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Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING . The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206 + myeloid cells and reduced effector CD8 + T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape. STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

Squamous cell carcinomas (SCC) are often preceded by potentially malignant precursor lesions, most of which remain benign. The terminal exhaustion phenotypes of effector T-cells and the accumulation of myeloid-derived suppressor cells (MDSC) have been thoroughly characterized in established SCC. However, it is unclear what precancerous lesions harbor a bona fide high risk for malignant transformation and how precancerous epithelial dysplasia drives the immune system to the point of no return. Here we show that expression of SRY-box transcription factor 2 (SOX2) in precancerous lesions imparts an irreversible risk that recruits suppressive myeloid cells by promoting the release of CCL2. We developed a unique genetically engineered mouse model (GEMM) to recapitulate the malignant transformation of epithelial dysplasia to SCC in the oral mucosa with high histologic and phenotypic fidelity. Using a combination of longitudinal human specimens and the Sox2-GEMM, we found that the myeloid cells in precancerous epithelial dysplasia exhibit a distinctive dichotomous profile featuring high levels of IL-1α-SLC2A1 and low levels of type-I interferon (IFN-I) signatures, which occurs before SCC emerges histologically. Brief priming of myeloid cells with IL-1α desensitizes them to IFN-I agonists and makes myeloid-derived suppressor cells (MDSC) even more suppressive of T-cell activation. Mechanistically, IL-1 activation represses the expression of DHHC3/7 enzymes, which are responsible for the palmitoylation of stimulator of interferon genes (STING). Early blockade of IL1 signaling using pharmacologic and genetic approaches similarly reduces MDSC and SLC2A1 myeloid cells, suppresses epithelial dysplasia transformation, and extends survival. This work establishes a previously unrecognized SOX2-CCL2-IL1 pathway that leads to irreversible immune escape when precancerous epithelial lesions transform.

Purpose This study is aimed to investigate whether there are any histopathological differences between diabetic and idiopathic carpal tunnel syndromes. Methods The biopsy specimens were taken from transverse carpal ligament (TCL), tenosynovium adjacent to median nerve and epineurium of median nerve and evaluated in 47 patients (21 diabetic and 26 idiopathic) who were diagnosed with carpal tunnel syndrome (CTS) and treated surgically with open carpal tunnel release. Fibroblast proliferation, fibrosis, perivascular inflammation, oedema, vascular proliferation and vascular wall thickness were determined and scored in all specimens. Results There weren’t any histopathological abnormalities in TCL specimens of both groups. Synovial hyperplasia, fibrosis and perivascular inflammation were not observed in tenosynovial analysis of both groups. Diabetic CTS patients, when compared with idiopathic CTS patients, had higher rates of synovial edema (idiopathic CTS 57 %, diabetic CTS 87 %), vascular proliferation (idiopathic CTS 30.8 %, diabetic CTS 90.5 %) and increased vascular wall thickness (idiopathic CTS 11.5 %, diabetic CTS 90.5 %). There was no oedema, fibrosis and perivascular inflammation of the epineurium in specimens of either group. But increases in vascular proliferation (idiopathic CTS 7.7 %, diabetic CTS 71.4 %) and vascular wall thickness (idiopathic CTS 3.8 %, diabetic CTS 71.4 %) was seen in the epineurium of diabetic patients and these differences were statistically significant ( p  < 0.05). Conclusion Because of the severe synovial and epineurial histopathological abnormalities and inadequate neural regeneration capacity, surgical open carpal tunnel decompression should be planned earlier in diabetic CTS patients. Further studies should be considered to evaluate the histopathological features of diabetic CTS patients early in the course of the disease.

Objectives: The aim of the present study is to investigate whether the variables of the disorder affect amygdala volumes in the adolescents with Bipolar Disorder (BD) type I and to compare the possible amygdala volume changes with healthy adolescents. Materials and Methods: Seventeen adolescents aged between 13 and 19 years, who had BD type I according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria that was either already been followed up or got the diagnosis after their admission to Dokuz Eylül University Faculty of Medicine, Department of Child and Adolescent Psychiatry between May 2008 and October 2008, were included in the study. Twelve adolescents between 13 and 19 years old and without any psychiatric diagnosis were included in the healthy control group. The magnetic resonance imaging (MRI) scans of all participants were performed by using an MRI machine with 1.5 Tesla power (Gyroscan Intero, Philips, Netherlands) and standard head coils. The MRI scans of the cases were made during euthymic phase. The phase of euthymia was defined according to Young Mania Rating Scale and Hamilton Depression Rating Scale. Results: The evaluation and comparison of both right and left amygdala volumes between the patient and the control group revealed no significant difference. However, in the patient group, negative correlation was found between right and left amygdala volumes and the duration of the disorder (for the right amygdala p=0.026; for the left amygdala p=0.031). Conclusion: The differences detected in amygdala volumes by structural MRI scans in adolescent and adult BD samples may reflect underlying pathophysiologic differences between the early onset and the late onset of the disorder.

The aim of this study was to investigate the protective effects of N -acetylcysteine (NAC) on peroxidative and apoptotic changes in the contused lungs of rats following blunt chest trauma. The rats were randomly divided into three groups: control, contusion, and contusion + NAC. All the rats, apart from those in the control group, performed moderate lung contusion. A daily intramuscular NAC injection (150 mg/kg) was given immediately following the blunt chest trauma and was continued for two additional days following cessation of the trauma. Samples of lung tissue were taken in order to evaluate the tissue malondialdehyde (MDA) level, histopathology, and epithelial cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and active caspase-3 immunostaining. In addition, we immunohistochemically evaluated the expression of surfactant protein D (SP-D) in the lung tissue. The blunt chest trauma-induced lung contusion resulted in severe histopathological injury, as well as an increase in the MDA level and in the number of cells identified on TUNEL assay together with active caspase-3 positive epithelial cells, but a decrease in the number of SP-D positive alveolar type 2 (AT-2) cells. NAC treatment effectively attenuated histopathologic, peroxidative, and apoptotic changes, as well as reducing alterations in SP-D expression in the lung tissue. These findings indicate that the beneficial effects of NAC administrated following blunt chest trauma is related to the regulation of oxidative stress and apoptosis.