Objective
The aim of this article is to conduct a literature review on first-generation TRK inhibitors (TRKi), namely entrectinib and larotrectinib, to describe the most common adverse events (AEs) ...and their management in adults.
Methods
A search strategy was conducted in MEDLINE, EMBASE, and Google Scholar using a list of predetermined keywords. Peer-reviewed articles written in English and published through June 2021 were included. Articles covered included randomized clinical trials and expert recommendations, as well as patent and other types of reviews.
Results
The discussed AEs include weight gain and withdrawal pain, as well as neuromuscular, central nervous system (dysesthesias and peripheral sensory neuropathies, dizziness and ataxia, and dysgeusia), gastrointestinal (nausea, vomiting, and diarrhea), and respiratory symptoms. Additionally, several AEs encountered with entrectinib specifically (cognitive and vision disorders, congestive heart failure, QTc elongation, and skeletal fractures) are discussed. First, an overall mechanism of action explaining these AEs is presented. Then, for each AE, incidence and severity are stated and followed by practical management recommendations. While nearly all AEs were reversible upon TRKi suspension, the proposed managements are mainly constituted of pharmacological and non-pharmacological interventions.
Conclusion
With the estimated growth of gene sequencing in the coming years, it is foreseeable that TRKi will take a larger position in the oncologic therapeutic arsenal. Therefore, adequate management of AEs associated with TRKi in adults should be a prime focus.
In diatoms, the main photosynthetic pigments are chlorophylls a and c, fucoxanthin, diadinoxanthin and diatoxanthin. The marine pennate diatom Haslea ostrearia has long been known for producing, in ...addition to these generic pigments, a water-soluble blue pigment, marennine. This pigment, responsible for the greening of oysters in western France, presents different biological activities: allelopathic, antioxidant, antibacterial, antiviral, and growth-inhibiting. A method to extract and purify marennine has been developed, but its chemical structure could hitherto not be resolved. For decades, H. ostrearia was the only organism known to produce marennine, and can be found worldwide. Our knowledge about H. ostrearia-like diatom biodiversity has recently been extended with the discovery of several new species of blue diatoms, the recently described H. karadagensis, H. silbo sp. inedit. and H. provincialis sp. inedit. These blue diatoms produce different marennine-like pigments, which belong to the same chemical family and present similar biological activities. Aside from being a potential source of natural blue pigments, H. ostrearia-like diatoms thus present a commercial potential for aquaculture, cosmetics, food and health industries.
Background
Little has been published about the association of venous thromboembolism (VTE) and sarcoma. In this study, we sought to identify clinical features of patients with sarcoma presenting at ...least one VTE episode.
Methods
Our study was a retrospective case–control study of a single‐institution database with univariate and multivariate analysis using chi‐square and Student's t test. A p value less than .05 was considered significant.
Results
The overall incidence of VTE in patients with sarcoma was 7.9%. Predictive factors identified by multivariate analysis were metastatic disease and administration of chemotherapy. It was not statistically possible to correlate the risk of VTE with specific sarcoma subtypes, but observations suggested malignant peripheral nerve sheath tumor, osteosarcoma, and liposarcoma as having the highest propension.
Conclusion
VTE is not infrequent in patients with sarcoma. Adoption of common guidelines for cancer‐associated thrombosis is recommended.
Risk factors and management guidelines for venous thromboembolism (VTE) are well established; however, little clinical research has been undertaken on VTE in sarcomas. This retrospective study aimed to identify the clinical characteristics of adult sarcoma patients with VTE.
Participation is a key determinant of successful aging and enables older adults to stay in their homes and be integrated into the community. Assessing participation needs involves identifying ...restrictions in the accomplishment of daily and social activities. Although meeting participation needs involves older adults, their caregivers and healthcare providers, little is known about their respective viewpoints. This study thus explored the participation needs of older adults having disabilities as perceived by the older adults themselves, their caregivers and healthcare providers.
A qualitative multiple case study consisted of conducting 33 semi-structured interviews in eleven triads, each composed of an older adult, his/her caregiver and a healthcare provider recruited in a Health and Social Services Centre (HSSC) in Québec, Canada. Interview transcripts and reviews of clinical records were analyzed using content analysis and descriptive statistics based on thematic saliency analysis methods.
Aged 66 to 88 years, five older adults had physical disabilities, five had mild cognitive impairment and one had psychological problems, leading to moderate to severe functional decline. Caregivers and healthcare providers were mainly women, respectively retired spouses and various professionals with four to 32 years of clinical experience. Participation needs reported by each triad included all domains of participation. Needs related to daily activities, such as personal care, nutrition, and housing, were generally met. Regarding social activities, few needs were met by various resources in the community and were generally limited to personal responsibilities, including making decisions and managing budgets, and some community life activities, such as going shopping. Unmet needs were mainly related to social activities, involving leisure, other community life activities and interpersonal relationships, and some daily activities, including fitness and mobility.
This study highlights the complexity of older adults' participation needs, involving daily as well as social activities. Properly assessing and addressing these needs is thus necessary to improve older adults' health and well-being. Discrepancies in the various actors' perceptions of participation needs must be further explored. Additional research would help better understand how to optimize the contribution of community organizations and caregivers.
Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome‐wide CRISPR‐Cas9 knockout screen, which revealed the LKB1‐SIK2 module ...in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria‐targeted antioxidant promotes enhanced cell death efficacy in LKB1‐ and SIK2‐negative uveal melanoma cells compared to control cells. Our study also identified an LKB1‐loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.
Synopsis
Most patients with metastatic uveal melanoma die within a year from diagnosis, highlighting an unmet clinical need. A genetic screen was launched to identify actionable vulnerabilities and uncovered the critical role of the kinases LKB1 and SIK2 in constraining metastatic uveal melanoma cell growth.
The sodium/calcium exchanger SLC8A1 mediated the effect of the LKB1‐SIK2 module.
Loss of the LKB1‐SIK2 module and increased SLC8A1 expression were associated with enhanced mitochondrial level of calcium and ROS and increased metastatic uveal melanoma cell growth.
SLC8A1 and mitochondrial ROS were validated as relevant therapeutic target as their combined inhibition induced cell death with a higher sensitivity in LKB1 or SIK2‐depleted metastatic uveal melanoma cells.
A molecular signature related to LKB1 loss was identified as a prognosis biomarker and a predictor of the response to SLC8A1 and mitochondrial ROS inhibition.
Most patients with metastatic uveal melanoma die within a year from diagnosis, highlighting an unmet clinical need. A genetic screen was launched to identify actionable vulnerabilities and uncovered the critical role of the kinases LKB1 and SIK2 in constraining metastatic uveal melanoma cell growth.
Dans cette étude, des tests de compréhension en lecture d’un récit et d’un texte informatif ont été créés à partir de modèles théoriques communs et en suivant des étapes de conception précises ...(DeVellis, 2003). Ils furent administrés auprès de 401 élèves francophones de 8 ans. Les données recueillies ont subi des analyses par items, factorielles et multiniveaux. Ceci a permis d’examiner les taux de réussite aux tests, de mieux déterminer leurs composantes et de les comparer afin de comprendre leur portée pour la communauté praticienne et scientifique. Les résultats révèlent que les deux tests ont une structure factorielle semblable. Or, les questions ouvertes suscitant des inférences anaphoriques, causales et lexicales sont plus ardues à réussir, surtout dans le test utilisant un texte informatif. Ces nouveaux instruments peuvent contribuer à dégager des pistes d’enseignement et favoriser la transition entre le premier et le deuxième cycle du primaire en lecture.
Pigs are major reservoirs of resistant
that can reach humans through consumption of contaminated meat or vegetables grown in manure-fertilized soil. Samples were collected from sows during lactation ...and their piglets at five time points spanning the production cycle. Cefotaxime-resistant bacteria were quantified and isolated from feed, feces, manures and carcasses of pigs reared with penicillin-using or antibiotic-free husbandries. The isolates were characterized by antibiotic susceptibility testing, whole genome sequencing and conjugation assays. The extended spectrum β-lactamase (ESBL) phenotype was more frequent in isolates originating from antibiotic-free animals, while the bacteria isolated from penicillin-using animals were on average resistant to a greater number of antibiotics. The ESBL-encoding genes identified were
,
and
and they co-localised on plasmids with various genes encoding resistance to ß-lactams, co-trimoxazole, phenicols and tetracycline, all antibiotics used in pig production. Groups of genes conferring the observed resistance and the mobile elements disseminating multidrug resistance were determined. The observed resistance to ß-lactams was mainly due to the complementary actions of penicillin-binding proteins, an efflux pump and ß-lactamases. Most resistance determinants were shared by animals raised with or without antimicrobials. This suggests a key contribution of indigenous enterobacteria maternally transmitted along the sow lineage, regardless of antimicrobial use. It is unclear if the antimicrobial resistance observed in the enterobacteria populations of the commercial pig herds studied were present before the use of antibiotics, or the extent to which historical antimicrobial use exerted a selective pressure defining the resistant bacterial populations in farms using penicillin prophylaxis.
