tbuckley/cabot-search huggingface dataset:
BCR-ABL kinase domain mutations and resistance in Ph+ acute lymphoblastic leukemia from the imatinib to the second-generation TKI era.
Authors: Simona Soverini, Alessandra Gnani, Caterina De Benedittis, Ilaria Iacobucci, Claudia Venturi, Cristina Papayannidis, Mario Luppi, Serena Merante, Michele Malagola, Domenico Russo, Mario Tiribelli, Marzia Salvucci, Antonella Vitale, Loredana Elia, Marco Vignetti, Robin Foà, Michele Baccarani, Giovanni Martinelli
Journal: Journal of Clinical Oncology (2012)

6531 Background: Advent of 2nd-generation TKIs has brought additional treatment options for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients (pts). To analyze the changes they have determined in mutation frequency and type, we have reviewed the database recording the results of BCR-ABL mutation analyses done in our laboratory from 2004 through 2011. Methods: 781 tests on 258 pts were performed by direct sequencing. Results: 143 pts were analyzed because of imatinib resistance; 101 (71%) had one or more mutations (a single mutation in 91 pts; two mutations in 10 pts). Three mutation types were by far the most frequent: T315I (38 pts, 37%), E255K (19 pts, 18%) and Y253H (19 pts, 18%). Of 84 pts who had developed resistance to 2nd- or 3rd-line therapy with dasatinib, nilotinib or bosutinib after imatinib failure, 65 (77%) were positive for Bcr-Abl mutations; 30 (46%) carried multiple mutations (up to four) and in 19 of them (63%) this was consequence of multiple lines of therapy. The most frequent newly acquired mutation in this setting was the T315I, detected in 35/57 (61%) cases acquiring mutations on dasatinib. Mutation analysis was also performed in 15 resistant pts enrolled in a study of dasatinib as 1st-line treatment of Ph+ ALL; 12 pts were positive, 11 of them had a T315I. Taking advantage of a next-generation sequencer (Roche 454), allowing a high sensitive and quantitative mutation scanning of Bcr-Abl, serially collected samples from 24 selected cases who developed mutations and resistance to one or more TKIs were retrospectively analyzed to study the kinetics of expansion of mutant clones. Results will be presented. Conclusions: Although 2 nd generation TKIs are more potent and have much fewer insensitive mutations, long-term disease control remains a problem and the T315I becomes an even tougher enemy. The high genetic instability fosters mutational events anytime during TKI treatment and some mutation types (T315I, Y253H) have been observed to emerge and take over very quickly (from &lt;0.01% to 90% in one-two months). Supported by PRIN, AIL, AIRC, Fondazione CARISBO.
Abstract #1198: Angiopoietin-like protein 1 (ANGPTL1) prevents invasion and metastasis of lung cancer
Authors: Tsang Chih Kuo, Jen Liang Su, Jean Chiou, Min Liang Kuo
Journal: Cancer Research (2009)

Metastasis is the major cause of treatment failure and death in cancer patients. During this process, migration/invasion ability of cancer cells is important for tumor metastasis. Angiopoietin-like protein 1 (ANGPTL1) is a secreted protein and has been reported as an anti-angiogenic molecule. In this study, we demonstrated that ANGPTL1 expression was inversely associated with invasiveness of lung cancer cell lines. ANGPTL1 overexpression or ANGPTL1 recombinant protein treatment significantly inhibited lung cancer cells migration/invasion ability of in vitro. Moreover, the cellular morphology was changed in ANGPTL1-overexpressed cells by reorganizing of the actin cytoskeleton through inhibition of actin stress fiber formation. By using tail vein xenograft models, ANGPTL1-overexpressed cells metastasized less efficiently to lung than did control cells. In addition IHC analysis of lung tumor tissues revealing that patients with higher level of ANGPTL1 have low metastasis as well as longer survival time. Together, our results suggest that ANGPTL1 inhibited lung cancer metastasis through reducing migration and invasion of cancer cells.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1198.
Minimal Residual Disease Assessment in CLL: Ready for Use in Clinical Routine?
Authors: Moritz Fürstenau, Nisha De Silva, Barbara Eichhorst, Michael Hallek
Journal: HemaSphere (2019)

