tbuckley/cabot-search huggingface dataset:
Phase I study of MRX-1024 in preventing oral mucositis (OM) in head and neck cancer patients undergoing chemoradiation therapy
Authors: N. Mur
Journal: Journal of Clinical Oncology (2005)

5605 Background: OM is a debilitating complication of radiotherapy (RT) and chemotherapy (CT). MRX-1024, a proprietary formulation of D-methionine, in rats selectively protects oral mucosa from chemoradiation without compromising antitumor activity. Methods: We evaluated oral MRX-1024 in patients (pts) with head and neck cancer who were receiving RT or RT+CT. Pts received 1.8–2.0 Gy of RT daily for 5 days each week, to a total of 60 Gy. Selected pts also received cisplatin, 50mg/m2 weekly. MRX-1024 suspension was given 1 hour before and again after each RT fraction. Pts were evaluated weekly using 4 accepted scales for assessing OM. Results: Twenty-five pts were treated. Pt 1 received 25mg/kg doses of MRX-1024 and developed Grade 3 OM. Subsequent pts received 100mg/kg doses. Vomiting occurred in 17 (68%) pts; only 3 pts had Grade 3 vomiting. Five pts withdrew due to vomiting. Additional AEs included weakness (6 pts), fungal infection (4 pts), fever (2 pts), body pains (2 pts), and dysphagia (1 pt). These were Grade 1 or 2 except for single reports of Grade 3 fungal infection and oral candidiasis. MRX-1024 did not compromise antitumor activity. The incidence of OM from 21 evaluable pts was compared with historical controls from the same institution, shown below using the WHO scale. No significant financial relationships to disclose.
Abstract 18865: A Novel in vivo Model of Amyloidogenic Light Chain Induced Cardiac Toxicity in Zebrafish
Authors: Shikha Mishra, Jian Guan, Eva Plovie, Giampaolo Merlini, Lawreen H Connors, David C Seldin, Calum A MacRae, Ronglih Liao
Journal: Circulation (2012)

Over 50% of amyloidogenic light chain (AL) amyloidosis patients present with cardiac involvement, characterized by fibril deposition in cardiac tissue, resulting in a rapidly progressing, fatal cardiomyopathy. Aside from cardiac transplantation, there are currently no targeted pharmacologic treatments available for cardiac amyloidosis. This is largely attributed to our limited understanding of the underlying molecular mechanisms of this disease, compounded by the lack of an in vivo model to study disease mechanisms. Previous work from our laboratory demonstrated that human AL- light chain (LC) proteins exhibit an inherent cardiac toxicity via a p38/MAPK dependent pathway, independent of fibril formation. Here we demonstrate a novel in vivo model of AL-LC cardiotoxicity in zebrafish. Zebrafish embryos were treated with AL-LC, Control-LC (Con-LC) or vehicle (Veh), injected directly into circulation via cardiac puncture. Consistent with our previous findings, AL-LC treatment elicited an increase in p38 activation. This was accompanied by increased cardiac cell death, as measured by Bax/Bcl2 ratio and TUNEL staining of isolated zebrafish hearts. Additionally, AL-LC treated embryos exhibited a decrease in cardiac output. Strikingly, AL-LC treatment resulted in a marked loss of survival (Figure 1), with 100% mortality at 13 days. Our lab recently identified a major role for stanniocalcin1 (STC1) in the pathogenesis of AL-LC-induced cardiotoxicity. STC1 expression was significantly increased by AL-LC treatment, but not by Con-LC. Morpholino-mediated silencing of STC1 expression protected against AL-LC induced cardiotoxicity, preventing cardiac cell death and mortality.Collectively, this work establishes a novel zebrafish model of cardiac amyloidosis, and identifies STC1 as a critical determinant of AL-LC mediated toxicity, demonstrating its requirement in downstream signaling pathways associated with AL-LC induced cardiac toxicity. .
Abstract 17546: Role of Infections in Cardiovascular Mortality: Insights from National Health and Nutrition Examination Survey-III
Authors: Nileshkumar J Patel, Vikas Singh, Apurva O Badheka, Ankit Rathod, Abhishek Deshmukh, Kaustubh Dabhadkar, George Marzouka, Tushar Tuliani, Mauro Moscucci, Mauricio G Cohen
Journal: Circulation (2012)

