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https://www.readbyqxmd.com/read/29048401/p53-dynamics-orchestrates-with-binding-affinity-to-target-genes-for-cell-fate-decision
#1
Mengqiu Wu, Hui Ye, Zhiyuan Tang, Chang Shao, Gaoyuan Lu, Baoqiang Chen, Yuyu Yang, Guangji Wang, Haiping Hao
Emerging evidence support that temporal dynamics is pivotal for signaling molecules in orchestrating smart responses to diverse stimuli. p53 is such a signaling molecule that employs temporal dynamics for the selective activation of downstream target genes and ultimately for cell fate decision. Yet how this fine-tuned p53 machinery is quantitatively decoded remains largely unclear. Here we report a quantitative mechanism defining how p53 dynamics orchestrates with binding affinity to target genes for cell fate decision...
October 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29029057/patient-specific-modelling-of-regional-tobramycin-concentration-levels-in-airways-of-patients-with-cystic-fibrosis-can-we-dose-once-daily
#2
Aukje C Bos, Johan W Mouton, Mireille van Westreenen, Eleni-Rosalina Andrinopoulou, Hettie M Janssens, Harm A W M Tiddens
Background: Inhaled tobramycin is important in the treatment of Pseudomonas aeruginosa ( Pa ) infections in cystic fibrosis (CF). However, despite its use it fails to attenuate the clinical progression of CF lung disease. The bactericidal efficacy of tobramycin is known to be concentration-dependent and hence changing the dosing regimen from a twice-daily (q12h) inhalation to a once-daily (q24h) inhaled double dose could improve treatment outcomes. Objectives: To predict local concentrations of nebulized tobramycin in the airways of patients with CF, delivered with the small airway-targeting Akita ® system or standard PARI-LC ® Plus system, with different inspiratory flow profiles...
September 23, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28993326/a-dynamic-stress-model-explains-the-delayed-drug-effect-in-artemisinin-treatment-of-plasmodium-falciparum
#3
Pengxing Cao, Nectarios Klonis, Sophie Zaloumis, Con Dogovski, Stanley C Xie, Sompob Saralamba, Lisa J White, Freya J I Fowkes, Leann Tilley, Julie A Simpson, James M McCaw
Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimisation of dosing regimens and the development of strategies to prolong the lifespan of current first-line treatment options. Recent short drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic(PK-PD) paradigm in which the killing rate depends only on drug concentration...
October 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28991889/trends-in-drug-resistance-prevalence-hiv-1-variants-and-clinical-status-in-hiv-1-infected-pediatric-population-in-madrid-1993-2015-analysis
#4
Patricia Rojas Sánchez, Sara Domínguez, Santiago Jiménez De Ory, Luis Prieto, Pablo Rojo, Pepa Mellado, Marisa Navarro, Rafael Delgado, José Tomas Ramos, África Holguín
BACKGROUND: The expanded use of long-term antiretroviral treatments in infected children may exacerbate the problem of drug resistance mutations (HIVDR) selection, which can compromise treatment efficiency. OBJECTIVE: We describe the temporal trends of HIVDR and the HIV-1 variants during 23 years (1993-March 2016) in the Madrid cohort of HIV-infected children and adolescents. METHODS: We selected patients with at least one available HIV-1 pol sequence/genotypic resistance profile, establishing different groups according to the sampling year of first resistance data...
October 6, 2017: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/28982739/discovery-of-methylated-circulating-dna-biomarkers-for-comprehensive-non-invasive-monitoring-of-treatment-response-in-metastatic-colorectal-cancer
#5
Ludovic Barault, Alessio Amatu, Giulia Siravegna, Agostino Ponzetti, Sebastian Moran, Andrea Cassingena, Benedetta Mussolin, Chiara Falcomatà, Alexandra M Binder, Carmen Cristiano, Daniele Oddo, Simonetta Guarrera, Carlotta Cancelliere, Sara Bustreo, Katia Bencardino, Sean Maden, Alice Vanzati, Patrizia Zavattari, Giuseppe Matullo, Mauro Truini, William M Grady, Patrizia Racca, Karin B Michels, Salvatore Siena, Manel Esteller, Alberto Bardelli, Andrea Sartore-Bianchi, Federica Di Nicolantonio
OBJECTIVE: Mutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC)...
