tbuckley/cabot-search huggingface dataset:
Maintenance with rituximab after autologous stem cell transplantation in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL): CORAL final analysis.
Authors: C. Gisselbrecht, B. Glass, G. Laurent, D. S. Gill, M. D. Linch, M. Trneny, D. Bron, O. Shpilberg, H. Hagberg, M. Bargetzi, D. Ma, J. Briere, C. Moskowitz, N. Schmitz
Journal: Journal of Clinical Oncology (2011)

8004 Background: Chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard treatment for chemosensitive relapses DLBCL. No study has compared different salvage therapies and evaluated maintenance post ASCT. Methods: DLBCL CD 20+ in first relapse or pts refractory after first line therapy were randomized between R ICE (rituximab, ifosfamide, etoposide, carboplatinum) or R DHAP (rituximab dexamethasone cytarabine and cisplatinum). Responding patients received BEAM and ASCT and were randomized between observation or maintenance with rituximab every 2 months for 1 yr (Gisselbrecht J Clin Oncol; 2010 28:4184-4190). Results: ITT analysis was made on 477 pts with R ICE: 243 pts and R DHAP: 234 pts: 255 relapses >12m, 213 refractory/early relapses; 306 pts with prior exposure to rituximab; secondary(s) IPI 0-1: 281 pts; s IPI 2-3:181pts. There was no difference in response rate between R ICE 63.6% and R DHAP 64.3%. There was no difference between R ICE and R DHAP at 4 yrs for EFS (26% vs 37% p=0.2) and OS (43% vs 51%, p=0.3). Factors affecting 4 yrs EFS, PFS and OS were: prior treatment with rituximab; early relapse < 12 m; s IPI 2-3. ASCT was performed in 255 pts and 242 randomized for maintenance:122pts rituximab (R), 120 pts observation(O). Distribution between R/O arms were respectively: median age 54 /53 yrs,Male 76/83; female 46/37;secondary IPI 0-1: 84/81; sIPI 2-3: 36/36. 89/76 relapses >12m., 33/41 refractory/early relapses. Median follow up was 44 m with 111 events. 4 yrs EFS was 52.8 % (CI 46-59) with 63% (CI 56-69) OS. There was no difference in EFS, PFS and OS between R and O arms. In multivariate analysis, sIPI2-3 significantly affected EFS, PFS, OS (p=0.0004). Women (83pts) had a better 4 yrs EFS 63% than male (159pts) 37% (p=0.01). The difference was only in the R arm (p=0.004). Gender was an independent prognostic factor in the R arm. Toxicity was mild with 12% SAE versus 4% for R /O respectively. Conclusions: There was no difference between R-ICE and R-DHAP and between post ASCT maintenance with R or O. Women did significantly better after ASCT with rituximab. Early relapses to upfront rituximab-based chemotherapy have a poor prognosis.
Chest Pain and Supplemental Oxygen
Authors: Maxime Cormier, Todd C. Lee
Journal: JAMA Internal Medicine (2016)

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Utility of the Revised Cardiac Index Score for Predicting Post-Surgical Outcome in Hb SC or SBeta+ -Thalassemia Sickle Cell Disease
Authors: Hamid Wardak, Ari Rosenberg, Vladimir Selounski, Michel Gowhari, Robert E. Molokie, Johara Hassan, Jin Han, Victor R. Gordeuk, Santosh L. Saraf
Journal: Blood (2015)
BCR-ABL1 Oncogene Down-regulates the Expression of OCT1 in CML.
Authors: Alexandra Bazeos, David Marin, Gareth Gerrard, Richard Szydlo, Dragana Milojkovic, Alistair Reid, Hugues de Lavallade, Jane F. Apperley, John M Goldman, Letizia Foroni, Jamshid Sorouri Khorashad
Journal: Blood (2009)
Abstract 2621: Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticles encapsulated aspirin, curcumin and free sulforaphane (ACS) combinations in BALB/c mice
Authors: Arvind Thakkar, Sushma Chenreddy, Jeffrey Wang, Sunil Prabhu
Journal: Cancer Research (2015)