Background: The role of infections in the pathogenesis of atherosclerosis and cardiovascular mortality (CM) is controversial. We assessed the prognostic significance of infectious disease burden on...
Accumulated Metabolites of Hydroxybutyric Acid Serve as Diagnostic and Prognostic Biomarkers of Ovarian High-Grade Serous Carcinomas
Authors: Mika Hilvo, Ines de Santiago, Peddinti Gopalacharyulu, Wolfgang D. Schmitt, Jan Budczies, Marc Kuhberg, Manfred Dietel, Tero Aittokallio, Florian Markowetz, Carsten Denkert, Jalid Sehouli, Christian Frezza, Silvia Darb-Esfahani, Elena Ioana Braicu
Journal: Cancer Research (2016)

Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but it is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities.
Bidirectional Synaptic Structural Plasticity after Chronic Cocaine Administration Occurs through Rap1 Small GTPase Signaling
Authors: Michael E. Cahill, Rosemary C. Bagot, Amy M. Gancarz, Deena M. Walker, HaoSheng Sun, Zi-Jun Wang, Elizabeth A. Heller, Jian Feng, Pamela J. Kennedy, Ja Wook Koo, Hannah M. Cates, Rachael L. Neve, Li Shen, David M. Dietz, Eric J. Nestler
Journal: Neuron (2016)
A Phase 2 Randomized, Double-Blind, Placebo Controlled Study of Simtuzumab or Placebo in Combination with Gemcitabine for the First Line Treatment of Pancreatic Adenocarcinoma
Authors: A. Benson, J. Bendell, Z.A. Wainberg, D. Vyushkov, P. Acs, F. Kudrik, H. Dong, D. Thai
Journal: Annals of Oncology (2014)
Clinical significance and therapeutic potential of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human colorectal cancer
Authors: M. Grimm, M. Gasser, M. Koenigshausen, C. Stein, J. Lutz, S. Krol, A. Thiede, U. Heemann, A. Waaga-Gasser
Journal: Journal of Clinical Oncology (2008)

15005 Background: The negative regulatory programmed death-1/programmed death-1ligand (PD-1/PD-L) pathway in T-cell activation has been suggested to play an important role in tumor evasion from host immunity. Levels of immune cells expressing PD-1 in clinical colorectal carcinoma (CRC) tumors have not been evaluated. Thus, we investigated whether PD-1 positive T cells were expressed within CRC tumors and the expression of PD-L1 and PD-L2 in human CRC to define their clinical significance in patients’ prognosis after surgery. Methods: Tissue samples from 116 patients operated between 2001 and 2005 were collected in our institution and histologically confirmed CRC were evaluated retrospectively for this study. PD-1 and PD-L gene expression was evaluated by real time quantitative PCR and the samples were immunostained. Outcome analyses were performed. Results: The protein and the mRNA levels of determination by immunohistochemistry and real time quantitative PCR were closely correlated. PD-L expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8+ T cells. T cell infiltration was observed in 105 (90.5%) specimens. 93 (80.2%) specimens were PD-1+ T cells. Intratumoral PD-1+ T cells were associated with advanced tumor stage (p=0.002). Patients with PD-1+ T cells had significantly more PD-L1 tumor cell expression. Multivariate analysis indicated that PD-L positive patients and those with PD-1+ T cells had a significantly poorer prognosis than the negative patients. This was more pronounced in the advanced stage of tumor than in the early stage. Conclusions: These data suggest that interactions of T cells expressing PD-1 and PD-L may promote cancer progression. PD-L1 and PD-L2 status may be a new predictor of prognosis for patients with colorectal carcinoma. No significant financial relationships to disclose.
Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation
Authors: Lena Allweiss, Sofia Gass, Katja Giersch, Anne Groth, Janine Kah, Tassilo Volz, Gianna Rapp, Anja Schöbel, Ansgar W. Lohse, Susanne Polywka, Sven Pischke, Eva Herker, Maura Dandri, Marc Lütgehetmann
Journal: Journal of Hepatology (2016)
Paclitaxel administration to gynecologic cancer patients with major cardiac risk factors.
Authors: M Markman, A Kennedy, K Webster, B Kulp, G Peterson, J Belinson
Journal: Journal of Clinical Oncology (1998)

