tbuckley/cabot-search huggingface dataset:
Pretransplantation Positron Emission Tomography Predicts Outcome Following Autologous Stem Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma
Authors: Remy Dulery, Zora Marjanovic, Malek Aoudjane, Elise Corre, Marie-Paule Lemonnier, Anne Vekhoff, Paul Coppo, Mohamad Mohty
Journal: Blood (2015)
Whole body hyperthermia combined with carboplatin/ paclitaxel in patients with ovarian carcinoma –Phase-II-study
Authors: B. Strobl, D. Rjosk, W. Janni, B. Rack, E. Klanner, M. Heinrigs, H. Sommer
Journal: Journal of Clinical Oncology (2004)

5128 Background: Despite good treatment susceptibility to chemotherapy, ovarian carcinoma frequently leads to recurrent disease with unfavorable prognosis. Synergistic effects of carboplatin and Whole Body Hyperthermia (WBH) have been demonstrated in preclinical studies.Methods: In a phase-II-study we investigated the feasibility, safety and efficacy of standard regimen Carboplatin AUC 6/ Paclitaxel 175 mg/m2 (CT) combined with WBH. Between 1999 and 2001 9 patients were included (7 patients with primary ovarian carcinoma > FIGO 1c (after surgery) and 2 patients with late 1st recurrence. Paclitaxel was given on day 1 under normothermic conditions, on day 3, carboplatin was combined with WBH. Treatment was repeated every 3 - 4 weeks. Body temperature was maintained at 41.5–41.8 °C for one hour. All patients were analgosedated with midazolam and fentanyl. Primary prophylactic G-CSF was given from day 3 to 10. Patients with Hb < 12 received Erythropoetin 3x/ week. The WBH device used in this study was WBH 2000 (Oncotherm, Troisdorf, Germany). Median follow up was 33.8 months. Results: 53 courses of chemotherapy combined with WBH were performed (mean 5,9/ patient). Allergic reactions included 4 events of skin rash and 1 event of dyspnea, never leading to therapy stop. 2 cycles were given with dose reduction due to thrombopenia grade 3 (NCI) or severe emesis. Therapy was discontinued in 1 case due to thrombopenia grade 4. Neutropenia grade 3 (and no grade 4) was observed in 5.7 %. Thrombopenia grade 3 and 4 occurred in 1.9 % each. 30.2 % of the courses were accompanied by anemia grade 2, only 3.8 % by grade 3. Skin burning grade 1 occurred in 3 courses (5.7 %), grade 2 in 2 courses (3.8 %). All patients developed alopecia grade 2. 33.3% suffered from grade 1 polyneuropathy. The median disease free interval was 23.0 months (range 6.9 - 51.7 mon). 4 patients are still free of recurrent disease after a median of 47.1 months. Conclusions: Systemic cytostatic treatment with paclitaxel and carboplatin combined with WBH is feasible and adequately safe for the treatment of ovarian cancer. No significant financial relationships to disclose.
Use of erectile dysfunction clinic among men with active, non-pelvic malignancies
Authors: T. Tanvetyanon, A. M. Choudhury
Journal: Journal of Clinical Oncology (2004)

8280 Background: Sexual dysfunction is common in patients with active cancer. Urogenital problems can cause erectile dysfunction (ED) in patients with cancers of pelvic organs; in other cancers, however, treatment, psychogenic factors, and cancer-related symptoms can also lead to ED. ED related to cancers of pelvic organs is well recognized by the publics and physicians; but those associated with non-pelvic malignancies receive little attention. We identify the prevalence of patients with active, non-pelvic cancers, who attended the ED clinic in a large VA hospital. Methods: Medical records of patients who attended the ED clinic, the only place treatment of ED was prescribed, during November 1999 - 2003 were reviewed. Patients were included if the first visit was made between 6 months before cancer was diagnosed and 12 months after cancer therapy was completed. Patients with indolent, non-invasive malignancies, or cancers of prostate, bladder, or rectum were excluded. Results: During the observation period, when 1781 visits were made to the clinic, and when 1394 new patients with non-pelvic malignancies were diagnosed; 18 patients with active, non-pelvic malignancies attended this clinic. Mean age was 63.9 years (range 46–82); 61% were Caucasian. Cancer diagnoses were lung 13; non-Hodgkin lymphoma 3; head and neck 2; liver 2; colon, kidney and pancreas 1 each. Hypertension was present in 72%; diabetes 18%; 28% were active smokers. Available testosterone level were normal in12/13 (92.3%). Nine patients visited the clinic before their cancers were discovered at a median of 3 months before diagnosis; 5/9 had lung cancer. The rest visited the clinic at a median of 7 months after diagnosed; 7/9 were actively undergoing chemotherapy or radiation. Treatment of ED were sildenafil in 50%, vacuum constriction device 28%, intraurethral prostaglandin E-1 6%, intracavernosal alprostadil 6%; and 11% chose no treatment. Treatment of ED was effective in many patients even during cancer treatment. Conclusions: Very few patients with active, non-pelvic cancers attend the ED clinic. Further studies to identify barrier to participation in the treatment of ED in this group of patients are warranted. No significant financial relationships to disclose.
T Cell Repertoire Diversity Is Decreased in Type 1 Diabetes Patients
Authors: Yin Tong, Zhoufang Li, Hua Zhang, Ligang Xia, Meng Zhang, Ying Xu, Zhanhui Wang, Michael W. Deem, Xiaojuan Sun, Jiankui He
Journal: Genomics Proteomics & Bioinformatics (2016)

