tbuckley/cabot-search huggingface dataset:
Lack of association of telomerase expression levels with telomere length variation in Lynch syndrome patients.
Authors: Sarah A. McGarrigle, Grainne O'Kane, Simon Hooper, Nadia Rehill, Michael P. Farrell, Jacinta O'Sullivan, C. Muldoon, Padraic M. Mac Mathuna, Desmond N. Carney, David J. Gallagher
Journal: Journal of Clinical Oncology (2015)

e12527 Background: Anticipation has been reported in Lynch Syndrome (LS) and linked to telomere length shortening. We recently investigated affected carriers (AC) and unaffected carriers (UAC) and found that younger age of onset in AC was associated with shorter telomere lengths. Telomerase activity is important in the maintenance of telomeres. We therefore analysed the expression of the main components of the telomerase complex TERT, TERC and DKC1 in both AC and UAC and assessed their relationship to telomere lengths. Methods: RNA was isolated from peripheral blood mononuclear cells and reverse transcribed to cDNA. Real-time polymerase chain reaction (RT-PCR) was used to quantitate expression levels of TERT, TERC and DKC1. Telomerase expression in AC and UAC was compared and Pearsons correlation coefficient was used to assess relationship between expression of telomerase complex components and telomere length in all patients and subsequently determine if telomerase correlated with age of onset in AC. Results: Thirty AC and 29 UAC were analysed. There was no difference in the mean expression of TERT, TERC and DKC1 between AC and UAC (p = 0.60, 0.27, 0.32). Furthermore telomerase expression did not correlate with telomere length in either group and in AC there was no relationship between telomerase expression and age of onset malignancy despite patients with shorter telomeres having earlier onset malignancies. Conclusions: Differences in telomere lengths in AC cannot be explained by altered telomerase expression. The maintenance of telomeres in Lynch Syndrome patients may be due to an alternate pathway.
Efficacy of abiraterone acetate in the treatment of castration-resistant prostate cancer: Early results from the German compassionate-use program.
Authors: Carsten Henning Ohlmann, Michael Stöckle, David A. Pfister, Axel Heidenreich, Axel S. Merseburger, Markus Kuczyk, Lukas Manka, Peter Hammerer, Peter Albers, Christian Arsov, Margitta Retz, Jürgen E. Gschwend, Susan Feyerabend, Arnulf Stenzl, Severine Banek, Jan Marin, Jochen Gleissner, Manfred Wirth, Stefan Zastrow, Matthias Heck
Journal: Journal of Clinical Oncology (2012)

e15195 Background: Abiraterone acetate (AA) plus prednisone (P) has demonstrated an improved survival of patients with castration-resistant prostate cancer (CRPC) compared to placebo plus P in a large phase III trial. In Germany, patients were able to receive AA within a compassionate-use program (CUP). Here, we report the first results of the program. Methods: Patients were eligible for the CUP if they progressed on or after at least one cytotoxic chemotherapy regimens. For CUP entry, patients were considered to have disease progression if they had radiographic evidence of disease progression in soft tissue or bone with or without PSA-progression and ongoing androgen deprivation. Patients received AA 1000mg daily plus prednisone 5mg BID until progression of disease or unacceptable toxicity. Results: Between 02-05/2011, 398 patients were registered for the CUP in Germany. Data from 191/350 (47.9%) of the patients treated at 10 different sites were available for evaluation of efficacy. Median age was 70.72yrs (52.35-87.61) and patients received a median of 1 (1-4) chemotherapy lines prior to CUP entry. Median PSA at baseline was 220.5 ng/ml (0.47-4245); 168 (88%) of patients presented with bone metastasis. With regard to efficacy, 64/191 (33.5%) of the patients showed an unconfirmed PSA-response ≥50%. At a median follow-up of 5.3 months, 51/191 (26.7%) patients had died, resulting in a median PSA-progression free and overall survival of 8.3 and 10.61 months, respectively. In a subset of patients (71/191, 37.2%) data regarding objective response was available with 25/71 (35.2%) achieving an objective response. Data from 114 pts. revealed fatigue (20.3%), hot flushes (15.8%), edema (10.6%), elevated liver enzymes (8.0%) and asthenia (7.9%) being the most frequent toxicities (any grade). Conclusions: Treatment of CRPC patients with AA outside controlled clinical trials leads to considerable PSA- and objective response rates with a favourable toxicity profile, comparable to the results from COU-AA-301 registration trial. Due to the short median follow-up, conclusions regarding PSA-progression free and overall survival may not be drawn.
Time from First Symptom Onset to the Final Diagnosis of Multiple Myeloma - Possible Risks and Future Solutions: Large Retrospective and Confirmatory Prospective Analysis
Authors: Giulia Graziani, Gabriele Ihorst, Johannes M. Waldschmidt, Georg W. Herget, Karl Henne, Annette M. May, Justus Duyster, Werner Vach, Ralph Wäsch, Monika Engelhardt
Journal: Blood (2016)
Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial
Authors: Bo Ahrén, Luis Masmiquel, Harish Kumar, Mehmet Sargin, Julie Derving Karsbøl, Sanja Hald Jacobsen, Francis Chow
Journal: The Lancet Diabetes & Endocrinology (2017)
Survival outcomes of early autologous stem cell transplant (ASCT) followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients with high-risk multiple myeloma (MM).
Authors: Jonathan L. Kaufman, Ajay K. Nooka, Samatha Muppidi, Leonard T. Heffner, Charise Gleason, Lawrence Boise, Sagar Lonial
Journal: Journal of Clinical Oncology (2012)

