As a form of immunomodulatory therapeutics, mesenchymal stromal/stem cells (MSCs) from umbilical cord (UC) tissue were assessed for their dynamic interplay with the Th-17 immune response pathway. ...UC-MSCs were able to modulate lymphocyte response by promoting a Th-17-like profile. Such modulation depended on the cell ratio of the cocultures as well as the presence of an inflammatory setting underlying their plasticity. UC-MSCs significantly increased the expression of IL-17A and RORγt but differentially modulated T cell expression of IL-23R. In parallel, the secretion profile of the fifteen factors (IL1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-22, IL-21, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40, and TNF-α) involved in the Th-17 immune response pathway was substantially altered during these cocultures. The modulation of these factors demonstrates the capacity of UC-MSCs to sense and actively respond to tissue challenges. Protein network and functional enrichment analysis indicated that several biological processes, molecular functions, and cellular components linked to distinct Th-17 signaling interactions are involved in several trophic, inflammatory, and immune network responses. These immunological changes and interactions with the Th-17 pathway are likely critical to tissue healing and may help to identify molecular targets that will improve therapeutic strategies involving UC-MSCs.
Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent ...dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 14 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism, reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated an overall milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, and some had alternative symptomatologies with rational biological links to SMC3. Analyses of tumor and model system transcriptomic data and epigenetic data in a subset of cases suggest that SMC3 pLoF variants reduce SMC3 expression but do not strongly support clustering with functional genomic signatures of typical CdLS. Our finding of substantial population-scale LoF intolerance in concert with variable growth and developmental features in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multilayered genomic data paired with careful phenotyping.
To date, heterozygous missense variants and in-frame indels have been reported in association with “atypical” Cornelia de Lange syndrome. Here, we describe variable developmental phenotypes in individuals with heterozygous, predicted loss-of-function SMC3 variants, and investigate the functional effects of this variant type.
The impact of the novel coronavirus pandemic (COVID-19) has spanned across the various aspects of life globally. Understanding public reactions is vital for effective risk communication and outbreak ...control and prevention. The Arab world has diverse cultural, economic, and social structures, so public choices and decisions also vary. To investigate the changes in behavior related to food shopping and handling, precautions measures, and hygiene practices of the public during the pandemic, a web-based survey tool was developed and conducted on 1074 subjects in three Arab countries, Lebanon, Jordan, and Tunisia, using a snowball sampling technique. The results showed a significant reduction in RTE consumption during the pandemic, as shown in the 19.2% and 12.2% rise in the proportion of respondents not ordering hot and cold RTE food delivery, respectively. Compared to pre-COVID-19 times, a substantial increase in behaviors related to hygiene and disinfection practices (22.0%–32.2%) was observed with a lesser increase (11.2%) in handwashing practices before food preparation. Moreover, public concerns about contracting COVID-19 from food led to almost doubling the number of Tunisians using cleaning agents for washing fresh fruits and vegetables (e.g., soaps, non-food grade chlorine bleach) besides a 16% and 26.1% increase in use among the Jordanian and Lebanese, respectively. However, a third of the respondents did not follow instructions on labels for the use of chemical products. In conclusion, this study identified culture-specific shortfalls in handwashing and unsafe food handling practices during COVID-19 in the Arab countries and sheds light on the paramount role of coordinated efforts between the local health authorities and the food safety and public health stakeholders in risk communication. To reduce health risks, there need to be rigorous educational campaigns and targeted messages that reach out to the general audience on hand hygiene, the health effects of haphazard use of unsafe chemical compounds on food, and recommendations on following label instructions.
•The use of chlorine and soaps for cleaning fresh fruits and vegetables increased during the pandemic in the Arab countries.•Although in-store food shopping frequency was low, reliance on the home delivery for food grocery was not common.•The consumption of ready-to-eat foods has significantly decreased during the pandemic.•Some hygienic practices increased during the pandemic, but the least reported was handwashing before food preparation.•The Lebanese showed a higher frequency of protection measures and hygiene practices than did the Jordanians and Tunisians.
An electroactive and luminescent foldamer based on an oligopyridine biscarboxamide skeleton was synthesized and characterised. Its conformation in the solid state proved to be strongly affected by ...the peripheral pyrene units. The latter also endow the target derivative with recognition abilities toward electron-withdrawing molecules, which allow tuning of the spectroscopic properties of the foldamer.
An electroactive and luminescent foldamer proved to have an original hybridized structure and interacts with electron-poor guests.