Abstract The present study aims to evaluate the preclinical systemic toxicity profile of chitosan-solid lipid nanoparticles (c-SLNs) encapsulated aspirin (ASP), curcumin (CUR), and free sulforaphane (SFN) combination (ACS) in BALB/c mice. Recently, we demonstrated pancreatic cancer chemopreventive efficacy using ACS-SLNs delivery system in the BOP carcinogen induced pancreatic cancer hamster model. In order to develop safe ACS c-SLNs for clinical applications, it is vital to investigate their toxicity. Thus, we performed acute 3-day, sub-acute 28-day and sub-chronic 90-day toxicity studies of ACS c-SLNs in the BALB/c mice model. The mice were orally gavaged once every 24h with 200 μl ACS c-SLNs at three concentrations: low dose ACS (2+4.5+0.16 mg/kg; 1/30th of high dose), medium dose ACS (20+45+1.6 mg/kg; 1/3rd of high dose) and high dose ACS (60+135+4.8 mg/kg). Total of 60 mice were used for this study (4 mice each group X 3 timepoints X 5 groups). A standard evaluation was performed, which included daily clinical signs, weekly body weight, end-of-study blood hematology, blood clinical chemistry, gross necropsy on all animals and hematoxylin and eosin-stained examination of range of tissues from each animal. The clinical chemistry tests include blood urea nitrogen (BUN) and creatine (CRE), which indicate renal toxicity. Alanine transaminase (ALT) and alkaline phosphatase (ALP) levels indicate hepatic toxicity, while glucose (GLU) and total protein are measures of healthy growth. At the end-of-study, data revealed that mean body weight gain was consistent with low-, medium- and high-ACS c-SLN dose during acute, sub-acute and sub-chronic treatment period. The blood count and blood chemistry profiles revealed lack of systemic toxicity as the numbers were within normal ranges. Extensive histopathological examination of liver, kidney, heart, brain and pancreatic tissues showed no increase in treatment-related microscopic lesions in any of the three ACS c-SLN dose groups. Collectively, these findings demonstrate that repetitive oral administration of ACS c-SLN even at high concentrations was not associated with local or systemic toxicity and did not adversely affect the blood clinical chemistry of mice. Hence, long-term ACS c-SLN oral therapy is deemed safe for prevention of pancreatic cancer. Citation Format: Arvind Thakkar, Sushma Chenreddy, Jeffrey Wang, Sunil Prabhu. Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticles encapsulated aspirin, curcumin and free sulforaphane (ACS) combinations in BALB/c mice. [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 2621. doi:10.1158/1538-7445.AM2015-2621
Abstract 3870: Telomeric non-coding RNA causes genome-wide alteration of gene expression in cancer
Authors: Kyotaro Hirashima, Hiroyuki Seimiya
Journal: Cancer Research (2015)

Abstract The end replication problem of linear chromosome DNA causes telomere shortening and eventual senescence of normal cells. Cancer cells reactivate telomerase to maintain their telomere length and exhibit an infinite replicative potential. However, telomerase activation does not necessarily increase the average telomere length in cancer cells. Actually, cancer cells often maintain shorter telomeres than the cells in the surrounding normal tissues. We previously demonstrated that forced telomere elongation in cancer cells promotes their differentiation in a xenograft tumor and represses innate immune genes that are upregulated in various human cancers. This implies that short telomeres of cancer cells contribute to their malignancy. However, it is completely unknown how such genetic repression is caused by elongated telomeres. Here, we report that telomeric repeat-containing RNA (TERRA) induces a genome-wide alteration of gene expression in telomere-elongated human cancer cells. Using three different cancer cell lines, including those from prostate, breast and stomach, we found that telomere elongation by hTERT overexpression up-regulates TERRA signals, which were detected by northern blot analysis, and down-regulates innate immune genes such as STAT1, ISG15, and OAS3 in vivo. These changes were caused by telomere elongation and not by enhanced telomerase activity or hTERT overexpression per se. Down-regulation of the innate immune genes was also observed in the telomere-elongated cells under three-dimensional (3D) culture conditions, which mimicked the tumor microenvironment in vivo. Introduction of TERRA oligonucleotides repressed the innate immune genes even in cells with short telomeres under 3D culture conditions. Intriguingly, this gene repression appeared to occur from the action of the non-canonical nucleic acid structure called G-quadruplex (G4) in TERRA, because non-telomeric (i.e., non-G4-forming) control oligonucleotides had no effect whereas another non-telomeric but G4-forming oligonucleotide phenocopied the TERRA oligonucleotides. Transcriptome analysis revealed that telomere elongation and G4-forming oligonucleotides showed similar gene expression signatures. Most of the commonly suppressed genes were involved in the innate immune system and were up-regulated in various human cancers. Taken together, these observations suggest that the telomeric non-coding RNA G4 counteracts cancer malignancy through suppression of innate immune genes, and give a new insight into our understanding of telomere shortening in human cancer. Citation Format: Kyotaro Hirashima, Hiroyuki Seimiya. Telomeric non-coding RNA causes genome-wide alteration of gene expression in 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 3870. doi:10.1158/1538-7445.AM2015-3870
Abstract 2306: Quantitative assessment of one-side directed in vivo angiogenesis
Authors: Gerald Prager, Matthias Unseld, Johannes Breuss, Clemens Pausz, Gernot Schabbauer, Christoph Zielinski, Pavel Uhrin
Journal: Cancer Research (2015)

