Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial

BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches

Neuropsychological function is related to irritable bowel syndrome in women with premenstrual syndrome and dysmenorrhea

Background There is increasing evidence demonstrating the co-occurrence of primary dysmenorrhea (PD), premenstrual syndrome (PMS), and irritable bowel syndrome (IBS) in women. This study aimed to investigate whether women who have symptoms of IBS in addition to PD and PMS also report more severe or frequent menstruation-associated symptoms and psychological complications compared to women with PD and PMS alone. Methods The study group included 182 female University students aged 18–25 years. IBS was diagnosed using the Rome III criteria. The severity of PMS and PD was determined using a 10-point visual analog scale and PSST (Premenstrual Syndrome Screening Tool), respectively. Neuropsychological functions including cognitive function, depression score, anxiety score, stress, insomnia, daytime sleepiness, quality of life and personality were assessed using standard questionnaires. Results Of the 182 young females, 31 (17.0%) had IBS. Average days of bleeding during the menstrual cycle and mean pain severity on the PSST scale were significantly greater in the group with IBS compared to the non-IBS group (p < 0.01). The non-IBS individuals scored more favorably than the women with IBS with respect to severity of depression, insomnia, daytime sleepiness (p < 0.05). The PSST scores were significantly correlated with scores for depression (r = 0.29; p < 0.001), anxiety (r = 0.28; p < 0.001), stress (r = 0.32; p < 0.001), insomnia (r = 0.34; p < 0.001) and daytime sleepiness (r = 0.31; p < 0.001); while, they were negatively correlated with cognitive abilities (r = − 0.20; p = 0.006) and quality of life (r = − 0.42; p < 0.001). Linear regression analysis showed that the PSST scores were possibly significant factors in determining the scores for depression, anxiety, stress, quality of life, insomnia and daytime sleepiness (p < 0.05). Conclusion IBS is related to psychological comorbidities, in particular depression, sleep problems and menstrual-associated disorders. IBS may exacerbate the features of PMS which should be taken into account in the management of PMS

Current status and trends of biological invasions in the Lagoon of Venice, a hotspot of marine NIS introductions in the Mediterranean Sea

This paper provides an updated account of the occurrence and abundance of non-indigenous species (NIS) in an area of high risk of introduction: the Lagoon of Venice (Italy). This site is a known hotspot of NIS introductions within the Mediterranean Sea, hosting all the most important vectors of introduction of marine NIS—shipping, recreational boating, shellfish culture and live seafood trade. The recent literature demonstrates that the number of NIS in Venice is continuously changing, because new species are being introduced or identified, and new evidence shows either an exotic origin of species previously believed to be native, or a native origin of formerly believed ‘‘aliens’’, or demonstrates the cryptogenic nature of others. The number of NIS introduced in the Venetian lagoon currently totals 71, out of which 55 are established. This number exceeds those displayed by some nations like Finland, Portugal or Libya. Macroalgae are the taxonomic group with the highest number of introduced species (41 % of NIS): the most likely vector for their introduction is shellfish culture. The source region of NIS introduced to Venice is mainly represented by other Mediterranean or European sites (76 %). The Lagoon of Venice represents a sink but also a source of NIS in the Mediterranean Sea, as it is the site of first record of several NIS, which have since further spread elsewhere.This paper provides an updated account of the occurrence and abundance of non-indigenous species (NIS) in an area of high risk of introduction: the Lagoon of Venice (Italy). This site is a known hotspot of NIS introductions within the Mediterranean Sea, hosting all the most important vectors of introduction of marine NIS-shipping, recreational boating, shellfish culture and live seafood trade. The recent literature demonstrates that the number of NIS in Venice is continuously changing, because new species are being introduced or identified, and new evidence shows either an exotic origin of species previously believed to be native, or a native origin of formerly believed "aliens", or demonstrates the cryptogenic nature of others. The number of NIS introduced in the Venetian lagoon currently totals 71, out of which 55 are established. This number exceeds those displayed by some nations like Finland, Portugal or Libya. Macroalgae are the taxonomic group with the highest number of introduced species (41 % of NIS): the most likely vector for their introduction is shellfish culture. The source region of NIS introduced to Venice is mainly represented by other Mediterranean or European sites (76 %). The Lagoon of Venice represents a sink but also a source of NIS in the Mediterranean Sea, as it is the site of first record of several NIS, which have since further spread elsewhere

Population-level risks of alcohol consumption by amount, geography, age, sex, and year: a systematic analysis for the Global Burden of Disease Study 2020

Background The health risks associated with moderate alcohol consumption continue to be debated. Small amounts of alcohol might lower the risk of some health outcomes but increase the risk of others, suggesting that the overall risk depends, in part, on background disease rates, which vary by region, age, sex, and year. Methods For this analysis, we constructed burden-weighted dose–response relative risk curves across 22 health outcomes to estimate the theoretical minimum risk exposure level (TMREL) and non-drinker equivalence (NDE), the consumption level at which the health risk is equivalent to that of a non-drinker, using disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for 21 regions, including 204 countries and territories, by 5-year age group, sex, and year for individuals aged 15–95 years and older from 1990 to 2020. Based on the NDE, we quantified the population consuming harmful amounts of alcohol. Findings The burden-weighted relative risk curves for alcohol use varied by region and age. Among individuals aged 15–39 years in 2020, the TMREL varied between 0 (95% uncertainty interval 0–0) and 0·603 (0·400–1·00) standard drinks per day, and the NDE varied between 0·002 (0–0) and 1·75 (0·698–4·30) standard drinks per day. Among individuals aged 40 years and older, the burden-weighted relative risk curve was J-shaped for all regions, with a 2020 TMREL that ranged from 0·114 (0–0·403) to 1·87 (0·500–3·30) standard drinks per day and an NDE that ranged between 0·193 (0–0·900) and 6·94 (3·40–8·30) standard drinks per day. Among individuals consuming harmful amounts of alcohol in 2020, 59·1% (54·3–65·4) were aged 15–39 years and 76·9% (73·0–81·3) were male. Interpretation There is strong evidence to support recommendations on alcohol consumption varying by age and location. Stronger interventions, particularly those tailored towards younger individuals, are needed to reduce the substantial global health loss attributable to alcohol. Funding Bill & Melinda Gates Foundation

SYNTHESIS OF HIGH REFRACTIVE-INDEX ACRYLIC COPOLYMERS

A series of brominated carbazole-containing monomers with a polymerizable acrylic or methacrylic functionality were synthesized and characterized. These monomers were polymerized thermally and characterized by differential scanning calorimetry (DSC) and refractive index via Brewster's angle. The monomer 4-(1,3,6,8-tetrabromo-9-carbazolyl)-1-butyl acrylate (4b) was copolymerized with methyl methacrylate (M(2)) yielding the reactivity ratios r(1)=1.08 and r(2)=0.93; these Values were used in the Skeist procedure to predict compositional drift with conversion. The Alfrey-Price Q and e values for (4b) were 0.86 and 0.46, respectively. The copolymers were all colourless and transparent, despite the absence of an azeotrope for this comonomer pair, and their refractive indices were found to lie between those of the constituent homopolymers. Copolymers rich in methyl methacrylate (MMA) were found to be soluble, yet those rich in 4b were found to be intractable

Phosphitylation via the Mitsunobu reaction

Treatment of a dialkyl phosphite with triphenylphosphine and diisopropyl azodicarboxylate in toluene, followed by addition of an alcohol, results in the formation of the corresponding trialkyl phosphite. Similarly, dialkyl phosphonites can be synthesised from monoalkyl phosphites (alkyl phosphinates)