October 5, 2017: Gut
https://www.readbyqxmd.com/read/28977932/inhibitor-of-h3k27-demethylase-jmjd3-utx-gsk-j4-is-a-potential-therapeutic-option-for-castration-resistant-prostate-cancer
#6
Viacheslav M Morozov, Ying Li, Matthew M Clowers, Alexander M Ishov
Androgen receptor (AR) mediates initiation and progression of prostate cancer (PCa); AR-driven transcription is activated by binding of androgens to the ligand-binding domain (LBD) of AR. Androgen ablation therapy offers only a temporary relief of locally advanced and metastatic PCa, and the disease eventually recurs as a lethal castration-resistant PCa (CRPC) as there is no effective treatment for CRPC patients. Thus, it is critical to identify novel targeted and combinatorial regimens for clinical management of CRPC...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28970735/arterioportal-shunt-incidental-to-treatment-with-oxaliplatin-that-mimics-recurrent-gastric-cancer
#7
Hong-Beum Kim, Sang-Gon Park
Arterioportal shunt (APS) is an organic communication between the hepatic arterial system and the portal venous system. The APS is one of the major causes of transient hepatic attenuation differences on dynamic computed tomography (CT) or magnetic resonance imaging (MRI). This condition is usually associated with trauma, liver cirrhosis, and malignancies of the liver. However, there has been no report about oxaliplatin-induced APS. A 41-year-old male was diagnosed with Stage IIIB gastric cancer. The patient initially underwent neoadjuvant chemotherapy with capecitabine and oxaliplatin After 3 cycles of therapy, the mass had markedly decreased, and a total gastrectomy with splenectomy was performed...
September 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28969664/perspective-on-the-dynamics-of-cancer
#8
REVIEW
Youcef Derbal
BACKGROUND: The genetic diversity of cancer and the dynamic interactions between heterogeneous tumor cells, the stroma and immune cells present daunting challenges to the development of effective cancer therapies. Although cancer biology is more understood than ever, this has not translated into therapies that overcome drug resistance, cancer recurrence and metastasis. The future development of effective therapies will require more understanding of the dynamics of homeostatic dysregulation that drives cancer growth and progression...
October 3, 2017: Theoretical Biology & Medical Modelling
https://www.readbyqxmd.com/read/28960845/simultaneous-modeling-of-biomarker-and-toxicity-response-predicted-optimal-regimen-of-guadecitabine-sgi-110-in-myeloid-malignancies
#9
Cong Xu, Timothy K Goggin, Xiang-Yao Su, Pietro Taverna, Aram Oganesian, James N Lowder, Mohammad Azab, Hagop Kantarjian
Guadecitabine (SGI-110) is a novel next-generation hypomethylating agent (HMA) administered as s.c. injection with extended decitabine exposure. Dose/exposure-response analyses of longitudinal measures of long interspersed nucleotide element-1 (LINE-1) methylation and absolute neutrophil counts (ANC) pooled from 79 and 369 patients in 2 phase I/II trials, respectively, were performed to assist, through modeling and simulation, the selection of dosing regimens for phase III. Simulation of ANC predicted a decrease after a 5-day regimen of 60 mg/m(2) with partial recovery before the next cycle, whereas the nadir of 90 mg/m(2) on the same schedule was below 100/µl...
September 28, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28950862/continental-scale-data-driven-predictive-assessment-of-eliminating-the-vector-borne-disease-lymphatic-filariasis-in-sub-saharan-africa-by-2020
#10
Edwin Michael, Brajendra K Singh, Benjamin K Mayala, Morgan E Smith, Scott Hampton, Jaroslaw Nabrzyski
BACKGROUND: There are growing demands for predicting the prospects of achieving the global elimination of neglected tropical diseases as a result of the institution of large-scale nation-wide intervention programs by the WHO-set target year of 2020. Such predictions will be uncertain due to the impacts that spatial heterogeneity and scaling effects will have on parasite transmission processes, which will introduce significant aggregation errors into any attempt aiming to predict the outcomes of interventions at the broader spatial levels relevant to policy making...
