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The effects of Piper malacophyllum (C. Pesl) C. DC extracts and its isolated compounds were analysed in a mouse model of primary dysmenorrhoea (PD). Female Swiss mice (6-8 weeks old) on proestrus were intraperitoneally treated with estradiol benzoate for 3 days, to induce PD. Twenty-four hours later, animals were treated 24 h later with vehicle, plant extract, gibbilimbol B, 4,6-dimethoxy-5-E-phenylbutenolide, mixture of 4,6-dimethoxy-5-E-phenylbutenolide and 4,6-dimethoxy-5-Z-phenylbutenolide, or ibuprofen. One hour later, oxytocin was injected and the numbers of abdominal writhing were counted. Then, mice were euthanized and uteri were collected for morphometrical and histological analyses. The effects of P. malacophyllum in inflammation were investigated in mouse peritoneal neutrophils culture stimulated with LPS or fMLP (chemotaxis and mediator release). Finally, uterus contractile and relaxing responses were assessed. Similar to ibuprofen, P. malacophyllum extract and isolated compounds reduced abdominal writhing in mice with PD. Histology indicated a marked neutrophil and mast cell infiltrate in the uterus of PD animals which was attenuated by the extract. The compounds and the extract reduced neutrophil chemotaxis and inflammatory mediator release by these cells. Reduced TNF levels were also observed in uteri of PD mice treated with P. malacophyllum. The extract did not affect spontaneous uterine contractions nor those induced by carbachol or KCl. However, it caused relaxation of oxytocin-induced uterine contraction, an effect blunted by H1 receptor antagonist. Overall the results indicate that P. malacophyllum may represent interesting natural tools for reliving PD symptoms, reducing the triad of pain, inflammation and spasmodic uterus behaviour.

Lateral flow antigen tests have been widely used in the Covid-19 pandemic, allowing faster diagnostic test results and preventing further viral spread through isolation of infected individuals. Accomplishment of this screening must be performed with tests that show satisfactory sensitivity in order to successfully detect the target protein and avoid false negatives. The aim of this study was to create a lateral flow test that could detect SARS-CoV-2 nucleocapsid protein in low concentrations that were comparable to the limits of detection claimed by existing tests from the market. To do so, several adjustments were necessary during research and development of the prototypes until they were consistent with these criteria. The proposed alternatives of increasing the test line antibody concentration and addition of an intermembrane between the conjugate pad and the nitrocellulose membrane were able to increase the sensitivity four-fold and generate a new rapid test prototype called “lateral flow intermembrane immunoassay test” (LFIIT). This prototype showed an adequate limit of detection (2.0 ng mL−1) while maintaining affordability and simplicity in manufacturing processes.

Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts.

Engineered T cells transiently expressing tumor-targeting receptors are an attractive form of engineered T cell therapy as they carry no risk of insertional mutagenesis or long-term adverse side-effects. However, multiple rounds of treatment are often required, increasing patient discomfort and cost. To mitigate this, we sought to improve the antitumor activity of transient engineered T cells by screening a panel of small molecules targeting epigenetic regulators for their effect on T cell cytotoxicity. Using a model for engineered T cells targetting hepatocellular carcinoma, we find that short-term inhibition of G9a/GLP increases T cell antitumor activity in in vitro models and an orthotopic mouse model. G9a/GLP inhibition increases granzyme expression without terminal T cell differentiation or exhaustion and results in specific changes in expression of genes and proteins involved in pro-inflammatory pathways, T cell activation and cytotoxicity.

Abstract Background The evolution of SARS-CoV-2 has led to the emergence of several new variants, and few data are available on the impact of vaccination on SARS-CoV-2 variants. We aimed to assess the association between natural (previous infection) and induced (partial or complete vaccination) exposure to SARS-CoV-2 and the onset of new infection supported by the delta variant, and of comparing it with that supported by alpha. Methods We performed a test-negative case-control study, by linking population-based registries of confirmed diagnoses of infection with SARS-CoV-2, vaccinations against Covid-19 and healthcare utilization databases of the Italian Lombardy Region. Four hundred ninety-six persons who between 27 December 2020 and 16 July 2021 had an infection by the delta variant were 1:1 matched with citizens affected by alphavariant and 1:10 matched with persons who had a negative molecular test, according to gender, age and date of molecular ascertainment. We used a conditional logistic regression for estimating relative risk reduction of either variants associated with natural and/or induced immunization and corresponding 95% confidence interval (CI). Results Previous infection was associated with 91% (95% CI 85% to 95%) reduced relative risk of reinfection, without evidence of significant differences between delta and alpha cases (p=0.547). Significant lower vaccinal protection against delta than alpha variant infection was observed with reduced relative risk associated with partial vaccination respectively of 29% (7% to 45%), and 62% (48% to 71%) (p=0.001), and with complete vaccination respectively of 75% (66% to 82%) and 90% (85% to 94%) (p=0.003). Conclusions Lower protection towards infections caused by the delta variant with respect to alpha variant was noticed, even after the completion of the vaccination cycle. This finding would support efforts to maximize both vaccine uptake with two doses and fulfilment with individual protection measures, especially as the delta variant is rampant worldwide presently.

