tbuckley/cabot-search huggingface dataset:
Efficacy of Ketogenic Diet, Modified Atkins Diet, and Low Glycemic Index Therapy Diet Among Children With Drug-Resistant Epilepsy
Authors: Vishal Sondhi, Anuja Agarwala, Ravindra M. Pandey, Biswaroop Chakrabarty, Prashant Jauhari, Rakesh Lodha, Gurudyal S. Toteja, Shobha Sharma, Vinod K. Paul, Eric Kossoff, Sheffali Gulati
Journal: JAMA Pediatrics (2020)

The ketogenic diet (KD) has been used successfully to treat children with drug-resistant epilepsy. Data assessing the efficacy of the modified Atkins diet (MAD) and low glycemic index therapy (LGIT) diet compared with the KD are scarce.To determine whether the MAD and LGIT diet are noninferior to the KD among children with drug-resistant epilepsy.One hundred seventy children aged between 1 and 15 years who had 4 or more seizures per month, had not responded to 2 or more antiseizure drugs, and had not been treated previously with the KD, MAD, or LGIT diet were enrolled between April 1, 2016, and August 20, 2017, at a tertiary care referral center in India.Children were randomly assigned to receive the KD, MAD, or LGIT diet as additions to ongoing therapy with antiseizure drugs.Primary outcome was percentage change in seizure frequency after 24 weeks of dietary therapy in the MAD cohort compared with the KD cohort and in the LGIT diet cohort compared with the KD cohort. The trial was powered to assess noninferiority of the MAD and LGIT diet compared with the KD with a predefined, noninferiority margin of -15 percentage points. Intention-to-treat analysis was used.One hundred fifty-eight children completed the trial: KD (n = 52), MAD (n = 52), and LGIT diet (n = 54). Intention-to-treat analysis showed that, after 24 weeks of intervention, the median (interquartile range [IQR]) change in seizure frequency (KD: -66%; IQR, -85% to -38%; MAD: -45%; IQR, -91% to -7%; and LGIT diet: -54%; IQR, -92% to -19%) was similar among the 3 arms (P = .39). The median difference, per intention-to-treat analysis, in seizure reduction between the KD and MAD arms was -21 percentage points (95% CI, -29 to -3 percentage points) and between the KD and LGIT arms was -12 percentage points (95% CI, -21 to 7 percentage points), with both breaching the noninferiority margin of -15 percentage points. Treatment-related adverse events were similar between the KD (31 of 55 [56.4%]) and MAD (33 of 58 [56.9%]) arms but were significantly less in the LGIT diet arm (19 of 57 [33.3%]).Neither the MAD nor the LGIT diet met the noninferiority criteria. However, the results of this study for the LGIT diet showed a balance between seizure reduction and relatively fewer adverse events compared with the KD and MAD. These potential benefits suggest that the risk-benefit decision with regard to the 3 diet interventions needs to be individualized.ClinicalTrials.gov Identifier: NCT02708030.
Natural killer cells in cancer biology and therapy
Authors: Song-Yang Wu, Tong Fu, Yi-Zhou Jiang, Zhi-Ming Shao
Journal: Molecular Cancer (2020)

Abstract The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.
BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation
Authors: Julia Volz, Charly Kusch, Sarah Beck, Michael Popp, Timo Vögtle, Mara Meub, Inga Scheller, Hannah S. Heil, Julia Preu, Michael K. Schuhmann, Katherina Hemmen, Thomas Premsler, Albert Sickmann, Katrin G. Heinze, David Stegner, Guido Stoll, Attila Braun, Markus Sauer, Bernhard Nieswandt
Journal: Journal of Clinical Investigation (2020)

Store-operated Ca2+ entry (SOCE) is the major route of Ca2+ influx in platelets. The Ca2+ sensor stromal interaction molecule 1 (STIM1) triggers SOCE by forming punctate structures with the Ca2+ channel Orai1 and the inositol trisphosphate receptor (IP3R), thereby linking the endo-/sarcoplasmic reticulum to the plasma membrane. Here, we identified the BAR domain superfamily member bridging integrator 2 (BIN2) as an interaction partner of STIM1 and IP3R in platelets. Deletion of platelet BIN2 (Bin2fl/fl,Pf4-Cre mice) resulted in reduced Ca2+ store release and Ca2+ influx in response to all tested platelet agonists. These defects were a consequence of impaired IP3R function in combination with defective STIM1-mediated SOC channel activation, while Ca2+ store content and agonist-induced IP3 production were unaltered. This severely defective Ca2+ signaling translated into impaired thrombus formation under flow and a protection of Bin2fl/fl,Pf4-Cre mice in models of arterial thrombosis and stroke. Our results establish BIN2 as a central regulator of platelet activation in thrombosis and thrombo-inflammatory disease settings.
Less Radiation but More Overall Advanced Imaging in Children—Good News or Bad News?
Authors: Alan R. Schroeder, Daniel L. Imler
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Diagnosis of mycoplasma aetiology in Stevens–Johnson syndrome/toxic epidermal necrolysis
Authors: E. Russell, S. Walker, T. McPherson
Journal: British Journal of Dermatology (2020)