To examine the safety of administering paclitaxel to patients with preexisting significant cardiac risk factors.The medical records of gynecologic cancer patients with major cardiac risk factors who had been treated with paclitaxel (single-agent or combination regimen with cisplatin or carboplatin) at The Cleveland Clinic Foundation from 1993 through February 1998 were examined to determine the acute toxicity of therapy.A total of 15 patients were found who met these criteria, of whom none were found to have suffered a worsening of cardiac function following treatment with paclitaxel. A single patient developed a severe paclitaxel-associated hypersensitivity reaction, but no cardiac sequela.This series suggests that paclitaxel can be safely administered as a single agent or in a combination regimen with a platinum agent to some patients with significant cardiac risk factors, such as those associated with ischemic heart disease. However, since few patients had baseline severe conduction defects before paclitaxel treatment, the safety of this drug in this clinical setting remains to be determined.
KS1 (KRAB suppressor of transformation 1) and BMP3b (bone morphogenetic protein 3b) gene promoter hypermethylation is a common epigenetic event in breast cancer
Authors: J. R. Molina, N. J. Alzein, W. L. Lingle, M. Fernandez-Zampico, R. Urrutia, L. C. Hartmann
Journal: Journal of Clinical Oncology (2004)

9608 Background: KS1 (KRAB Suppressor of Transformation 1) is a member of the Krüppel-associated box-zinc finger proteins (KRAB-ZFPs). Indirect evidence suggests that KS1 is a tumor suppressor gene. The Bone Morphogenetic Protein 3b (BMP3b), also known as GDF10, localizes to chromosome 10q11.1, a region of LOH in several cancers. This gene has putative tumor suppressor functions, being hypermethylated and down-regulated in lung cancers. We present here evidence that the KS1 and BMP3b genes are hypermethylated in breast cancer and not in normal breast tissues. We also present data to show methylation of KS1 in benign breast disease (BBD). Goals: We designed this study to find methylated genes in breast cancer and BBD with the goal of finding markers with potential for risk prediction/early detection of breast cancer. Methods: Aberrant promoter methylation of KS1 and BMP3b was studied by methylation-specific PCR using bisulfite treated DNA from 45 frozen breast cancer samples,12 normal controls, 5 paraffin embedded benign breast disease (BBD) tissues and 5 breast cancer cell lines. All samples were collected from separate patients within the predefined groups. KS1 and BMP3b mRNA expression was quantified by real-time reverse-transcription PCR. Results: The lung cancer cell line A549 which has high levels of RNA expression for these two genes and is not methylated for KS1 or BMP3B was used as a positive control. KS1 was found methylated in 58% of breast cancers, 50% of BBD and 0% of normal breast tissues. The BMP3B gene promoter was methylated in 46% of breast cancers, 5% of BBD and 0% of normal breast tissues. Conclusions: KS1 and BMP3b hypermethylation is a common epigenetic event in breast cancer. KS1 is also methylated in tissue samples from patients with BBD. KS1 may have potential as a marker for early detection/risk prediction of breast cancer in patients with BBD. No significant financial relationships to disclose.
Virus Studies With Germfree Mice. II. Comparative Responses of Germfree Mice to Virus Infection&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: R W TENNANT, J C PARKER, T G WARD
Journal: JNCI Journal of the National Cancer Institute (1965)