Abstract The introduction of chemoimmunotherapy and more recently the implementation of novel agents into first‐line and relapse treatment have substantially improved treatment outcomes in patients with chronic lymphocytic leukaemia (CLL). With longer progression‐free survival and more frequently observed deep remissions there is an emerging need for sensitive methods quantitating residual disease after therapy. Over the last decade, assessment of minimal residual disease (MRD) has increasingly been implemented in CLL trials. The predictive value of MRD status on survival outcomes has repeatedly been proven in the context of chemoimmunotherapy and cellular therapies. Recent data suggests a similar correlation for Bcl‐2 inhibitor‐based therapy. While the relevance of MRD assessment as a surrogate endpoint in clinical trials is largely undisputed, its role in routine clinical practice has not yet been well defined. This review outlines current methods of MRD detection in CLL and summarizes MRD data from relevant trials. The significance of MRD testing in clinical studies and in routine patient care is assessed and new MRD‐guided treatment strategies are discussed.
The novel tumor suppressor HINT1 plays a role in DNA repair
Authors: Haiyang Li, Adayabalam Balajee, Tom Hei, I. Bernard Weinstein
Journal: Cancer Research (2008)

4325  Our previous studies demonstrated that HINT1 is a haplo-insufficient tumor suppressor. However, the underlying molecular mechanism(s) of its tumor suppressor function remains unclear. In this study, we demonstrate that HINT1 participates in the cellular response to ionizing radiation (IR)-induced DNA damage. Upon exposure to IR, HINT1 forms distinct foci which spatially associate with gamma-H2AX and ATM in the interphase nuclei. HINT1 deficiency also results in the impaired acetylation of both gamma-H2AX and ATM. In response to IR, HINT1 deficient cells exhibit attenuated activation of ATM and its downstream effectors, and resistance to IR-induced apoptosis. Although HINT1 deficiency does not affect IR-induced gamma-H2AX foci formation, it abolishes the ability of 53BP1 to form foci at the sites of DNA double strand breaks. HINT1 deficient cells also display retarded DNA repair of spontaneous and IR-induced DNA strand breaks, compared with the HINT1 competent cells. Consistent with the DNA repair deficiency, cells derived from Hint1 -/- mice display significantly increased frequencies of spontaneous chromosomal anomalies, such as breaks (chromosome and chromatid types), fragments (centric and acentric), and exchange type aberrations. These results suggest that HINT1 deficiency causes a marked increase in spontaneous chromosomal abnormalities, presumably due to impaired DNA repair responses. Taken together, our findings suggest that HINT1 protects the genomic integrity against tumorigenesis through effective regulation of cellular DNA repair processes.
Molecular tools for preventing and improving diagnosis of peri‐implant diseases
Authors: Francesco Carinci, Georgios E. Romanos, Luca Scapoli
Journal: Periodontology 2000 (2019)

Abstract Peri‐implantitis is an inflammatory disease of tissues surrounding osseointegrated dental implants. Inflammation affecting soft and hard peri‐implant tissues can cause alveolar bone resorption and subsequent implant loss. Clinical surveillance and early diagnosis are of paramount importance to reduce clinical failures and improve implant survival. Current diagnosis of implants is based on clinical and radiological signs. Molecular tests are an emerging diagnostic methodology, which potentially can help to detect and prevent early peri‐implantitis and monitor the efficacy of therapy as well. A plethora of potential biomarkers are potentially available to support the clinical diagnosis of peri‐implantitis. However, conflicting diagnostic conclusions have been reached, probably related to weak statistical results due to limited sample size or disease heterogeneity. The present paper reviews candidate diagnostic biomarkers for peri‐implantitis, including infective agents, genetic susceptibility factors, and key proteins related to inflammation and tissue remodeling.
A phase I dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erlotinib in advanced stage solid malignancies
Authors: S. K. Chia, K. N. Chi, C. Kollmannsberger, K. Paton, K. Bhagat, S. D’Aloisio, A. Das-Gupta, H. Kletzl, E. Zwanziger, K. Gelmon
Journal: Journal of Clinical Oncology (2007)