8100 Background: Despite markedly improved survival rates for MM pts in the last decade, 15-20% of pts with high risk genetics continue to have dismal outcomes with a median PFS of 18.5 months (Kapoor P et al). In this subset of pts, efforts are needed to improve response rates and prolong the response duration, but doing so without genotoxic therapy as this has been shown not to improve outcomes (Barlogie et al). Methods: We evaluated 37 pts with high risk features [del17p (n=16), t(4;14) (n=1), t(14;16) (n=4) by FISH/CTG; hypodiploidy (n=9), del 13 (n=16); complex karyotype (n=14) by CTG; PCL (n=7) and atypical presentation (n=4)]. After completing induction therapy, all pts underwent ASCT followed by RVD maintenance. 60 days after ASCT following hematological recovery, pts began maintenance [lenalidomide 10 mg/day (days1–21), bortezomib 1.3 mg/m2 and dexamethasone 40 mg once a week (days 1, 8, 15) every 28 days]. Results: The response rates are summarized in the table. 7/36 pts progressed while on RVD maintenance. The median PFS and OS for pts on RVD maintenance has not been reached. Pts with &lt;VGPR pre-ASCT and with &lt;VGPR on RVD maintenance have median PFS of 28 months and 11 months, respectively. 4 pts with prior h/o DVT received anticoagulation, while all others received ASA for DVT prophylaxis. No thrombotic events were seen. There were no grade 3/4 toxicities or treatment-related mortality. The most common toxicities during maintenance schedule were: PN-40% (G1: 26%; G2:14%); G1 rash-10% and G1 fatigue in 78% pts. Cytopenias were seen in 25% pts and dose reductions were made in 50% pts. There is no report of secondary malignancies. Conclusions: Early ASCT followed by RVD maintenance delivers superior response rates in this high risk segment achieving sCR in 47% and ≥VGPR in 73% pts and prevents early relapses. The median PFS and OS have not been reached. RVD maintenance regimen is well tolerated and promising. [Table: see text]
Neuropsychiatric side effects of high-dose IL-2 on patient with advanced melanoma or renal cell carcinoma.
Authors: Vani Ray, Ran Guan, Jonathan S Treisman, Vani Nilakantan, Han Yang Chen, Ishan Sinha, Julie Offutt
Journal: Journal of Clinical Oncology (2012)

e19030 Background: Treatment of patients with end stage renal cell carcinoma (RCC) or melanoma remains difficult. Immunotherapy with high-dose bolus interleukin (IL-2) is the first biological product clinically approved for the treatment of these cancers. Although effective in 15-20% of patients, high-dose IL-2 treatment has significant neuropsychiatric side effects that mandate treatment cessation. Currently, there is little information available on patients who are prone to these neuro-psychiatric side effects. The main objective was to investigate whether occult brain metastases predispose the patient to developing neuro-psychiatric side effects. Methods: We performed retrospective medical chart reviews of patients who had either RCC or malignant melanoma. Variables considered include patient demographics, cancer type, IL-2 treatment, response to treatment, location of metastasis, prior surgery, prior psychiatric history, and substance abuse. We conducted multivariable log-binomial regression analyses to examine the association between risk factors and neuro-psychiatric side effects. Results: Our study population included 261 cancer patients, among them 54% had melanoma (N=141) and 31% had post neuro-psychiatric disorders (N=81). We found that nicotine abstinence in past smokers (remission) was significantly associated with increased neuro psychiatric side-effects (RR=1.88, P=.015) among melanoma patients, but not RCC patients. The multivariable regression analysis showed that having pre-existing psychiatric disorders was the only factor significantly associated with neuropsychiatric effects (aRR=1.92, P&lt;0.0001), after adjusting for potential confounders. Having brain metastasis, however, was not significantly associated with neuropsychiatric effects (aRR=1.10, P=0.627). Conclusions: Contrary to our original hypothesis, prior psychiatric history was the only significant factor predisposing patients to develop neuro-psychiatric side effects during IL-2 treatment and not occult brain metastases. Future studies with larger patient numbers and longitudinal design will help to refine the findings from this research.
Abstract 101: The Continuous Administration of Sevoflurane Protects the Heart Against Ischemic Injury via Distinct Mitochondrial Mechanisms.
Authors: Christopher Lotz, Tobias Tischer-Zeitz, Anja Frank, Jan Stumpner, Norbert Roewer, Thorsten M Smul
Journal: Circulation Research (2013)