Abstract Angiogenesis, the sprouting of new blood vessels from pre-existing vasculature, is an essential process under physiologic and pathological conditions, and is in focus of therapeutic intervention. Reliable in vivo models to study angiogenesis are a pre-requisite for the characterization of novel therapeutic targets. Several methods like the matrigel plug assay, the chick chorioallantoic membrane assay or the cornea assay have addressed the objective to analyse angiogenesis in vivo, but a precise method to quantify one side-directed angiogenesis is lacking so far. Here, we describe an assay, which is based on the use of small matrigel-filled silicone cylinders that are implanted subcutaneously into mice for a period of up to 15 days. In C57BL/6J mice, the effect of the incubation period as well as the dose of the growth factors VEGF and FGF on angiogenic ingrowth was investigated. We describe the appropriate explantation procedure of the silicon tubes, ensuring the complete recovery of the in-grown vessels. The subsequent ex vivo assessment of neo-angiogenesis was then achieved by anti-CD31 as well as anti-endomucin immuno-histochemical staining of ingrown endothelial cells. Additionally, we show that vessel perfusion can be assessed by intravenous injection of a cell staining dye. Altogether, the elaborated protocol offers an effective and reliable assay which facilitates in vivo research on angiogenesis thus might support the development of novel therapeutic agents. Citation Format: Gerald Prager, Matthias Unseld, Johannes Breuss, Clemens Pausz, Gernot Schabbauer, Christoph Zielinski, Pavel Uhrin. Quantitative assessment of one-side directed in vivo angiogenesis. [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 2306. doi:10.1158/1538-7445.AM2015-2306
267. Phase I Gene Therapy Preliminary Clinical Results for Treatment of ND4 Leber Hereditary Optic Neuropathy with rAAV2-2-ND4
Authors: Scott Uretsky, Catherine Vignal, Samuel Bidot, Serge Fitoussi, Anne Galy, Sandrine Meunier, Roxane Noel, Céline Bouquet, Nitza Thomasson, Jean-Philippe Combal, José A. Sahel
Journal: Molecular Therapy (2016)

