In vivo effectiveness and safety of probiotics on prophylaxis and treatment of oral candidiasis: a systematic review and meta-analysis

BACKGROUND: To systematically review and assess the in vivo effectiveness and safety of probiotics for prophylaxis and treating oral candidiasis. METHODS: A literature search for studies published in English until August 1, 2018 was conducted in the following databases: PubMed, EMBASE, Cochrane Library, and Web of Science. Randomized controlled clinical trials and experimental mouse animal model studies comparing probiotics (at any dosage and in any form) with control groups (placebo, blank control or other agents) and reporting outcomes of the prophylactic and therapeutic effects were considered for inclusion. A descriptive study and, potentially, a meta-analysis were planned. RESULTS: Six randomized controlled clinical trials and 5 controlled experiments of mouse animal models were included in the systematic review. Four randomized controlled clinical trials comparing a probiotics group with a placebo/blank control group in 480 elderly and denture wearers were included in the meta-analysis. The overall combined odds ratio of the (random effects) meta-analysis was 0.24 (95% CI =0.09-0.63, P \u3c 0.01). The overall combined odds ratio of the (fixed effects) sensitivity analysis was 0.39 (95% CI =0.25-0.60, P \u3c 0.01) by excluding a study with the smallest sample size. These analyses showed that there was a statistically significant difference in the effect of probiotics compared with the control groups in elderly and denture wearers. The remaining 2 studies compared probiotics with other agents in a population aged 18-75 years and children aged 6-14 years respectively, and were analyzed descriptively. Meta-analysis and descriptive analyses indicated that probiotics were potentially effective in reducing morbidity, improving clinical symptoms and reducing oral Candida counts in oral candidiasis. The biases of the included studies were low or uncertain. The relatively common complaints reported were gastrointestinal discomfort and unpleasant taste, and no severe adverse events were reported. CONCLUSIONS: Probiotics were superior to the placebo and blank control in preventing and treating oral candidiasis in the elderly and denture wearers. Although probiotics showed a favorable effect in treating oral candidiasis, more evidence is required to warrant their effectiveness when compared with conventional antifungal treatments. Moreover, data on the safety of probiotics are still insufficient, and further research is needed

Challenges Associated with Tyrosine Kinase Inhibitor Therapy for Metastatic Thyroid Cancer

Tyrosine kinase inhibitors (TKIs) which target angiogenesis are promising treatments for patients with metastatic medullary and differentiated thyroid cancers. Sorafenib, sunitinib, and pazopanib are commercially available drugs which have been studied in these diseases. Vandetanib is the first drug approved in the United States for treatment of medullary thyroid cancer. These TKIs are used as chronic therapies, and therefore it is imperative to understand the adverse event profile in order to avoid excessive toxicity and maintain patients on therapy as long as it proves beneficial. Here we review common toxicities, management of these, and other challenging situations that arise when using TKIs in patients with thyroid cancer

Valuing Nature in Business-A Case Study of Chemical Manufacturing and Forest Products Industries

Over the past several decades, there has been an increased realization of the extent to which the means of production in human society depend on and impact increasingly fragile natural systems. Working with our client, The Nature Conservancy, we researched trends in ecosystem valuation within the chemical manufacturing and forest product industries, discerning ways to identify and evaluate future ecosystem investment opportunities. This research resulted in a framework that businesses could use to identify future ecosystem service opportunities and then score the opportunities’ business values using a multi-criteria analysis approach. We identified potential ecosystem service opportunities by overlaying classifications of business risk on major operational subsectors within the industries, populating the resulting table with key ecosystem impacts and opportunities. Through the application of this process, we identified three hypothetical ecosystem service projects applicable to both the chemical manufacturing and forest product industries and used them to test our scoring framework. The identified projects were constructed wetlands for wastewater treatment, coastal habitat protection for storm surge protection, and forest carbon sequestration. We ranked the business value of each project using five criteria important to businesses: financial value, reputational benefits, environmental risk reduction, political and regulatory enabling conditions, and level of knowledge and activity in the field. According to our research, businesses emphasize financial benefits most highly when evaluating potential investments, so we weighted financial values most heavily in our ranking scheme. Our analysis indicated that a forest carbon sequestration project had the highest potential business value relative to the other project types due to its higher expected financial benefits. The constructed wetland project, which also had a relatively high expected financial benefit, followed second. Finally, the coastal habitat protection project had the lowest relative business value due to high costs, a low level of scientific knowledge, and weak regulatory support. The identification and ranking methodologies are designed to be flexible, allowing adaptation for use given varying business objectives. The weights on the five valuation criteria can be adjusted to reflect a business’s concerns. This scoring methodology is useful for businesses because few tools exist to enable comparative analysis of business ecosystem service investments. We believe this tool provides a useful approach to determining the value that nature and ecosystem services provide to a wide range of businesses, and we recommend its application outside the chemical manufacturing and forest products industry for further refinement

