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Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia.

Oncotarget. 2017 May 23;8(21):34687-34697

Authors: Li Q, Li B, Hu L, Ning H, Jiang M, Wang D, Liu T, Zhang B, Chen H

Abstract
The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice. Moreover, a high sensitivity to the JAK1/2 inhibitor ruxolitinib was observed in S646P mutant model. Exploration in a total of 209 ALL cases showed that JAK1 mutations occur at a frequency of 10.5% in T-ALL (2/19) and 1.6% in B-ALL (3/190). Collectively, our results suggested that JAK1 S646P is an activating mutation in vitro and in vivo. JAK-STAT pathway might represent a promising therapeutic target for ALL.

PMID: 28410228 [PubMed - indexed for MEDLINE]

Selenium - a fascinating antioxidant of protective properties.

Adv Clin Exp Med. 2018 Feb;27(2):245-255

Authors: Kiełczykowska M, Kocot J, Paździor M, Musik I

Abstract
Selenium is a trace element which fulfils important functions in the organism. Its deficit may cause acute disorders, but an overdose can also lead to severe consequences. The functions of selenium in the organism are mainly connected with its antioxidant properties, as it is an essential part of important antioxidant enzymes. Disturbances of oxidant balance have been found to be involved in the activity of numerous harmful factors as well as in the pathogenesis of diverse illnesses. Selenium administration has proved to be effective against the toxicity of many agents and the side effects of drugs. However, the narrow range between therapeutic and toxic doses of selenium, as well as the dependence of its effect on the applied form, dose and method of treatment, makes the choice of the most effective supplement a very complex issue. Divergent forms of selenium are still being studied, including both inorganic and organic compounds as well as Se-enriched natural products. The newest research has also involved selenium nanoparticles. The aim of this review is to present the great potential of selenium for protecting the organism against a wide variety of environmental pollutants, drugs and physical factors.

PMID: 29521069 [PubMed - in process]

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Recurrent dysphasia due to nivolumab-induced encephalopathy with presence of Hu autoantibody.

Lung Cancer. 2017 Jul;109:74-77

Authors: Raskin J, Masrori P, Cant A, Snoeckx A, Hiddinga B, Kohl S, Janssens A, Cras P, Van Meerbeeck JP

Abstract
A 58-year-old man was being treated for squamous non-small-cell lung cancer with nivolumab. At the 17th of biweekly administrations he presented with global dysphasia, dysarthria and myoclonus in the right upper extremity. MRI showed multiple T2/FLAIR hyperintense lesions in the left hemisphere; lumbar puncture showed lymphocytic pleiocytosis in the CSF without identifiable pathogens. Hu antibodies were present in serum and CSF. Nivolumab was discontinued and corticosteroids were administered. The neurological symptoms gradually improved; MRI showed complete remission of cerebral lesions. After rechallenge with nivolumab his symptoms and cerebral lesions recurred, proving the causal relationship with nivolumab. After tapering of corticosteroids, a second relapse occurred.

PMID: 28577954 [PubMed - indexed for MEDLINE]

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Vitiligo in a patient with lung adenocarcinoma treated with nivolumab: A case report.

Lung Cancer. 2017 Jul;109:42-44

Authors: Uenami T, Hosono Y, Ishijima M, Kanazu M, Akazawa Y, Yano Y, Mori M, Yamaguchi T, Yokota S

Abstract
Nivolumab, an anti-programmed cell death-1 protein monoclonal antibody, is effective for treating patients with late-stage non-small-cell lung cancer. Immune checkpoint inhibitors such as nivolumab induce various kinds of immune-related adverse events, including vitiligo. Vitiligo has been reported in patients with melanoma but not lung cancer. We describe a 75-year-old man with lung adenocarcinoma, stage 4 with pleural and pericardial effusion, that progressed after first-line chemotherapy. Subsequently, he was treated with nivolumab as second-line therapy. After 6days of administering nivolumab, he developed vitiligo suddenly on the trunk of his body. Except for vitiligo, his physical examination was normal, and treatment with nivolumab was well tolerated. Therefore, this treatment was continued without further development or expansion of vitiligo. A computed tomography scan showed a reduction in the size of the lung nodule and stabilization of the pleural and pericardial effusion. This is the first case of vitiligo associated with the use of nivolumab in a patient with lung adenocarcinoma.

PMID: 28577948 [PubMed - indexed for MEDLINE]

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Venous thromboembolism in hospitalized patients receiving chemotherapy for malignancies at Japanese community hospital: prospective observational study.

