Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex ...mechanisms to control and regulate bacterial interactions with the mucosal surface. Apical tight junction proteins are critical in the maintenance of epithelial barrier function and control of paracellular permeability. The characterisation of alterations in tight junction proteins as key players in epithelial barrier function in inflammatory bowel diseases is rapidly enhancing our understanding of critical mechanisms in disease pathogenesis as well as novel therapeutic opportunities. Here we give an overview of recent literature focusing on the role of tight junction proteins, in particular claudins, in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.
Primary liver cancer (PLC) is the sixth most common cancer worldwide and the second most common cause of cancer death. Future predictions can inform health planners and raise awareness of the need ...for cancer control action. We predicted the future burden of PLC in 30 countries around 2030. Incident cases of PLC (International Classification of Diseases, Tenth Revision, C22) were obtained from 30 countries for 1993‐2007. We projected new PLC cases to 2030 using age‐period‐cohort models (NORDPRED software). Age‐standardized incidence rates per 100,000 person‐years were calculated by country and sex. Increases in new cases and rates of PLC are projected in both sexes. The largest increases in rates are, among men, in Norway (2.9% per annum), US whites (2.6%), and Canada (2.4%) and, among women, in the United States (blacks 4.0%), Switzerland (3.4%), and Germany (3.0%). The projected declines are in China, Japan, Singapore, and parts of Europe (e.g., Estonia, Czech Republic, Slovakia). A 35% increase in the number of new cases annually is expected compared to 2005. This increasing burden reflects both increasing rates (and the underlying prevalence of risk factors) and demographic changes. Japan is the only country with a predicted decline in the net number of cases and annual rates by 2030. Conclusion: Our reporting of a projected increase in PLC incidence to 2030 in 30 countries serves as a baseline for anticipated declines in the longer term through the control of hepatitis B virus and hepatitis C virus infections by vaccination and treatment; however, the prospect that rising levels of obesity and its metabolic complications may lead to an increased risk of PLC that potentially offsets these gains is a concern. (Hepatology 2018;67:600‐611).
Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to ...anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).
Using targeted exome sequencing, we identified mutations in NNT, an antioxidant defense gene, in individuals with familial glucocorticoid deficiency. In mice with Nnt loss, higher levels of ...adrenocortical cell apoptosis and impaired glucocorticoid production were observed. NNT knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased reactive oxygen species (ROS) levels. Our results suggest that NNT may have a role in ROS detoxification in human adrenal glands.
Detection and parameter estimation of binary neutron star merger remnants can shed light on the physics of hot matter at supranuclear densities. Here we develop a fast, simple model that can generate ...gravitational waveforms, and show it can be used for both detection and parameter estimation of postmerger remnants. The model consists of three exponentially damped sinusoids with a linear frequency-drift term. We test the model against nine equal-mass numerical-relativity simulations selected for emission of gravitational waves for ≳ 25 ms. The median fitting factors between the model waveforms and numerical-relativity simulations exceed 0.90. We detect remnants at a postmerger signal-to-noise ratio of ≥ 7 using a Bayes-factor detection statistic with a threshold of 3000. We can constrain the primary postmerger frequency to ±1.41.2% at postmerger signal-to-noise ratios of 15 with an increase in precision to ±0.30.2% for postmerger signal-to-noise ratios of 50. The tidal coupling constant can be constrained to ±912% at postmerger signal-to-noise ratios of 15, and ± 5 % at postmerger signal-to-noise ratios of 50 using a hierarchical inference model.
Purpose To update the ASCO guideline for antiemetics in oncology. Methods ASCO convened an Expert Panel and conducted a systematic review of the medical literature for the period of November 2009 to ...June 2016. Results Forty-one publications were included in this systematic review. A phase III randomized controlled trial demonstrated that adding olanzapine to antiemetic prophylaxis reduces the likelihood of nausea among adult patients who are treated with high emetic risk antineoplastic agents. Randomized controlled trials also support an expanded role for neurokinin 1 receptor antagonists in patients who are treated with chemotherapy. Recommendation Key updates include the addition of olanzapine to antiemetic regimens for adults who receive high-emetic-risk antineoplastic agents or who experience breakthrough nausea and vomiting; a recommendation to administer dexamethasone on day 1 only for adults who receive anthracycline and cyclophosphamide chemotherapy; and the addition of a neurokinin 1 receptor antagonist for adults who receive carboplatin area under the curve ≥ 4 mg/mL per minute or high-dose chemotherapy, and for pediatric patients who receive high-emetic-risk antineoplastic agents. For radiation-induced nausea and vomiting, adjustments were made to anatomic regions, risk levels, and antiemetic administration schedules. Rescue therapy alone is now recommended for low-emetic-risk radiation therapy. The Expert Panel reiterated the importance of using the most effective antiemetic regimens that are appropriate for antineoplastic agents or radiotherapy being administered. Such regimens should be used with initial treatment, rather than first assessing the patient's emetic response with less-effective treatment. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .
Antiemetics: ASCO Guideline Update Hesketh, Paul J; Kris, Mark G; Basch, Ethan ...
Journal of clinical oncology,
08/2020, Volume:
38, Issue:
24
Journal Article
Peer reviewed
To update the guideline to include new anticancer agents, antiemetics, and antiemetic regimens and to provide recommendations on the use of dexamethasone as a prophylactic antiemetic in patients ...receiving checkpoint inhibitors (CPIs).
ASCO convened an Expert Panel and updated the systematic review to include randomized controlled trials (RCTs) and meta-analyses of RCTs published between June 1, 2016, and January 24, 2020. To address the dexamethasone and CPI question, we conducted a systematic review of RCTs that evaluated the addition of a CPI to chemotherapy.
The systematic reviews included 3 publications from the updated search and 10 publications on CPIs. Two phase III trials in adult patients with non-small-cell lung cancers evaluating a platinum-based doublet with or without the programmed death 1 (PD-1) inhibitor pembrolizumab recommended that all patients receive dexamethasone as a component of the prophylactic antiemetic regimen. In both studies, superior outcomes were noted in the PD-1 inhibitor-containing arms. Other important findings address olanzapine in adults and fosaprepitant in pediatric patients.
Recommendations for adults are unchanged with the exception of the option of adding olanzapine in the setting of hematopoietic stem cell transplantation. Dosing information now includes the option of a 5-mg dose of olanzapine in adults and intravenous formulations of aprepitant and netupitant-palonosetron. The option of fosaprepitant is added to pediatric recommendations. There is no clinical evidence to warrant omission of dexamethasone from guideline-compliant prophylactic antiemetic regimens when CPIs are administered to adults in combination with chemotherapy. CPIs administered alone or in combination with another CPI do not require the routine use of a prophylactic antiemetic.Additional information is available at www.asco.org/supportive-care-guidelines.
Hydrologic projections are of vital socio-economic importance. However, they are also prone to uncertainty. In order to establish a meaningful range of storylines to support water managers in ...decision making, we need to reveal the relevant sources of uncertainty. Here, we systematically and extensively investigate uncertainty in hydrologic projections for 605 basins throughout the contiguous US. We show that in the majority of the basins, the sign of change in average annual runoff and discharge timing for the period 2070–2100 compared to 1985–2008 differs among combinations of climate models, hydrologic models, and parameters. Mapping the results revealed that different sources of uncertainty dominate in different regions. Hydrologic model induced uncertainty in the sign of change in mean runoff was related to snow processes and aridity, whereas uncertainty in both mean runoff and discharge timing induced by the climate models was related to disagreement among the models regarding the change in precipitation. Overall, disagreement on the sign of change was more widespread for the mean runoff than for the discharge timing. The results demonstrate the need to define a wide range of quantitative hydrologic storylines, including parameter, hydrologic model, and climate model forcing uncertainty, to support water resource planning.
A meta-analysis on 192 peer-reviewed articles reporting on applications of the variable infiltration capacity (VIC) model in a distributed way reveals that the spatial resolution at which the model ...is applied has increased over the years, while the calibration and validation time interval has remained unchanged. We argue that the calibration and validation time interval should keep pace with the increase in spatial resolution in order to resolve the processes that are relevant at the applied spatial resolution. We identified six time concepts in hydrological models, which all impact the model results and conclusions. Process-based model evaluation is particularly relevant when models are applied at hyper-resolution, where stakeholders expect credible results both at a high spatial and temporal resolution.
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