tbuckley/cabot-search huggingface dataset:
Maintenance immunotherapy in stage IV cancer patients who have a clinical benefit from chemotherapy.
Authors: Francesco Recchia, Giampiero Candeloro, Silvio Rea
Journal: Journal of Clinical Oncology (2017)

3021 Background: Even if patients with stage IV cancer (AC) may have prolonged remissions with chemotherapy (CT), the majority of them, will eventually relapse. In vitro studies suggest that natural killer (NK) cells mediate lytic activity against cancer cell lines and that high expression of vascular endothelial growth factor (VEGF) promotes tumor progression through neoangiogenesis. We have shown that low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) increased NK cells and decreased VEGF, in patients with AC and a clinical benefit on CT (Clin Cancer Res 7: 1251, 2001). We hypothesized that IL-2 and RA, increasing NK and decreasing VEGF, could improve disease-free survival (DFS) and overall survival (OS) in a minimal residual disease setting. Primary endpoint was the evaluation of NK cells and VEGF; secondary endpoints were DFS, OS and toxicity. Methods: 500 patients with AC, and a clinical benefit from CT, were given subcutaneous IL-2, 1.8 X 10 6 IU and oral RA, 0.5 mg/Kg, 5 days/week, 3 weeks/month, until progression. NK cells, VEGF, response and toxicity were assessed every 4 months. Results: After a median follow-up of 112 months (range 63-200), a total of 4400 courses of CT and 2634 courses of immunotherapy were delivered. A statistically significant improvement of NK cells [from a mean of 309 ± 76/mm 3 to a mean of 579 ± 74/mm 3 (p &lt; 0.001)] and a decrease of VEGF [from a mean of 520 ± 75 pg/mm 3 to a mean of 150 ± 12 pg/mm 3 , (p &lt; 0.001)], were observed. Eighteen-years DFS and OS were 29% and 32%, respectively. A significant improvement, with respect to NCI SEER data (*), was observed in the 5-year OS rate for the most common treated AC: Breast cancer 55% vs. 6% *; Lung cancer 22% vs. 4.3% *; Colorectal cancer 43.5% vs. 21%*. No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: Our data show that immunotherapy with IL-2/RA, may determine, with an acceptable toxicity profile, a statistically significant improvement of NK cells, a decrease of VEGF, and better 5-year survival rates with respect to NCI SEER data, for all major stage IV cancers.
Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women—A double-blind, randomized non-inferiority trial
Authors: Ingvild Vik, Marianne Bollestad, Nils Grude, Anders Bærheim, Eivind Damsgaard, Thomas Neumark, Lars Bjerrum, Gloria Cordoba, Inge Christoffer Olsen, Morten Lindbæk
Journal: PLoS Medicine (2018)

Background Although uncomplicated urinary tract infections (UTIs) are often self-limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%. Methods and findings This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, and Denmark. Non-pregnant women aged 18–60 years presenting with symptoms of uncomplicated UTI were screened for eligibility from 11 April 2013 to 22 April 2016. Patients with informed consent were randomized (1:1 ratio) to treatment with either 600 mg ibuprofen or 200 mg pivmecillinam 3 times a day for 3 days. The patient, treating physician, and study personnel were blinded to treatment allocation. The primary outcome was the proportion of patients who felt cured by day 4, as assessed from a patient diary. Secondary outcomes included the proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis. A total of 383 women were randomly assigned to treatment with either ibuprofen (n = 194, 181 analyzed) or pivmecillinam (n = 189, 178 analyzed). By day 4, 38.7% of the patients in the ibuprofen group felt cured versus 73.6% in the pivmecillinam group. The adjusted risk difference with 90% confidence interval was 35% (27% to 43%) in favor of pivmecillinam, which crossed the prespecified non-inferiority margin. Secondary endpoints were generally in favor of pivmecillinam. After 4 weeks' follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group, giving a number needed to harm of 26 (95% CI 13 to 103). Five of these patients were hospitalized and classified as having serious adverse events; 2 recovered as outpatients. A limitation of the study was the extensive list of exclusion criteria, eliminating almost half of the patients screened. We did not register symptoms in the screening process; hence, we do not know the symptom burden for those who declined to participate. This might make our results less generalizable. Conclusions Ibuprofen was inferior to pivmecillinam for treating uncomplicated UTIs. More than half of the women in the ibuprofen group recovered without antibiotics. However, pyelonephritis occurred in 7 out of 181 women using ibuprofen. Until we can identify those women who will develop complications, we cannot recommend ibuprofen alone as initial treatment to women with uncomplicated UTIs. Trial registration ClinicalTrials.gov NCT01849926 EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14
Sixty seconds on . . . eggs
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