Immunosuppressive cells such as regulatory T cells (Tregs) have an ambiguous role in breast cancer prognosis, with studies reporting both positive and negative correlations between Treg infiltration ...and prognosis. This discrepancy could be due to the different immunosuppressive molecules present in these cells. In the present study, we phenotypically characterize different Treg subsets infiltrating the tumor microenvironment (TME), compared to adjacent normal tissue and peripheral blood of primary breast cancer (PBC) patients. We report that the majority of tumor-infiltrating CD4+ and CD8+ T cells have terminally exhaustive phenotype as assessed by CD39 and PD-1 expressions. We also show that Tregs are accumulated in breast TME compared to normal tissue. Further characterization of Tregs showed that these are mainly FoxP3+Helios+ and express high levels of CTLA-4 and PD-1. This preferential accumulation of FoxP3+Helios+ Treg subset with co-expression of different immune inhibitory molecules might have a negative effect on breast cancer prognosis. Taken together, our results suggest that breast tumor cells might utilize Tregs, and different suppressive pathways involving CD39, PD-1 and CTLA-4 molecules in creating an immune-subversive environment for them to survive, and a dual blockade of these immunosuppressive molecules might be considered as an effective method in breast cancer treatment.
12053
Background: ICIs are commonly used across solid tumors and although better tolerated than chemotherapy, patients may develop immune related adverse events (irAEs) requiring hospitalization. ...Older adults were poorly represented in trials evaluating ICIs. We previously demonstrated that among older adults receiving ICIs, increasing age was associated with reduced risk of irAE hospitalizations, while frailty was associated with increased acute care use (ASCO 2022). However, sex may impact irAE rates. Here, we evaluated sex-specific differences based on age and frailty, on acute care use and irAEs among older adults receiving ICIs. Methods: We performed a retrospective, population-based study of a cohort of patients with cancer, age ≥ 65, receiving ICIs between June 2012 and October 2018 in Ontario, Canada using administrative data. Databases were deterministically linked to obtain socio-demographic and clinical covariates, and acute care outcomes. Acute care use was defined as emergency department visits or hospitalizations from the start of ICIs to 120 days following last dose; irAE specific hospitalizations were identified using ICD-10 codes. Frailty was assessed using the McIsaac Frailty Index. Using death as the competing risk, multivariable competing risk analyses with Fine Gray sub-distribution hazards evaluated the effect of age and frailty on both acute care use and irAE hospitalizations, adjusted for body mass index (BMI), history of autoimmune condition, comorbidity score, rurality, and hospitalization within 60 days prior to starting ICI, stratified by sex. Results: 2737 patients were identified; 60% male. Median age 73 (IQR 69-78); 43% received Nivolumab, 41% Pembrolizumab and 13% Ipilimumab; 53% had lung cancer, 34% melanoma. 70% were robust (R), 26% pre-frail (PF) and 4% frail (F). 72% of patients had an acute care episode and 8% had an irAE hospitalization, which did not differ by sex (72%/8% male; 71%/8% female). Increasing frailty was associated with greater acute care use in males (PF vs R aHR 1.20 95% CI 1.02-1.40 p = 0.03, F vs R aHR 1.42 1.05-1.91 p = 0.02) and females (PF vs R aHR 1.24 1.03-1.49 p = 0.02, F vs R aHR 1.55 0.99-2.40 p = 0.05) but was not associated with irAE hospitalization in either sex. Using age as a continuous variable, increasing age was associated with reduced irAE hospitalizations in males (aHR 0.97 per year 0.94-0.99 p = 0.04), but not in females (p = 0.18); no significant associations were identified modelling age as a categorical variable. Conclusions: Among older adults receiving ICIs, increasing age was associated with reduced rates of irAE related hospitalization in males but not in females, while increasing frailty was associated with increased acute care use among both sexes. Sex should be taken into consideration when evaluating potential toxicity among older adults receiving ICIs.
•Wheat-fava bean rotation showed a better productivity than wheat-wheat rotation regardless the soil water holding capacity.•Wheat-fava bean rotation has shown less economic risk than other wheat ...based rotations.•Wheat-potato is the most profitable rotation, yet the most economically risky one.•Inputs-use efficiency of wheat would significantly increase when cultivated in deep soils.