Type 1 diabetes mellitus (T1D) is an immune-mediated disease. The autoreactive T cells in T1D patients attack and destroy their own pancreatic cells. In order to systematically investigate the potential autoreactive T cell receptors (TCRs), we used a high-throughput immune repertoire sequencing technique to profile the spectrum of TCRs in individual T1D patients and controls. We sequenced the T cell repertoire of nine T1D patients, four type 2 diabetes (T2D) patients, and six nondiabetic controls. The diversity of the T cell repertoire in T1D patients was significantly decreased in comparison with T2D patients (P=7.0E-08 for CD4+ T cells, P=1.4E-04 for CD8+ T cells) and nondiabetic controls (P=2.7E-09 for CD4+ T cells, P=7.6E-06 for CD8+ T cells). Moreover, T1D patients had significantly more highly-expanded T cell clones than T2D patients (P=5.2E-06 for CD4+ T cells, P=1.9E-07 for CD8+ T cells) and nondiabetic controls (P=1.7E-07 for CD4+ T cells, P=3.3E-03 for CD8+ T cells). Furthermore, we identified a group of highly-expanded T cell receptor clones that are shared by more than two T1D patients. Although further validation in larger cohorts is needed, our data suggest that T cell receptor diversity measurements may become a valuable tool in investigating diabetes, such as using the diversity as an index to distinguish different types of diabetes.
PP-001 Transanal endoscopic microsurgery: a useful technique but not without complication
Authors: S J Dalton, O J Old, P G Vaughan-Shaw, M G Thomas
Journal: Gut (2010)

<h3>Introduction</h3> Transanal endoscopic microsurgery (TEMS) is well established as a technique for the resection of rectal lesions and, with the advent of the Bowel Cancer Screening Programme its role is likely to increase. TEMS is less invasive than trans-abdominal surgery and causes less sphincter injury than a trans-anal approach however it is not without risk. In this retrospective cohort study we review the complications occurring with TEMS in our unit. <h3>Methods</h3> An electronic database was used to identify the outcomes of patients undergoing TEMS procedures; operation and anaesthetic notes and pathology reports were reviewed. <h3>Results</h3> 100 patients were included, (59 male 41 female), mean age was 69. ASA grade I,15; II,60; III,23 and IV,2. All patients underwent preoperative assessment with endoanal ultrasound; in 80 patients TEMS was performed for benign disease and in 20 patients for carcinoma. In 18 cases the lesion was located in the lower rectum and in 82 in the mid or upper third. Resections were carried out in the submucosal plane in 33 patients and in 67 a full thickness resection was performed, full thickness defects were closed in all cases. Mean operating time was 110 min (95% CI 84 to 126) and median length of stay 3 days (range 1–31). 21 patients had complications; eight patients bled post operatively with two requiring re-exploration, two patients developed post operative emphysema, one patient sustained a caecal perforation requiring an emergency right hemicolectomy, one patient perforated a diverticulum, one developed a recto-vaginal fistula postoperatively and one sustained a bladder injury which was repaired intraoperatively. Two patients developed symptomatic strictures at the resection site, two had cardiac complications, one developed pneumonia, one went into retention and one developed a para-rectal abscess. Complications were associated with those patients undergoing a full thickness resection and with resections in the upper rectum. <h3>Conclusion</h3> TEMS remains a useful technique for the resection of rectal lesions however the potential complications associated with this technique should not be underplayed. Here we describe the complications associated with TEMS in our unit.
GCS-100 Induces Apoptosis of Acute Myeloid Leukemia Cells By Disrupting Galectin-Mediated Survival Signaling
Authors: Richard E. Davis, Vivian R Ruvolo, Zhiqiang Wang, Wencai Ma, Wendy D. Schober, James Rolke, George Tidmarsh, Michael Andreeff, Peter P. Ruvolo
Journal: Blood (2014)
119. Engineering a Self-Inactivating CRISPR System for AAV Vectors
Authors: Benjamin E. Epstein, David V. Schaffer
Journal: Molecular Therapy (2016)