LIBRETTO-531: a phase III study of selpercatinib in multikinase inhibitor-naïve RET-mutant medullary thyroid cancer

Medullary thyroid cancer; Selpercatinib; Targeted therapyCáncer medular de tiroides; Selpercatinib; Terapia dirigidaCàncer medul·lar de tiroide; Selpercatinib; Teràpia dirigidaSelpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib

Insulin-Like Growth Factor Axis and Risk of Type 2 Diabetes in Women

IGF-I shares structural homology and in vitro metabolic activity with insulin. Laboratory models suggest that IGF-I and its binding proteins IGFBP-1 and IGFBP-2 have potentially beneficial effects on diabetes risk, whereas IGFBP-3 may have adverse effects. We therefore conducted a prospective nested case-control investigation of incident diabetes (n = 742 case subjects matched 1:1 to control subjects) and its associations with IGF-axis protein levels in the Nurses’ Health Study, a cohort of middle-aged women. The median time to diabetes was 9 years. Statistical analyses were adjusted for multiple risk factors, including insulin and C-reactive protein. Diabetes risk was fivefold lower among women with baseline IGFBP-2 levels in the top versus bottom quintile (odds ratio [OR]q5–q1 = 0.17 [95% CI 0.08–0.35]; P trend < 0.0001) and was also negatively associated with IGFBP-1 levels (ORq5–q1 = 0.37 [0.18–0.73]; P trend = 0.0009). IGFBP-3 was positively associated with diabetes (ORq5–q1 = 2.05 [1.20–3.51]; P trend = 0.002). Diabetes was not associated with total IGF-I levels, but free IGF-I and diabetes had a significant association that varied (P interaction = 0.003) by insulin levels above the median (ORq5–q1 = 0.48 [0.26–0.90]; P trend = 0.0001) versus below the median (ORq5–q1 = 2.52 [1.05–6.06]; P trend < 0.05). Thus, this prospective study found strong associations of incident diabetes with baseline levels of three IGFBPs and free IGF-I, consistent with hypotheses that the IGF axis might influence diabetes risk

Review article: new treatments for advanced differentiated thyroid cancers and potential mechanisms of drug resistance

The treatment of advanced, radioiodine refractory, differentiated thyroid cancers (RR-DTCs) has undergone major advancements in the last decade, causing a paradigm shift in the management and prognosis of these patients. Better understanding of the molecular drivers of tumorigenesis and access to next generation sequencing of tumors have led to the development and Food and Drug Administration (FDA)-approval of numerous targeted therapies for RR-DTCs, including antiangiogenic multikinase inhibitors, and more recently, fusion-specific kinase inhibitors such as RET inhibitors and NTRK inhibitors. BRAF + MEK inhibitors have also been approved for BRAF-mutated solid tumors and are routinely used in RR-DTCs in many centers. However, none of the currently available treatments are curative, and most patients will ultimately show progression. Current research efforts are therefore focused on identifying resistance mechanisms to tyrosine kinase inhibitors and ways to overcome them. Various novel treatment strategies are under investigation, including immunotherapy, redifferentiation therapy, and second-generation kinase inhibitors. In this review, we will discuss currently available drugs for advanced RR-DTCs, potential mechanisms of drug resistance and future therapeutic avenues

LIBRETTO-531: A Phase III Study of Selpercatinib in Multikinase Inhibitor-Naïve

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib

Uterine Epithelial Cell Regulation of DC-SIGN Expression Inhibits Transmitted/Founder HIV-1 Trans Infection by Immature Dendritic Cells

Sexual transmission accounts for the majority of HIV-1 infections. In over 75% of cases, infection is initiated by a single variant (transmitted/founder virus). However, the determinants of virus selection during transmission are unknown. Host cell-cell interactions in the mucosa may be critical in regulating susceptibility to infection. We hypothesized in this study that specific immune modulators secreted by uterine epithelial cells modulate susceptibility of dendritic cells (DC) to infection with HIV-1.Here we report that uterine epithelial cell secretions (i.e. conditioned medium, CM) decreased DC-SIGN expression on immature dendritic cells via a transforming growth factor beta (TGF-β) mechanism. Further, CM inhibited dendritic cell-mediated trans infection of HIV-1 expressing envelope proteins of prototypic reference. Similarly, CM inhibited trans infection of HIV-1 constructs expressing envelopes of transmitted/founder viruses, variants that are selected during sexual transmission. In contrast, whereas recombinant TGF- β1 inhibited trans infection of prototypic reference HIV-1 by dendritic cells, TGF-β1 had a minimal effect on trans infection of transmitted/founder variants irrespective of the reporter system used to measure trans infection.Our results provide the first direct evidence for uterine epithelial cell regulation of dendritic cell transmission of infection with reference and transmitted/founder HIV-1 variants. These findings have immediate implications for designing strategies to prevent sexual transmission of HIV-1

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder