tbuckley/cabot-search huggingface dataset:
Comparison of the biology of Down syndrome (DS) acute lymphoblastic leukemia (ALL) and non-DS ALL: Children’s Oncology Group (COG) study P9900
Authors: K. Maloney, W. L. Carroll, A. Carroll, M. Devidas, S. P. Hunger, P. L. Martin, C. L. Willman, N. Winick, J. Whitlock, B. M. Camitta
Journal: Journal of Clinical Oncology (2008)

10003 Background: DS ALL is a heterogeneous disorder with inferior survival compared to non-DS. Controversy exists regarding the relative frequencies of sentinel cytogenetic lesions in children with DS and ALL. Methods: COG P9900 was a laboratory classification study for ALL therapeutic trials from 12/99 to 2/05. Flow cytometry for DNA index; molecular testing for TEL-AML1, E2A-PBX1, BCR-ABL and FISH testing for trisomies 4 and 10 and for MLL rearrangements were done centrally for risk group stratification in a prospective manner to assign continuing treatment. Results: Eighty of 2811 (3%) consecutively enrolled eligible B-precursor ALL patients (pts) had DS. Age > or < than 10 years of age, gender, presenting white blood cell count (WBC) and NCI risk group were similar between ALL patients with/without DS. However, the genetic lesions present in DS-ALL patients and the event-free survival (EFS) and overall survival (OS) differed from those of non-DS patients. No BCR/ABL or MLL translocations were found in the DS pts. TEL-AML1 fusion was present in 2.5% (2/80) of DS-ALL pts vs. 24% (651/2710) (p<0.0001) of non-DS-ALL pts. Trisomies of chromosomes 4 and 10 were present in 7.7% (6/78) of DS-ALL pts vs. 24% (643/2689) (p=0.0004) of non-DS-ALL pts. Five-year EFS and OS were inferior in pts with DS-ALL; 70% vs. 76% (p=0.078), and 86% vs. 90% (p=0.0333). However, when pts with MLL, BCR/ABL, TEL-AML 1 and trisomies 4 and 10 were excluded, the EFS and OS for both groups were equivalent with EFS for DS 68% vs. 70% for non-DS (p=0.8174), and OS for DS 87% vs. 85% for non-DS (p=0.8519). Conclusions: The inferior outcome of patients with ALL and DS is related to a much lower incidence of favorable genetic features (TEL- AML 1 and trisomies of chromosomes 4 and 10). Further investigation into the distinct pathogenesis of DS ALL is warranted to improve treatment response. No significant financial relationships to disclose.
Mutant Rad50-mediated cisplatin chemosensitization for the treatment of human head and neck cancer
Authors: Waleed Abuzeid, Guoli Shi, Joung Rhee, James Carney, Bert O'Malley, Daqing Li
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3314 

In 2006, there were 40,000 new cases of head and neck squamous cell carcinoma (HNSCC) and 11,000 deaths in the US. Survival from HNSCC has not improved over many decades. Cisplatin is the mainstay of adjuvant treatment. Escalating cisplatin dose to overcome drug resistance leads to severe systemic toxicity. Repair of DNA double-strand breaks (DSBs) by the Mre11, Rad50, and Nbs1 (MRN) complex contributes to resistance.

With the goal of developing molecular therapies to enhance the cytotoxicity of cisplatin and, thus, improve therapeutic outcome in the treatment of HNSCC, we have created a novel, recombinant adenoviral vector containing a mutant Rad50 gene (Ad-Rad50). Ad-Rad50 interrupts the function of the MRN DNA repair complex, thereby sensitizing HNSCC cells to cisplatin-induced damage.

Cell proliferation assay showed that Ad-Rad50, with cisplatin, produced significantly slower cancer cell growth than any other treatment group. Neutral comet assay demonstrated a higher number of DNA DSBs in the Ad-Rad50 with cisplatin group, versus all other groups (P<0.01). Ad-Rad50, through impairment of MRN-mediated DNA repair, permits lethal cell damage to accumulate in cisplatin-treated cells.

It has been demonstrated that 90% of HNSCC tumor cells achieve immortality through telomerase activation. MRN is required for telomerase function. Telomere shortening beyond a critical threshold causes cellular senescence. PNA-FISH telomere length analysis showed significantly shorter telomeres in the Ad-Rad50 with cisplatin group, relative to all other groups (P<0.01), contributing to enhanced cisplatin cytotoxicity.