We were pleased that the first national guidelines for paediatric Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) were published in your journal last year1 . They highlighted the higher rate of infectious triggers in children compared to adults. This message is especially important for us, as author SW's son had SJS/TEN triggered by Mycoplasma pneumoniae, which accounts for up to 50% of infectious causes. SW experienced first-hand the frustration of aetiological uncertainty in this disease. Accurate diagnosis of Mycoplasma-induced SJS/TEN is important as it allows for continuation of simple analgesia (otherwise implicated as a possible trigger), possible avoidance of further drug allergy testing (which can be inconclusive), focused treatment of Mycoplasma with antibiotics, and management of recurrence risk.
Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement
Authors: Matthias Schieker, Philip G. Conaghan, Linda Mindeholm, Jens Praestgaard, Daniel H. Solomon, Celeste Scotti, Herman Gram, Tom Thuren, Ronenn Roubenoff, Paul M Ridker
Journal: Annals of Internal Medicine (2020)

Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear.To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR).Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846).1091 clinical sites in 39 countries.10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants.Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months.The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases.Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis.Because the parent trial was not designed to examine the efficacy of IL-1β inhibitors in osteoarthritis, information on structural joint outcomes was not collected.Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1β inhibition for treatment of large joint osteoarthritis.Novartis Pharmaceuticals.
Outcome of Acute Myeloid Leukemia Patients with Abnormal 12p after Allogeneic Hematopoietic Cell Transplantation at Fred Hutchinson Cancer Research Center
Authors: Eric Konnick, Yi Li, Emily Silgard, Chris Davis, Ted Gooley, Frederick R. Appelbaum, Lue Ping Zhao, Min Fang
Journal: Blood (2017)
Is there a link between very early changes of primary and secondary lymphoid organs in <sup>18</sup>F-FDG-PET/MRI and treatment response to checkpoint inhibitor therapy?
Authors: Ferdinand Seith, Andrea Forschner, Benjamin Weide, Brigitte Gückel, Martin Schwartz, Johannes Schwenck, Ahmed E Othman, Matthias Fenchel, Claus Garbe, Konstantin Nikolaou, Nina Schwenzer, Christian la Fougère, Christina Pfannenberg
Journal: Journal for ImmunoTherapy of Cancer (2020)

Response assessment or prediction to checkpoint inhibitor therapy (CIT) is an unsolved problem in current routine diagnostics of patients with melanoma. Here, we evaluated very early changes of primary and secondary lymphoid organs under CIT in multiparametric [ 18 F]-labeled fluorodeoxyglucose-positron emission tomography ( 18 F-FDG-PET)/MRI as possible predictors of treatment response and investigated their correlation with baseline blood immune biomarkers. Between October 2014 and November 2017, 17 patients with unresectable melanoma (8 females; 65±11 years) undergoing CIT were prospectively evaluated using whole-body 18 F-FDG-PET/MRI before CIT start (t 0 ), 2 weeks (t 1 ) and 3 months after CIT initiation (t 2 ). At each time point, the volume, the 18 F-FDG-uptake and the mean apparent diffusion coefficient (ADC) of the spleen as well as the 18 F-FDG uptake of the bone marrow were assessed. Relative lymphocyte count (RLC), relative eosinophil count (REC) and neutrophil-lymphocyte ratio (NLR) were assessed at baseline. Response Evaluation Criteria in Solid Tumours modified for immune-based therapeutics (iRECIST) and decisions from an interdisciplinary tumor board were used for treatment response evaluation at t 2 . iRECIST was compared with PET response criteria in solid tumors for image-based response evaluation at different time points. Comparative analysis was conducted with Mann-Whitney U test with false discovery rate correction for multiple testing and correlation coefficients were computed. In lymphoid organs, significant differences (p&lt;0.05) between responders (9/17) and non-responders were found for the 18 F-FDG-uptake in the spleen at t 1 and the increase of the uptake t 1 -t 0 (responders/non-responders: standardized uptake value lean body mass 1.19/0.93; +49%/−1%). The best correlation coefficients to baseline biomarkers were found for the 18 F-FDG-uptake in the spleen at t 1 : NLR, r=−0.46; RLC, r=0.43; REC, r=0.58 (p&lt;0.05), respectively. Compared with the non-responder group, the responder group showed marked increases also in the volume of the spleen (+22%/+10%), the 18 F-FDG-uptake of bone marrow (+31%/−9%) at t 1 and the ADCmean at t 2 (+46%/+15%) compared with t 0 , however, not reaching significance. Our findings indicate that an effective systemic immune response in patients undergoing CIT can be detected as a significantly increased spleen activity in 18 F-FDG-PET as early as 2 weeks after treatment initiation. Trial registration number NCT03132090 , DRKS00013925.
The combi-targeting concept: an optimized single-molecule dual-targeting model for the treatment of Chronic Myelogenous Leukemia
Authors: Athanasia Katsoulas, Zakaria Rachid, James McNamee, Bertrand Jean-Claude
Journal: Cancer Research (2007)

