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  • 1
    Publication Date: 2018-06-27
    Description: Although guidelines recommend amikacin (AMK) inhalation therapy for difficult-to-treat nontuberculous mycobacterial lung disease (NTM-LD), data are limited regarding the safety and clinical efficacy of this salvage therapy. We retrospectively evaluated the treatment outcomes of 77 patients with refractory NTM-LD caused by Mycobacterium abscessus complex (MABC) or M. avium complex (MAC) who initiated AMK inhalation therapy between February 2015 and June 2016. MABC was the most common etiology ( n = 48, 62%), followed by MAC ( n = 20, 26%) and mixed infections ( n = 9, 12%). Isolates with macrolide resistance and baseline AMK resistance were identified in 63 (82%) patients and 5 (6%) patients, respectively. At 12 months after AMK inhalation therapy, 49% of patients had symptomatic improvement, whereas 42% had radiological improvement. Conversion to a negative sputum culture occurred in 14 (18%) patients, and the culture conversion rate was higher in patients infected with macrolide-susceptible isolates (7/14, 50%) than in those infected with macrolide-resistant isolates (7/63, 11%) ( P = 0.003). Significant decreases in sputum semiquantitative culture positivity occurred after AMK inhalation therapy ( P 〈 0.001). On multivariate analysis, conversion to a negative sputum culture was associated with mixed infections ( P = 0.009), a forced expiratory volume in 1 s of greater than 60% ( P = 0.008), and the absence of macrolide resistance ( P = 0.003). Thirty-eight percent of patients experienced adverse effects, with ototoxicity ( n = 15) being the most common. AMK inhalation salvage therapy may improve the treatment responses in some patients with refractory NTM-LD. However, considering the common adverse effects, further evaluation of the optimal dosage and intervals for AMK inhalation therapy is needed.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2018-11-06
    Description: Background/Aim: High-carbohydrate diets are generally provided to post-pancreatectomy cancer patients. Low energy density of this diet may obstruct proper energy intake and recovery. This study aimed to assess the effects of high-fat, high-energy ketogenic diet (KD) in these patients. Patients and Methods: After pancreatectomy, 9 patients were provided with general diet (GD) while 10 were served KD. Meal compliance, energy intake rate, meal satisfaction and presence of complications were monitored throughout hospital stay. Data on nutritional status, serum lipids and body composition were collected and compared between groups. Results: Meal compliance, energy intake rate and meal satisfaction score were higher in KD. There were no differences in complications, nutritional status and serum lipids. The decrease in body cell mass (BCM) was greater in GD. Conclusion: Post-pancreatectomy cancer patients who consumed KD had a higher energy intake and BCM. These results suggest the potential use of KD as an adjuvant anti-cancer therapy.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 3
    Publication Date: 2018-02-28
    Description: Objective Accurate cardiovascular risk estimations by patients and doctors are important as these affect health behaviour and medical decision making. We aimed to determine if doctors and patients were accurately estimating the absolute cardiovascular risk of patients in primary care. Methods A cross-sectional study was carried out in primary care clinics in Malaysia in 2014. Patients aged 35 years and above without known cardiovascular disease (CVDs) were included. Face-to-face interviews with a structured questionnaire were used to collect sociodemographic and clinical data as well as patients’ perception and doctors’ estimate of the patients’ CVD risk. Associations were tested using 2 , correlation and independent t-tests. Results We recruited 1094 patients and 57 doctors. Using the Framingham Risk Score (FRS) alone, 508 patients (46.4%) were in the high-risk group. When diabetes was included as high risk, the number increased to 776 (70.9%). Only 34.4% of patients and 55.7% of doctors correctly estimated the patient’s CVD risk in comparison with the reference FRS. Of the high-risk patients, 664 (85.6%) underestimated their CV risk. Factors associated with underestimation by patients included not having family history of CVD (adjusted OR (AOR): 2.705, 95% CI 1.538 to 4.757), smaller waist circumference (AOR: 0.979,95% CI 0.960 to 0.999) and ethnicity in comparison with the Malay as reference group (indigenous/others: AOR: 0.129, 95% CI 0.071 to 0.235). Doctors underestimated risk in 59.8% of the high-risk group. Factors associated with underestimation by doctors were patients factors such as being female (AOR: 2.232, 95% CI 1.460 to 3.410), younger age (AOR: 0.908, 95% CI 0.886 to 0.930), non-hypertensive (AOR: 1.731, 95% CI 1.067 to 2.808), non-diabetic (AOR: 1.931, 95% CI 1.114 to 3.348), higher high-density lipoprotein levels (AOR: 3.546, 95% CI 2.025 to 6.209), lower systolic blood pressure (AOR: 0.970, 95% CI 0.957 to 0.982), non-smoker (AOR: 2.246, 95% CI 1.354 to 3.726) and ethnicity in comparison with the Malay as reference group (Indian: AOR: 0.430, 95% CI 0.257 to 0.720; indigenous/others: AOR: 2.498, 95% CI 1.346 to 4.636). Conclusions The majority of consultations occurring between doctors and patients are being informed by inaccurate cardiovascular risk estimation.
