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Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self and non-self through cell-intrinsic and cell-extrinsic mechanisms. Peripheral Tregs survival and clonal expansion largely depend on IL-2 and access to co-stimulatory signals such as CD28. Engagement of tumor necrosis factor receptor (TNFR) superfamily members, in particular TNFR2 and DR3, contribute to promote peripheral Tregs expansion and sustain their survival. This property can be leveraged to enhance tolerance to allogeneic transplants by tipping the balance of Tregs over conventional T cells during the course of immune reconstitution. This is of particular interest in peri-transplant tolerance induction protocols in which T cell depletion is applied to reduce the frequency of alloreactive T cells or in conditioning regimens that allow allogeneic bone marrow transplantation. These conditioning regimens are being implemented to limit long-term side effects of continuous immunosuppression and facilitate the establishment of a state of donor-specific tolerance. Lymphopenia-induced homeostatic proliferation in response to cytoreductive conditioning is a window of opportunity to enhance preferential expansion of Tregs during homeostatic proliferation that can be potentiated by agonist stimulation of TNFR.

Diabetes mellitus is a prevalent chronic autoimmune disease with a high impact on global health, affecting millions of adults and resulting in significant morbidity and mortality. Achieving optimal blood glucose levels is crucial for diabetes management to prevent acute and long-term complications. Carbohydrate counting (CC) is widely used by patients with type 1 diabetes to adjust prandial insulin bolus doses based on estimated carbohydrate content, contributing to better glycemic control and improved quality of life. However, accurately estimating the carbohydrate content of meals remains challenging for patients, leading to errors in bolus insulin dosing. This review explores the current limitations and challenges in CC accuracy and emphasizes the importance of personalized educational programs to enhance patients’ abilities in carbohydrate estimation. Existing tools for assessing patient learning outcomes in CC are discussed, highlighting the need for individualized approaches tailored to each patient’s needs. A comprehensive review of the relevant literature was conducted to identify educational programs and assessment tools dedicated to training diabetes patients on carbohydrate counting. The research aims to provide insights into the benefits and limitations of existing tools and identifies future research directions to advance personalized CC training approaches. By adopting a personalized approach to CC education and assessment, healthcare professionals can empower patients to achieve better glycemic control and improve diabetes management. Moreover, this review identifies potential avenues for future research, paving the way for advancements in personalized CC training and assessment approaches and further enhancing diabetes management strategies.

Misdiagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can occur when different case definitions are used by clinicians (relative misdiagnosis) or when failing the genuine diagnosis of another disease (misdiagnosis in a strict sense). This problem translates to a recurrent difficulty in reproducing research findings. To tackle this problem, we simulated data from case-control studies under misdiagnosis in a strict sense. We then estimated the power to detect a genuine association between a potential causal factor and ME/CFS. A minimum power of 80% was obtained for studies with more than 500 individuals per study group. When the simulation study was extended to the situation where the potential causal factor could not be determined perfectly (e.g., seropositive/seronegative in serological association studies), the minimum power of 80% could only be achieved in studies with more than 1000 individuals per group. In conclusion, current ME/CFS studies have suboptimal power under the assumption of misdiagnosis. This power can be improved by increasing the overall sample size using multi-centric studies, reporting the excluded illnesses and their exclusion criteria, or focusing on a homogeneous cohort of ME/CFS patients with a specific pathological mechanism where the chance of misdiagnosis is reduced.