Sevoflurane induced cardioprotection against ischemia/reperfusion (I/R) injury represents a well-established phenomenon. Salutary effects of the volatile anesthetic are not only limited to pre- or post-ischemic use, but clinical data also indicate its continuous administration as a beneficial mean. We investigated the hypothesis that the administration of sevoflurane during I/R-injury results in cardioprotection via the recruitment of distinct mitochondrial mechanisms. After IRB approval New Zealand White rabbits (9-12 weeks of age) received sevoflurane (1.0 MAC) or propofol (10 mg/kg/h) during 30 min of coronary artery occlusion followed by 3 h of reperfusion (n=7 per group). Cardiac mitochondria were isolated at the end of reperfusion. TTC-staining was used to determine the myocardial infarct size; in addition, mitochondrial O2 consumption was quantified and expressed as the respiratory control ratio (RCR). Mitochondrial electron transport chain (ETC) complex activities (I-IV) were assayed; including the analysis of an active to dormant (A/D) ratio of complex I. Statistics: ANOVA followed by posthoc Bonferroni, Mean ± SD. Our data indicate a significant infarct size reduction in animals receiving sevoflurane throughout the I/R-injury (p&lt;0,05). The salutary effects were characterized by the maintenance of the RCR (p&lt;0,05), as well as a preserved activity of complex I (p&lt;0,05). Furthermore, the volatile anesthetic stabilized the A/D-ratio of the complex, indicating enhanced stability of the enzyme (p&lt;0,05). Taken together, our findings support the notion that sevoflurane protects the heart against ischemic injury in a setting closely mimicking daily clinical work via the maintenance of mitochondrial respiratory physiology.
Comprehensive characterization of cisplatin-related hearing loss in U.S. and Canadian Testicular Cancer Survivors (TCS).
Authors: Heather E. Wheeler, Lois B. Travis, Amy Budnick, Darren Richard Feldman, Lawrence H. Einhorn, Robert James Hamilton, David J. Vaughn, Clair Beard, Chunkit Fung, Eileen Johnson, Malcolm J. Moore, Deepak M. Sahasrabudhe, Sophie D. Fossa, Howard D. Sesso, M. Eileen Dolan, Robert D Frisina
Journal: Journal of Clinical Oncology (2015)

9570 Background: Cisplatin is one of the most ototoxic drugs in use, causing permanent, bilateral sensorineural hearing loss in substantial numbers of patients, with many developing permanent tinnitus. Few studies, however, have systematically quantified the entire range of hearing loss (0.25-12 kHz) in patients given homogenous cisplatin-based chemotherapy using comprehensive audiometric methods and patient-reported outcomes. Methods: We performed detailed audiometry for 359 patients enrolled in an ongoing multi-center clinical study of TCS given cisplatin-based chemotherapy at centers in North America (NCI R01CA157823). Air conduction thresholds were measured at frequencies ranging from 0.25-12 kHz and bone conduction thresholds from 0.25-4 kHz in each ear. Results: Median age at evaluation was 39 years (range 20-63 years) with approximately 43% previously having seminomas and 57% nonseminomas. Over 90% of patients were white, while most (66%) had Stage II or III disease. Chemotherapy consisted largely of standardized regimens and doses, i.e., BEP X 3 (51%), EP X 4 (19%), slight modifications (27%) of either regimen, or VIP (3%). We identified 85.2% patients with hearing loss ( > 20 dB) at any frequency for either ear. Of these, 48.7% had conductive hearing loss and 39.2% showed evidence for noise-induced hearing loss for either ear. For each patient, we compared the area under the air conduction audiogram curve (AUC) (mean of both ears) to the expected AUC for this age group. Patients with AUCs greater than respective normal-aging AUCs were considered to have cisplatin-induced hearing loss (32.6%). Measured on a Likert scale from 0-3, 39.2% and 29.8% reported tinnitus and hearing loss (score 1+), respectively. The audiogram AUC correlated strongly with both self-reported tinnitus (R = 0.31, P = 1.1e-08) and self-reported hearing loss (R = 0.36, P = 7.0e-11). Conclusions: Cisplatin-induced ototoxic phenotypes affect 29-40% of TCS in this North American study. Future analytic investigations will focus on genetic and mechanistic investigations to facilitate the development of predictive, management and preventive efforts for ototoxicity in high-risk patients.
Expression patterns and prognostic significance of human epidermal growth factor receptors (HER family) in squamous cell carcinoma of the cervix
Authors: N. Vorsteher, H. Bühler, B. Duvnjak, K. Evers, B. Heine, S. Landt, N. Bangemann, G. Schaller
Journal: Journal of Clinical Oncology (2004)