LB-299  Blockade of bcr-abl by the inhibitor imatinib (GleevecTM) has proven efficacious in the therapy of CML. However resistance to the drug emerges at the advanced phases of the disease. Therefore, novel therapy models remained to be designed. We have developed a novel approach based on the development of a dual targeted agent termed combi-molecule designed to not only block bcr-abl but also to damage DNA. ZRF1, the first optimized prototype of the approach was “programmed” to degrade into another inhibitor ZRF0 + a methyldiazonium species. It was an approximately 2-fold stronger abl tyrosine kinase (TK) inhibitor than GleevecTM and a more potent DNA damaging agent than Temodar®. In the p53 wild-type Mo7p210 cells ZRF1 was approximately 1000-fold superior to that of equieffective combinations of GleevecTM+Temodar®. More importantly, its superior potency over GleevecTM was more pronounced in bcr-abl+ cells co-expressing wild-type p53. Studies to rationalize these results showed that, through its bcr-abl inhibitory function it down-regulates p53. However, sufficient levels of the latter protein are available for transactivating p21 and bax which are required for cell cycle arrest and apoptosis. The results suggest that in p53 wild-type cells, apoptosis is induced by the combi-molecule both through the intrinsic apoptotic machinery normally activated by bcr-abl inhibition and through the p53-controlled DNA damaging pathway. This additive effect translates into pronounced cell death in wild-type p53 expressing cells. The study conclusively demonstrated that p53 is a major determinant for the cytotoxic advantages of the novel combi-molecular approach in CML. The latter being a disease in which 70-85% of all the cases express wild-type p53.
Abstract #447: ITK-SYK requires membrane localisation, via its pleckstrin homology domain, for activation, signal transduction and cellular transformation
Authors: Suzanne Rigby, Y Huang, B Streubel, A Chott, M Du, S Turner, C Bacon
Journal: Cancer Research (2009)

The genetics of peripheral T cell lymphomas (PTCL) are poorly understood. Recently, a chromosomal translocation, t(5;9)(q33;q22), was discovered in a rare subset of PTCL with a follicular growth pattern. This translocation involved the SYK (Spleen tyrosine kinase) and ITK (Inducible T cell kinase) genes and generated an ITK-SYK fusion protein. The functional attributes of ITK-SYK are thus far uncharacterised. Here we demonstrate that ITK-SYK is an active tyrosine kinase, the expression of which resulted in ERK activation in 293T cells and transformation of NIH-3T3 cells, inducing loss of contact inhibition and formation of anchorage-independent colonies in soft agar. These observations were a direct result of the kinase activity of ITK-SYK as a kinase dead mutant was unable to induce NIH-3T3 transformation or phosphorylation of ERK. ITK-SYK is unusual amongst fusion tyrosine kinases (FTKs) as it does not contain a known oligomerisation domain but does have an N-terminal phosphatidylinositol-3,4,5-trisphosphate (PIP3)-binding pleckstrin homology (PH) domain. To investigate the importance of this domain for ITK-SYK activity we introduced a well characterised point mutation (R29C) that prevented membrane localisation. This point mutation abrogated ITK-SYK catalytic activity and inhibited its phosphorylation on its activation loop tyrosines in the kinase domain. Importantly, the R29C mutation also prevented the ability of ITK-SYK to activate the ERK signaling pathway and to transform NIH3T3 cells. However, each of these functions could be recovered by retargeting ITK-SYK-R29C back to the membrane by the addition of an N-terminal myristylation tag, thus demonstrating the importance of membrane localisation for ITK-SYK function. Furthermore, inhibition of phosphatidyl-inositol-3-kinase (PI3K) by LY294002, a well characterised PI3K inhibitor, also reduced ITK-SYK phosphorylation in a dose dependent response. Therefore, ITK-SYK activation requires PIP3 mediated membrane localisation, as seen with other PH domain containing kinases. Finally, we show that pharmacological inhibition of Syk in patients with PTCL-U carrying ITK-SYK could represent an effective treatment strategy as ITK-SYK phosphorylation was inhibited by the Syk inhibitor Piceatannol. Together these findings identify ITK-SYK as an active FTK, that is dependent upon PH domain-mediated membrane localisation for activation, signal transduction and transformation and establish it as a rational therapeutic target for t(5;9)(q33;q22)-positive PTCL.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 447.
Safety and COVID-19 Symptoms in Individuals Recently Vaccinated with BCG: a Retrospective Cohort Study
Authors: Simone J.C.F.M. Moorlag, Rosanne C. van Deuren, Cornelis H. van Werkhoven, Martin Jaeger, Priya Debisarun, Esther Taks, Vera P. Mourits, Valerie A.C.M. Koeken, L. Charlotte J. de Bree, Thijs ten Doesschate, Maartje C. Cleophas, Sanne Smeekens, Marije Oosting, Frank L. van de Veerdonk, Leo A.B. Joosten, Jaap ten Oever, Jos W.M. van der Meer, Nigel Curtis, Peter Aaby, Christine Stabell-Benn, Evangelos J. Giamarellos-Bourboulis, Marc Bonten, Reinout van Crevel, Mihai G. Netea
Journal: Cell Reports Medicine (2020)

Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last 5 years or did not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (adjusted odds ratio [AOR] 0.58, p < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe, and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection.
Molecular Signatures That Predict Response to Azacitidine Treatment for Myelodysplastic Syndromes
Authors: Yasuhito Nannya, June Takeda, Shinya Sato, Yusuke Shiozawa, Yuichi Shiraishi, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Shigeru Chiba, Norio Asou, Hitoshi Kiyoi, Kiyotoshi Imai, Chikara Hirase, Nobuaki Dobashi, Toru Kiguchi, Shinji Nakao, Kazuma Ohyashiki, Yasushi Miyazaki, Tomoki Naoe, Hideki Makishima, Satoru Miyano, Kenichi Yoshida, Seishi Ogawa
Journal: Blood (2017)
Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for <i>RAS</i> Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial
Authors: Wentao Tang, Li Ren, Tianshu Liu, Qinghai Ye, Ye Wei, Guodong He, Qi Lin, Xiaoying Wang, Mingliang Wang, Fei Liang, Yuehong Cui, Jianmin Xu
Journal: Journal of Clinical Oncology (2020)

To assess the effects of bevacizumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) as first-line treatment of RAS mutant unresectable colorectal liver metastases.From October 2013 to December 2017, patients with RAS mutant unresectable liver-limited metastases from colorectal cancer were randomly assigned to receive mFOLFOX6 plus bevacizumab (arm A) or mFOLFOX6 alone (arm B). The resectability of liver metastases was determined by a local multidisciplinary team. The primary end point was the actual rate of patients converted to R0 resection for liver metastases. Secondary end points included tumor response, survival, and toxicity. The block randomization method was used.The intention-to-treat population comprised 241 patients. A total of 121 patients were randomly assigned to arm A and 120 to arm B. The median follow-up time was 37.0 months for all patients. The R0 resection rates for liver metastases were 22.3% (27 of 121 patients) in arm A and 5.8% (7 of 120 patients) in arm B, with a significant difference (P < .01). Patients in arm A had significantly better objective response rates (54.5% v 36.7%; P < .01), median progression-free survival (9.5 v 5.6 months; P < .01) and median overall survival (25.7 v 20.5 months; P = .03) compared with those in arm B. The addition of bevacizumab was associated with more frequent proteinuria (9.9% v 3.3%; P = .04) and hypertension (8.3% v 2.5%; P < .05).For patients with initially unresectable RAS mutant colorectal liver metastases, bevacizumab combined with mFOLFOX6 increased the resectability of liver metastases and improved response rates and survival compared with mFOLFOX6 alone.
Reply to Sharma and Zeki: Does Vaping Increase Susceptibility to COVID-19?
Authors: Haijun Zhang, Mahboubeh R. Rostamim, Philip L. Leopold, Jason G. Mezey, Sarah L. O’Beirne, Yael Strulovici-Barel, Ronald G. Crystal
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

The article presents reply to Sharma and Zeki, which includes cigarette smokers may play a role in the increased susceptibility to the severe acute respiratory syndrome coronavirus, exposure to electronic cigarettes with or without nicotine may influence ACE2 expression in the airways and subjects were documented to be never-smokers on the basis of their self-reported smoking history and by the absence of urine tobacco metabolites