A large prospective cohort study published in the journal Heart has found that people who eat about five eggs a week are less likely to have a stroke and other cardiac events than those who eat no eggs.1 The effect was especially noticeable for haemorrhagic stroke.

Eggs are a major source of dietary cholesterol, but their overall contribution to cardiovascular risk is very small. The Heart authors said that eggs may enhance high density lipoprotein function …
Safety and dose modification for patients receiving niraparib
Authors: J.S. Berek, U.A. Matulonis, U. Peen, P. Ghatage, S. Mahner, A. Redondo, A. Lesoin, N. Colombo, I. Vergote, O. Rosengarten, J. Ledermann, M. Pineda, S. Ellard, J. Sehouli, A. Gonzalez-Martin, D. Berton-Rigaud, R. Madry, A. Reinthaller, S. Hazard, W. Guo, M.R. Mirza
Journal: Annals of Oncology (2018)

Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions.All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables.Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose ∼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose.The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day.NCT01847274.
Molecular Tension Probes to Investigate the Mechanopharmacology of Single Cells: A Step toward Personalized Mechanomedicine
Authors: Kornelia Galior, Victor Pui‐Yan Ma, Yang Liu, Hanquan Su, Nusaiba Baker, Reynold A. Panettieri, Cherry Wongtrakool, Khalid Salaita
Journal: Advanced Healthcare Materials (2018)

Abstract Given that dysregulation of mechanics contributes to diseases ranging from cancer metastasis to lung disease, it is important to develop methods for screening the efficacy of drugs that target cellular forces. Here, nanoparticle‐based tension sensors are used to quantify the mechanical response of individual cells upon drug treatment. As a proof‐of‐concept, the activity of bronchodilators is tested on human airway smooth muscle cells derived from seven donors, four of which are asthmatic. It is revealed that airway smooth muscle cells isolated from asthmatic donors exhibit greater traction forces compared to the control donors. Additionally, the mechanical signal is abolished using myosin inhibitors or further enhanced in the presence of inflammatory inducers, such as nicotine. Using the signal generated by the probes, single‐cell dose‐response measurements are performed to determine the “mechano” effective concentration (mechano‐EC 50 ) of albuterol, a bronchodilator, which reduces integrin forces by 50%. Mechano‐EC 50 values for each donor present discrete readings that are differentially enhanced as a function of nicotine treatment. Importantly, donor mechano‐EC 50 values varied by orders of magnitude, suggesting significant variability in their sensitivity to nicotine and albuterol treatment. To the best of the authors’ knowledge, this is the first study harnessing a piconewton tension sensor platform for mechanopharmacology.
Lab-on-chip technology for chronic disease diagnosis
Authors: Jiandong Wu, Meili Dong, Claudio Rigatto, Yong Liu, Francis Lin
Journal: npj Digital Medicine (2018)