Introduction Leber Hereditary Optic Neuropathy (LHON) is a rare mitochondrial genetic disorder predominantly affecting young males. Affected patients experience bilateral severe central vision loss. Currently no therapy is approved in the United States to prevent, halt or reverse vision loss due to LHON. Preliminary safety and pharmacodynamic results of a first-in-man trial of GS010, a gene therapy candidate for patients with LHON carrying the ND4 mutation will be presented. Methods GS010 is a recombinant adeno-associated viral vector, serotype 2, carrying the wild-type ND4 gene (rAAV2/2-ND4) and is an experimental gene therapy for the treatment of LHON due to the G11778A ND4 mitochondrial mutation. GS010 has received orphan drug designation in EU & USA. GS010 contains a Mitochondrial Targeting Sequence (MTS) that allows localization of the wild-type protein to the mitochondrion, enabling restoration of mitochondrial function. An open-label Phase I/IIa safety study (NCT02064569) included patients with vision loss due to ND4 LHON and has completed recruitment. Four dose escalation cohorts and an extension cohort were comprised of 3 patients each. Patients received a single intra-vitreal injection of rAAV2/2-ND4 in their worse seeing eye. Primary outcome was the occurrence of adverse events (AE). Secondary outcomes included immune response to AAV2 and evaluation of visual function. Results Systemic safety was excellent as no unexpected adverse events occurred. Ocular tolerability was good with mostly mild inflammation that were responsive to and resolve with standard therapies. Of the first 9 patients with 48 week follow up, preliminary results indicate that symptom duration could impact magnitude of treatment effect. Additionally, baseline vision status at time of treatment also indicate a relation with potential greater magnitude of effect which was noted with relatively shorter disease duration (< 2 years). These data confirm the importance of treating early from onset of vision loss. The RESCUE (NCT02652767) and REVERSE (NCT02652780) Phase III studies of GS010 have been initiated in the United States and some European Union countries. Both studies are randomized, double-masked, sham-controlled trials and will specifically include patients up to 6 months and one year after the onset of vision loss.
Measurement of tidal breathing flows in infants using impedance pneumography
Authors: Leo Pekka Malmberg, Ville-Pekka Seppä, Anne Kotaniemi-Syrjänen, Kristiina Malmström, Merja Kajosaari, Anna S. Pelkonen, Jari Viik, Mika J. Mäkelä
Journal: European Respiratory Journal (2016)

Tidal breathing flow volume (TBFV) profiles have been used to characterise altered lung function. Impedance pneumography (IP) is a novel option for assessing TBFV curves noninvasively. The aim of this study was to extend the application of IP for infants and to estimate the agreement between IP and direct pneumotachograph (PNT) measurements in assessing tidal airflow and flow-derived indices.Tidal flow profiles were recorded for 1 min simultaneously with PNT and uncalibrated IP at baseline in 44 symptomatic infants, and after methacholine-induced bronchoconstriction in a subgroup (n=20).The agreement expressed as the mean deviation from linearity ranged between 3.9 and 4.3% of tidal peak inspiratory flow, but was associated with specific airway conductance (p=0.002) and maximal flow at functional residual capacity (V'maxFRC) (p=0.004) at baseline. Acute bronchoconstriction induced by methacholine did not significantly affect the agreement of IP with PNT. TBFV indices derived from IP were slightly underestimated compared to PNT, but were equally well repeatable and associated with baseline V'maxFRC (p=0.012 and p=0.013, respectively).TBFV profiles were consistent between IP and PNT in most infants, but the agreement was affected by reduced lung function. TBFV parameters were not interchangeable between IP and PNT, but had a similar association with lung function in infants.
Abstract PL-2: Patient Derived Xenografts - Pre-Clinical Models for Prevention and Treatment of Metastasis
Authors: Alana L. Welm
Journal: Cancer Research (2015)

Abstract Twenty to thirty percent of breast cancer patients eventually develop metastasis despite receiving state-of-the-art therapies. Clearly, identifying better ways to eliminate micro-metastatic tumor cells is paramount to eradicating death from breast cancer. Unfortunately, history suggests that developing yet another drug to target yet another pathway involved in tumor progression will not cure breast cancer. We now know that every tumor is unique; each tumor is heterogenous; tumors hijack multiple, redundant pathways to survive and grow; dormant tumor cells are resistant to chemotherapy; and tumors evolve resistance under pressure of therapy. To better understand the problem of metastasis, and to develop better treatments, we must utilize in vivo models of metastasis that best recapitulate heterogenous human breast cancers. We have generated a collection of orthotopic patient-derived breast tumor xenograft (PDX) models from all of the major breast cancer subtypes. We found remarkable fidelity between PDX models and bona fide breast tumors, including the ability to metastasize and to evolve under pressure of treatment. This presentation will highlight the strengths and pitfalls of PDX models of breast cancer and how they might be utilized to develop new strategies for treatment. Citation Format: Alana L. Welm. Patient Derived Xenografts - Pre-Clinical Models for Prevention and Treatment of Metastasis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PL-2.
617. Histologic Assessment of Geriatric Esophagus Revels Therapeutic Targets in Wild-Type and Dystrophic Mouse Models
Authors: John K. Hall, Ladan L. Mozaffarian, Jeffrey S. Chamberlain
Journal: Molecular Therapy (2015)

