tbuckley/cabot-search huggingface dataset:
Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response
Authors: Mariëtte I.E. van Poelgeest, Marij J.P. Welters, Renee Vermeij, Linda F.M. Stynenbosch, Nikki M. Loof, Dorien M.A. Berends-van der Meer, Margriet J.G. Löwik, Ineke L.E. Hamming, Edith M.G. van Esch, Bart W.J. Hellebrekers, Marc van Beurden, Henk W. Schreuder, Marjolein J. Kagie, J. Baptist M.Z. Trimbos, Lorraine M. Fathers, Toos Daemen, Harry Hollema, A. Rob P.M. Valentijn, Jaap Oostendorp, J. Hanneke N.G. Oude Elberink, Gertjan J. Fleuren, Tjalling Bosse, Gemma G. Kenter, Theo Stijnen, Hans W. Nijman, Cornelis J.M. Melief, Sjoerd H. van der Burg
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8+ T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8+ T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101). Experimental Design: A multicenter open-label, randomized controlled trial was conducted in patients with HPV16+ high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8+ T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses. Results: Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1–70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5–70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance. Conclusions: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. Clin Cancer Res; 22(10); 2342–50. ©2016 AACR. See related commentary by Karaki et al., p. 2317
Early results of a phase I clinical trial of an Ii-Key/Her2/neu MHC class II peptide-based vaccine in breast cancer patients
Authors: E. A. Mittendorf, S. Khoo, C. E. Storrer, K. A. Harris, Y. H. Jama, Z. A. Dehqanzada, J. L. Murray, C. D. Shriver, E. Von Hofe, S. Ponniah, G. E. Peoples
Journal: Journal of Clinical Oncology (2006)

2532 Background: HER2/neu is over-expressed in breast cancer (BCa) and is the source of immunogenic peptides currently being evaluated in clinical trials as cancer vaccines. Ii-Key is a 4-amino-acid modification of peptides that has been reported to increase their occupancy of MHC class II molecules and enhance CD4 T cell responses. We are currently conducting a phase I clinical trial with an Ii-Key/HER2/neu MHC class II peptide (AE37) in BCa patients. Methods: The dose escalation safety trial design is for 3 groups of 3 patients to receive either 100, 500, or 1,000 μg of AE37 with 250 μg of GM-CSF in 6 monthly inoculations. Six additional patients will then be vaccinated at the optimal dose. Local and systemic toxicity is monitored and graded by the Common Toxicity Criteria. Immunologic response is monitored by peptide-stimulated proliferation ( 3 H-thymidine incorporation) and ELISPOT (IFN-γ) assays for both AE37 and AE36 [the unmodified peptide HER2 776–790 (GVGSPYVSRLLGICL)]. Thus far 6 BCa patients have been vaccinated. Results: The 100μg dose group has completed all 6 vaccinations with maximum local and systemic toxicities of grade 2 and 1, respectively. All 3 patients developed increasing peptide-specific proliferation post-vaccination to both AE37 and AE36. ELISPOT responses were more variable with 1 minimal responder (30 IFN-γ spot-forming cells (SFC)/10 6 cells), 1 moderate responder (600 IFN-γ SFC/10 6 cells), and 1 good responder (1500 IFN-γ SFC/10 6 cells) post-vaccination. The 500μg dose group has thus far experienced earlier and larger local reactions but limited systemic toxicity. All 3 patients have demonstrated &gt;1500 IFN-γ SFC /10 6 cells after just 2 inoculations. Peptide-specific proliferation after 2 inoculations has ranged between 3200–11500 cpm for the 500μg patients compared with 1200–2000 cpm after 6 inoculations for the 100μg dose group. Conclusions: AE37 appears to be safe and well-tolerated. A dose-dependent immunologic response has been demonstrated to the Ii-Key modified peptide as well as the naturally occurring sequence. These encouraging early results suggest that AE37 may prove to be useful as a CD4-specific vaccine either alone or in combination with CD8-specific HER2/neu peptides for improved cancer immunotherapy. [Table: see text]
CALGB 140803—Association between cardiorespiratory fitness and overall survival in operable lung cancer patients: Ancillary analysis of protocol 9238
Authors: L. Kohman, D. Watson, J. Herndon, N. Eves, B. Haithcock, G. Loewen, L. Jones
Journal: Journal of Clinical Oncology (2009)

