Hypofunctionality of Gi proteins as aetiopathogenic mechanism for migraine and cluster headache

The involvement of Gi proteins in the modulation of pain perception has been widely established, and mutations in G-proteins have already been identified as the aetiopathological cause of human diseases. The aim of the present study was to determine whether a deficiency or a hypofunctionality of the Gi proteins occurred in primary headache. The functionality and the level of expression of Gi proteins were investigated in lymphocytes from migraine without aura, migraine with aura and cluster headache sufferers. A reduced capability to inhibit forskolin-stimulated adenylyl cyclase activity in headache patients was observed. Migraine patients also showed basal adenosine cAMP levels about four times higher than controls. The reduced activity of Gi proteins seems not to be related to a reduction of protein levels since no significant reduction of the Gialpha subunits was observed. These results indicate Gi protein hypofunctionality as an aetiopathogenic mechanism in migraine and cluster headache.     

Alterações no nível de TNF‐α após bloqueio do nervo femoral guiado por ultrassom em idosos com fratura de quadril

Background and objectives

An ultrasound guided femoral nerve block is an established analgesic method in patients with a hip fracture. Elevated cytokine levels correlate with poor patient outcomes after surgery. Hence, the aim of the study was to describe the levels of tumor necrosis factor‐α after an ultrasound‐guided femoral nerve block in elderly patients having a femoral neck fracture.

A curative treatment strategy using tumor debulking surgery combined with immune checkpoint inhibitors for advanced pediatric solid tumors: An in vivo study using a murine model of osteosarcoma

Background/purpose

This study aimed to assess the significance of tumor debulking surgery by using immune checkpoint inhibitors for advanced pediatric solid tumors in a murine model of advanced osteosarcoma.

The contribution of active and passive mechanisms of 5mC and 5hmC removal in human T lymphocytes is differentiation‐ and activation‐dependent

In mammals, the 5’‐methylcytosine (5mC) modification in the genomic DNA contributes to the dynamic control of gene expression. 5mC erasure is required for the activation of developmental programs and occurs either by passive dilution through DNA replication, or by enzymatic oxidation of the methyl mark to 5‐hydroxymethylcytosine (5hmC), which can persist as such or undergo further oxidation and enzymatic removal. The relative contribution of each mechanism to epigenetic control in dynamic biological systems still remains a compelling question. To explore this critical issue, we used primary human T lymphocytes, in which two cellular states can be clearly identified, namely quiescent naïve T cells, which are slowly or rarely proliferating, and rapidly proliferating activated T cells. We found that active mechanisms of methylation removal were selectively at work in naïve T cells, while memory T lymphocytes entirely relied on passive, replication‐dependent dilution, suggesting that proliferative capacity influences the choice of the preferential demethylation mechanism. Active processes of demethylation appear to be critical in quiescent naïve T lymphocytes for the maintenance of regulatory regions poised for rapid responses to physiological stimuli.     

Poly(I:C) stimulation is superior than Imiquimod to induce the antitumoral functional profile of tumor‐conditioned macrophages

Macrophage plasticity is the ability of mononuclear phagocytes to change phenotype, function, and genetic reprogramming upon encounter of specific local stimuli. In the tumor microenvironment, Tumor‐Associated Macrophages (TAMs) acquire an immune‐suppressive and tumor‐promoting phenotype. With the aim to re‐educate TAMs to antitumor effectors, in this study, we used two immunestimulatory compounds: the TLR7 agonist Imiquimod (IMQ) and the TLR3 agonist Poly(I:C). To better mimic in vitro the response of TAMs, we used Tumor‐Conditioned Macrophages (TC‐M?) differentiated in the presence of tumor cell supernatants. Our results show that TC‐M? respond differently from conventional M2‐polarized macrophages. Upon stimulation with IMQ, TC‐M? did not upregulate major histocompatibility complex (MHC II) molecules and unexpectedly expressed increased CD206. With both compounds, TC‐M? produced higher levels of inflammatory cytokines than M2 macrophages. IMQ and Poly(I:C) differed in the types of regulated genes and secreted mediators. Reflecting their signaling pathways, only IMQ significantly induced IL‐1β and IL‐6, while only Poly(I:C) stimulated CXCL10, and both upregulated CCL5. Of note, using a novel cytotoxicity assay, Poly(I:C), but not IMQ, was effective in triggering the cytotoxic activity of TC‐M? against cancer cells. Overall, the results demonstrate that Poly(I:C) stimulation of TC‐M? is superior than IMQ in terms of macrophage re‐education toward antitumor effectors.     