    Keywords: Open access, General practice / Family practice, Communication
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 4
    Publication Date: 2018-01-09
    Description: Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44 −/− and CD44 +/+ OT-I CD8 T cells were adoptively transferred into mice challenged with Listeria -OVA, there was a slight increase in the percentage of CD44 +/+ cells at the effector site. However, CD44 +/+ cells were out-competed by CD44 −/− cells after the contraction phase in the lymphoid tissues, and the CD44 −/− cells preferentially formed more memory cells. The hyaluronan-binding CD44 +/+ CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non-binding CD44 +/+ and CD44 −/− OT-I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells towards a terminal effector differentiation state that reduces their ability to form memory cells. This article is protected by copyright. All rights reserved
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 5
    Publication Date: 2016-01-19
    Description: Many procedures in modern clinical medicine rely on the use of electronic implants in treating conditions that range from acute coronary events to traumatic injury. However, standard permanent electronic hardware acts as a nidus for infection: bacteria form biofilms along percutaneous wires, or seed haematogenously, with the potential to migrate within the body and to provoke immune-mediated pathological tissue reactions. The associated surgical retrieval procedures, meanwhile, subject patients to the distress associated with re-operation and expose them to additional complications. Here, we report materials, device architectures, integration strategies, and in vivo demonstrations in rats of implantable, multifunctional silicon sensors for the brain, for which all of the constituent materials naturally resorb via hydrolysis and/or metabolic action, eliminating the need for extraction. Continuous monitoring of intracranial pressure and temperature illustrates functionality essential to the treatment of traumatic brain injury; the measurement performance of our resorbable devices compares favourably with that of non-resorbable clinical standards. In our experiments, insulated percutaneous wires connect to an externally mounted, miniaturized wireless potentiostat for data transmission. In a separate set-up, we connect a sensor to an implanted (but only partially resorbable) data-communication system, proving the principle that there is no need for any percutaneous wiring. The devices can be adapted to sense fluid flow, motion, pH or thermal characteristics, in formats that are compatible with the body's abdomen and extremities, as well as the deep brain, suggesting that the sensors might meet many needs in clinical medicine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Seung-Kyun -- Murphy, Rory K J -- Hwang, Suk-Won -- Lee, Seung Min -- Harburg, Daniel V -- Krueger, Neil A -- Shin, Jiho -- Gamble, Paul -- Cheng, Huanyu -- Yu, Sooyoun -- Liu, Zhuangjian -- McCall, Jordan G -- Stephen, Manu -- Ying, Hanze -- Kim, Jeonghyun -- Park, Gayoung -- Webb, R Chad -- Lee, Chi Hwan -- Chung, Sangjin -- Wie, Dae Seung -- Gujar, Amit D -- Vemulapalli, Bharat -- Kim, Albert H -- Lee, Kyung-Mi -- Cheng, Jianjun -- Huang, Younggang -- Lee, Sang Hoon -- Braun, Paul V -- Ray, Wilson Z -- Rogers, John A -- F31MH101956/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Feb 4;530(7588):71-6. doi: 10.1038/nature16492. Epub 2016 Jan 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, Republic of Korea. ; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Engineering Science and Mechanics, Materials Research Institute, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Institute of High Performance Computing, Singapore 138632, Singapore. ; Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Biomicrosystem Technology, Korea University, Seoul 136-701, South Korea. ; Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-713, South Korea. ; Weldon School of Biomedical Engineering, School of Mechanical Engineering, The Center for Implantable Devices, Birck Nanotechnology Center, Purdue University, West Lafayette, Indiana 47907, USA. ; School of Mechanical Engineering, Purdue University, West Lafayette, Indiana 47907, USA. ; Department of Mechanical Engineering, Civil and Environmental Engineering, Materials Science and Engineering, and Skin Disease Research Center, Northwestern University, Evanston, Illinois 60208, USA. ; Department of Biomedical Engineering, College of Health Science, Korea University, Seoul 136-703, South Korea. ; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26779949" target="_blank"〉PubMed〈/a〉
    Keywords: *Absorbable Implants/adverse effects ; Administration, Cutaneous ; Animals ; Body Temperature ; Brain/*metabolism/surgery ; Electronics/*instrumentation ; Equipment Design ; Hydrolysis ; Male ; Monitoring, Physiologic/adverse effects/*instrumentation ; Organ Specificity ; Pressure ; *Prostheses and Implants/adverse effects ; Rats ; Rats, Inbred Lew ; *Silicon ; Telemetry/instrumentation ; Wireless Technology/instrumentation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2018-06-02
    Description: Quinacrine (QNC), antiprotozoan drug commonly used against Malaria and Giardiasis , has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest antitumor effects of QNC through suppression of NF-B and activation of p53. This study demonstrates the anticancer effect of QNC via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-inactivated conditions. Inhibition of p53 by PFT-α or siRNA promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells. Considering that Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by QNC may induce cell death via uncontrolled cell cycle progression. Indeed, QNC reduces Chk1/2 expression under p53-impaired cancer cells and induces cell death in the G 2 –M phase. QNC increases the binding between p-Chk1/2 and β-TrCP and promotes proteasome-dependent degradation. Moreover, QNC treatment displayed antitumor effects in a Villin-Cre;p53 +/LSL-R172H intestinal cancer mouse model system as well as HCT116 p53 –/– xenografts. Implications: QNC has been used for the past over 70 years without obvious side effects, as such it is a plausible drug candidate for relapsed cancers, small-cell lung cancer, breast cancer as well as various p53-inactivated human malignancies. Mol Cancer Res; 16(6); 935–46. ©2018 AACR .
