Diatom teratologies as biomarkers of contamination: Are all deformities ecologically meaningful?

Contaminant-related stress on aquatic biota is difficult to assess when lethal impacts are not observed. Diatoms, by displaying deformities (teratologies) in their valves, have the potential to reflect sub-lethal responses to environmental stressors such as metals and organic compounds. For this reason, there is great interest in using diatom morphological aberrations in biomonitoring. However, the detection and mostly the quantification of teratologies is still a challenge; not all studies have succeeded in showing a relationship between the proportion of abnormal valves and contamination level along a gradient of exposure. This limitation in part reflects the loss of ecological information from diatom teratologies during analyses when all deformities are considered. The type of deformity, the severity of aberration, species proneness to deformity formation, and propagation of deformities throughout the population are key components and constraints in quantifying teratologies. Before a metric based on diatom deformities can be used as an indicator of contamination, it is important to better understand the “ecological signal” provided by this biomarker. Using the overall abundance of teratologies has proved to be an excellent tool for identifying contaminated and non-contaminated environments (presence/absence), but refining this biomonitoring approach may bring additional insights allowing for a better assessment of contamination level along a gradient. The dilemma: are all teratologies significant, equal and/or meaningful in assessing changing levels of contamination? This viewpoint article examines numerous interrogatives relative to the use of diatom teratologies in water quality monitoring, provides selected examples of differential responses to contamination, and proposes solutions that may refine our understanding and quantification of the stress. This paper highlights the logistical problems associated with accurately evaluating and interpreting teratologies and stimulates more discussion and research on the subject to enhance the sensitivity of this metric in bioassessments

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)—a white paper

PurposeThis white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research.MethodsAn international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science.ResultsExperts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship.ConclusionRecommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide.Relevance to inform research policyOur suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship

Monocyte Gene Expression Signature of Patients with Early Onset Coronary Artery Disease

The burden of cardiovascular disease (CVD) cannot be fully addressed by therapy targeting known pathophysiological pathways. Even with stringent control of all risk factors CVD events are only diminished by half. A number of additional pathways probably play a role in the development of CVD and might serve as novel therapeutic targets. Genome wide expression studies represent a powerful tool to identify such novel pathways. We compared the expression profiles in monocytes from twenty two young male patients with premature familial CAD with those from controls matched for age, sex and smoking status, without a family history of CVD. Since all patients were on statins and aspirin treatment, potentially affecting the expression of genes in monocytes, twelve controls were subsequently treated with simvastatin and aspirin for 6 and 2 weeks, respectively

Targeting CD73 with flavonoids inhibits cancer stem cells and increases lymphocyte infiltration in a triple-negative breast cancer mouse model

IntroductionChemotherapy remains the mainstay treatment for triple-negative breast cancer (TNBC) due to the lack of specific targets. Given a modest response of immune checkpoint inhibitors in TNBC patients, improving immunotherapy is an urgent and crucial task in this field. CD73 has emerged as a novel immunotherapeutic target, given its elevated expression on tumor, stromal, and specific immune cells, and its established role in inhibiting anti-cancer immunity. CD73-generated adenosine suppresses immunity by attenuating tumor-infiltrating T- and NK-cell activation, while amplifying regulatory T cell activation. Chemotherapy often leads to increased CD73 expression and activity, further suppressing anti-tumor immunity. While debulking the tumor mass, chemotherapy also enriches heterogenous cancer stem cells (CSC), potentially leading to tumor relapse. Therefore, drugs targeting both CD73, and CSCs hold promise for enhancing chemotherapy efficacy, overcoming treatment resistance, and improving clinical outcomes. However, safe and effective inhibitors of CD73 have not been developed as of now.MethodsWe used in silico docking to screen compounds that may be repurposed for inhibiting CD73. The efficacy of these compounds was investigated through flow cytometry, RT-qPCR, CD73 activity, cell viability, tumorsphere formation, and other in vitro functional assays. For assessment of clinical translatability, TNBC patient-derived xenograft organotypic cultures were utilized. We also employed the ovalbumin-expressing AT3 TNBC mouse model to evaluate tumor-specific lymphocyte responses.ResultsWe identified quercetin and luteolin, currently used as over-the-counter supplements, to have high in silico complementarity with CD73. When quercetin and luteolin were combined with the chemotherapeutic paclitaxel in a triple-drug regimen, we found an effective downregulation in paclitaxel-enhanced CD73 and CSC-promoting pathways YAP and Wnt. We found that CD73 expression was required for the maintenance of CD44highCD24low CSCs, and co-targeting CD73, YAP, and Wnt effectively suppressed the growth of human TNBC cell lines and patient-derived xenograft organotypic cultures. Furthermore, triple-drug combination inhibited paclitaxel-enriched CSCs and simultaneously improved lymphocyte infiltration in syngeneic TNBC mouse tumors.DiscussionConclusively, our findings elucidate the significance of CSCs in impairing anti-tumor immunity. The high efficacy of our triple-drug regimen in clinically relevant platforms not only underscores the importance for further mechanistic investigations but also paves the way for potential development of new, safe, and cost-effective therapeutic strategies for TNBC

Distribution of Corbicula fluminea (Müller, 1774) in the invaded range: a geographic approach with notes on species traits variability

Corbicula fluminea is considered one of the most important non-native invasive species (NIS) in aquatic systems mainly due to its widespread distribution and ecological and economic impacts. This species is known to negatively affect native bivalves, also with severe effects on biodiversity and ecosystem functioning. Throughout an exhaustive bibliographic survey and with the aid of Geographic Information Systems tools, this study tracks the species dispersion from its native range, including the description of important physical and environmental barriers. Additional analyses were conducted to examine possible influences of latitudinal/ temperature gradients on important traits (e.g. life span, maximum and mean body length, growth at the end of first year). Altitude and winter minimum temperature appear to be delaying the invasion worldwide, but it seems inevitable that the species will spread across the globe. Latitude and summer temperature show a relationship with growth and life span. Overall, the information gathered in this review may be relevant to forecast future distribution patterns of this NIS, and to anticipate the possible implementation of effective management measures. Moreover, it may constitute a valuabletool inthe prediction of population responses to an increasingly changing environment.This research was supported by FCT (Portuguese Foundation for Science and Technology), through a PhD grant attributed to D. Crespo (SFRH/BD/80252/2011), a post-doc grant attributed to S. Leston (SFRH/BPD/91828/2012) and M Dolbeth (SFRH/BPD/41117/2007) and BIOCHANGED project (PTDC/MAR/111901/2009), subsidized by the European Social Fund and MCTES (Ministério da Ciência, Tecnologia e Ensino Superior) National Funds, through the POPH (Human Potential Operational Programme), QREN (National Strategic Reference Framework) and COMPETE (Programa Operacional Factores de Competitividade).info:eu-repo/semantics/publishedVersio

Hypotension following Patent Ductus Arteriosus Ligation: The Role of Adrenal Hormones

OBJECTIVE: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. STUDY DESIGN: We performed a multicenter study of infants born at <32 weeks gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured three times: before and after a cosyntropin (1.0 microgram/kg) stimulation test (performed prior to the ligation), and at 10–12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified Inotrope Score (1 x dopamine (μg/kg/min) + 1 x dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their highest Inotrope Score was >15. RESULTS: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low post-operative cortisol levels were not associated with the overall incidence of hypotension following ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the odds ratio for developing catecholamine-resistant hypotension was OR=36.6, CI=2.8–476, p=0.006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not due to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. CONCLUSION: Infants with low cortisol concentrations following PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production