Significant strides in nuclease engineering have enabled a broad range of biomedical applications. However, numerous challenges remain, and in particular the long term expression mediated by AAV delivery of nuclease-encoding constructs to post-mitotic cells raises concerns with specificity and immunogenicity. That is, off-target nuclease activity can induce genotoxicity, and expression of an exogenous nuclease has the potential to elicit an immune response against transduced cells. Thus, it would be advantageous to limit the duration of nuclease expression following delivery. We have engineered self-inactivating nuclease constructs using the CRISPR/Cas9 system, which consist of a Cas9 nuclease such as that from Streptococcus pyogenes (SpCas9), a chimeric single guide RNA (sgRNA) molecule for targeting, and flanking sites targeted by that sgRNA. For example, we modified an SpCas9/sgRNA construct targeted at the VEGFA locus by introducing copies of the target site flanking the nuclease construct. The result is a negative feedback loop where Cas9 cuts both the target genomic locus and its own coding construct and thereby self-limits its expression. We demonstrate that this construct can eliminate >90% of its expression within 72 hours, and tuning of different parameters enables retention of up to 65% on-target efficiency and reduction of off target-cutting by up to 80%. We further show that by engineering the flanking target sites to contain mismatches to the sgRNA, the Cas9 expression duration can be modulated and the on-target/off-target cutting ratios improved. By retaining strong activity while minimizing off-target effects and by eliminating potentially immunogenic, long-term expression of foreign protein, these self-inactivating constructs have the potential to address two substantial concerns with therapeutic application of engineered nucleases.
Abstract 2256: GLI2 inhibition suppresses metastasis of HER2+ breast cancer
Authors: Parul Gupta, Alok Ranjan, Neel M. Fofaria, Sanjay K. Srivastava
Journal: Cancer Research (2015)

Abstract Metastasis of breast cancer is a significant problem majorly in HER2 positive cancer, as there are no therapeutic targets known. Due to inherent complexity of the process, underlying mechanisms of metastasis are largely unknown. We have shown previously that HER2 overexpression enhances the metastatic potential of breast cancer cells. The results from our previous studies showed that a 22 fold increase in HER2 expression in MDA-MB-231 cells lead to several orders of magnitude increase in the metastasis of the MDA-MB-231 cells. However, HER2 inhibition alone did not significantly suppress metastasis. Hence we investigated the molecular changes induced by HER2 expression that may promote metastasis of breast cancer cells. Interestingly, we observed an increased expression of GLI2 in the metastatic tumors formed by HER2+ cells in the mice lungs. GLI2 is a transcription factor of sonic hedgehog pathway and aberrant signaling of this pathway has been implicated in several cancers. In addition, GLI2 is overexpressed in breast tumors and associated with poor prognosis in breast cancer patients. GLI2 was therefore silenced using shRNA to study its role in metastasis of MDA-MB-231 high HER2 (HH) breast cancer cells. We achieved about 66% knock down of GLI2 expression using GLI2 shRNA. Our results showed that silencing of GLI2 inhibited the migration of HH cells by more than 60%. Our results also demonstrated over 80% inhibition of the invasion of (HH) cells with silenced GLI2. Furthermore, HH luciferase expressing cells were transfected with GLI2 shRNA or scrambled shRNA and equal numbers of live cells were injected intravenously in athymic nude mice. The trajectory and growth of control and GLI2 silenced MDA-MB-231 HH cells were monitored by non-invasive IVIS imaging system. A drastic reduction of luminescence was observed in the lungs of mice injected with GLI2 silenced HH cells as compared to mice injected with control HH cells, indicating inhibition of metastasis. Taken together our results establish GLI2 as an important target for therapy in HER2+ metastatic breast cancer. Further mechanistic studies are in progress. [Supported in part by R01 grant CA129038 awarded to S.K.S. by the National Cancer Institute] Citation Format: Parul Gupta, Alok Ranjan, Neel M. Fofaria, Sanjay K. Srivastava. GLI2 inhibition suppresses metastasis of HER2+ breast 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 2256. doi:10.1158/1538-7445.AM2015-2256
Re: Wells et al.: Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial (Ophthalmology 2016;123:1351-1359)
Authors: Mahesh P. Shanmugam, Kaustubh B. Harshey, Rajesh Ramanjulu, Divyansh K. Mishra
Journal: Ophthalmology (2016)
226. Next-Generation Sleeping Beauty Integration Profiles of T-Cell Adoptive Immunotherapy
Authors: Sonny O. Ang, Jianrong Dong, Luay Nakhleh, Laurence J.N. Cooper
Journal: Molecular Therapy (2015)