3594 Background: Erlotinib is a potent oral TKI of the epidermal growth factor receptor (EGFR). At the current recommended daily dose of 150 mg/day there is activity in advanced stage NSCLC, but with frequent grade 1/2 rash and diarrhea. We performed a phase I dose escalation study of erlotinib with a once and twice weekly schedule to assess the PKs, PDs, and to determine if toxicities would be less on an intermittent but high dose schedule. Methods: A standard dose escalation schedule starting at 1,400 mg once/week and 600 mg twice/week with increments of 200 mg to 4 dose cohorts/schedule was utilized with three patients per cohort. A cycle consisted of 3 weeks of therapy. PKs were performed on cycle 1 and 2. PDs on normal skin punch biopsies were performed at baseline and after cycle 1. Tumour evaluation was done following every 2 nd cycle. Subjects were treated until progression or unacceptable toxicity. Results: 32 patients were enrolled from Oct 2004-April 2006. Median age 58 years (28–74 years); median PS 1 (0–2); and median prior palliative systemic regimens 2 (0–6). In the once weekly schedule the maximum tolerated dose (MTD) was not reached with the top dose of 2,000 mg/week. A median of 2 cycles were delivered (1–14), with 3/13 patients achieving stable disease = 3 months. 4/13 patients had G1 rash and 6/13 patients G1 diarrhea during the first 2 cycles. In the twice weekly schedule the MTD was reached at 1,200 mg twice/week with 2/6 subjects experiencing G3 rash. The recommended dose level is 1,000 mg twice/week. A median of 4 cycles were delivered (1–28) with 2 partial responses, 1 minor response and 6 stable disease = 3 months out of 19 patients in total. G1/2 rash or diarrhea occurred in 13 and 9 patients respectively. No corneal toxicity was seen. The PK data demonstrated a variable but linear pattern. At 1,000 mg twice/week the median C max , T max and AUC 0–24 hr was 6.28 μg/ml, 2 hours and 135 μg.h/ml respectively. PD analysis is ongoing. Conclusions: A once weekly and twice weekly high dose schedule of erlotinib is feasible, with MTD not reached in the once weekly schedule. A recommended dose of 1,000 mg twice/week has clinical activity, is generally well tolerated, and results in significantly higher systemic exposure than the 150 mg once daily dose. No significant financial relationships to disclose.
Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia
Authors: Yun Chen, Liguang Chen, Jian Yu, Emanuela M. Ghia, Michael Y. Choi, Ling Zhang, Suping Zhang, Elsa Sanchez-Lopez, George F. Widhopf, Karen Messer, Laura Z. Rassenti, Catriona Jamieson, Thomas J. Kipps
Journal: Blood (2019)
Abstract 12765: Effects of a Cyborg-Type Robot Hal During Squat Exercise in Healthy Subjects
Authors: Hiroki Watanabe, Akira Koike, Yo J Pak, Longmei Wu, Hiroshi Kubota, Hirotomo Konno, Akira Sato, Akira Matsumura, Kazutaka Aonuma, Masaki Ieda, Yoshiyuki Sankai
Journal: Circulation (2018)

Introduction: The Hybrid Assistive Limb (HAL) is the world’s first cyborg-type robot that improves, supports and expands wearer’s physical functions, by detecting bioelectrical signals on skin surf...
A nutrient mixture consisting of lysine, proline, ascorbic acid and green tea extract inhibits lung metastasis by B16 melanoma cells in mice
Authors: M. Waheed Roomi, Nusrath Roomi, Vadim Ivanov, Aleksandra Niedzwiecki, Matthias Rath
Journal: Cancer Research (2006)