Abstract Various types of chronic diseases (CD) are the leading causes of disability and death worldwide. While those diseases are chronic in nature, accurate and timely clinical decision making is critically required. Current diagnosis procedures are often lengthy and costly, which present a major bottleneck for effective CD healthcare. Rapid, reliable and low-cost diagnostic tools at point-of-care (PoC) are therefore on high demand. Owing to miniaturization, lab-on-chip (LoC) technology has high potential to enable improved biomedical applications in terms of low-cost, high-throughput, ease-of-operation and analysis. In this direction, research toward developing new LoC-based PoC systems for CD diagnosis is fast growing into an emerging area. Some studies in this area began to incorporate digital and mobile technologies. Here we review the recent developments of this area with the focus on chronic respiratory diseases (CRD), diabetes, and chronic kidney diseases (CKD). We conclude by discussing the challenges, opportunities and future perspectives of this field.
Targeting prostate cancer: Prostate‐specific membrane antigen based diagnosis and therapy
Authors: Till Wüstemann, Uwe Haberkorn, John Babich, Walter Mier
Journal: Medicinal Research Reviews (2018)

Abstract The high incidence rates of prostate cancer (PCa) raise demand for improved therapeutic strategies. Prostate tumors specifically express the prostate‐specific membrane antigen (PSMA), a membrane‐bound protease. As PSMA is highly overexpressed on malignant prostate tumor cells and as its expression rate correlates with the aggressiveness of the disease, this tumor‐associated biomarker provides the possibility to develop new strategies for diagnostics and therapy of PCa. Major advances have been made in PSMA targeting, ranging from immunotherapeutic approaches to therapeutic small molecules. This review elaborates the diversity of PSMA targeting agents while focusing on the radioactively labeled tracers for diagnosis and endoradiotherapy. A variety of radionuclides have been shown to either enable precise diagnosis or efficiently treat the tumor with minimal effects to nontargeted organs. Most small molecules with affinity for PSMA are based on either a phosphonate or a urea‐based binding motif. Based on these pharmacophores, major effort has been made to identify modifications to achieve ideal pharmacokinetics while retaining the specific targeting of the PSMA binding pocket. Several tracers have now shown excellent clinical usability in particular for molecular imaging and therapy as proven by the efficiency of theranostic approaches in current studies. The archetypal expression profile of PSMA may be exploited for the treatment with alpha emitters to break radioresistance and thus to bring the power of systemic therapy to higher levels.
Ultra-small nanocluster mediated synthesis of Nd 3+ -doped core-shell nanocrystals with emission in the second near-infrared window for multimodal imaging of tumor vasculature
Authors: Feng Ren, Lihua Ding, Hanghang Liu, Qian Huang, Hao Zhang, Lijuan Zhang, Jianfeng Zeng, Qiao Sun, Zhen Li, Mingyuan Gao
Journal: Biomaterials (2018)
Abstract 19869: Genome Wide Association Study of Perioperative Myocardial Infarction Following Coronary Bypass Grafting
Authors: Mihai R Podgoreanu, Miklos Kertai, Yi-Ju Li, John H Alexander, Mark F Newman, Peter K Smith, Joseph P Mathew
Journal: Circulation (2012)

The incidence of perioperative myocardial infarction (PMI) after cardiac surgery can be as high as 19%, and is associated with long-term mortality and morbidity. Identification of populations at risk for developing large infarcts or alternatively indicating presence of a cardioprotective state, as well as responsiveness to a protective agent remain high-priority knowledge gaps. We sought to identify novel common genetic variants associated with PMI in a genome-wide association study (GWAS) of patients undergoing CABG. Methods: Using the Illumina 610quad chip, we conducted a GWAS for PMI in 1254 patients enrolled in the multicenter Genetics of Myocardial Adverse Outcomes and Graft Failure (GeneMagic) study, followed by a replication analysis in 644 patients from the Duke PEGASUS cohort. PMI was defined as CK-MB values ≥10xULN in the first two postoperative days, and was CEC adjudicated in the GeneMagic cohort. Sample and genotype QC analyses included assessing gender matching, autosome heterozygosity, cryptic relatedness, and population stratification, as well as filtering polymorphisms with minor allele frequencies &lt;0.01 and departing from HWE. Results: Following QC, 1193 patients in discovery cohort (100 cases/1093 controls), and 588 patients in replication cohort (108 cases/480 controls), all of European descent, were analyzed at 519,499 markers. In replicated analyses, we identified 14 SNPs associated with altered susceptibility to PMI (12 with increased risk [OR 1.35-2.44] and 2 with decreased risk [OR 0.4-0.73]), p&lt;0.01 in both cohorts. The chromosomal distribution of association tests p-values in pooled analyses in presented in Fig A, and a quantile-quantile plot of observed vs expected p-values in Fig B. Conclusion: Herein, we present a preliminary report of the first GWAS identifying multiple novel susceptibility loci for PMI. Further replication analyses in independent cohorts of cardiac surgical patients are ongoing.
Enhanced expression of histone chaperone APLF associate with breast cancer
Authors: Aditi Majumder, Khaja Moheiddin Syed, Ananda Mukherjee, Manendra Babu Lankadasari, Juberiya Mohammed Azeez, Sreeharshan Sreeja, Kuzhuvelil B. Harikumar, Madhavan Radhakrishna Pillai, Debasree Dutta
Journal: Molecular Cancer (2018)

