Search

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved T cells that recognize microbial metabolites. They are abundant in humans and conserved during mammalian evolution, which suggests that they have important nonredundant functions. In this article, we discuss the evolutionary conservation of MAIT cells and describe their original developmental process. MAIT cells exert a wide variety of effector functions, from killing infected cells and promoting inflammation to repairing tissues. We provide insights into these functions and discuss how they result from the context of stimulation encountered by MAIT cells in different tissues and pathological settings. We describe how MAIT cell numbers and features are modified in disease states, focusing mainly on in vivo models. Lastly, we discuss emerging strategies to manipulate MAIT cells for therapeutic purposes.

Mucosal-associated invariant T (MAIT) cells harbor evolutionarily conserved TCRs, suggesting important functions. As human and mouse MAIT functional programs appear distinct, the evolutionarily conserved MAIT functional features remain unidentified. Using species-specific tetramers coupled to single-cell RNA sequencing, we characterized MAIT cell development in six species spanning 110 million years of evolution. Cross-species analyses revealed conserved transcriptional events underlying MAIT cell maturation, marked by ZBTB16 induction in all species. MAIT cells in human, sheep, cattle, and opossum acquired a shared type-1/17 transcriptional program, reflecting ancestral features. This program was also acquired by human iNKT cells, indicating common differentiation for innate-like T cells. Distinct type-1 and type-17 MAIT subsets developed in rodents, including pet mice and genetically diverse mouse strains. However, MAIT cells further matured in mouse intestines to acquire a remarkably conserved program characterized by concomitant expression of type-1, type-17, cytotoxicity, and tissue-repair genes. Altogether, the study provides a unifying view of the transcriptional features of innate-like T cells across evolution., (© 2023 Bugaut et al.)

Introduction: colonoscopy is the best method for detecting polyps, with a reduction in colorectal cancer mortality of 29% and reaching 47% for distal tumors. However, it fails to demonstrate a significant reduction in proximal colon cancer mortality, and is the most common segment with interval neoplasm. The present study aimed to evaluate the impact on detection of polyps of a second sequential evaluation of cecum and ascending colon, with or without the use of indigo carmine chromoendoscopy., Methods: prospective, non-randomized clinical trial. Patients were divided into two groups. The first (G1) underwent a routine colonoscopy, followed by a second endoscopy assessment of ascending colon and cecum. The second group (G2) underwent a routine colonoscopy, followed by a second assessment of the ascending colon and cecum with indigo carmine chromoendoscopy., Results: In total, 203 patients were analyzed, 101 in the G1 and 102 in the G2. Newer polyps were identified in both groups after the second assessment with a significantly higher number of polyps detected in the patients in the G2 (p=0.0001). The number of patients who had at least one polyp in the two endoscopic assessments was significantly higher in the G2 (53 or 52% vs 27 or 26.7%, p=0.0002). In the second endoscopic assessment, the number of polyps found was also significantly higher in the G2 (50 or 76.9%) compared to the G1 (15 or 23.1%), p<0.0001., Conclusions: the second assessment with dye-based chromoendoscopy increases the detection of polyps in the ascending colon and cecum.

Objectives: the purpose of this study was to evaluate the outcome of rectal cancer surgery, in a unit adopting the principles of total mesorectal excision (TME) with a high restorative procedure rate and with a low rate of abdominoperineal excision (APE)., Methods: we enrolles patients with extraperitoneal rectal cancer undergoing TME or TME+APE. Patients with mid rectal tumors underwent TME, and patients with tumors of the lower rectum and no criteria for APE underwent TME and intersphincteric resection. Those in which the intersphincteric space was invaded and in those with a free distal margin less than 1cm or a tumor free radial margin were unattainable underwent APE or extralevator abdominoperineal excision (ELAPE). We assessed local recurrence rates, overall survival and involvement of the radial margin., Results: sixty (89.6%) patients underwent TME and seven (10.4%) TME + APE, of which five underwent ELAPE. The local recurrence, in pacientes undergoing TME+LAR, was 3.3% and in patients undergoing APE, 14.3%. The local recurrence rate (p=0.286) or the distant recurrence rate (p=1.000) was similar between groups. There was no involvement of radial margins. Survival after 120 months was similar (p=0.239)., Conclusion: rectal malignancies, including those located in the low rectum, may be surgically treated with a low rate of APE without compromising oncological principles and with a low local recurrence rates.