1903  Introduction: Metastatic malignant melanoma is an extremely aggressive cancer with no current viable therapy. A unique non-toxic nutrient mixture (NM) consisting of lysine, proline, ascorbic acid and green tea extract has shown potent anti-tumor effects in a number of cancer cell lines in vitro and in vivo. Objective: The present study investigated whether NM could also inhibit lung metastasis by B16F0 melanoma cell in C57BL/6 female mice. Method and Materials: C57BL/6 female mice were divided into 6 groups of 6 mice per group; Groups 1-4 were injected via tail vein with B16F0 melanoma cells (5x104/mouse) and Group 5 (control group) received the vehicle saline. Group 1 was fed the control diet, Group 2 was fed the same diet supplemented with 0.5% NM, Group 3 and 4 were given NM by IP and IV (4 mg/mouse, three times a week) respectively, and fed the control diet. Group 6 mice were fed the control diet but injected with B16F0 melanoma cells pretreated with NM (500 μg/ml for 24 hrs). In another study, mice were injected either with 106 or 105 B16F melanoma cells per mouse and divided into four groups (A-D). Groups A ,C were fed the control diet, while Groups B, D fed the same diet supplemented with 0.5% NM. Two weeks later mice in all the groups were euthanized, lungs were excised, weighed, fixed, pulmonary metastatic colonies were counted, and lung tissue processed for histology. Results: Pulmonary colonization was reduced to 63% in Group 2 (NM diet) compared to Group 1 (control). Pulmonary colonization was further inhibited by 86% in mice receiving MN by ip and iv injections (Groups 3, 4). Complete inhibition of pulmonary colonization was seen in mice that received melanoma cells pretreated with NM (Group 6). Findings were corroborated with histological analysis. Furthermore, inhibitory effect of NM was also confirmed by comparing the weight of lungs. Of mice that received 106 cells, the NM fed group (B) had an average lung weight of 0.55 gm, compared to 0.92 gm in the control group (A). Histopathology revealed metastasis in all lobes with back-to-back colonies. Similar inhibition was seen in the mice that received 105 cells. For example, an average lung weight of mice fed NM (Group D) was 0.11, compared to 0.15 gm in mice fed the control diet (Group E). Metastasis involved 40-45% of the lung. The average number of colonies in control Group C was 600, while in NM-fed Group D it was 400 (33% reduction). Results from the control and the test groups for weight of lungs and number of cells inoculated were pooled and the correlation coefficient was calculated. An excellent correlation was obtained (r=0.93, P
Abstract 19509: In-Hospital Outcomes of Patients With ST-Elevation Myocardial Infarction and Atrial Fibrillation
Authors: Subir Bhatia, Parshva Patel, Sravya Bhatia, Ghanshyam Shantha, Kanishk Agnihotri, Danesh Kella, Shilpkumar Arora, Abhishek Deshmukh
Journal: Circulation (2017)

Introduction: Atrial fibrillation (AF) is one of the most frequently encountered arrhythmias in the setting of acute ST-elevation myocardial infarction (STEMI). AF in the setting of STEMI has been ...
Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices
Authors: Elissa Meites, Peter G. Szilagyi, Harrell W. Chesson, Elizabeth R. Unger, José R. Romero, Lauri E. Markowitz
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Vaccination against human papillomavirus (HPV) is recommended to prevent new HPV infections and HPV-associated diseases, including some cancers. The Advisory Committee on Immunization Practices (ACIP)* routinely recommends HPV vaccination at age 11 or 12 years; vaccination can be given starting at age 9 years. Catch-up vaccination has been recommended since 2006 for females through age 26 years, and since 2011 for males through age 21 years and certain special populations through age 26 years. This report updates ACIP catch-up HPV vaccination recommendations and guidance published in 2014, 2015, and 2016 (1-3). Routine recommendations for vaccination of adolescents have not changed. In June 2019, ACIP recommended catch-up HPV vaccination for all persons through age 26 years. ACIP did not recommend catch-up vaccination for all adults aged 27 through 45 years, but recognized that some persons who are not adequately vaccinated might be at risk for new HPV infection and might benefit from vaccination in this age range; therefore, ACIP recommended shared clinical decision-making regarding potential HPV vaccination for these persons.
Proteomics and Cr(VI) exposure: exploring new biomarkers in humans
Authors: Qingshan Qu, Yixin Lin, Xiaomei Li, Roy Shore, Feiyun An, Guang Jia, Lanzheng Liu, Yu Hu, Beverly Cohen, Max Costa
Journal: Cancer Research (2005)

2207  Hexavalent chromium [Cr(VI)] is present as one of the major contaminants at numerous Superfund toxic waste dump sites and is a well established human carcinogen. In the present study, 10 exposed and 10 unexposed male subjects were recruited from a Chinese occupational population for proteomic analyses using SELDI ProteinChip® technology to determine if there are proteins in plasma that can be used to distinguish between exposed and unexposed subjects. In the meantime, a number of biomarkers for Cr(VI) exposure and biological effects, including Cr levels in red blood cells (RBC), DNA protein cross link (DPC), comet assay in lymphocytes, and urinary 8-hydroxydeoxyguanosine (8-OHdG), were also determined. The mean personal exposure levels of Cr(VI) were 0.09 μg/m3 and 265.9 μg/m3 in unexposed and exposed subjects, respectively. DPC was found significantly higher in exposed than in unexposed subjects (p
Variation of the 3’ telomeric overhang size in various human cells
Authors: Myung Eun Lee, Sun Young Rha, Tae Soo Kim, Jae Kyung Roh, Ho-Yeoug Lim, Hyun Cheol Chung, Bong-Kyeong Oh
Journal: Cancer Research (2007)