September 27, 2017: BMC Medicine
https://www.readbyqxmd.com/read/28948528/co-delivery-of-vorinostat-and-etoposide-via-disulfide-cross-linked-biodegradable-polymeric-nanogels-synthesis-characterization-biodegradation-and-anticancer-activity
#11
Parveen Kumar, Lubna Wasim, Madhu Chopra, Aruna Chhikara
Treatment regimens for cancer patients using single chemotherapeutic agents often lead to undesirable toxicity, drug resistance, reduced uptake etc. Combination of two or more drugs is therefore becoming an imperative strategy to overcome these limitations. A step forward can be taken through delivery of the drugs used in combination via nanoparticles. Co-administration of chemotherapeutic drugs encapsulated in nanoparticles has been shown to result in synergistic effects and enhanced therapeutic efficacy. In present study, we explored the combination treatment of histone deacetylase inhibitor vorinostat (VOR) and topoisomerase II inhibitor etoposide (ETOP)...
September 25, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28944989/the-combination-of-valsartan-and-sacubitril-in-the-treatment-of-hypertension-and-heart-failure-an-update
#12
REVIEW
Peter Munch Nielsen, Daniela Grimm, Markus Wehland, Ulf Simonsen, Marcus Krüger
A novel antihypertensive drug, LCZ696 (Entresto®), has recently been introduced, which combines the action of an antagonist of the renin-angiotensin-aldosterone system (RAAS), effectively decreasing the blood pressure, with an inhibition of neprilysin, which is responsible for metabolizing natriuretic peptides exerting antihypertensive and antifibrotic effects. In this MiniReview, we describe the pharmacokinetics and pharmacodynamics, efficacy and side effects of the combined angiotensin receptor antagonist and neprilysin inhibitor LCZ696...
September 25, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28944163/weathering-the-storm-improving-therapeutic-interventions-for-cytokine-storm-syndromes-by-targeting-disease-pathogenesis
#13
Lehn K Weaver, Edward M Behrens
Cytokine storm syndromes require rapid diagnosis and treatment to limit the morbidity and mortality caused by the hyperinflammatory state that characterizes these devastating conditions. Herein, we discuss the current knowledge that guides our therapeutic decision-making and personalization of treatment for patients with cytokine storm syndromes. Firstly, ICU-level supportive care is often required to stabilize patients with fulminant disease while additional diagnostic evaluations proceed to determine the underlying cause of cytokine storm...
March 2017: Current Treatment Options in Rheumatology
https://www.readbyqxmd.com/read/28934679/the-kinetics-of-white-blood-cell-and-the-predictive-factors-of-leukocytosis-under-oral-or-intravenous-arsenic-as-the-first-line-treatment-for-acute-promyelocytic-leukemia
#14
Fang Wang, Jin-Song Jia, Jing Wang, Ting Zhao, Qian Jiang, Hao Jiang, Hong-Hu Zhu
OBJECTIVE: We aimed to compare the kinetics of white blood cell (WBC) and explore predictive factors of leukocytosis in non-high-risk acute promyelocytic leukemia (APL), with oral arsenic plus all-trans retinoic acid (ATRA) or intravenous arsenic trioxide (ATO) plus ATRA as a first-line treatment. METHODS: The absolute count, doubling time and peak time of WBC were analyzed in 64 newly diagnosed non-high-risk APL patients who were treated with different induction regimens containing either oral Realgar-indigo naturalis formula (RIF) (n=35) or ATO (n=29)...
October 2017: Leukemia Research
https://www.readbyqxmd.com/read/28844816/guadecitabine-sgi-110-in-treatment-naive-patients-with-acute-myeloid-leukaemia-phase-2-results-from-a-multicentre-randomised-phase-1-2-trial
#15
RANDOMIZED CONTROLLED TRIAL
Hagop M Kantarjian, Gail J Roboz, Patricia L Kropf, Karen W L Yee, Casey L O'Connell, Raoul Tibes, Katherine J Walsh, Nikolai A Podoltsev, Elizabeth A Griffiths, Elias Jabbour, Guillermo Garcia-Manero, David Rizzieri, Wendy Stock, Michael R Savona, Todd L Rosenblat, Jesus G Berdeja, Farhad Ravandi, Edwin P Rock, Yong Hao, Mohammad Azab, Jean-Pierre J Issa
BACKGROUND: The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m(2) guadecitabine for 5 days as an effective treatment schedule...