Since the first human Gene Therapy clinical trial was initiated 25 years ago, many technological advances have dove-tailed into the field, moving personalized genetic treatments from concept towards routine reality. In particular, widespread adoption of next-generation sequencing technologies have enabled faster vector integration profiling to assay for potential genotoxities. Genomic data generation since 2007 has grown faster than Moore's law for computing power, now making data analysis the new bottleneck in the workflow. Newer and accelerated solutions are needed to manage exponential increases in data accumulation. Our goal is to compress sequence data generation and downstream data analysis within 5 work days, enabling the utility of genotoxicity assay to support time-sensitive clinical decision making. Time and cost savings in integrated and streamlined data processing should translate into easier and faster implementation in clinical settings. We use non-viral transfections, based on the Sleeping Beauty transposition system, to reprogram T cells for Adoptive Immunotherapy. We exploit the fact that Sleeping Beauty transposons invariably inserts into "TA" sites via a cut-and-paste mechanism driven by cognate transposases, to develop an analysis platform, SBhashmap, to quickly locate and unlock insights associated with the genomic integration sites. We chose hash tables over other table data structures for speed, an advantage which is more apparent when the number of entries is large. SBhashmap consists of pre-populated hash tables with over 150 million entries corresponding to the "TA" sites from the human genome and hash functions to match for quick site matching. By cataloging the TA sites ahead of time, we can cut the mapping time significantly. To benchmark SBhashmap, we compared transposon integration mapping to BLAST and BLAT matching for human genomic sequences, and found a 20-fold reduction in processing time, while maintaining similar levels of accuracy. This kind of hash maps is particularly efficient because the maximum number of entries is known in advance, such that the bucket array can be allocated once with the optimum size fixed (not resized, with no insertions and deletions necessary). With collision-free hash functions, the keys are not stored in the tables. With minor adaptations, SBhashmap can process genomic data from experimentally relevant model organisms such mice, worms, and fruitflies.
360. Genotype/Phenotype Correlation of Cellular Function and AAV-Mediated Gene Delivery to Treat Xeroderma Pigmentosum - Cockayne Syndrome (XP - CS)
Authors: Skylar Rizzo, Amy L. Donate, Michael Jones, Kelsey Manko, Katherine E. Santostefano, Nao Terada, Fowzan S. Alkuraya, Peter B. Kang, Christina A. Pacak
Journal: Molecular Therapy (2016)