1204  Human telomeres are composed of 8-15 kbs of double stranded DNA and 100-300 bps of G-rich single stranded DNA at the 3’ end. The G-rich 3’overhang is invaded into the duplex telomeric DNA region, forming telomeric loop structure which is critical for the protection of the chromosome end from DNA degradation. The 3’ overhang length is known to shorten as normal fibroblasts reach to senescence. However, the regulation of 3’ overhang length is not completely understood, and the 3’overhang size has not been analyzed in various tumor tissues. Here, we examined the 3’ overhang and telomere length in human cells including 6 immortalized normal cells and 58 cancer cell lines from 8 breast, 4 cervix, 5 colorectal, 23 gastric, 6 hepatoma, 4 brain, 5 lung, 3 hematoma, using in-gel hybridization. The 3’ overhang size in each sample was determined as a ratio relative to HeLa’s overhang intensity. In cancer cells, the 3’ overhang was detected in the range from 23% to 308%, but most (45/58) was found in below 100%. Different pattern was not found according to tissue types, although low intensity was noted in brain, cervix and colon cells. Telomere length in cancer cells were detected in range from 2.7 to 9.3, except two cells that had long telomeres in 20 kb. Immortal normal cells showed the intensity in the range from 92 to 208 with mean value of 155±52.6%, which was 2-4 times strong compared to cancer cells (p=0.002), and interestingly, 5 of the normal cells (5/6) were found to be established from fetus. However, telomere length in immortal normal cells was detected in the range similar to that in cancer cells. Interestingly, the 3’ overhang size was positively correlated with the telomere length (p
A phase II trial of ZD6474 in patients with hereditary metastatic medullary thyroid cancer
Authors: S. Wells, Y. N. You, V. Lakhani, J. Hou, P. Langmuir, D. Headley, M. Skinner, M. Morse, W. Burch, M. Schlumberger
Journal: Journal of Clinical Oncology (2006)

5533 Background: Medullary thyroid carcinoma (MTC) is the most common cause of death in patients with hereditary syndromes caused by specific mutations in the RET protooncogene. RET activation is the oncogenic event, which results in intrinsic RET receptor tyrosine kinase activity, but other pathways, such as VEGFR- and EGFR-dependent signaling, also participate in tumor growth and development. ZD6474 is a once-daily oral agent that selectively targets RET, VEGFR and EGFR tyrosine kinases. The clinical activity of ZD6474 was evaluated in patients with hereditary MTC. Methods: In this open-label Phase II study, patients with unresectable, measurable, locally advanced or metastatic hereditary MTC and a RET germline mutation received once-daily oral doses of ZD6474 300 mg. The primary objective was to assess the objective tumor response (RECIST). Secondary objectives included assessments of biochemical response (determined by changes in plasma levels of calcitonin [CTN]) and safety/tolerability of ZD6474. An exploratory objective was to measure plasma levels of carcinoembryonic antigen (CEA). Results: As of 30 November 2005, 16 patients (6 male/10 female; median age 50 years, range 22–77) had entered the study and received initial treatment with ZD6474 300mg. The median duration of treatment was 136 days (range 16–353). Fifteen patients were evaluable for tumor response, CTN, and CEA. Objective tumor assessments have demonstrated partial responses in 3 patients (n = 2 confirmed; n = 1 unconfirmed), stable disease in 10 patients (n = 8, ≥8 and &lt;24 weeks; n = 2, ≥24 weeks) and progressive disease in 2 patients. A &gt;50% decrease from baseline in plasma CTN levels has been maintained for at least 4 weeks in 12/15 patients; a decrease in plasma CEA levels of the same magnitude and duration has been observed in 6/15 patients. Common adverse events (AEs) were diarrhea (n = 12) and nausea, rash and fatigue (each n = 11). CTC grade 3 AEs attributable to ZD6474 were QTc interval prolongation (n = 3), and diarrhea, skin rash and hypertension (each n = 2). Conclusions: ZD6474 shows promising evidence of clinical activity in patients with hereditary MTC. These are preliminary data and patients are still being recruited to this ongoing study. [Table: see text]