BMC Cancer. 2017 May 19;17(1):351

Authors: Kitayama H, Kondo T, Sugiyama J, Kurimoto K, Nishino Y, Hirayama M, Tsuji Y

Abstract
BACKGROUND: Although Asian population was recognized to have a lower risk of venous thromboembolism (VTE), its increasing prevalence and incidence remain unclear in patients with malignancies. We attempted to predict VTE development using activation markers of coagulation and fibrinolysis.
METHODS: We enrolled patients with malignancy admitted to Tonan Hospital between April and December 2014 to receive a new-for-them chemotherapy regimen. All patients were examined for VTE by computed tomography and whole-leg compression ultrasonography before chemotherapy and three months later. We also examined plasma levels of thrombin-antithrombin complex (TAT) and plasmin α2-plasmin inhibitor complex (PIC) before chemotherapy. The cut off values of TAT and PIC were set at 2.1 ng/mL and 1.8 μg/mL, respectively.
RESULTS: Of 97 patients, the majority (67%) had distant metastases. The most common malignancies were colorectal (26%), breast (23%), and stomach (19%) cancer. VTE was detected in 29 patients (31%); all were asymptomatic. VTE was newly developed in 12 patients in the three-month observation period, which means the incidence was 49 per 1000 person-years. Non-increased PIC with increased TAT was the only significant risk factor for both VTE prevalence and incidence in multivariate analysis, and the odds ratios were 3.0 (95% confidence interval, 1.1-8.2; P = 0.034) and 9.4 (95% confidence interval, 1.7-51.9; P = 0.011), respectively.
CONCLUSIONS: The prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies. Non-increased PIC with increased levels of TAT may be an independent risk factor for VTE development.

PMID: 28525975 [PubMed - indexed for MEDLINE]

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Exploring consumer opinions on the presentation of side-effects information in Australian Consumer Medicine Information leaflets.

Health Expect. 2016 Jun;19(3):543-56

Authors: Tong V, Raynor DK, Blalock SJ, Aslani P

Abstract
BACKGROUND: Consumer Medicine Information (CMI) is a brand-specific and standardized source of written medicine information available in Australia for all prescription medicines. Side-effect information is poorly presented in CMI and may not adequately address consumer information needs.
OBJECTIVE: To explore consumer opinions on (i) the presentation of side-effect information in existing Australian CMI leaflets and alternative study-designed CMIs and (ii) side-effect risk information and its impact on treatment decision making.
DESIGN: Fuzzy trace, affect heuristic, frequency hypothesis and cognitive-experiential theories were applied when revising existing CMI side-effects sections. Together with good information design, functional linguistics and medicine information expertise, alternative ramipril and clopidogrel CMI versions were proposed. Focus groups were then conducted to address the study objectives.
PARTICIPANTS AND SETTING: Three focus groups (n = 18) were conducted in Sydney, Australia. Mean consumer age was 58 years (range 50-65 years), with equal number of males and females.
RESULTS: All consumers preferred the alternative CMIs developed as part of the study, with unequivocal preference for the side-effects presented in a simple tabular format, as it allowed quick and easy access to information. Consumer misunderstandings reflected literacy and numeracy issues inherent in consumer risk appraisal. Many preferred no numerical information and a large proportion preferred natural frequencies.
CONCLUSIONS: One single method of risk presentation in CMI is unable to cater for all consumers. Consumer misunderstandings are indicative of possible health literacy and numeracy factors that influence consumer risk appraisal, which should be explored further.

PMID: 24905668 [PubMed - indexed for MEDLINE]

Notice NOT-OD-18-148 from the NIH Guide for Grants and Contracts

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Notice NOT-OD-18-150 from the NIH Guide for Grants and Contracts

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"Rare Diseases"[Mesh] OR "orphan disease"

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pharmacogenomics

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Funding Opportunity RFA-CA-18-020 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support research projects designed to solve specific problems and paradoxes in cancer research identified by the National Cancer Institute (NCI) Provocative Questions initiative. These problems and paradoxes phrased as questions are not intended to represent the full range of NCI's priorities in cancer research. Rather, they are meant to challenge cancer researchers to think about and elucidate specific problems in key areas of cancer research that are deemed important but have not received sufficient attention. Some of these "Provocative Questions" (PQs) stem from intriguing but older, neglected observations that have never been adequately explored. Other PQs are built on more recent findings that are perplexing or paradoxical, revealing important gaps in current knowledge. Finally, some PQs reflect problems that traditionally have been thought to be intractable but that now may be open to investigations using new strategies and recent technical advances. The current issuance of the PQ Initiative includes an updated set of 12 PQs. Each research project proposed in response to this FOA must be focused on addressing one particular research problem defined by one specific PQ selected from the list. Projects proposed to address specific PQs may use strategies that incorporate ideas and approaches from multiple disciplines, as appropriate. Transdisciplinary projects are encouraged as long as they serve the scientific focus of the specific PQ chosen.