Objective: Peritoneal carcinomatosis (PC) indicates advanced stage cancer, which is generally associated with a poor outcome and a 6 to 12 months. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an option for treating patients with primary PC, such as mesothelioma, or secondary PC, such as colorectal cancer (CRC) or pseudomixoma. Until recently, such patients were deemed untreatable. The purpose of this study was to assess the results of CRS + HIPEC in patients with PC. Postoperative complications, mortality and survival rates were evaluated according to the diagnosis., Results: Fifty-six patients with PC, undergoing full CRS + HIPEC between October 2004 and January 2020, were enrolled. The mortality rate was 3.8% and the morbidity rate was 61.5%. Complications were significantly higher in proportion to the duration of surgery (p<0.001). The overall survival rates, as shown in the Kaplan-Meyer curve, were respectively 81%, 74% and 53% at 12, 24 and 60 months. Survival rates according to each diagnosis for the same periods were 87%, 82% and 47% in patients with pseudomixoma, and 77%, 72% and 57% in patients with CRC (log-rank 0.371, p=0.543)., Conclusion: CRS with HIPEC is an option for pacients with primary or secondary PC. Although complication rates are high, a longer survival rate may be attained compared to those seen in previously published results; in some cases, patients may even be cured.

IL-7 and IL-7R are essential for T lymphocyte differentiation by driving proliferation and survival of specific developmental stages. Although early T lineage progenitors (ETPs), the most immature thymocyte population known, have a history of IL-7R expression, it is unclear whether IL-7R is required at this stage. In this study, we show that mice lacking IL-7 or IL-7R have a marked loss of ETPs that results mostly from a cell-autonomous defect in proliferation and survival, although no changes were detected in Bcl2 protein levels. Furthermore, a fraction of ETPs responded to IL-7 stimulation ex vivo by phosphorylating Stat5, and IL-7R was enriched in the most immature Flt3+Ccr9+ ETPs. Consistently, IL-7 promoted the expansion of Flt3+ but not Flt3- ETPs on OP9-DLL4 cocultures, without affecting differentiation at either stage. Taken together, our data show that IL-7/IL-7R is necessary following thymus seeding by promoting proliferation and survival of the most immature thymocytes., (Copyright © 2022 by The American Association of Immunologists, Inc.)

