most popular viral DNA vectors in the development of gene therapies and oncolytic therapy. Oncolytic adenoviruses are genetically modified to provide a means of tumor-selectivity by conditionally replicating in tumor cells and substantially killing them via their viral lytic cycle. The p53 molecule is a tumor suppressor protein that regulates the genomic integrity of the cell by controlling apoptosis and cell cycle events. Upon viral infection, normal cell (p53 intact cell) responds through the activation of apoptosis by the p53 dependent pathway. The adenovirus E1B 55kDa protein inactivates p53 and prevents apoptosis leading to progressive viral lytic cycle. Although demonstrating a moderate successes rate in some cancers, Ad deleted E1B 55kDa has not been approved as a standard therapy for all cancer types. Several studies have revealed that E1B deleted Ad replication was independent of p53 status in the cell, as the virus replicated better in some p53 deficient cancers more than others. However, this relationship has not been investigated deeply on the molecular level. However, this relationship has not been investigated deeply on the molecular level. Therefore, the objective of this study is to understand the correlation between p53 status, levels, and functional activity, and oncolytic Ad5dl E1B 55kDa replication efficiency at the molecular level. We evaluated the effect of p53's functional status on the replication efficiency of oncolytic Ad5dl E1B 55kDa. Multiple mutant p53 were engineered and viral growth was evaluated with each mutant form in H1299 cells. P53-R175H mutant successfully rescued viral growth and its transcriptome analysis showed partial loss of wild type activity as well as gain of new function by allowing the virus to grow and to exert its mechanism of selectivity. The mechanism entailed deregulating the expression of specific cellular genes in the p53 pathway, cell cycle and apoptosis, to promote its production leading to efficient oncolytic effect. These results confirmed that onclytic Ad5dl E1B 55kDa sensitivity is mutation type-specific. Therefore, before it is applied clinically as cancer therapy for p53 deficient tumors, the type of p53 mutation must be determined and also more screening for the effect of other mutations should be done for successful rescuing and efficient antitumor effect. Citation Format: Moemen Abdalla, Basma M. Abbas, Yousef Haj-Ahmad. Oncolytic adenovirus Ad5dlE1b replication efficiency is dependent on p53 mutation type in cancer cells. [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 3548. doi:10.1158/1538-7445.AM2015-3548
Population levels and geographical distribution of HIV RNA in rural Ugandan and Kenyan communities, including serodiscordant couples: a cross-sectional analysis
Authors: Vivek Jain, Maya L Petersen, Teri Liegler, Dathan M Byonanebye, Dalsone Kwarisiima, Gabriel Chamie, Norton Sang, Doug Black, Tamara D Clark, Andras Ladai, Albert Plenty, Jane Kabami, Emmanuel Ssemmondo, Elizabeth A Bukusi, Craig R Cohen, Edwin D Charlebois, Moses R Kamya, Diane V Havlir
Journal: The Lancet HIV (2016)
160. Successful Treatment of Neonatal Metachromatic Leukodystrophy Model Mice by Low Dose of Self-Complementary AAV Type9 Vector Expressing ASA
Authors: Noriko Miyake, Koichi Miyake, Motoko Yamamoto, Takashi Shimada, Takashi Okada
Journal: Molecular Therapy (2016)

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease (LSD) caused by a functional deficiency of the lysosomal enzyme arylsulfatase A (ASA) and characterized by severe neurological symptoms due to widespread and progressive demyelination in the both central and peripheral nervous systems. Enzyme replacement therapy (ERT) has been applied to treat certain types of LSDs, but correction of neurological abnormalities is usually hampered by the blood brain barrier (BBB). We have previously shown that MLD mice can be treated by intravenous (IV) injection of classical single-stranded AAV type 9 vector expressing ASA (ssAAV9/ASA) for neonate and self-complementary AAV9/ASA (scAAV9/ASA) for adult. To develop the clinical MLD gene therapy, it is important to decrease the amount of viral vectors because of safety. In this study, we evaluated the therapeutic potential of scAAV9/ ASA-mediated systemic transduction of neonatal MLD mice at 10 times lower dose (2 × 1011 v.g./body) compared to the treatable dose of the ssAAV9/ASA (2 × 1012 v.g./body). We generated both ssAAV9/ASA and scAAV9/ASA to intravenously inject then into the neonatal MLD mice (n=6-9). ELISA analysis showed that sustained high-level expression of ASA was detected in the brain and spinal cord of the scAAV9/ASA-treated mice (cerebral cortex, 2.1 times; cerebellum, 2 times; spinal cord, 5.5 times) compared to the ssAAV9/ASA for more than one year. Furthermore, in the behavior test, both scAAV9/ASA and ssAAV9/ASA-treated mice showed a significant improvement in their ability to traverse narrow balance beams, as compared to the non-treated MLD mice (latency; 7.2±0.9, 9.3±1.1 vs. 16.6±0.8 sec, P<0.05: slips; 3.4±0.8, 3.6±0.6 vs. 7.3±1.8 times, P<0.05). These data clearly demonstrate that MLD model mice can be treated by systemic neonatal transduction with low dose of scAAV9/ASA. Therefore, neonatal gene therapy would be an important option for parents faced with the prenatal diagnosis of a genetically affected child. Since ten times lower dose of scAAV9/ASA is enough to treat the neonatal MLD mice compared to ssAAV9/ASA, transduction strategy to use scAAV9/ASA should be safe and more practical for the clinical MLD gene therapy.