Funding Opportunity RFA-CA-18-019 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support research projects designed to solve specific problems and paradoxes in cancer research identified by the National Cancer Institute (NCI) Provocative Questions initiative. These problems and paradoxes phrased as questions are not intended to represent the full range of NCI's priorities in cancer research. Rather, they are meant to challenge cancer researchers to think about and elucidate specific problems in key areas of cancer research that are deemed important but have not received sufficient attention. Some of these "Provocative Questions" (PQs) stem from intriguing but older, neglected observations that have never been adequately explored. Other PQs are built on more recent findings that are perplexing or paradoxical, revealing important gaps in current knowledge. Finally, some PQs reflect problems that traditionally have been thought to be intractable but that now may be open to investigations using new strategies and recent technical advances. The current issuance of the PQ Initiative includes an updated set of 12 PQs. Each research project proposed in response to this FOA must be focused on addressing one particular research problem defined by one specific PQ selected from the list. Projects proposed to address specific PQs may use strategies that incorporate ideas and approaches from multiple disciplines, as appropriate. Transdisciplinary projects are encouraged as long as they serve the scientific focus of the specific PQ chosen.

Notice NOT-DA-18-009 from the NIH Guide for Grants and Contracts

Notice NOT-AT-18-008 from the NIH Guide for Grants and Contracts

In silico identification of potent small molecule inhibitors targeting epidermal growth factor receptor 1.

J Cancer Res Ther. 2018 Jan;14(1):18-23

Authors: Shi Z, Chen J, Guo X, Cheng L, Guo X, Yu T

Abstract
Background: The receptor tyrosine kinase of the epidermal growth factor receptor (EGFR, ErbB) family played an important role in multisignaling pathways, which controlled numerous biological activities including proliferation, differentiation, apoptosis, etc. EGFR abnormalities have been associated with a variety of human tumors, which was a well-characterized target for cancer treatment. It was known to all that drug repositioning has been considered as a useful tool to accelerate the process of drug development.
Materials and Methods: Herein, a total of 1408 small molecule drugs approved by the Food and Drug Administration (FDA) were employed to identify potential EGFR inhibitors by a series of bioinformatics approaches, including virtual screening and molecular dynamics (MD) simulations.
Results: According to the docking score, five small molecules were chosed for further MD simulations. Following the 5 ns MD simulations, ZINC03830276 (Benzonatate) were finally recognized as "new use" of FDA-approved EGFR-targeting drug.
Conclusions: Our findings suggested that the small molecule ZINC03830276 (Benzonatate) could be a promising EGFR inhibitor candidate and may also provide new ideas for designing more potent EGFR inhibitors for the future study.

PMID: 29516953 [PubMed - in process]

Low Molecular Weight Chitosan-Coated PLGA Nanoparticles for Pulmonary Delivery of Tobramycin for Cystic Fibrosis.

Pharmaceuticals (Basel). 2018 Mar 08;11(1):

Authors: Al-Nemrawi NK, Alshraiedeh NH, Zayed AL, Altaani BM

Abstract
(1) Background: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Tobramycin were prepared using a solvent-evaporation method. (2) Methods: The NPs were coated with low molecular weight chitosan (LMWC) to enhance the mucoadhesiveness of PLGA-NPs. The following w/w ratios of tobramycin to LMWC were prepared: control (0:0.50), F₀ (1:0.25), F₀.₅ (1:0.5), and F₁ (1:1). (3) Results: The results showed that the size of the particles increased from 220.7 nm to 575.77 nm as the concentration of LMWC used in the formulation increased. The surface charge was also affected by the amount of LMWC, where uncoated-PLGA nanoparticles had negative charges (-2.8 mV), while coated-PLGA NPs had positive charges (+33.47 to +50.13 mV). SEM confirmed the size and the spherical homogeneous morphology of the NPs. Coating the NPs with LMWC enhanced the mucoadhesive properties of the NPs and sustained the tobramycin release over two days. Finally, all NPs had antimicrobial activity that increased as the amount of LMWC increased. (4) Conclusion: In conclusion, the formulation of mucoadhesive, controlled-release, tobramycin-LMWC-PLGA nanoparticles for the treatment of P. aeruginosa in cystic fibrosis patients is possible, and their properties could be controlled by controlling the concentration of LMWC.