7518 Background: Cardiorespiratory fitness is a well-established independent predictor of all-cause mortality in a broad range of adult populations. The association between cardiorespiratory fitness and mortality has not been investigated among individuals diagnosed with cancer. We examined the association between cardiorespiratory fitness and all-cause mortality in 398 patients with non-small cell lung cancer (NSCLC). Methods: Using a prospective, observational design, patients with known or suspected NSCLC enrolled in CALGB 9238 were studied. Prior to pulmonary resection, all participants performed an incremental exercise test with expired gas analysis to assess cardiorespiratory fitness (i.e., peak oxygen consumption; VO 2peak ) and were observed for death or until June 2008. Cox proportional hazards models were used to estimate the risk of all-cause mortality according to cardiorespiratory fitness category defined by VO 2peak (&lt;0.96 / 0.96–1.29 / &gt;1.29 L.min -1 ) with adjustment for age, gender, and performance status. Results: Of the 398 patients, 335 underwent surgical resection and 63 were deemed not eligible for resection. Median follow-up was 30.8 months, 294 deaths were reported during this period. For the entire sample, mortality rates declined across increasing VO 2peak categories (adjusted P trend = 0.012). Compared with patients achieving a VO 2peak &lt;0.96 L.min -1 , the adjusted hazard ratio (HR) for all-cause mortality was 0.64 (95% CI, 0.46 to 0.88) for a VO 2peak of 0.96–1.29 L.min -1 , and 0.56 (95% CI, 0.39 to 0.80) for a VO 2peak of &gt;1.29 L.min -1 . The corresponding HRs for surgical patients were 0.65 (95% CI, 0.44 to 0.96) and 0.62 (95% CI, 0.42 to 0.90) relative to the lowest VO 2peak category (p trend =0.03), respectively. For non-surgical patients, the HRs were 0.74 (95% CI, 0.32 to 1.75) and 0.43 (95% CI, 0.18 to 1.00) relative to the lowest category (p trend &lt;0.04). Conclusions: Low VO 2peak is associated with poorer survival among surgical candidates with NSCLC. Further work is required to investigate the prognostic value of objective measures of functional capacity in NSCLC and other cancer populations. No significant financial relationships to disclose.
Biologic study of the effects of lapatinib in PI3K/akt- and ras/raf/MAK-signaling pathways in HER2-positive ductal breast carcinoma in situ (DCIS).
Authors: L. García-Estevez
Journal: Journal of Clinical Oncology (2011)

e13581 Background: DCIS is a heterogeneous disease, with increasing incidence. Up to 37% of DCIS overexpress HER2. Lapatinib is a tyrosine kinase inhibitor that directly inhibits HER2 receptor signaling by blocking the receptor’s kinase activity. This study tested the hypothesis that lapatinib works inhibiting Ras/Raf/MAK and PI3K/AKT signaling in HER2-positive DCIS. Methods: Patients with HER2-positive (FISH rate >2.2) DCIS diagnosed by core needle biopsy with low risk of having a hidden invasive component were eligible. Neoadjuvant lapatinib 1500mg daily was administered for 4 weeks prior to surgical resection. EGFR was analyzed by FISH in the biopsy specimen. Ki67, PTEN, AKT, pAKT and pERK were evaluated by IHQ. PI3KCA mutations were screened at exons 9 and 20 by PCR. Apoptosis was analyzed by TUNEL assay. All biological markers were measured before and after lapatinib treatment. Results: Eighteen pts with HER2-positive DCIS have been included to date. Median FISH amplification was 7 (range 2.70-14). Evaluation pre-lapatinib showed that: none of the pts had EGFR amplification; eight pts (44%) had a Ki67 >25%; pAKT was overexpressed (3+) in 4 pts (22%) and pERK in 2 pts (11%); PTEN was deleted in 4 pts (22%). PI3KCA mutations were detected in only 1 pt (6%). After lapatinib treatment, 17 pts were evaluable. We observed a trend for inactivation of the Ras/Raf/MAK signaling pathway in 12 pts (71%) patients and 2 out of these 12 pts with no evidence of residual DCIS. Interestingly, 5 of these pts had paradoxical activation of PI3K/Akt suggesting a compensatory feed back loop. One out of these 2 pts has PTEN deleted. In addition, 3 pts (33%) showed an increase in the apoptotic index. Conclusions: In our study, four weeks of lapatinib against HER2-positive DCIS resulted mainly in inactivation of Ras/Raf/MAK pathway; however an activation of the PI3K/Akt was seen as the same time in 5 pts suggesting a compensatory effect. This could generate the hypothesis of the benefit of adding a PI3K/Akt inhibitor to lapatinib.
The molecular mechanisms of hemodialysis vascular access failure
Authors: Akshaar Brahmbhatt, Andrea Remuzzi, Marco Franzoni, Sanjay Misra
Journal: Kidney International (2016)