The promotion of optimum rotations and agricultural management of winter wheat-based cropping systems is very critical, as wheat is considered an essential component in the Mediterranean diet. Considering the delicate economic situation of farmers in the Mediterranean area, recommending a low risk, sustainable farming system is desirable. In this study, an innovative application of a multi-criteria field-level approach is presented, targeting food security, farmer profitability and environmental sustainability. The CropSyst biophysical simulation model was calibrated and implemented for the study site. It was chosen for its agro-environmental robustness to simulate four rotations (wheat-wheat, wheat-fallow, wheat-potato, and wheat-fava bean). Four types of wheat agricultural management systems (full fertilization and full irrigation, full fertilization and zero irrigation, zero fertilization and full irrigation, and zero fertilization and irrigation) were tested in low and high soil water holding capacity (WHC) types. The effects of soil conditions, management practices and rotation type on wheat grain yields were assessed. Furthermore, the performance of each winter wheat-based cropping system was evaluated in terms of productivity (protein production and profitability) and the efficient use of resources (nitrogen and water), as well as the economic risk of low relative productivity each one engenders. The results show that there is no particular optimal scenario that can simultaneously ensure high productivity, reduce economic risk of low relative productivity, and achieve high wheat- water- and nitrogen-use efficiency. However, the wheat-fava bean rotation cultivated with no wheat fertilization appeared to be a better substitute to the wheat-wheat rotation in terms of protein production (0.93 t/ha versus 0.8 t/ha in low WHC soil and 1.34 t/ha versus 1.17 t/ha in high WHC). This cropping system achieved a higher net profit (2111 US$/ha versus 1222US$/ha in low WHC and 3550 US$/ha versus 2450 US$/ha in high WHC), showing high resource-use efficiency and was less risky for farmers. Moreover, a very high profit could only be attained with the wheat-potato rotation (8640 US$/ha and 12,170 US$/ha in low and high WHC, respectively), yet with low input-efficiency and high economic risk of low relative productivity.
Display omitted
•Hybrids from tetrahydro-1H-pyrazolo3,4-bquinolines were designed and prepared.•The compounds were tested for their dual activity as AChE / COX-2 inhibitors.•All compounds showed ...activities comparable to or significantly higher than tacrine.•Most of the compounds showed activities comparable to celecoxib.•All compounds showed a safe hepatic profile via hepatotoxicity testing.
New tetrahydro-1H-pyrazolo3,4-bquinoline derivatives were designed, synthesized and characterized as dual anticholinestrase and cyclooxygenase-2 inhibitors. The in vitro and in vivo anti-cholinesterase evaluation exhibited promising activities with lower hepatotoxicity for many candidates compared to tacrine as a reference. Furthermore, their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay demonstrated superior activity to celecoxib with higher selectivity indices for some compounds. In addition, some candidates showed extended anti-inflammatory activity by inhibiting COX-2 protein induction. Besides, in silico docking experiments of the active compounds against hAChE rationalized the observed in vitro AChE inhibitory activity. In conclusion, this work provides an extension of the chemical space of tetrahydro-1H-pyrazolo3,4-bquinoline chemotype for the anticholinestrase and anti-inflammatory activity. This would aid to minimize the possible neuroinflammation linked to the pathogenesis of Alzheimer's disease.
This study reports the synthesis of two series of new purine bioisosteres comprising a pyrazolo3,4‐dpyrimidine scaffold linked to piperazine moiety through different amide linkages. The newly ...synthesized compounds were evaluated for anticancer activity against four cell lines (MDA‐MB‐231, MCF‐7, SF‐268, B16F‐10) and cyclooxygenase (COX‐2) protein expression inhibition in lipopolysaccharide (LPS)‐activated rat monocytes. The results revealed that most of the synthesized compounds showed moderate‐to‐high cytotoxic activity against at least one cell line, with compound 10b being the most active against all used cell lines (IC50 values 5.5–11 μg/ml) comparable to cisplatin. In addition, six of these compounds (7b, 10a–d, and 12c) demonstrated inhibition of LPS‐induced COX‐2 protein expression at low concentration (25 μg/ml) as compared to the control non‐stimulated cells and showed a COX‐2 selectivity index range comparable to diclofenac sodium. The overall results indicate that many of these pyrazolopyrimidine derivatives possess in vitro anti‐inflammatory and anticancer activities at varying doses, and the most active compounds will be subjected to in vivo pharmacological evaluation.
Compounds showing dual anticancer/anti‐inflammatory activity are of increasing interest for the treatment of cancer due to the implication of inflammatory mechanisms in most malignancies. This spurred the synthesis of compounds containing a purine character (a scaffold for anticancer drugs) together with a pyrazole moiety (a scaffold for anti‐inflammatory agents). Among these compounds, 10b was the most active against all used cell lines.
PDF