Antimicrobial resistance is a global threat that needs to be fought on numerous fronts along the One Health continuum. Vast quantities of antimicrobials are used in agriculture to ensure animal welfare and productivity, and are arguably a driving force for the persistence of environmental and food-borne resistant bacteria. This study evaluated the impact of conventional, organic and other antibiotic-free husbandry practices on the frequency and nature of antimicrobial resistance genes and multidrug resistant enterobacteria. It provides knowledge about the relative contribution of specific resistance determinants to observed antibiotic resistance. It also showed the clear co-selection of genes coding for extended-spectrum beta-lactamases and genes coding for the resistance to antibiotics commonly used for prophylaxis or in curative treatments in pig operations.
Abstract This double-blind study compared initial combination therapy against monotherapy using two antidepressant drugs with complementary mechanisms of action on the serotonin (5-HT) and ...norepinephrine (NE) systems. Sixty one adult patients with a DSM-IV diagnosis of unipolar depression were randomized to receive mirtazapine (30 mg/day), paroxetine (20 mg/day), or the combination of both drugs for 6 weeks. Response at week 4 was defined as a 30% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS), and at week 6 as a 50% reduction in the MADRS. Remission was defined as a reduction in the MADRS score to 10 points or less. After 4 weeks, non-responders in the monotherapy groups had their medication dose increased by 50%. After 6 weeks, non-responders on monotherapy had the second trial drug added to their current regimen. Non-responders on combination therapy had the dosage of both drugs increased by 50%. There was a significantly greater decrease in MADRS scores in the combination group compared to the monotherapy groups at days 28, 35 and 42, with a 10 point difference separating the combination from the monotherapies at day 42. Remission rates at week 6 were 19% on mirtazapine, 26% on paroxetine, and 43% on the combination. Fifteen patients in the mirtazapine arm and 10 in the paroxetine arm who did not respond had the other drug added to their current regimen, and 5 on the combination had an increase in dose of both drugs secondary to non-response. Of these 30 patients, approximately 50% went on to achieve remission in the subsequent 2 weeks. These results indicate that the combined use of two antidepressants was well tolerated and produced a greater improvement than monotherapy.
Untreated HIV infection leads to alterations in HIV-specific CD4+ T cells including increased expression of co-inhibitory receptors (IRs) and skewing toward a T follicular helper cell (Tfh) ...signature. However, which changes are maintained after suppression of viral replication with antiretroviral therapy (ART) is poorly known.
We analyzed blood CD4+ T cells specific to HIV and comparative viral antigens in ART-treated people using a cytokine-independent activation-induced marker assay alone or in combination with functional readouts.
In intra-individual comparisons, HIV-specific CD4+ T cells were characterized by a larger fraction of circulating Tfh (cTfh) cells than CMV- and HBV-specific cells and preferentially expressed multiple IRs and showed elevated production of the Tfh cytokines CXCL13 and IL-21. In addition, HIV-specific cTfh exhibited a predominant Th1-like phenotype and function when compared to cTfh of other specificities, contrasting with a reduction in Th1-functions in HIV-specific non-cTfh. Using longitudinal samples, we demonstrate that this distinct HIV-specific cTfh profile was induced during chronic untreated HIV infection, persisted on ART and correlated with the translation-competent HIV reservoir but not with the total HIV DNA reservoir.
Expansion and altered features of HIV-specific cTfh cells are maintained during ART and may be driven by persistent HIV antigen expression.
This work was supported by the National Institutes of Health (NIH), the Canadian Institutes of Health Research (CIHR) and the FRQS AIDS and Infectious Diseases Network.
•An approach to include climate change to compute PMP and PMF with RCMs is proposed.•Projected increases in spring PMP except for the most northern basin.•Projected change in spring PMF ranges from ...−1.5% to 20% for all basins.•Future PMFs can be accommodated by existing infrastructure and operating rules.
Study Region: In Canada, dams which represent a high risk to human loss of life, along with important environmental and financial losses in case of failure, have to accommodate the Probable Maximum Flood (PMF). Five Canadian basins with different physiographic characteristics and geographic locations, and where the PMF is a relevant metric have been selected: Nelson, Mattagami, Kénogami, Saguenay and Manic-5.
Study Focus: One of the main drivers of the PMF is the Probable Maximum Precipitation (PMP). Traditionally, the computation of the PMP relies on moisture maximization of high efficiency observed storms without consideration for climate change. The current study attempts to develop a novel approach based on traditional methods to take into account the non-stationarity of the climate using an ensemble of 14 regional climate model (RCM) simulations. PMPs, the 100-year snowpack and resulting PMF changes were computed between the 1971-2000 and 2041-2070 periods.
New Hydrological Insights for the Region: The study reveals an overall increase in future spring PMP with the exception of the most northern basin Nelson. It showed a projected increase of the 100-year snowpack for the two northernmost basins, Nelson (8%) and Manic-5 (3%), and a decrease for the three more southern basins, Mattagami (-1%), Saguenay (-5%) and Kénogami (-9%). The future spring PMF is projected to increase with median values between -1.5% and 20%.
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