    Print ISSN: 1541-7786
    Electronic ISSN: 1557-3125
    Topics: Medicine
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  • 7
    Publication Date: 2018-11-16
    Description: Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8 + T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors. Patients and Methods: Patients with incurable advanced melanoma, renal cell, non–small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 μg/kg weekly intravenously or 6 to 20 μg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8 + T-cell expansion were modest, NK cell numbers rose significantly. Neither anti–ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803. Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552–61. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 8
    Publication Date: 2018-01-28
    Description: Aim: The purpose of this study was to investigate whether splenectomy influences tumor recurrence after fluorescence-guided surgery (FGS) in an orthotopic nude-mouse model of pancreatic cancer. Materials and Methods: Green fluorescence protein (GFP)-labeled human pancreatic cancer cells (MiaPaCa2-GFP) were subcutaneously injected into the flanks of nude mice. Subcutaneous tumors were harvested and surgical orthotopic implantation (SOI) was performed in the tail of the pancreas with small tumor fragments. FGS was performed 21 days after SOI. Mice were then randomly divided into FGS-only control group (n=7) and FGS plus splenectomy group (n=8). Tumor recurrence was analyzed by laparotomy 21 days after FGS. Results: In the control group, no recurrence was found. In contrast, multiple peritoneal seeded nodules were observed in two mice of the splenectomy group (0% vs. 25%, p=0.467). Conclusion: Postoperative tumor recurrence only occurred in the splenectomy-treated group suggesting that FGS can spare the patient the morbidity of splenectomy.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 9
    Publication Date: 2018-05-11
    Description: This phase 1 study evaluated frontline brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab vedotin monotherapy) in 26 patients with CD30 + peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789.
    Keywords: Lymphoid Neoplasia, Brief Reports, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2018-05-25
    Description: Objectives To validate the performances of two prediction models (Brock and Lee models) for the differentiation of minimally invasive adenocarcinoma (MIA) and invasive pulmonary adenocarcinoma (IPA) from preinvasive lesions among subsolid nodules (SSNs). Design A retrospective cohort study. Setting A tertiary university hospital in South Korea. Participants 410 patients with 410 incidentally detected SSNs who underwent surgical resection for the pulmonary adenocarcinoma spectrum between 2011 and 2015. Primary and secondary outcome measures Using clinical and radiological variables, the predicted probability of MIA/IPA was calculated from pre-existing logistic models (Brock and Lee models). Areas under the receiver operating characteristic curve (AUCs) were calculated and compared between models. Performance metrics including sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were also obtained. Results For pure ground-glass nodules (n=101), the AUC of the Brock model in differentiating MIA/IPA (59/101) from preinvasive lesions (42/101) was 0.671. Sensitivity, specificity, accuracy, PPV and NPV based on the optimal cut-off value were 64.4%, 64.3%, 64.4%, 71.7% and 56.3%, respectively. Sensitivity, specificity, accuracy, PPV and NPV according to the Lee criteria were 76.3%, 42.9%, 62.4%, 65.2% and 56.3%, respectively. AUC was not obtained for the Lee model as a single cut-off of nodule size (≥10 mm) was suggested by this model for the assessment of pure ground-glass nodules. For part-solid nodules (n=309; 26 preinvasive lesions and 283 MIA/IPAs), the AUC was 0.746 for the Brock model and 0.771 for the Lee model (p=0.574). Sensitivity, specificity, accuracy, PPV and NPV were 82.3%, 53.8%, 79.9%, 95.1% and 21.9%, respectively, for the Brock model and 77.0%, 69.2%, 76.4%, 96.5% and 21.7%, respectively, for the Lee model. Conclusions The performance of prediction models for the incidentally detected SSNs in differentiating MIA/IPA from preinvasive lesions might be suboptimal. Thus, an alternative risk calculation model is required for the incidentally detected SSNs.
    Keywords: Open access, Oncology
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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