The arteriovenous fistula has been used for more than 50 years to provide vascular access for patients undergoing hemodialysis. More than 1.5 million patients worldwide have end stage renal disease and this population will continue to grow. The arteriovenous fistula is the preferred vascular access for patients, but its patency rate at 1 year is only 60%. The majority of arteriovenous fistulas fail because of intimal hyperplasia. In recent years, there have been many studies investigating the molecular mechanisms responsible for intimal hyperplasia and subsequent thrombosis. These studies have identified common pathways including inflammation, uremia, hypoxia, sheer stress, and increased thrombogenicity. These cellular mechanisms lead to increased proliferation, migration, and eventually stenosis. These pathways work synergistically through shared molecular messengers. In this review, we will examine the literature concerning the molecular basis of hemodialysis vascular access malfunction.
Phase I and translational study of capecitabine, cisplatin, and irinotecan in patients with solid tumors
Authors: C. F. Verschraegen, F. C. Lee, I. Rabinowitz, A. Mangalik, C. Jennings, A. Maestas, Z. Shen
Journal: Journal of Clinical Oncology (2004)

2114 Purpose: 5-Fluorouracil (5-FU) has been shown to modulate DNA repair activity. This study tests (1) what is the maximum tolerated dose of capecitabine (C) given for 10 days prior to cisplatin (P) and irinotecan (I); (2) the changes in DNA repair induced by C. Patients and Methods: Patients (pt) with incurable cancers were eligible if they had normal hematologic, renal and liver functions, and had not failed 5-FU analogs or topoisomerase I inhibitors. The first cycle was P+I day 1 and I day 8 and 15, 50 mg/m2 each, to serve as control. C was started at the second cycle at a dose of 500 mg/m2/day x 10 days for the first cohort prior to P+I, which was administered on day 11, 18, and 25. Increments were by 250 mg/m2/cohort. A 3+3 design was used. Blood was drawn for DNA repair studies before the first 3 cycles and before cisplatin for the first 2 cycles. DNA repair analyses will be performed by measuring the residual cisplatin concentrations in DNAs collected from these patients. Patients stayed on study until progression of disease. Results: Today 6 patients were accrued on cohort 1 and 2. Median patient characteristics were age, 70 (42–83); Karnofsky PS, 90 (100–70); with cancer diagnosis of lung (2), breast, appendix, cervix, and larynx. Hematologic toxicity was mild with grade 1 anemia (4 pts), and no thrombocytopenia. Only 1 pt had grade 2 neutropenia on the first cycle (P+I). Neutropenia was worse on the second cycle (C+P+I) with 1 grade 3, 2 grade 2, and 1 grade 1. All non-hematologic side effects were grade 1 and included fatigue (3 pts), nausea (4 pts), vomiting (2 pts), diarrhea (3 pts), anorexia (2 pts), and alopecia (1 pt). Three patients progressed, 2 had minor responses, and one was not evaluable. Conclusions: This combination is well tolerated and may turn out to have some clinical benefit for patients with advanced disease. The study will continue until the dose of C is determined. DNA repair studies will be presented at the annual meeting. Supported by the Oxnard Foundation No significant financial relationships to disclose.
THE PHARMACOLOGY OF CENTRAL AND PERIPHERAL INHIBITION
Authors: DAVID R. CURTIS
Journal: Pharmacological Reviews (1963)

The principal aim of pharmacological studies upon chemical inhibitory processes is the elucidation of the nature of transmitter agents. Before a given compound can be fully identified as the inhibitory transmitter operating at a particular synaptic region, it must satisfy all of the following requirements (73, 293): the conductance change induced in the inhibitory subsynaptic membrane must be identical with that of the natural transmitter; the substance must be present or synthesized in the appropriate synaptic terminals and released by stimulation of the inhibitory nerve fibres; the interactions of the compound with blocking and potentiating agents must be identical with those of the transmitter. When examined in the light of these requirements very few substances qualify as proven transmitters. In particular, it is difficult to satisfy the criterion that the substance be located in and released from inhibitory nerve terminals, and it is usually sufficient to demonstrate that the substance can be extracted from the tissue and is released by inhibitory nerve stimulation. Future investigations of this nature will be aided by several comparatively recent techniques. These include the histochemical localization within tissues of particular compounds; the technique of separating subcellular particles, especially nerve endings (94, 375); and the ability to determine quantitatively enzymes of single neurones (169) which may be associated with the manufacture and inactivation of transmitters.