Regulatory T cells and TGF-β1 in clinically localized renal cell carcinoma: Comparison with age-matched healthy controls

PurposeWe investigated the proportion of regulatory T cells (Treg cells) in the peripheral blood (PB) and among tumor-infiltrating lymphocytes (TILs) of patients with renal cell carcinoma (RCC) compared with age-matched healthy controls (HCs). We also assessed the presence of several immunomodulatory cytokines in these patients.MethodsThe proportion of Treg cells in the PB of 59 patients with clinically localized RCC and 65 HCs, as well as the prevalence of Treg cells among TILs and lymphocytes in normal kidney tissue, were evaluated by flow cytometry using specific monoclonal antibodies recognizing CD4⁺, CD25⁺, and Foxp3⁺ markers. In addition, the levels of transforming growth factor (TGF)-β1, interleukin-6, tumor necrosis factor-α, and interferon-γ were determined using standard enzyme-linked immunosorbent assay.ResultsThere was no difference between the mean percentage of Treg cells in the PB of patients with RCC and HCs (P = 0.148). However, the proportion of Treg cells showed a significant positive correlation with tumor size (r = 0.295, P = 0.029), with the percentage of PB Treg cells significantly higher in patients with RCC with large tumors (≥7 cm) than in HCs (4.6±5.8% vs. 1.9±2.6%, P = 0.023). There was no statistically significant difference in the percentage of Treg cells among TILs and lymphocytes in normal kidney tissue (P = 0.629). The mean TGF-β1 level in patients with RCC was statistically significantly higher than in HCs (P<0.001).ConclusionsIn this study, we provide evidence for an increased proportion of Treg cells in the PB of clinically localized patients with RCC with substantial tumor burden and a higher level of TGF-β1 compared with age-matched HCs.     

Small renal masses in the era of personalized medicine: Tumor heterogeneity,growth kinetics,and risk of metastasis

Small renal masses (SRMs) represent a heterogeneous group showing a variety of clinical and biological behaviors. The best treatment for SRMs has been the focus of much debate over the past decades. Present strategies include surgery (partial or radical nephrectomy), local treatments (radiofrequency and cryoablation), or active surveillance. The choice among these therapeutic options is based on patient clinical features such as age or comorbidities rather than on tumor characteristics. Several studies have recently focused on the molecular behavior of SRMs. They showed that SRMs present histotype and nuclear grading heterogeneity, together with not unvarying growth kinetics and risk of recurrence or metastasis, suggesting that personalized approaches should be designed to optimize the management of these patients. At present, several studies are in course to identify predictive biomarkers to guide the decision-making process in this subpopulation. In this review, we summarized the data on growth kinetics, tumor heterogeneity, and risk of metastasis in patients with SRMs, with focus on the current role of biopsies and imaging in the management of these patients.     

自然杀伤T细胞失能的相关研究进展

自然杀伤T细胞同时表达自然杀伤细胞和T细胞受体,发挥免疫调节和细胞毒作用.相关研究证实激活自然杀伤T细胞可以抑制肿瘤进展,但短暂活化的自然杀伤T细胞常常因为未知原因迅速进入失活状态.本文就目前自然杀伤T细胞失能可能机制及应对措施的研究进展作一综述.     

Giant fibrokeratoma,a rare soft tissue tumor presenting like an accessory digit,a case report and review of literature

IntroductionAcquired digital fibrokeratoma is an uncommon, benign fibrous tumour that usually occurs in adults as a solitary lesion with a typical size of less than 1 cm.Case presentationA 48-year-old Afro-Caribbean man presented to our foot and ankle clinic with a long-standing growth over the plantar aspect of the distal phalanx of the left great toe. The growth was painful and affected the patient’s mobility. It had gradually increased in size over a period of 17 years. The growth was completely excised, and the base was allowed to heal by secondary intention. The skin eventually healed, and the patient had a good outcome. The histological results confirmed that the growth was a digital fibrokeratoma.ConclusionThis case is of interest because of the rarity of digital fibrokeratoma and the unique morphological appearance of the tumor in this case. Additionally, we emphasise the importance of ruling out other causes of abnormal growths and considering fibrokeratoma during differential diagnoses.