This paper investigates the potential application of red ceramic waste as supplementary cementitious materials in structural concrete as a strategy to implement a circular economy in the Brazilian construction industry from a sustainable infrastructure perspective. The experimental program comprehends the waste characterization and application in concrete mixtures produced with different w/b (0.35, 0.45, and 0.55) and Portland cement replacement (5%, 10%, 20%, and 40%). Eco-efficiency intensity indicators considering cement consumption, carbon dioxide emission, and embodied energy complement the structural concrete assessment. Concrete mixtures with up to 40% of waste, combined with w/b 0.35 and 0.45, did not compromise the concrete structural performance regarding compressive strength. The relatively low water absorption in concrete mixtures produced with up to 40% Portland replacement by red ceramic waste suggests concrete ability to restrain water and vapor ingress on a satisfactory level. Structural concrete with Portland cement replacement by 20% or 40% of waste showed better performance from the eco-efficiency perspective. Structural concrete with Portland cement replacement by 20% or 40% of waste can preserve mechanical properties, reduce carbon dioxide release, and implement a circular economy in the construction industry.

Stereotactic gamma knife radiosurgery (GKS) may induce a transient enlargement of vestibular schwannomas (VS). This phenomenon, known as pseudoprogression or swelling, starts at about 3 months following GKS, peaks at about 6 months, and typically subsides thereafter, usually without significant neurological deterioration. We describe a 34-year-old female who developed an aggressive enlargement of a VS 1 month after GKS. The patient was treated with an immediate external ventricular drainage and surgical resection via retrosigmoid approach for an acute neurological deterioration due to hydrocephalus and brainstem compression. Histopathological examination revealed a VS with abundant intratumoral thrombosis and necrosis, suggesting that its rapid expansion could be related to massive radiation-induced tumor necrosis. The present case indicated that rapid life-threating enlargement of a VS may occur as an early complication following GKS.

To date, there is no compilation of evidence-based information associating photobiomodulation effect and salivary glands. This systematic review aims to assess photobiomodulation effect of low intensity laser on salivary glands in the presence of systemic diseases. MEDLINE databases were searched in duplicate through December 2018. In vivo studies and clinical trials were included if photobiomodulation was performed in salivary glands of animal (rat or mice) or human in the presence of systemic disease. The methodological quality was assessed in duplicate using the modified Newcastle-Ottawa scale (NOS). Search strategy identified 483 potentially eligible articles, and 449 were included. The Boolean search naturally leads to a high amount of works the majority of which were excluded because the analysis of the title and abstract demonstrated it was not focusing on PBM. Only 34 studies were selected for the full-text analysis, of which 5 were excluded due to non-use of photobiomodulation, 4 due to lack of control group, 2 because they were studies of cell cultures and 1 because they did not have the total of animals used. Thus, 21 papers were included for the critical evaluation of the impact of photobiomodulation on the major salivary glands; the studies used rats (n = 10) and humans (n = 11). Although studies reported an increase in the salivary rate, decrease in pain, and increase in quality of life after the PBM, the lack of standards for the application of light and reporting of the parameters, make it hard to reproduce the results. This topic is still in need for further research.

Tumor targeting by genetically modified mesenchymal stromal/stem cells (MSCs) carrying anti-cancer molecules represents a promising cell-based strategy. We previously showed that the pro-apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be successfully delivered by MSCs to cancer sites. While the interaction between TRAIL and its receptors is clear, more obscure is the way in which MSCs can selectively target tumors and their antigens. Several neuroectoderm-derived neoplasms, including glioblastoma (GBM), sarcomas, and neuroblastoma, express high levels of the tumor-associated antigen GD2. We have already challenged this cell surface disialoganglioside by a chimeric antigen receptor (CAR)-T cell approach against neuroblastoma. With the intent to maximize the therapeutic profile of MSCs delivering TRAIL, we here originally developed a bi-functional strategy where TRAIL is delivered by MSCs that are also gene modified with the truncated form of the anti-GD2 CAR (GD2 tCAR) to mediate an immunoselective recognition of GD2-positive tumors. These bi-functional MSCs expressed high levels of TRAIL and GD2 tCAR associated with a robust anti-tumor activity against GD2-positive GBM cells. Most importantly, the anti-cancer action was reinforced by the enhanced targeting potential of such bi-functional cells. Collectively, our results suggest that a truncated anti-GD2 CAR might be a powerful new tool to redirect MSCs carrying TRAIL against GD2-expressing tumors. This affinity-based dual targeting holds the promise to combine site-specific and prolonged retention of MSCs in GD2-expressing tumors, thereby providing a more effective delivery of TRAIL for still incurable cancers.

Salmonella Typhimurium (including S.Typhimurium 1,4,[5],12:i-) and other enteric pathogens cause acute infection in pigs during the weaning stage, often evolving into chronic infections responsible for the introduction of zoonotic bacteria into the slaughterhouse and thus determining carcass contamination. In addition to being zoonotic hazards, these pathogens are responsible for economic losses in affected farms. Traditionally, antibiotic treatments have been largely administered in order to reduce the infection burden but it favored, as a direct consequence, an increase in the number of multi-drug resistance strains. In order to overcome antibiotic-resistance concerns, new alternative control strategies should be developed. In this context, a blend of organic acids, phytochemicals and a permeabilizing complex, administered in feed (Group A - 459 piglets) or water (Group B - 458 piglets), was tested in field conditions for its capability of reducing Salmonella-infection in weaned piglets of an endemic farm. Data recorded were compared to results of a control group (Group C - 456 piglets). Zootechnical parameters were recorded in all animals, while microbiological, serological and PCR analyses were conducted in 15 piglets for each group. Results demonstrated that additive administered in feed improved animal weight gain (better average daily gain [A.D.G.] and increment), and rapidly reduced Salmonella-shedding in feces. Administration of additive in feed gave better results than in water.