DNA damage-specific histone chaperone Aprataxin PNK-like factor (APLF) regulates mesenchymal-to-epithelial transition (MET) during cellular reprogramming. We investigated the role of APLF in epithelial-to-mesenchymal transition (EMT) linked to breast cancer invasiveness and metastasis. Here, we show that a significant manifestation of APLF is present in tumor sections of patients with invasive ductal carcinoma when compared to their normal adjacent tissues. APLF was significantly induced in triple negative breast cancer (TNBC) cells, MDAMB-231, in comparison to invasive MCF7 or normal MCF10A breast cells and supported by studies on invasive breast carcinoma in The Cancer Genome Atlas (TCGA). Functionally, APLF downregulation inhibited proliferative capacity, altered cell cycle behavior, induced apoptosis and impaired DNA repair ability of MDAMB-231 cells. Reduction in APLF level impeded invasive, migratory, tumorigenic and metastatic potential of TNBC cells with loss in expression of genes associated with EMT while upregulation of MET-specific gene E-cadherin (CDH1). So, here we provided novel evidence for enrichment of APLF in breast tumors, which could regulate metastasis-associated EMT in invasive breast cancer. We anticipate that APLF could be exploited as a biomarker for breast tumors and additionally could be targeted in sensitizing cancer cells towards DNA damaging agents.
The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes
Authors: Ruth E Patterson, Catherine R Marinac, Dorothy D Sears, Jacqueline Kerr, Sheri J Hartman, Lisa Cadmus-Bertram, Adriana Villaseñor, Shirley W Flatt, Suneeta Godbole, Hongying Li, Gail A Laughlin, Jesica Oratowski-Coleman, Barbara A Parker, Loki Natarajan
Journal: JNCI Journal of the National Cancer Institute (2018)

This study investigated the effects of metformin and weight loss on biomarkers associated with breast cancer prognosis.
Ex vivo expanded natural regulatory T cells from patients with end-stage renal disease or kidney transplantation are useful for autologous cell therapy
Authors: Sybille Landwehr-Kenzel, Anne Zobel, Henrike Hoffmann, Niels Landwehr, Michael Schmueck-Henneresse, Thomas Schachtner, Andy Roemhild, Petra Reinke
Journal: Kidney International (2018)
Integration of multi-omics data and deep phenotyping enables prediction of cytokine responses
Authors: Olivier B. Bakker, Raul Aguirre-Gamboa, Serena Sanna, Marije Oosting, Sanne P. Smeekens, Martin Jaeger, Maria Zorro, Urmo Võsa, Sebo Withoff, Romana T. Netea-Maier, Hans J. P. M. Koenen, Irma Joosten, Ramnik J. Xavier, Lude Franke, Leo A. B. Joosten, Vinod Kumar, Cisca Wijmenga, Mihai G. Netea, Yang Li
Journal: Nature Immunology (2018)
Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome
Authors: Norifumi Shioda, Yasushi Yabuki, Kouya Yamaguchi, Misaki Onozato, Yue Li, Kenji Kurosawa, Hideyuki Tanabe, Nobuhiko Okamoto, Takumi Era, Hiroshi Sugiyama, Takahito Wada, Kohji Fukunaga
Journal: Nature Medicine (2018)
Abstract 19692: Pressure-Flow Derived Hemodynamic Predictors of Reduced Kidney Function With Age in a Community Dwelling Population
Authors: Matt Oberdier, Stephanie Studenski, Edward Lakatta, Majd AlGhatrif
Journal: Circulation (2016)