Cisplatin induces dose-dependent G2/M cell cycle arrest. Flow cytometry revealed that, at tested doses, cisplatin did not increase the proportion of cells in G2/M arrest. The addition of Ad-Rad50 produced G2/M arrest in the majority of HNSCC cells (P<0.005). Abrogation of MRN function by Ad-Rad50 may allow cisplatin-induced damage to accumulate, producing arrest.

An animal model of human HNSCC was used to further investigate the feasibility of this novel treatment strategy. Mice, treated with Ad-Rad50 and cisplatin in combination, had significantly smaller tumors than untreated controls, cisplatin alone, or Rad50 alone groups. Preliminary data suggests that low-dose cisplatin, with Ad-Rad50, results in smaller tumors than a higher cisplatin dose, used as the standard in clinical applications.

Our study demonstrates that Ad-Rad50 enhances the cytotoxicity of cisplatin in HNSCC by increasing DNA DSBs, telomere shortening, and enhancing G2/M cell cycle arrest. This translates to tumor volume reduction in vivo. The implications are considerable as sensitizing HNSCC to cisplatin with Ad-Rad50 may allow for the use of lower cisplatin doses, clinically.

This work is supported by FAMRI.
An RNA Molecule Derived From Sendai Virus DI Particles Induces Antitumor Immunity and Cancer Cell-selective Apoptosis
Authors: Li-Wen Liu, Tomoyuki Nishikawa, Yasufumi Kaneda
Journal: Molecular Therapy (2015)

Inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) induces anticancer immunity and cancer cell-selective apoptosis through the recognition of viral RNA genome fragments by retinoic acid-inducible gene-I (RIG-I). Here, we discovered that the "copy-back" type of defective-interfering (DI) particles that exist in the Cantell strain of HVJ induced the human PC3 prostate cancer cell death more effectively than the Sendai/52 strain or Cantell strain, which contain fewer DI particles. DI particle genomic RNA (~550 bases) activated proapoptotic genes such as Noxa and/or TNF-related apoptosis-inducing ligand (TRAIL) in human prostate cancer cells to induce cancer cell-selective apoptosis. DI particle-derived RNA was synthesized by in vitro transcription (in vitro transcribed (IVT)-B2). IVT-B2 RNA, which has a double-stranded region in its secondary structure, promoted a stronger anticancer effect than IVT-HN RNA, which does not have a double-stranded region in its secondary structure. The intratumoral transfection of IVT-B2 significantly reduced the volume of a human prostate tumor and induced tumor cell apoptosis in the xenograft mouse model. Moreover, the involvement of natural killer (NK) cells in IVT-B2-RNA-induced anticancer effects was also suggested. These findings provide a novel nucleic acid medicine for the treatment of cancer. Inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) induces anticancer immunity and cancer cell-selective apoptosis through the recognition of viral RNA genome fragments by retinoic acid-inducible gene-I (RIG-I). Here, we discovered that the "copy-back" type of defective-interfering (DI) particles that exist in the Cantell strain of HVJ induced the human PC3 prostate cancer cell death more effectively than the Sendai/52 strain or Cantell strain, which contain fewer DI particles. DI particle genomic RNA (~550 bases) activated proapoptotic genes such as Noxa and/or TNF-related apoptosis-inducing ligand (TRAIL) in human prostate cancer cells to induce cancer cell-selective apoptosis. DI particle-derived RNA was synthesized by in vitro transcription (in vitro transcribed (IVT)-B2). IVT-B2 RNA, which has a double-stranded region in its secondary structure, promoted a stronger anticancer effect than IVT-HN RNA, which does not have a double-stranded region in its secondary structure. The intratumoral transfection of IVT-B2 significantly reduced the volume of a human prostate tumor and induced tumor cell apoptosis in the xenograft mouse model. Moreover, the involvement of natural killer (NK) cells in IVT-B2-RNA-induced anticancer effects was also suggested. These findings provide a novel nucleic acid medicine for the treatment of cancer.
Prevertebrate Local Gene Duplication Facilitated Expansion of the Neuropeptide GPCR Superfamily
Authors: Seongsik Yun, Michael Furlong, Mikang Sim, Minah Cho, Sumi Park, Eun Bee Cho, Arfaxad Reyes-Alcaraz, Jong-Ik Hwang, Jaebum Kim, Jae Young Seong
Journal: Molecular Biology and Evolution (2015)