T lymphocyte differentiation in the steady state is characterized by high cellular turnover whereby thymocytes do not self-renew. However, if deprived of competent progenitors, the thymus can temporarily maintain thymopoiesis autonomously. This bears a heavy cost, because prolongation of thymus autonomy causes leukemia. Here, we show that, at an early stage, thymus autonomy relies on double-negative 3 early (DN3e) thymocytes that acquire stem-cell-like properties. Following competent progenitor deprivation, DN3e thymocytes become long lived, are required for thymus autonomy, differentiate in vivo, and include DNA-label-retaining cells. At the single-cell level, the transcriptional programs of thymopoiesis in autonomy and the steady state are similar. However, a new cell population emerges in autonomy that expresses an aberrant Notch target gene signature and bypasses the β-selection checkpoint. In summary, DN3e thymocytes have the potential to self-renew and differentiate in vivo if cell competition is impaired, but this generates atypical cells, probably the precursors of leukemia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cell competition in the thymus is a homeostatic process that drives turnover. If the process is impaired, thymopoiesis can be autonomously maintained for several weeks, but this causes leukemia. We aimed to understand the effect of cell competition on thymopoiesis, identify the cells involved, and determine how the process is regulated. Using thymus transplantation experiments, we found that cell competition occurs within the double-negative 2 (DN2) and 3 early (DN3e) thymocytes and inhibits thymus autonomy. Furthermore, the expansion of DN2b is regulated by a negative feedback loop that is imposed by double-positive thymocytes and determines the kinetics of thymopoiesis. This feedback loop affects the cell cycle duration of DN2b, in a response controlled by interleukin 7 availability. Altogether, we show that thymocytes do not merely follow a pre-determined path if provided with the correct signals. Instead, thymopoiesis dynamically integrates cell-autonomous and non-cell-autonomous aspects that fine-tune normal thymus function., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Thymus autonomy is the capacity of the thymus to maintain T lymphocyte development and export independently of bone marrow contribution. Prolonging thymus autonomy was shown to be permissive to the development of T cell acute lymphoblastic leukemia (T-ALL), similar to the human disease. In this study, performing thymus transplantation experiments in mice, we report that thymus autonomy can occur in several experimental conditions, and all are permissive to T-ALL. We show that wild type thymi maintain their function of T lymphocyte production upon transplantation into recipients with several genotypes (and corresponding phenotypic differences), i.e., Rag2 - / - γ c - / - , γ c - / - , Rag2 - / - IL-7rα - / - , and IL-7rα - / - We found that the cellularity of the thymus grafts is influenced exclusively by the genotype of the host, i.e., IL-7rα -/- versus γ c -/- Nonetheless, the difference in cellularity detected in thymus autonomy bore no impact on onset, incidence, immunophenotype, or pathologic condition of T-ALL. In all tested conditions, T-ALL reached an incidence of 80%, demonstrating that thymus autonomy bears a high risk of leukemia. We also analyzed the microbiota composition of the recipients and their genetic background, but none of the differences found influenced the development of T-ALL. Taken together, our data support that IL-7 drives cellular turnover non-cell autonomously, which is required for prevention of T-ALL. We found no influence for T-ALL in the specific combination of the genotypic mutations tested (including the developmental block caused by Rag deficiency), in microbiota composition, or minor differences in the genetic background of the strains., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Cell competition in the thymus promotes turnover and functions as a tumor suppressor by inhibiting leukemia. Using thymus transplantation experiments, we have shown that the presence of T lymphocyte precursors, recently seeding the thymus, promotes the clearance of precursors with a longer time of thymus residency. If cell competition is impaired and no cells seed the thymus, the organ is capable of sustaining T lymphocyte production, a state termed thymus autonomy. However, we observed consistently that prolonged autonomy is permissive to the emergence of T cell acute lymphoblastic leukemia (T-ALL). This resembled the onset of T-ALL in patients treated by gene therapy for X-linked severe combined immunodeficiency (SCID-X1). Following treatment, thymus activity was established, with T lymphocyte production, although no bone marrow contribution was detected. However, some patients developed T-ALL. The favored explanation for malignant transformation was considered to be genotoxicity due to integration of the retroviral vector next to oncogenes, thereby activating them ectopically. Although plausible, we consider an alternative, mutually nonexclusive explanation: that any condition enabling prolonged thymus autonomy will promote leukemogenesis. In support of this view, two independent studies have recently shown that the efficacy of reconstitution of the bone marrow in the context of SCID-X1 dramatically influences the outcome of treatment, and that lymphoid malignancies emerge following transplantation of a small number of healthy progenitors. Here, we discuss the most recent data in light of our own studies in thymopoiesis and the conditions that trigger malignant transformation of thymocytes in various experimental and clinical settings., (© 2018 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: The aim of this study was to evaluate the prevalence of hypopituitarism in