Background: Significant hemodynamic changes with age have been implicated in age-associated kidney function decline. Pulse pressure, augmentation index, and pulse wave velocity have been found to b...
Unusual Scrotal Swelling
Authors: Sante Capitano, Daniele Castellani
Journal: JAMA Surgery (2018)

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Risk factors for mortality and effect of correct fluid prescription in children with diarrhoea and dehydration without severe acute malnutrition admitted to Kenyan hospitals: an observational, association study
Authors: Samuel Akech, Philip Ayieko, David Gathara, Ambrose Agweyu, Grace Irimu, Kasia Stepniewska, Mike English, Samuel Ngarngar, Nick Aduro, Loice Mutai, David Kimutai, Caren Emadau, Cecilia Mutiso, Celia Muturi, Charles Nzioki, Francis Kanyingi, Agnes Mithamo, Magdalene Kuria, Samuel Otido, Anne Kamunya, Alice Kariuki, Peris Njiiri, Rachel Inginia, Melab Musabi, Barnabas Kigen, Grace Akech Ochieng, Lydia Thuranira, Morris Ogero, Thomas Julius, Boniface Makone, Mercy Chepkirui, James Wafula
Journal: The Lancet Child & Adolescent Health (2018)

Diarrhoea causes many deaths in children younger than 5 years and identification of risk factors for death is considered a global priority. The effectiveness of currently recommended fluid management for dehydration in routine settings has also not been examined.
Up-front short-course radiotherapy and systemic chemotherapy for locally advanced rectal cancers with distant metastasis: Does it provide meaningful benefit?
Authors: Akhil Kapoor, Vikas S. Ostwal, Nikhil Pande, Anant Ramaswamy, Rushab Kothari, Reena Engineer, Ashwin Desouja, Suprita Arya, Mukta Ramadwar, Avanish Saklani
Journal: Journal of Clinical Oncology (2018)

778 Background: The optimal sequencing of treatment for locally advanced rectal cancer with distant metastasis (mLARC) is not well established. Methods: We retrospectively reviewed the records of mLARC patients receiving SCRT (25Gy/5#) and chemotherapy between July 2013 and December 2016. Patients were evaluated for surgery after SCRT and chemotherapy with the decision for further treatment being taken in a multidisciplinary team. Those patients who underwent surgery also received adjuvant chemotherapy as per the standard practice. Results: One hundred five consecutive mLARC patients were included in this study. Median age was 48 years (range 16-78) and 60 patients (57%) were male. Thirty-six patients (34%) had a single site of metastases. Sixty-one patients (58%) had obstruction at baseline and required stoma placement and another 19 patients (18%) had near obstructive lesions; these patients did not require stoma post SCRT and chemotherapy. With first line chemotherapy, objective response rate was 39% while 29% patients had stable disease. Twenty-four patients (23%) underwent definitive surgery. Median PFS and OS for entire cohort was 10.5 months (95% CI: 9.1-11.8) and 15.7 months (95% CI: 10.2-21.2), respectively. Median PFS was 23 months (95% CI: 18.7-27.7) for patients who could undergo surgery while it was 7.7 months (95% CI: 5.9-9.5, HR 5.0) (log rank &lt;0.001) for patients in whom surgery was not possible. Median OS was not reached for patients who underwent surgery while it was 10.9 months (95% CI: 9.6-12.3, HR 9.8) (log rank p&lt;0.001) for patients in whom surgery was not possible. OS at 3 years was 60% for patients who underwent surgery while it was only 7% in whom surgery was not possible. Conclusions: Upfront SCRT followed by systemic chemotherapy with delayed surgery in locally advanced rectal cancer with distant metastasis is an effective, feasible and attractive option. [Table: see text]