In humans, numerous genes encode neuropeptides that comprise a superfamily of more than 70 genes in approximately 30 families and act mainly through rhodopsin-like G protein-coupled receptors (GPCRs). Two rounds of whole-genome duplication (2R WGD) during early vertebrate evolution greatly contributed to proliferation within gene families; however, the mechanisms underlying the initial emergence and diversification of these gene families before 2R WGD are largely unknown. In this study, we analyzed 25 vertebrate rhodopsin-like neuropeptide GPCR families and their cognate peptides using phylogeny, synteny, and localization of these genes on reconstructed vertebrate ancestral chromosomes (VACs). Based on phylogeny, these GPCR families can be divided into five distinct clades, and members of each clade tend to be located on the same VACs. Similarly, their neuropeptide gene families also tend to reside on distinct VACs. Comparison of these GPCR genes with those of invertebrates including Drosophila melanogaster, Caenorhabditis elegans, Branchiostoma floridae, and Ciona intestinalis indicates that these GPCR families emerged through tandem local duplication during metazoan evolution prior to 2R WGD. Our study describes a presumptive evolutionary mechanism and development pathway of the vertebrate rhodopsin-like GPCR and cognate neuropeptide families from the urbilaterian ancestor to modern vertebrates.
Prognostic significance of p53 immunostaining in epithelial ovarian cancer.
Authors: L C Hartmann, K C Podratz, G L Keeney, N A Kamel, J H Edmonson, J P Grill, J Q Su, J A Katzmann, P C Roche
Journal: Journal of Clinical Oncology (1994)

PURPOSE To evaluate the prognostic significance of p53 expression in epithelial ovarian cancer, including a subset of stage I patients, and to look for correlations between p53 expression and other disease parameters, including stage, grade, age, histologic subtype, second-look results, ploidy, and percent S phase. PATIENTS AND METHODS We analyzed p53 expression in 284 patients with epithelial ovarian cancer using immunohistochemical techniques in paraffin-embedded specimens. There were 36 patients with stage I disease, 20 with stage II disease, 186 with stage III disease, and 42 with stage IV disease. RESULTS p53 immunoreactivity was present in 177 cases (62%). p53 expression was associated with grade 3 to 4 disease (P = .003). The following factors were associated with a decrease in overall survival in a univarate analysis: stage III or IV disease (P = .0001), grade 3 or 4 disease (P = .0001), age above the median (P = .0002), and p53 reactivity (P = .04). In a multivariate analysis, stage, grade, and age retained independent prognostic significance. In the subset of 36 stage I patients, p53 positively approached statistical significance (P = .10) as a negative prognostic factor in a univariate analysis. CONCLUSION Abnormalities of p53 expression occur commonly in epithelial ovarian cancer. Although associated with decreased survival in a univariate analysis, this biologic marker did not retain independent prognostic significance in a multivariate analysis. p53 expression should be studied in a larger cohort of early-stage patients, where accurate prognostic information is needed to direct therapy.
Adverse events in the treatment of multidrug-resistant tuberculosis
Authors: Shahina Qayyum, Iftekhar Ahmed, Saifullah Baig, Nadeem Rizvi
Journal: European Respiratory Journal (2011)