PMID: 29517998 [PubMed]

Disease-modifying genetic factors in cystic fibrosis.

Curr Opin Pulm Med. 2018 Mar 06;:

Authors: Marson FAL

Abstract
PURPOSE OF REVIEW: To compile data from the past 10 years regarding the role of modifying genes in cystic fibrosis (CF).
RECENT FINDINGS: CF is a model disease for understanding of the action of modifying genes. Although it is a monogenic (CFTR) autosomal recessive disease, CF presents with wide phenotypic variability. In CF, variability occurs with different intensity among patients by each organ, being organ-specific, resulting from the mutual interaction of environmental and genetic factors, including CFTR mutations and various other genes, most of which are associated with inflammatory processes. In individuals, using precision medicine, gene modification studies have revealed individualized responses to drugs depending on particular CFTR mutations and modifying genes, most of which are alternative ion channels.
SUMMARY: Studies of modifying genes in CF allow: understanding of clinical variability among patients with the same CFTR genotype; evaluation of precision medicine; understanding of environmental and genetic effects at the organ level; understanding the involvement of genetic variants in inflammatory responses; improvements in genetic counseling; understanding the involvement of genetic variants in inflammatory responses in lung diseases, such as asthma; and understanding the individuality of the person with the disease.

PMID: 29517584 [PubMed - as supplied by publisher]

DEVELOPMENT OF A POLARIZED PANCREATIC DUCTULAR CELL EPITHELIA FOR PHYSIOLOGICAL STUDIES.

J Appl Physiol (1985). 2018 Mar 08;:

Authors: O'Malley Y, Rotti PG, Thornell IM, Vanegas Calderón OG, Febres-Aldana C, Durham K, Yao J, Li X, Zhu Z, Norris AW, Zabner J, Engelhardt JF, Uc A

Abstract
Pancreatic ductular epithelial cells comprise the majority of duct cells in pancreas, control cystic fibrosis transmembrane conductance regulator (CFTR)-dependent bicarbonate [HCO3-] secretion, but are difficult to grow as a polarized monolayer. Using NIH-3T3-J2 fibroblast feeder cells and a Rho-associated kinase inhibitor, we produced well-differentiated and polarized porcine pancreatic ductular epithelial cells. Cells grown on semipermeable filters at air-liquid interface (ALI) developed typical epithelial cell morphology and stable transepithelial resistance (TER), expressed epithelial cell markers (zona occludens-1 and beta catenin), duct cell markers (SOX-9 and CFTR), but no acinar (amylase) or islet cell (chromogranin) markers. Polarized cells were studied in Ussing chambers bathed in Krebs Ringer [HCO3-] solution, at 37oC gassed with 5% CO2 to measure short circuit currents (Isc). Ratiometric measurement of extracellular pH was performed using fluorescent SNARF-conjugated dextran at 5% CO2. Cells demonstrated a baseline Isc (12.2+3.2 μA/cm2) that increased significantly in response to apical forskolin/IBMX (∆Isc: 35.4{plus minus}3.8, p<0.001) or basolateral secretin (∆Isc: 31.4{plus minus}2.5 μA/cm2, p<0.001), both of which increase cellular levels of cAMP. Subsequent addition of apical GlyH-101, a CFTR inhibitor decreased the current (∆Isc: 20.4{plus minus}3.8, p<0.01). Extracellular pH and bicarbonate concentration increased significantly after forskolin/IBMX (pH: 7.18{plus minus}0.23 vs 7.53{plus minus}0.19; [HCO3-] in mM 14.5{plus minus}5.9 vs 31.8{plus minus}13.4, p<0.05 for both). We demonstrate the development of a polarized pancreatic ductular epithelial cell epithelia with CFTR-dependent bicarbonate secretion in response to secretin and cAMP. This model is highly relevant as porcine pancreas physiology is very similar to humans and pancreatic damage in cystic fibrosis pig model recapitulates that of humans.

PMID: 29517421 [PubMed - as supplied by publisher]