Cockayne Syndrome (CS) is a rare, autosomal recessive, neurodegenerative disorder characterized by deficiencies which all contribute to an overall phenotype of premature aging. The underlying cause is a defect in genes involving DNA repair mechanisms. This includes CSA and CSB as well as several genes associated with Xeroderma Pigmentosum (XP). Specifically, Xeroderma Pigmentosum Group G (XPG) is a disorder with two distinct clinical presentations: photosensitivity alone (XP) and photosensitivity with neurodegeneration (XP-CS). XPG's role as an endonuclease in nucleotide excision repair following UV exposure is well-described and explains the photosensitivity phenotype, yet a separate function for XPG that explains the neurological/early aging deficit that occurs in some patients remains obscure. Other CS proteins known to be involved in nuclear DNA repair have been shown to also function as free radical scavengers in mitochondria. As growing bodies of data illustrate the importance of mitochondria in aging, neuronal cell development and maintenance, and tissue repair, we hypothesize that XPG is trafficked to mitochondria where it could play an important role in mitochondrial function via free radical regulation. Such a deficiency could explain the neurodegeneration and multi-system early aging phenotype observed in CS patients. Our preliminary data (expansion rates, oxygen consumption, ATP generation, free radical sensitivity, Metronidazole [a drug that causes liver failure in CS patients] sensitivity) support this hypothesis through demonstration of decreased viability and mitochondrial function in fibroblasts derived from XPG patients displaying the XP-CS phenotype but not in those from patients displaying the XP phenotype alone. Mitochondrial isolations are being performed to confirm the presence of XPG in these organelles, as well as to better evaluate mitochondrial function. These characterizations will be used as outcome measures to determine the efficacy of AAV mediated gene therapy for XP-CS. A functional CMV-XPG plasmid has been cloned, and is being packaged into Adeno-associated virus (AAV). Further analyses in XP and XP-CS patient induced pluripotent stem cells differentiated into neurons and an XPG mouse model which closely replicates the human phenotype will yield useful information regarding the dual roles of this protein and provide data to support translation of gene therapy for CS. If successful, this will be the first therapeutic measure to demonstrate correction of the debilitating effects of XP-CS.
Estimating the Prevalence of Myelodysplasia: A Retrospective Review of Bone Marrow Histopathology in 322 Cases of Unexplained Cytopenia(s) in a Teaching Hospital.
Authors: K. Jang, Richard A. Wells, Alden Chesney, Marciano D. Reis, J. Friedlich, L. Zhang, Rena Buckstein
Journal: Blood (2006)
Granulocyte-Colony-Stimulating Factor (G-CSF) Accelerates Normal Myeloid Recovery More Efficiently in Patients with Favorable Than with Intermediate or Unfavorable Cytogenetic Risk Acute Myeloid Leukemias (AML): A Retrospective Analysis of the East German Hematology Oncology Study Group (OSHO).
Authors: Peter R. Moosmann, Rainer Krahl, Lutz Uharek, Cornelia Becker, Astrid Franke, Rita Pasold, Norma Peter, Antje Schulze, Ulrich Wedding, Dietger W. Niederwieser
Journal: Blood (2004)
Whole blood transcriptomics analysis of 24h responses to bevacizumab/erlotinib in nonsquamous non-small cell lung cancer: A multicenter phase II trial SAKK19/05.
Authors: F. Baty, M. Frueh, S. Crowe, K. J. Na, C. Droege, D. C. Betticher, R. Cathomas, F. Zappa, M. Pless, M. H. Brutsche
Journal: Journal of Clinical Oncology (2011)

e21069 Background: It is essential to understand the mechanisms of action of new therapies in advanced lung cancer. The SAKK investigated the response to bevacizumab/erlotinib (BE) on disease stabilization at week 12 in non-squamous non-small cell lung cancer (NSCLC) patients in a single arm phase II trial (SAKK 19/05). In this translational research project we investigated the 24-h effect of the combined BE therapy on these patients using whole blood transcriptomics. Methods: The blood gene expression level of 43 out of 101 treatment-naïve non-squamous stage IIIB and IV NSCLC patients who received BE was profiled at 24h and compared to baseline. The within-patient gene variations were analyzed using multivariate between-group correspondence analysis (BGA) together with univariate paired t-tests. All analyses were blinded for the patients' mutational status and clinical outcome. Results: BE induced few gene expression changes at 24h. Out of 26'116 annotated probe sets, 638 (2.4%) showed a significant 24h-variation at the nominal level (p<0.05). Functional analysis showed a significant gene enrichment in pathways such as hematopoietic cell lineage, cytokine-cytokine receptor interactions, T-cell receptor signaling and cell-adhesion molecules. Matrix metalloproteinase-9 (MMP-9) was top ranked in lists obtained by both gene-by-gene approach and multivariate analysis. MMP-9 showed a significant down-regulation after 24h (p=0.02). The 24h-response varied among patients, 72% of patients showed a down-regulation of MMP-9. Conclusions: The 24h-effect of BE, as measured in the blood, induced the regulation of a limited, yet consistent number of genes among which MMP-9. This gene, which is involved in the pathogenesis of metastatization, may be a potential early marker of clinical response to BE therapy. After unblinding for clinical outcome it is planned to identify potential early markers of 12-week disease stabilization, tumor response and overall survival with BE.