Objective:  To study the frequency and nature of side effect in patients receiving second line anti TB drugs   Introduction:  Ojha Institute of Chest Diseases (DUHS) Karachi Pakistan is managing drug resistant TB patients since 1996. AAdverse events associated with second line drugs have a severe impact on adherence. Frequency of adverse events is not studied in resource-limited settings. Since 2009 patients are being managed according to WHO guideline. Treatment regimen is tailored t and data management i and account of side effect is maintained   Method:  Patients registered from 1st -01- 2009 to 30-09-10 were included Data from DR TB 01 was recorded in Microsoft excel and o SPSS 16 and analyzed   Results:  440 patients were registered.Age range from 9 -76 year (mean 32.9,). ratio of male to female was 54.7: 45.3. 99.3% had pulmonary tuberculosis  Abdominal symptom were present in 51.4%, heart burn 48 (11.3%), abdominal pain/discomfort in 71 16.7%, epigastric pain in 29.3%, nausea and vomiting in 28.2%.  Vertigo observed in 140 (31.7%), hearing loss in 3.5% Depression in 5%, anxiety in 22 (5%), headache in 56 (12.7%) and 0.7%. had uneasiness.Psychosis in 12 (2.8%).y one had seizure, 43 joint pain. Hypothyroidism in 15 patients. Mild itching present in 7,5% cases one had exfoliated dermatitis. The onset of symptom was from seven days to 120 day. Most patients responded to symptomatic treatment, Drug were transiently stopped in patients with psychosis, completely in patient with exfoliative dermatitis and changed in 02 patients with gasteritis and one with psychosis   Conclusion:  Gastrointestinal event were most frequent.Treatment can be continued with treatment of adverse event in most of the cases.
A phase II trial of weekly gemcitabine and bevacizumab in combination with abdominal radiation therapy in patients with localized pancreatic cancer
Authors: W. Small, M. Mulcahy, A. Benson, S. Gold, R. Bredesen, F. Rademaker, M. Talamonti
Journal: Journal of Clinical Oncology (2007)

15043 Purpose: To evaluate the response rate, survival and toxicity of non-metastatic pancreatic cancer patients treated with a combination of, Gemcitabine, Bevacizumab and Radiotherapy. Materials and Methods: Eligibility included patients with non- metastatic pancreatic cancer, standard organ function and ECOG performance status of 0 or 1. The patients received three cycles of therapy. Cycle one was 21 days and consisted of Gemcitabine days 1 and 8 and Bevacizumab days 1 and 15. Cycle 2 was 28 days and consisted of Gemcitabine days 1, 8, and 15, Bevacizumab days 8 and 22 and Radiotherapy days 1–5, 8–12, and 15–19. Cycle three was 21 days and delivered Gemcitabine days 1 and 8, and Bevacizumab day 8. The Gemcitabine dose was 1,000 mg/m2, Bevacizumab at 10 mg/kg and Radiotherapy was delivered to the gross tumor volume only for a total dose of 36 Gy at 2.4 Gy/fraction. Response was determined on week ten with cross sectional imaging and CA 19–9. Toxicities were scored utilizing CTC version 3.0. Resectable patients were to undergo surgery 8 (currently amended to 6) weeks after the last dose of Bevacizumab. Results: Ninteen patients have been enrolled on study from 10/10/05 - 1/4/07. Twelve patients are evaluable for toxicity and response. Ten (83%) had a grade 3 toxicity. The grade 3 toxicities included cytopenias (9), DVT (2), Dehydration (2), hypotension (1), mucositis (1), increased LFT’s (2), Anorexia (1), nausea (1) and fatigue (1).There were no Grade 4 or 5 toxicities. All but one patient completed all three cycles. Radiographic response at 10 weeks was noted to be stable in 10 (83%) patients. Two patients progressed distantly (liver and abdomen). The mean CA 19–9 pre and post treatment CA 19–9 was 1519.56 and 356.09 respectively. One patient underwent surgical resection. The mean follow up is 4.83 months. At last follow up nine patients were alive. Conclusions: The combination of full dose Gemcitabine, Bevacizumab and Radiotherapy was generally well tolerated with no Grade 4 toxicities and the majority of Grade 3 toxicities hematologic. All but one patient completed all three cycles. Responses were limited to a reduction in CA 19–9. Nine patients remain alive. Accrual to the trial continues. No significant financial relationships to disclose.
Pharmacokinetic and pharmacogenetic study of S-1 in Korean patients with metastatic biliary cancer
Authors: K. Kim, G. D. Jang, H. S. Lim, H. S. Kim, J. G. Shin, J. L. Lee, M. H. Ryu, H. M. Chang, Y. K. Kang, T. W. Kim
Journal: Journal of Clinical Oncology (2009)