5030 Background: Systemic therapy of cervical cancer has revealed mainly unsatisfying results so far. New targets for specific tumor therapies have to be identified. A promising approach is inactivating thyrosine kinase receptors by small molecule inhibitors or blocking antibodies like trastuzumab. In this study, we therefore evaluated the expression pattern and prognostic value of the HER family in cervical tumor tissue. Methods: Paraffin embedded tissue of 78 cervical carcinomas was stained immunohistochemically with antibodies against HER1 (EGFR), HER2, HER3, and HER4. In addition, the number of HER2 gene copies was determined by FISH. Results: A moderate to strong EGFR-expression was found in 63% of the tumors. HER2 was overexpressed strongly (3+) in 6.4% and moderately (2+) in 20,5% of the specimens. Amplification of the gene (>4 copies) was observed in overall 21% with 80% of the 3+ (4/5) but only 19% of the 2+ (3/16) cases being positive. Expression of HER3 was weak and mainly cytoplasmic in 26% of the tumors. HER4 staining was found in 21% of the cases localized also mainly in the cytoplasma, but in addition accompanied by a strong nuclear expression in some cases. As expected we found a significant correlation between poor prognosis and HER2 overexpression as well as amplification. The expression of HER3 was also significantly associated with poor prognosis particularly when coexpressed with HER2. The expression of HER4 also seemed to be correlated with a poor outcome. In contrast EGFR expression was significantly correlated with a better prognosis, especially in the absence of HER2. Conclusion: All members of the HER family were identified in cervical carcinomas. A strong HER2 expression or amplification is correlated with a poor prognosis. Thus inactivation of this receptor seems to be clinically relevant. In contrast to breast cancer EGFR is associated with a better outcome. Therapeutic approaches should consider this. No significant financial relationships to disclose.
A phase II study of capecitabine (CAP) and pre-operative radiation therapy (RT) in resectable, locally advanced rectal cancer (LARC)
Authors: A. De Paoli, S. Chiara, G. Luppi, M. L. Friso, G. Beretta, S. Delprete, L. Pasetto, S. Frustaci, M. Santantonio, R. Corvò
Journal: Journal of Clinical Oncology (2004)