Despite the consequences of a microorganism-free existence, germfree mice responded to infection with certain viruses in a manner comparable to that of conventionally reared mice. Serologic responses of germfree and conventional mice to polyoma and pneumonia virus of mice, measured by hemagglutination-inhibition, and to reovirus type 3, measured by complement fixation as well, were comparable both in time course and final antibody titer. Further, the susceptibility of germfree mice to infection with influenza, pneumonia virus of mice, epizootic diarrhea of infant mice, and possibly Theiler's mouse encephalomyelitis viruses was not different from that of conventional mice. No differences in the quantity or rate of influenza virus replication were detected between the groups.
Pulmonary Consolidations due to Secondary Syphilis with Positive Bronchial Washing Immunohistochemistry
Authors: Florence Jeny, André Fargelat, Sara Laurent-Roussel, Jean-Charles Nault, Nicolas Dupin, Philippe Grange, Hilario Nunes, Dominique Valeyre
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Pulmonary Consolidations due to Secondary Syphilis with Positive Bronchial Washing Immunohistochemistry Florence Jeny, Andre Fargelat, Sara Laurent-Roussel, Jean-Charles Nault, Nicolas Dupin, Philippe Grange, Hilario Nunes, and Dominique Valeyre Assistance Publique Hopitaux de Paris, Service de Pneumologie, Hopital Avicenne, Bobigny, France; Universite Paris 13, Communaute d’Universites et etablissements Sorbonne Paris-Cite, Bobigny, France; INSERM U1016, Laboratoire de Recherche en Dermatologie, Centre National de Reference Syphilis, Paris, France; and Assistance Publique Hopitaux de Paris, Service d’Hepatologie, Hopital Jean Verdier, Bondy, France
S-phase fraction is a prognostic factor in stage I breast carcinoma.
Authors: O Stål, M Dufmats, T Hatschek, J Carstensen, C Klintenberg, L E Rutqvist, L Skoog, S Sullivan, S Wingren, B Nordenskjöld
Journal: Journal of Clinical Oncology (1993)

PURPOSE AND METHODS The prognostic significance of cell proliferation, estimated as cytometric S-phase fraction (SPF), was investigated in node-negative breast cancer patients with small tumors (T1, NO). The 219 stage I patients originated from two series and were diagnosed either from 1978 to 1981 or from 1981 to 1985. The tumors were analyzed for estrogen receptors (ERs) by isoelectric focusing and for cellular DNA content by static cytofluorometry or flow cytometry. RESULTS A high SPF correlated with the absence of ERs and abnormal DNA content, and was less often found in tumors smaller than 11 mm compared with those with a diameter between 11 and 20 mm. Among the variables age, tumor size, DNA ploidy, ER status, and SPF, only SPF showed a significant association with distant recurrence and breast cancer survival in systemically untreated patients. The relative recurrence rate for patients with an SPF of 10% or greater was three times that for patients with lower SPFs. Estimated 8-year breast cancer survival rates for the same groups were 72% and 91%, respectively. CONCLUSION This study suggests that cytometric SPF has prognostic significance in stage I breast carcinoma.
Chemosensitisation by poly(ADP-ribose) polymerase-1 (PARP-1) inhitor 5-aminoisoquinoline (5-AIQ) on various melanoma cell lines
Authors: S. Radulovic, S. Bjelogrlic, Z. Todorovic, M. Prostran
Journal: Journal of Clinical Oncology (2006)