Gastroesophageal disorders increase as a process of aging and are exacerbated in degenerative neuromuscular disease such as Duchenne muscular dystrophy (DMD). DMD affects ≈1/5000 male births and is a catastrophic and ultimately fatal muscle wasting disease resulting from a mutation in the gene encoding the integral muscle protein dystrophin. Advancements in the treatment for DMD patients has increased patient lifespan and underscores a need to assess the impact of the disease in a range of organ systems, including the esophagus, likely to present new therapeutic challenges over time. Severity of esophageal pathology is varied to include reflux disease, achalasia, and megaesophagus. Defined as a pathologic enlargement of the esophagus, megaesophagus can result in a failure to complete peristalsis, impaction, severe weight loss and increased morbidity. Although poorly defined in human DMD patients, megaesophagus has been documented in canine and mouse models of DMD, however, a detailed cellular and mechanistic understanding remains unclear. We have performed a comprehensive morphologic and histologic examination of wild-type (C57/BL6) and dystrophic (mdx4cv) mouse esophagus to determine onset, pathology and changes in cellular composition accompanying megaesophagus onset. Age-associated presentation of megaesophagus was highly penetrant in both mouse models, with a four-fold increase in lumen dilation and coincident rate of impaction seen in aged dystrophic mice. In comparison, skeletal muscle area increased in both models with age, however, wild-type mice presented significantly greater hypertrophy than that observed in dystrophic mice. Interestingly, strain specific differences were not identified in esophagus mucosa strata with both strains presenting significant and similar increases in mucosa area and aging-dependent changes in mucosa composition. Further, a pronounced, aging-specific degradation of smooth musculature was observed in both mouse strains independent of dystrophin expression within wild-type mice. We demonstrate that esophageal smooth muscle is targetable via AAV-mediated gene therapy with future efforts aimed at correcting degeneration present within geriatric wild-type and dystrophic mouse models.
States sue generic drug makers for alleged price fixing
Authors: Michael McCarthy
Journal: BMJ (2016)

Twenty states have filed suit against six generic drug makers, charging that the companies were conspiring to artificially inflate prices and reduce competition for two generic drugs—the antibiotic doxycycline hyclate delayed release, and the diabetes drug glyburide.

The complaint said that an investigation, which is ongoing, had “uncovered evidence of a broad, well coordinated, and long running series of schemes to fix prices and allocate markets for a number of generic drugs.”

The companies named in the lawsuit are: Heritage Pharmaceuticals; …
CC-010 Laying on of the healing hands
Authors: R Sweis, A Anggiansah, I Forgacs, T Wong, M Fox
Journal: Gut (2010)

<h3>Introduction</h3> Rumination Syndrome is common yet under-diagnosed and is becoming increasingly recognised in healthy individuals. The primary feature is regurgitation occurring 5–10 min after initiating a meal. It is often confused with disorders such as gastro-oesophageal reflux disease, and patients may be subject to extensive yet unnecessary investigations. Treatment effectiveness with acid reducing medications and prokinetics is limited. The most favourable outcome is achieved with Diaphragmatic Breathing exercises. This case presentation describes the journey of a patient who was found to have rumination syndrome following high-resolution manometry (HRM) and was treated successfully with Diaphragmatic Breathing. <h3>Methods</h3> HRM (Manoscan 360°, SSI) with 10×5 ml water and 5×1 cm<sup>3</sup> solid (bread) swallows and a 250 ml milkshake was performed in the in the upright seated position. This was followed by dual channel 24-h catheter-based pH monitoring. Treatment encompassed two sessions of diaphragmatic therapy. <h3>Results</h3> HRM: During the bread swallows and after drinking the milkshake, typical symptoms of regurgitation were reproduced. These were associated with short, sharp increases in the intragastric pressure sensors typical of Rumination Syndrome. 24-h Ambulatory reflux study: This exhibited a normal measurement for frequency of reflux events and a positive Symptom Index (87.1%; positive greater than or equal to 50%) for regurgitation. <h3>Conclusion</h3> Although in this example it was discovered with the use of HRM in a tertiary centre, Rumination Syndrome should be easily diagnosed based only on clinical history. This condition is usually treated with diaphragmatic breathing techniques, however patient commitment to therapy and perseverance is paramount. Diaphragmatic breathing is thought to overwhelm the subconscious yet voluntary abdominal wall muscle contractions which lead to regurgitation, and was successful in this case.