At the present time it is generally accepted that acetylcholine is the cardiac vagal inhibitory transmitter in mammals and amphibia. However, no other vertebrate inhibitory transmitter has been identified, and none of the substances which have been proposed as transmitters satisfies the requirements discussed above. The only positive finding with respect to postsynaptic inhibition in mammals and amphibia is the specific blocking action of tetanus toxin, strychnine, and closely related compounds. Presynaptic inhibition in the mammalian spinal cord, which is resistant to strychnine, appears to be diminished by picrotoxin, which does not diminish postsynaptic inhibition. It is unknown to what extent this action of picrotoxin explains its stimulant effect upon the central nervous system.

Studies upon invertebrate inhibition indicate the strong possibility that acetylcholine is an inhibitory transmitter in Aplysia depilans , but the transmitters for the inhibition of crustacean stretch receptors and at the crustacean neuromuscular junction remain unknown. At both of these latter sites the blocking action of picrotoxin appears to be specific.
American ginseng is an anti-oxidant that prevents and treats colitis
Authors: Yu Jin, Venkata Kotakadi, Lei Ying, Anne Hofseth, Patricia Wood, Anthony Windust, David Reisman, Lydia Matesic, Narendra Singh, Mitzi Nagarkatti, Prakash Nagarkatti, Michael Wargovich, Lorne Hofseth
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3067 

Ulcerative colitis (UC) is a dynamic, idiopathic, chronic inflammatory condition associated with an increased colon cancer risk. American ginseng is a putative anti-oxidant. The aim of this study was to test whether American ginseng extract prevents and treats colitis. Colitis in mice was induced by the presence of 1% dextran sodium sulfate (DSS) in the drinking water. American ginseng extract was mixed in the chow at levels consistent with that consumed by humans (75 ppm, equivalent to 835 mg daily). To test prevention, American ginseng extract was given prior to the addition of 1% DSS in drinking water; to test treatment, American ginseng extract was given after the addition of 1% DSS and onset of colitis. In vitro studies were performed to examine mechanisms. Results indicate that American ginseng extract not only prevents, but it treats colitis. Mucosal and DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes. We therefore tested the hypothesis that American ginseng extract can inhibit leukocyte activation, and subsequent epithelial cell DNA damage in vitro and in vivo . Results are consistent with this hypothesis. The use of American ginseng extract represents a novel therapeutic approach for the prevention and treatment of UC. These results provide important preliminary data supporting an expansion of testing American ginseng in patients with UC to abate this disease.
CPR 11: a mobile application that can help in saving lives (Mobile App User Guide)
Authors: Luis J Serratosa, Efraim B Kramer, Helder D Pereira, Jiri Dvorak, Pedro L Ripoll
Journal: British Journal of Sports Medicine (2016)

CPR 11.

Health.

IOS (iPhone 4 and above), Android (versions 2.3.3 and above), Windows Phone.

Free.

In just 11 steps, the CPR 11 mobile application presents a simple plan, with clear and precise instructions, on how to recognise a sudden cardiac arrest (SCA), provide immediate and adequate response with efficient compressions and ventilations, how to use the automated external defibrillator (AED) and how to transfer the player from the field of play.