12019 Background: PARP-1 facilitates DNA strand brakes repair and PARP inhibitors were investigated as enhancers of chemoradiotherapy. We investigated whether 5-AIQ potentates the effect of doxorubicin (DOXO), cisplatin (CDDP) and paclitaxel (Ptx) on human (slow-growing) FemX and murine (fast-growing) B16 melanoma cell lines. Methods: Twenty-four hours after cells were seeded in 96 well plates, cytotoxic drugs and 5-AIQ were added to cell medium. For evaluation of single-agent activity, drugs were applied in concentration ranges as follows: CDDP (0.3–30 μM), DOXO (0.1–3 μM), Ptx (1–100 ηM), 5-AIQ (1–100 μM). 5-AIQ (3μM) was combined with CDDP (0.1, 0.3, 1 μM), DOXO (10, 3, 100 ηM), or Ptx (1, 3, 10 ηM). Incubation lasted for 72 hrs when SRB assay was utilized to determine individual and combine activity (interactions calculated with isobole method). For cell cycle analysis B16 cells were seeded on 6 well plates and treated with each drug alone and combinations, using the same concentrations as those for investigation of combine cytotoxic activity. Cell cycle was determined after 72 hrs, on FACS Calibur with propidium iodide dye. Results: 5-AIQ induced minimal changes in cell viability and cell cycle progression on both cell lines, compared to non-treated control. CDDP revealed high activity against FemX (IC50 = 2.85 μM) and B16 cells (IC50 = 8.84 μM), and G0/G1 arrest. In B16 cells 5-AIQ multiply enhanced CDDP’s activity with strong synergistic interaction and cells slightly driven to S phase. Synergism was also detected on B16 cells treated with combination of DOXO (IC50 = 0.2 μM on B16 and 0.89 μM on FemX) and 5-AIQ when DOXO was applied in low concentrations (10 and 30 ηM), while 5-AIQ did not interfere with cell cycle changes. Cytotoxicity of Ptx (IC50 = 6.16 ηM on B16 and &lt;1 ηM on FemX) was stimulated only at higher concentrations. 5-AIQ stimulated G0/G1 and S phase arrest on B16 cells with Ptx of 3 and 10 ηM, respectively. In FemX cells, most of the interactions of 5-AIQ with CDDP, DOXO, and Ptx revealed as antagonistic. Conclusions: PARP-1 inhibitor 5-AIQ enhances cytotoxic activity of both DNA damaging and agents with different mechanism of action, but the effect varies between cell lines with different proliferation rate. No significant financial relationships to disclose.
Multicenter Phase Ii Trial of Adjuvant S-1 Plus Docetaxel for 6 Months in Patients with Pathological Stage III Gastric Cancer (Ogsg-1002)
Authors: K. Yamamoto, K. Fujitani, S. Tamura, J. Fujita, J. Matsuyama, Y. Kimura, H. Imamura, Y. Makari, Y. Kurokawa, T. Satoh, T. Tsujinaka, H. Furukawa
Journal: Annals of Oncology (2014)
Follicular lymphomas' BCL-2/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation
Authors: Ulrich Jäger, Silke Böcskör, Trang Le, Gerlinde Mitterbauer, Ingrid Bolz, Andreas Chott, Michael Kneba, Christine Mannhalter, Bertrand Nadel
Journal: Blood (2000)
Evaluation of CYP3A activity as a predictive covariate for docetaxel clearance
Authors: S. D. Baker, A. J. Ten Tije, M. A. Carducci, H. Gelderblom, F. W. Dawkins, W. P. McGuire, J. Verweij
Journal: Journal of Clinical Oncology (2004)