2505 Background: S-1 is an oral anticancer agent composed of tegafur (FT), CDHP, and oxonate. CYP2A6 is related to the biotransformation of FT to 5-FU. We evaluated associations of genetic variants of CYP2A6 with PK/PD of S-1 when combined with oxaliplatin in metastatic biliary cancer. Methods: This is a prospective study of patients with histologically confirmed metastatic adenocarcinoma of the biliary tract. S-1 was administered orally at a dose of 40 mg/m 2 twice daily for 14 days followed by a 7-day rest period. For PK study, S-1 was given only once at day 1 of cycle 1. From day 2, it was administered twice daily. Oxaliplatin was administered intravenously at a dose of 130 mg/m 2 for 2 hours every 3 weeks. CYP2A6 polymorphism (*1, *4, *7, *9 or *10) were genotyped. Results: A total of 49 patients were enrolled. Median age was 52 years (range 23–68) and male accounted for 63%. Thirty patients (61%) had intrahepatic cholangiocarcinoma and 10 (20%) gallbladder cancer. Response rate was observed in 24.5%. The median PFS and OS were 3.7 months and 8.7 months . Grade 3–4 adverse events include vomiting (22%), diarrhea (4%) and neutropenia (14%). The allele frequencies of CYP2A6*4, *7, *9 and *10 were 10.2%, 8.2%, 19.4%, and 4.1%, respectively. AUC 0–24hr of 5-FU was 1030±617.3 hr*ng/mL (range 249.5–3969, CV: 59.9%). Log- transformed AUC 0–24hr were significantly different for FT and 5-FU in the *1/*1 group; metabolic ratio (AUC 0- 24hr of 5-FU/AUC 0–24hr of FT) of the *1/*1 group was 1.85-times higher than the other group (90% CI 1.37–2.49). AUC 0–24hr of CDHP was not significantly associated with CYP2A6 genotype. Despite differences in exposure, CYP2A6 genotypes were not significantly associated with diarrhea (P=0.0740), neutropenia (P=0.396) and clinical efficacy (response rate: P=0.583, PFS: P=0.916). Conclusions: CYP2A6 genotypes was associated with transformation of FT to 5-FU; however, this association did not translate into different clinical efficacy or toxicity. [Table: see text] No significant financial relationships to disclose.
Final safety findings from a randomized phase III trial of capecitabine + oxaliplatin (XELOX) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with stage III colon cancer
Authors: H. J. Schmoll, J. Tabernero, M. Nowacki, J. Maroun, T. Price, R. Lim, E. Van Cutsem, F. De Braud, D. Haller
Journal: Journal of Clinical Oncology (2006)

3569 Background: Adjuvant capecitabine results in at least equivalent disease-free survival (DFS) to i.v. bolus 5-FU/LV in stage III colon cancer [Twelves et al. 2005]. Early phase III data in 1 st -line metastatic colorectal cancer suggest that XELOX is as safe as oxaliplatin + infusional 5-FU ± LV [Sastre et al. 2005; Ducreux et al. 2005]. The XELOXA study compared safety and efficacy of XELOX vs. bolus 5-FU/LV (the standard regimen at study start) as adjuvant therapy for stage III colon cancer. Methods: Pts with resected disease were randomized to receive either XELOX (capecitabine 1000 mg/m 2 bid d1–14 + oxaliplatin 130 mg/m 2 d1, q3w for 8 cycles) or i.v. bolus 5-FU/LV (Mayo Clinic, LV 20 mg/m 2 + 5-FU 425 mg/m 2 d1–5, q4w for 6 cycles; or Roswell Park [RP], LV 500 mg/m 2 + 5-FU 500 mg/m 2 d1, w1–6 in 8w cycles x4). Centers’ preferred 5-FU/LV regimen was selected at study start and used in all pts. Results: 1861/1886 pts randomized between Apr 03 and Oct 04 are evaluable for safety. The rate of related grade 3/4 adverse events (AEs) was 54% for XELOX and 45% for 5-FU/LV ( table ). 60-day all cause mortality was 1.0% in both arms. Treatment-related death rate within 28 days from last dose was 0.7% for XELOX and 0.5% for 5-FU/LV. Conclusions: XELOX causes less myelosuppression and stomatitis but more skin toxicity than 5-FU/LV. The inclusion of oxaliplatin adds neurosensory toxicity. Cross-study comparison of grade 3/4 AEs in the current and MOSAIC trials suggests that XELOX safety is similar to FOLFOX4, with the advantage of an oral fluoropyrimidine-based regimen. Final safety data will be presented at the meeting, and efficacy data will be available in 2007. [Table: see text] [Table: see text]
Dopamine, Striatum, Antipsychotics, and Questions About Weight Gain
Authors: Shitij Kapur, Tiago Reis Marques
Journal: JAMA Psychiatry (2016)

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