Solid tumors are generally characterized by an acidic tumor microenvironment (TME) that favors cancer progression, therapy resistance and immune evasion. By single-cell RNA-sequencing analysis in ...individuals with pancreatic ductal adenocarcinoma (PDAC), we reveal solute carrier family 4 member 4 (SLC4A4) as the most abundant bicarbonate transporter, predominantly expressed by epithelial ductal cells. Functionally, SLC4A4 inhibition in PDAC cancer cells mitigates the acidosis of the TME due to bicarbonate accumulation in the extracellular space and a decrease in lactate production by cancer cells as the result of reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological SLC4A4 targeting improves T cell-mediated immune response and breaches macrophage-mediated immunosuppression, thus inhibiting tumor growth and metastases. In addition, Slc4a4 targeting in combination with immune checkpoint blockade is able to overcome immunotherapy resistance and prolong survival. Overall, our data propose SLC4A4 as a therapeutic target to unleash an antitumor immune response in PDAC.
Since the introduction of brain mapping, evidences of functional gender differences have been corroborating previous behavioral and neuropsychological results showing a sex-specific brain ...organization. We investigated gender differences in brain activation during the performance of the Tower of London (TOL) task which is a standardized test to assess executive functions. Eighteen healthy subjects (9 females and 9 males) underwent fMRI scanning while solving a series of TOL problems with different levels of difficulty. Data were analyzed by modeling both genders and difficulty task load. Task-elicited brain activations comprised a bilateral fronto-parietal network, common to both genders; within this network, females activated more than males in dorsolateral prefrontal cortex (DLPFC) and right parietal cortex, whereas males showed higher activity in precuneus. A prominent parietal activity was found at low level of difficulty while, with heavier task demand, several frontal regions and subcortical structures were recruited. Our results suggest peculiar gender strategies, with males relying more on visuospatial abilities and females on executive processing.
We hypothesized that the IL-1β-511 C>T polymorphism could be associated with the development of neurotoxicity and that it could be a possible biomarker to rate the risk of occurrence of neurotoxicity ...in cancer patients. Genomic DNA was extracted from 85 cancer patients: 49 received systemic chemotherapeutic treatment (CHT) and 36 patients did not receive it (No-CHT). All subjects were genotyped for the functionally active polymorphisms of IL-1β-511 C>T. We estimated neurotoxicity with the evaluation of neurological deficits. CHT patients showed erythrocytopenia, neurological deficit and a slight lowering of cognitive performance. The subgroup of patients carrying the CC genotype of the IL-1β-511 C>T gene showed lesser neurological deficits. In the context of cancer treatment, we suggested the potential value of IL-1β-511 C>T as genetic biomarkers to identify patients with higher risk to develop neurological deficits.
Abstract
STUDY QUESTION
We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research.
WHAT IS KNOWN ALREADY
Research into male ...infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research.
STUDY DESIGN, SIZE, DURATION
Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health’s consensus development conference.
PARTICIPANTS/MATERIALS, SETTING, METHODS
An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes.
STUDY FUNDING/COMPETING INTEREST(S)
This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open. K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests.
TRIAL REGISTRATION NUMBER
Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586.
TRIAL REGISTRATION DATE
N/A.
DATE OF FIRST PATIENT’S ENROLMENT
N/A.
The abundance, biomass and size-structure of planktonic populations, and the microbial metabolic processes were studied in the Sicily Channel, one of the most important spawning areas in the ...Mediterranean for anchovy (Engraulis encrasicolus), a pelagic species of commercial interest. Results showed that prokaryotes contribute for the 83% of total carbon biomass. Microphytoplankton abundances and biomasses were dominated by autotrophic nanoflagellates and dinoflagellates (36 identified species) and contribute 11% of total biomass. The microzooplanktonic biomass showed its maximum at the surface or subsurface and its contribution was low (4%). In agreement with the general oligotrophy of the investigated area, the study highlights the prevalence of pico-sized fractions within the whole phytoplankton biomass expressed as chlorophyll content, suggesting the importance of picophytoplankton in sustaining the microbial food web. At the same time, the levels of microbial hydrolytic activities are related to productive processes recycling the organic matter and releasing nutrients (P and N), indicating also an active functioning of ecosystem at low trophic levels. Autotrophic production exceeded oxidation by respiration; at the same time, the co-variation of prokaryotic activities and eggs distribution with temperature in summer was observed. The results obtained confirmed that the area acted as a nursery for small fish and both autotrophic and heterotrophic processes supported by microorganisms were in synergy.
•This study focused on the planktonic populations and the functioning of the microbial food web in a spawning area.•The prevalence of pico-sized populations as chlorophyll was observed.•Microbial hydrolysis of organic matter, recycling nutrients, was related to productive processes.•The small-size cells were relevant in sustaining the microbial food web in oligotrophic area.•Co-variations of microbial loop and eggs deposition with environment parameters were discussed.
Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy ...is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients.
To develop a risk score to predict SM in adults with MIS.
We examined 1145 patients with MIS from the European Competence Network on Mastocytosis Registry who underwent a bone marrow biopsy. A total of 944 patients had SM and 201 patients had cutaneous mastocytosis; 63.7% were female, and 36.3% were male. Median age was 44 ± 13.3 years. The median serum tryptase level amounted to 29.3 ± 81.9 ng/mL. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver-operating curves.
In the multivariate model, the tryptase level (P < .001), constitutional/cardiovascular symptoms (P = .014), and bone symptoms/osteoporosis (P < .001) were independent predictors of SM (P < .001; sensitivity, 90.7%; specificity, 69.1%). A 6-point risk score was established (risk, 10.7%-98.0%) and validated.
Using a large data set of the European Competence Network on Mastocytosis Registry, we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure cutaneous mastocytosis.
•Serum chemistry profiling is of diagnostic and prognostic relevance based on easily accessible parameters.•Serum chemistry markers help to assess and quantify organ damage.
Display omitted
Certain ...laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, β2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308μg/L vs 146μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio HR, 2.1; 95% confidence interval CI, 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis–AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.
The composition of fatty acids was studied in the mussels collected in the Mar Grande of Taranto (northern Ionian Sea) during the four seasons. Micro-, nano- and picophytoplankton abundance, biomass ...and composition have been also evaluated. Fatty acids compositions were investigated for lipid biomarkers to establish the contribution of phytoplankton to the mussel diet. Saturated (SAFA) and monounsaturated fatty acids (MUFA) were the most abundant components, followed by polyunsaturated fatty acids (PUFA). The seasonal variations in the SAFAs, MUFAs and PUFAs were not significantly different during the whole study period (ANOVA, P < 0.05). The most abundant identified FAs were 16:0 (27.51–33.80% of total FAs), 14:1 (3.35–9.91% of total FAs), 18:1n9 (2.92–8.87%), 16:1 n7 (4.53– 7.61%) and 24:1n9 (0.43–8.84%). The most important PUFAs were 22:2 (2.35–3.48% of total FAs) and also 18:2n-6 (1.66–2.61%). PUFAs were characterized by low percentages of n3 and n6 FAs. Analysis of specific FA markers for diatoms (16:1n7, 20:5n3), phytoflagellates and dinoflagellates (16:0, 18:4n3) showed a negligible contribution of phytoplankton to the mussel diet.
PDF