2006 Background: Docetaxel exhibits wide interindividual variation in drug clearance (CL). Reduction in CL by ≥25% is associated with increased neutropenia. Docetaxel is metabolized by cytochrome P4503A (CYP3A) and pts with liver impairment have reduced CL. The objective of this study was to prospectively evaluate the association between liver function tests (LFTs), CYP3A activity and docetaxel CL. Methods: PK studies were performed during cycle 1 of therapy in 58 cancer pts. Docetaxel was administered once every 3 weeks according to LFT group (gp): (Gp 1) 75 mg/m2, normal LF; (Gp 2) 75 mg/m2, total bilirubin [Tbili] <1.5 x ULN and AST/ALT >1 x ULN with alkaline phosphatase [AP] ≥2.5 x ULN, or AST/ALT ≥1.5 x ULN with AP >1 x ULN, or isolated elevations of AST/ALT or AP ≥5 x ULN; (Gp 3A) 50mg/m2, Tbili <1.5 x ULN and AST/ALT ≥1.5 x ULN with AP ≥2.5 x ULN; and (Gp 3B) 40 mg/m2, Tbili ≥1.5 x ULN with any AST/ALT and/or AP elevations. CL was calculated from compartmental modelling. Pre-treatment CYP3A activity was determined using the erythromycin breath test (ERMBT). Results: CL was lower in pts with more abnormal LFTs (mean [range], 11.0 [6.1 - 23.7] L/h [gp 3] vs 28.7 [9.5 - 92.6] [gp 1–2]; P = .0014). CL was similar yet highly variable in pts in gp 1–2 (P = .75). Log-transformed CYP3A correlated well with docetaxel CL in all pts (R = 0.48; P = .0001). CL was lower in pts with CYP3A values in the lower quartile (<1.7%) (P = .0003) (Table 1); five of 8 (63%) pts with normal LFTs (gp 1) but CYP3A <1.7% had reduced CL by ≥25%. Six of 9 (67%) pts in LFT group 2 with CYP3A ≥1.7% did not have reduced CL ≥25%, although recent manufacturer's dosing guidelines recommend against treating these patients with docetaxel.Conclusions: LF alone does not explain variability in drug CL. These data indicate that CYP3A activity is an additional predictive covariate for drug CL and may deserve consideration as a factor in dose calculation for docetaxel. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals Aventis Pharmaceuticals
Concurrent chemoradiotherapy using biweekly cisplatin/tegafur plus uracil/leucovorin in stage III nasopharyngeal carcinoma
Authors: H.-M. Wang, P.-T. Chen, T.-C. J. Chang, C.-L. Hsu, C.-Y. Lin, C.-T. Liao, I.-H. Chen
Journal: Journal of Clinical Oncology (2005)

5510 Background: Concomitant chemoradiotherapy (CCRT) is considered to be the most effective way to improve overall survival in nasopharyngeal carcinoma (NPC). The purpose of this study is to assess the feasibility, efficacy, and toxicity of a CCRT using outpatient-based biweekly cisplatin/tegafur-uracil/leucovorin regimen in patients (pts) of stage III NPC. Methods: Pts were evaluated by clinical examination, nasofibroscopy with biopsy, MRI of nasopharynx, and systemic evaluation. Previously untreated pts with histologically diagnosed NPC of stages III (AJCC 1997) were enrolled. The chemotherapy PUL regimen was cisplatin (P) 50 mg/m2 day 1, and tegafur plus uracil (U) 300 mg/m2/day plus leucovorin (L) 60 mg/day daily for 14 days. Radiation was administered using 6 MV photon beams 1.8–2 Gy/fraction/day 5-day a week to tumor area and neck for 46–46.8 Gy, then cone down boost to the tumor area with margins to total 68.4–72 Gy. Intensity modulation radiotherapy was administered to the majority of pts. Results: 58 pts (45 male, 13 female) with a median age of 46 years (range 31 - 67) and a WHO performance status of 0–1 were consecutively enrolled from Apr. 2002 to Jun. 2004. Histologic classification was WHO type I: 4(6.9%), II: 13(22.4%), and III: 41(70.7%). The median number of CT cycle was 4 (range 2–6). Grade 3 & 4 toxicity (NCI CTC) experienced by pts were pharyngitis 81.4%, stomatitis 50.9%, dermatitis 13.6%, vomiting 28.8%. Radiotherapy was incomplete in 1 pt, and hospitalization for managing complication was needed in 15 pts. Tube feeding was needed during CCRT in 37 pts (64%). The compliance to CT schema was cisplatin 87%, UFUR 77%. With a median follow-up of 15 months (range 5–30), the overall survival was 97%. The relapse-free survival and disease-free survival were both 93%. Relapse of disease was neck node: 2 pts, distant metastasis: 1 pt, and secondary thyroid cancer: 1 pt. Conclusions: CCRT with outpatient-based PUL regimen is feasible and effective for stage III NPC pts. No significant financial relationships to disclose.