the acute stage after aneurysmal subarachnoid hemorrhage (SAH) as well at the chronic stage, at least 1 year after bleeding, to assess its implications and correlation with clinical features of the studied population., Patients and Methods: This was a prospective cohort study that evaluated patients admitted between December 2009 and May 2011 with a diagnosis of SAH secondary to cerebral aneurysm rupture. Clinical and endocrine assessment was performed during the acute stage after hospital admission and before treatment at a mean of 7.5 days (SD ± 3.8) following SAH, and also at the follow-up visit at a mean of 25.5 months (range: 12-55 months) after the bleeding., Results: Out of the 119 patients initially assessed, 92 were enrolled for acute stage, 82 underwent hormonal levels analysis, and 68 (82.9%) were followed up in both acute and chronic phases. The mean age and median age were lower among patients with dysfunction in the acute phase compared to those without dysfunction (P < .05). The prevalence of dysfunction in the acute phase was higher among patients with hydrocephalus on admission computed tomography (57.9%) than among those without it (P < .05). At chronic phase, there was an association between dysfunction and Hunt & Hess scale score greater than 2 (P < .05)., Conclusions: We believe that there is not enough literature evidence to incorporate routine endocrinological evaluation for patient victims of SAH, but we should always keep this differential diagnosis in mind when conducting long-term assessments of this population., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Intussusception in adult is rarely caused by idiopathic conditions. Main causes are inflammatory diseases, benign or malignant tumors and motility disorders. As a benign cause, lipomas appear as a particularly rare gastrointestinal intraluminal tumor occurring with highest incidence in the colon, mostly in the caecum and ascending colon., Presentation of Case: A 57-year-old male patient was admitted at the surgical emergency in Belo Horizonte, with history of chronic and intermittent diffuse abdominal pain, associated with variations of his bowel habits and rare episodes of vomiting starting around 3days prior to admission., Discussion: Intussusception is the cause of adult symptomatic bowel obstruction in 1% of the cases and its colocolonic occurrence represents 17% of all intestinal intussusceptions in adults. The reported case presents itself as even rarer considering its evaluation according to the epidemiological statistics of 1:5 men/women ratio and lipoma's most common location being the right colon. Intussusception and intestinal obstructions caused by intraluminal lipomas are not often described in the literature and its occurrence is directly related to its size, usually larger than 2cm diameter. The management of lipomatous intraluminal lesions of the colon is traditionally surgical, and it allows a selective resection, depending on the size of the tumor, length of intussusception, and the amount of inflammation., Conclusion: Patients with chronic abdominal symptoms and semi-obstruction caused by intussusception are rarely diagnosed before surgery unless there is a high index of suspicion. Colonoscopy contributes to diagnosis given that it provides direct visualization and biopsy., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Adenoid cystic carcinoma is the most frequent malignant tumor of the submandibular gland and the minor salivary glands. It is a malignant neoplasm that, despite its slow growth, shows an unfavorable prognosis., Objectives: The aim of this study was to perform a systematic review of the literature on Adenoid cystic carcinoma in the head and neck region and its clinicopathological characteristics, with emphasis on the perineural invasion capacity of the tumor., Methods: A systematic search of articles published between January 2000 and January 2014 was performed in the PubMed/MEDLINE, SciELO, Science Direct, and Scopus databases., Results: Nine articles were selected for this systematic review. These demonstrated that the female gender was more often affected and that malignant tumors showed a high rate of distant metastasis, recurrence, and a low survival rate. The presence of perineural invasion ranged from 29.4% to 62.5% and was associated with local tumor recurrence., Conclusion: Adenoid cystic carcinoma is commonly characterized by the presence of pain, high rate of recurrence, metastasis, and a low survival rate. Reporting studies with patient follow-up is of utmost importance for a better clinical-pathological understanding and to improve the prognosis of this pathology., (Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Piper claussenianum inflorescences crude methanol extract was tested for hypoglycemic effect in streptozotocin-induced diabetic rats. The blood glucose levels of rats treated with methanol extract were reduced from 318.4±28.1 mg/dl before treatment to 174.2±38.3 mg/dl after 12 days of treatment (P<0.05). Phytochemical studies were carried out on inflorescences methanol crude extract in order to investigate the possible metabolites responsible for the pharmacological properties of the extract. After chromatographic procedures, three flavonoids were isolated and characterized. The major compound 2',6'-dihydroxy-4'-methoxychalcone was also tested. Rats that received the chalcone content also displayed a reduction in blood glucose levels from 277.4±7.7 mg/dl before treatment to 158.8±9.2 mg/dl after 12 days of treatment (P<0.05). The results suggest this chalcone is one of the metabolite responsible for the blood glucose levels reduction in rats with streptozotocin-induced diabetes. The inflorescence crude extract of P. claussenianum was found to be composed mainly by flavonoids and may be a potential natural source of compounds with hypoglycemic properties.