3540 Background: Preoperative RT with c.i. 5-fluorouracil (5-FU) improves local tumor control, sphincter preservation, and yields pathologic complete remissions (pCR) in 10–30% of patients (pts) with LARC. Capecitabine (CAP) is an oral fluoropyrimidine which is converted into 5-FU preferentially in tumor cells by the high intra-tumor activity of thymidine phosphorylase (TP). TP can be further up-regulated by RT. Moreover, CAP may mimic c.i. 5-FU via daily oral administration thus simplifying chemoradiation. Methods: Based on phase I data (Dunst et al., JCO 20:3983, 2002) a multicentric phase II study of CAP (825 mg/m2, twice daily, 7 days/week) with RT (45 Gy/ 25 fr. to the posterior pelvis followed by 5.4 Gy / 3 fr. boost to the tumor) was planned in resectable, LARC. Patients (pts) with T3 or T4, N0 or N1–2 disease were eligible. Surgery was scheduled 6 weeks after the end of CAP-RT and 4-month adjuvant CAP was also provided based on physician indications. The primary endpoint was to determine the pCR rate and secondary endpoints were to assess clinical response rate and safety profile of CAP-RT combination. Results: From September 2001 to July 2003, 53 pts (median age: 63yrs; ECOG-PS 0–1; M/F: 39/14) with T3 N0–2 (87%) and T4 N0–2 (13%) disease entered the study. All pts but 2 completed the RT as planned whereas 7 pts did not receive the entire planned dose of CAP because of toxicity (G 2–3 leukopenia, G 2–3 cystitis, G 2–3 skin toxicity). Overall, all the 53 pts are evaluable for clinical response and safety, whereas 51 pts are evaluable for pathologic response and downstaging (1 pt refused surgery, 1 pt was unresectable at operation). Complete or partial clinical response was 58% (31/53 pts) and tumor downstaging 57% (29/51 pts) with 12 pCR (24%). The most common adverse events were G 1–2 leukopenia, diarrhea, proctitis, occurring in 72%, 42% and 34% of pts, respectively; only 6 pts (11%) had G3 toxicity. No G4 toxicity was reported. Conclusions: chemoradiation with CAP and pre-op RT appeared to be effective and well tolerated and it could replace c.i. 5-FU in LARC. Its favourable safety profile support a possible combination with other effective drugs. No significant financial relationships to disclose.
Neuromodulation and Strategic Action Choice in <i>Drosophila</i> Aggression
Authors: Kenta Asahina
Journal: Annual Review of Neuroscience (2017)

In this review, I discuss current knowledge and outstanding questions on the neuromodulators that influence aggressive behavior of the fruit fly Drosophila melanogaster. I first present evidence that Drosophila exchange information during an agonistic interaction and choose appropriate actions based on this information. I then discuss the influence of several biogenic amines and neuropeptides on aggressive behavior. One striking characteristic of neuromodulation is that it can configure a neural circuit dynamically, enabling one circuit to generate multiple outcomes. I suggest a consensus effect of each neuromodulatory molecule on Drosophila aggression, as well as effects of receptor proteins where relevant data are available. Lastly, I consider neuromodulation in the context of strategic action choices during agonistic interactions. Genetic components of neuromodulatory systems are highly conserved across animals, suggesting that molecular and cellular mechanisms controlling Drosophila aggression can shed light on neural principles governing action choice during social interactions.
Uterine cancer cells proliferate differently in response to 17β-estradiol in presence or absence of tamoxifen, raloxifen and ICI 182 780
Authors: Kim Leblanc, Émilie Sexton, Eric Asselin
Journal: Cancer Research (2005)

4020   Antiestrogens like tamoxifen, raloxifen and ICI 182 780 are medication for preventing and treating hormonodependant cancers such as breast cancers. However, long-term exposure to tamoxifen has been shown to induce endometrial cancers. The aim of this study was to determine the effect of 17β-estradiol in presence or absence of antiestrogens in human uterine cancer cells (HeLa, HEC-1-A, KLE, RL-95-2, Ishikawa et TOV-1078D) and to further investigate how they act at the intracellular level. Real-time RT-PCR and Western analyses were carried out to measure ERα and ERβ expressions. Total protein and RNA were extracted and the results indicated that ERβ is expressed in all cell lines but at different levels. The presence of ERα was detected only in Ishikawa cells at low level and was strongly expressed in TOV-1078D, a novel endometrial cancer cell line. 17β-estradiol induced cell proliferation at low dose in cell lines expressing ERα protein. Proliferation in most of the cell lines was reduced at high concentrations (10 -7 -10 -5  M) from 5-40% with 17β-estradiol, 20-75% with tamoxifen, 5-55% with raloxifen and 25-40% with ICI 182 780. Interestingly, in HEC-1-A cells, raloxifen and ICI 182 780 at high concentrations caused an increased of 180% and 110% of cell proliferation respectively. In experiment two, cells were treated with the same agents in a phenol red-free media containing 10% charcoal-dextran stripped FBS.Preliminary results in these conditions showed a significant and different effect of those factors. Cell proliferation of five cell lines was reduced (except KLE cells) by 50-70% in presence of 10 -6  M tamoxifen. However, at the same concentration raloxifen and ICI 182 780 had no effect on cell proliferation in the six cell lines. Because 17β-estradiol has been shown to act through the PI3-K/Akt pathway in many systems, we hypothesised that Akt might be involved in regulating this process. However, no significant fluctuations were observed in term of Akt activity/phosphorylation in response to antiestrogens. Further investigation are currently being carried out to confirm these observations and to explore other signalling pathways that might influence survival/death of endometrial cells in response to antiestrogens. Supported by CIHR (MOP-66987).