October 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28843398/effect-of-hpv-e6-e7-sirna-with-chemotherapeutic-agents-on-the-regulation-of-tp53-e2f-dynamic-behavior-for-cell-fate-decisions
#16
Nirmal Rajasekaran, Hun Soon Jung, Soo Hyeon Bae, Chaithanya Chelakkot, Sungyoul Hong, Jong-Sun Choi, Dong-Seok Yim, Yu-Kyoung Oh, Yoon-La Choi, Young Kee Shin
Toxicity and resistance remain major challenges for advanced or recurrent cervical cancer therapies, as treatment requires high doses of chemotherapeutic agents. Restoration of TP53 and hypophosphorylated-retinoblastoma (pRB) proteins by human papillomavirus (HPV) E6/E7 siRNA sensitizes HPV-positive cervical cancer cells toward chemotherapeutic agents. Here, we investigated the therapeutic effects of E6/E7 siRNA on the dynamic behavior of TP53 and RB/E2F signaling networks in deciding the cell fate. The synergistic effect of HPV E6/E7 siRNA pool (SP) with chemotherapeutic agents on TP53 and RB/E2F signaling, proliferation, and apoptosis was analyzed in vitro and in vivo...
August 23, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28837330/development-of-a-drug-delivery-system-based-on-chitosan-nanoparticles-for-oral-administration-of-interferon-%C3%AE
#17
Camila Cánepa, Julieta C Imperiale, Carolina A Berini, Marianela Lewicki, Alejandro Sosnik, Mirna M Biglione
Despite the good clinical efficacy of interferon-alpha (IFNα) to treat some types of cancer and viral infections, this biological drug is underused given its severe adverse effects and high dosing parenteral regimens. Aiming to achieve a breakthrough in therapy with IFNα, this work reports for the first time on the design and full characterization of a novel nanomedicine of IFNα-2b-loaded chitosan nanoparticles (IFN-CT NPs) for oral delivery. IFN-CT NPs produced by ionotropic gelation, encapsulating approximately 100% of the drug, showed a size of 36 ± 8 nm, zeta potential of +30 mV (dynamic light scattering), and spherical morphology (transmission electron microscopy)...
September 8, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28793071/nonbioequivalent-prescription-drug-interchangeability-concerns-on-patient-safety-and-drug-market-dynamics-in-brazil
#18
Francisco José Roma Paumgartten, Ana Cecilia Amado Xavier de Oliveira
Since the enforcement of Generics Act (1999), three types of pharmaceutically equivalent products are marketed in Brazil: innovative reference (REF), "similar" (S) and generic (G) drugs. The S (brand name) and G (generic name) borrow from REF (brand name) clinical data on safety and efficacy and dosage regimen. G (but not S) is bioequivalent to and interchangeable with REF. Starting in 2003, Brazilian Sanitary Surveillance Agency (Anvisa) has required data on relative bioavailability tests (with REF) to approve (or renew registration of) S drugs...
August 2017: Ciência & Saúde Coletiva
https://www.readbyqxmd.com/read/28792497/history-of-antibiotic-adaptation-influences-microbial-evolutionary-dynamics-during-subsequent-treatment
#19
Phillip Yen, Jason A Papin
Antibiotic regimens often include the sequential changing of drugs to limit the development and evolution of resistance of bacterial pathogens. It remains unclear how history of adaptation to one antibiotic can influence the resistance profiles when bacteria subsequently adapt to a different antibiotic. Here, we experimentally evolved Pseudomonas aeruginosa to six 2-drug sequences. We observed drug order-specific effects, whereby adaptation to the first drug can limit the rate of subsequent adaptation to the second drug, adaptation to the second drug can restore susceptibility to the first drug, or final resistance levels depend on the order of the 2-drug sequence...
August 2017: PLoS Biology
https://www.readbyqxmd.com/read/28755314/checkpoint-inhibitors-for-non-small-cell-lung-cancer-among-older-adults
#20
REVIEW
Rawad Elias, Joshua Morales, Carolyn Presley
Non-small cell lung cancer (NSCLC) is mostly a disease of older adults, with its incidence and mortality rates increasing exponentially after the age of 65 years. Immune checkpoint inhibitors (ICIs) have changed the scene of NSCLC treatment after a long and relatively stagnant period of standard treatment regimens. However, little is known about the specific impact of these agents in older adults for whom care is often complicated by a variety of syndromes. This underlines the importance of understanding the dynamics of new cancer treatments in an older patient population...
September 2017: Current Oncology Reports
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