Introduction: Breast cancer is the most incident cancer in the world, accounting for 25% of new cancers per year in females. It is the most frequent malignancy in women, being the fifth cause of death from cancer worldwide. Approximately 5 to 10% of patients already present with metastases at diagnosis, and the liver is the site of metastases in half of these cases. Liver metastasis (LM) resection, performed after neoadjuvant systemic treatment, has been reported to increase median overall survival in this population. Aim: The aim of this analysis is to assess the outcomes of patients undergoing breast cancer liver metastasis surgical resection, including impact on survival, compared to patients where metastasectomy was not performed. Methods: retrospective review of 55 female patients with breast cancer liver metastases, diagnosed and treated in a single tertiary university hospital from January 2011 to December 2016 was performed. Results: In 32/55 patients (58.2%), multi-organ metastases were identified (the most common sites being bone, lungs, and lymph nodes). Of the remaining 23 patients, the liver was the unique metastatic site; thirteen patients had diffuse bilobar hepatic metastases. The remaining ten patients were proposed for surgical treatment; three of them had peritoneal carcinomatosis identified during surgery, and no hepatic metastasectomy was performed. As a result, only seven (12.7%) patients underwent liver metastasectomy. Overall survival was higher in patients who had LM surgery (65 months [Interquartile Range (IQR) 54–120]), in comparison to those diagnosed with diffuse bilobar hepatic metastases (17.5 months [IQR 11–41]), and with those showing concurrent liver and bone metastases (16.5 months [IQR 6–36]) (p = 0.012). In univariable analysis, the latter two groups showed worse overall survival outcomes (Hazard Ratio (HR) = 3.447, 95%CI: 1.218–9.756, p = 0.02 and HR = 3.855, 95% Confidence Interval (CI): 1.475–10.077, p = 0.006, respectively) when compared to patients with LM. Conclusion: In our series, patients submitted to metastasectomy had a median overall survival after diagnosis of LM three times greater than the non-operated patients with isolated LM, or concurrent LM and bone metastases (65 vs. 17.5 and 16.5 months, respectively). As is vastly known for colorectal cancer liver metastasis, resection of breast cancer liver metastasis may reduce tumor burden, and therefore may improve patient outcome.

Development of new immunogens eliciting broadly neutralizing antibodies (bNAbs) is a main priority for the HIV-1 vaccine field. Envelope glycoproteins from non-B-non-C HIV-1clades have not been fully explored as components of a vaccine. We produced Vaccinia viruses expressing a truncated version of gp120 (gp120t) from HIV-1 clades CRF02_AG, H, J, B, and C and examined their immunogenicity in mice and rabbits. Mice primed with the recombinant Vaccinia viruses and boosted with the homologous gp120t or C2V3C3 polypeptides developed antibodies that bind potently to homologous and heterologous envelope glycoproteins. Notably, a subset of mice immunized with the CRF02_AG-based envelope immunogens developed a cross-reactive neutralizing response against tier 2 HIV-1 Env-pseudoviruses and primary isolates. Rabbits vaccinated with the CRF02_AG-based envelope immunogens also generated potent binding antibodies, and one animal elicited antibodies that neutralized almost all (13 of 16, 81.3%) tier 2 HIV-1 isolates tested. Overall, the results suggest that the novel CRF02_AG-based envelope immunogens and prime-boost immunization strategy elicit the type of immune responses required for a preventive HIV-1 vaccine.

Elevated levels of immunoglobulin E (IgE) are associated with allergies and other immunological disorders. Sensitization with alum adjuvant favours IgE production while CpG-ODN adjuvant, a synthetic toll-like receptor 9 (TLR9) agonist, inhibits it. The cellular mechanisms underlying in vivo TLR regulation of immunoglobulin production, specially IgE, are still controversial. Specifically, TLR-mediated IgE regulation in vivo is not yet known. In this study we showed that augmented levels of IgE induced by sensitizations to OVA with or without alum adjuvant or with OVA-pulsed dendritic cells (DCs) were inhibited by co-administration of CpG. Notably, CpG-mediated suppression of IgE production required MyD88-expression on DCs but not on B-cells. This finding contrasts with previous in vitro studies reporting regulation of IgE by a direct action of CpG on B cells via MyD88 pathway. In addition, we showed that CpG also inhibited IgE production in a MyD88-dependent manner when sensitization was performed with OVA-pulsed DCs. Finally, CpG signalling through MyD88 pathway was also necessary and sufficient to prevent anaphylactic antibody production involved in active cutaneous anaphylaxis.