With the help of text and voice messages, each of the 11 steps includes a brief, clear video that aims to make it possible for anyone, even those with no previous first aid or medical training, to be able to recognise a SCA and meet the objective of starting resuscitation manoeuvres in the first minute and defibrillation in …
Abstract 15808: SIRT6 Deacetylase Blocks Cardiac Hypertrophic Response by Blocking Expression of IGF/Akt Signaling Related Genes at the Level of Chromatin
Authors: Nagalingam Ravi Sundaresan, Prabhakaran Vasudevan, Zhong Lei, Gene Kim, Samant Sadhana, P.V. Ravindra, Vinodkumar Pillai, Valluvan Jeevananadam, Madhu Gupta, Raul Mostoslavsky, Mahesh P Gupta
Journal: Circulation (2012)

Physical exercise and calorie restriction (CR) have been shown to exert beneficial effects to patient with heart failure. A great body of evidence also suggests that these interventions increase ac...
The significance of cancer pain in pancreatic cancer
Authors: M. Ueno, S. Ohkawa, Y. Sugimasa, Y. Sakamoto, K. Miyakawa, N. Sugano, S. Morinaga
Journal: Journal of Clinical Oncology (2008)

15590 Background: Pancreatic cancer patients often have cancer pains. Although the therapeutic plans for pancreatic cancer are mainly based on imaging studies (CT, MRI, US, and ERCP) and performance status (PS), the presence of tumor cancer is usually not considered. In this study, we analyzed the significance of cancer pain in pancreatic cancer. Methods: The subjects were pancreatic cancer patients (UICC stage II - IV) who received medical treatments between Mar 2001 and Feb 2007 in our hospital. We divided these patients into two groups (no cancer pain, cancer pain (taking opioids or NSAIDs). We compared the presence of cancer pain with the overall survival by UICC stages and treatments using the log-rank test. Results: We examined 217 patients (stage II: 41, stage III: 47, stage IV: 129). The treatments were operation (44), chemotherapy (159), or supportive care (14). The status of cancer pain before treatment was as follows (nothing: 114, opioids: 75, NSAIDs: 24). Concerning UICC stages, the cancer pain group had significantly poor prognosis only at stage IV (p=0.001). Concerning treatments, the patients who received chemotherapy (p=0.002) or operation (p=0.04) in the cancer pain group had poor prognosis. Conclusions: The presence of cancer pain may correlate with the prognosis of pancreatic cancer. Especially on determining the indication of operation, we should consider the presence of cancer pain besides the imaging studies and PS. No significant financial relationships to disclose.
Validation of sentinel lymph node (SLN) mapping (M) in colon cancer (Cca) over three continents: An international experience
Authors: S. Saha, M. Patel, A. Bilchik, T. Beutler, M. Zuber, A. Bembenek, Y. Kitagawa, J. Duben, C. Codignola, G. Cserni
Journal: Journal of Clinical Oncology (2007)

4047 Background: Lymph node (LN) status is the most important prognostic factor in colon cancer (Cca). In various trials, the average nodal positivity of conventional surgery in Cca is about 33%. Ultrastaging of SLNs results in higher and more accurate nodal staging of patients (pts) with Cca. However, some recent publications of SLNM in Cca have shown variable results with differing conclusions. Hence, prospective data from 3 continents were analyzed to study the international experience of SLNM in Cca. Methods: Only centers with experience of 40 or more cases of SLNM in Cca were included in the study. SLNM was performed by peri-tumoral injections of 1–3 ml of 1% lymphazurin. First 1–4 blue nodes marked as SLNs were ultrastaged by multilevel microsections for H&amp;E and IHC. Data for calculating the success rate, accuracy, skip metastases (mets), sensitivity, negative predictive value; nodal positivity and upstaging were collected from each center. Results: Our study included a total of 1,216 Cca pts from 9 centers over 3 continents. SLNM was successful in 92.9% pts ( Table 1 ). The average number of LN/pt was 18.5 and the average number of SLN/pt was 2.7. The overall sensitivity, accuracy rate and negative predictive value were 78.3%, 89.4% and 82.8% respectively. Nodal mets were found in 52.9% pts. Of these, SLNs were the exclusive site for mets in 30.1% pts while 18.3% pts were upstaged by SLNM. Skip mets were seen in 21.7% pts (range 9.5% - 44.1%). Conclusions: SLNM is highly successful in Cca when performed by experienced surgeons worldwide. Nodal positivity was found to be much higher in pts undergoing SLNM compared to conventional surgery. Upstaged pts may benefit from adjuvant chemotherapy. Though the variation of skip mets was wide, the clinical impact of skip mets in Cca is negligible compared to that in melanoma and breast cancer, since all pts undergo standard lymphadenectomy and all node positive pts (true +ve &amp; skip mets) are usually treated with adjuvant chemotherapy. [Table: see text] No significant financial relationships to disclose.