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TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive. By integrating in vivo analyses with multi-omics approaches and functional assays, we have uncovered an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Our findings demonstrate that constitutive loss of TFEB in knock-out mice is associated with defective formation of the syncytiotrophoblast layer. Indeed, using in vitro models of syncytialization, we demonstrated that TFEB translocates into the nucleus during syncytiotrophoblast formation and binds to the promoters of crucial placental genes, including genes encoding fusogenic proteins (Syncytin-1 and Syncytin-2) and enzymes involved in steroidogenic pathways, such as CYP19A1, the rate-limiting enzyme for the synthesis of 17β-Estradiol (E2). Conversely, TFEB depletion impairs both syncytial fusion and endocrine properties of syncytiotrophoblast, as demonstrated by a significant decrease in the secretion of placental hormones and E2 production. Notably, restoration of TFEB expression resets syncytiotrophoblast identity. Our findings identify that TFEB controls placental development and function by orchestrating both the transcriptional program underlying trophoblast fusion and the acquisition of endocrine function, which are crucial for the bioenergetic requirements of embryonic development., (© 2024. The Author(s).)

To fulfill their function, pancreatic beta cells require precise nutrient-sensing mechanisms that control insulin production. Transcription factor EB (TFEB) and its homolog TFE3 have emerged as crucial regulators of the adaptive response of cell metabolism to environmental cues. Here, we show that TFEB and TFE3 regulate beta-cell function and insulin gene expression in response to variations in nutrient availability. We found that nutrient deprivation in beta cells promoted TFEB/TFE3 activation, which resulted in suppression of insulin gene expression. TFEB overexpression was sufficient to inhibit insulin transcription, whereas beta cells depleted of both TFEB and TFE3 failed to suppress insulin gene expression in response to amino acid deprivation. Interestingly, ChIP-seq analysis showed binding of TFEB to super-enhancer regions that regulate insulin transcription. Conditional, beta-cell-specific, Tfeb-overexpressing, and Tfeb/Tfe3 double-KO mice showed severe alteration of insulin transcription, secretion, and glucose tolerance, indicating that TFEB and TFE3 are important physiological mediators of pancreatic function. Our findings reveal a nutrient-controlled transcriptional mechanism that regulates insulin production, thus playing a key role in glucose homeostasis at both cellular and organismal levels., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

The stress-responsive transcription factor EB (TFEB) is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. TFEB is regulated at the posttranslational level by the nutrient-sensitive kinase complex mTORC1. However, little is known about the regulation of TFEB transcription. Here, through integrative genomic approaches, we identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression in human cells and demonstrate that, in the absence of EGR1, TFEB-mediated transcriptional response to starvation is impaired. Remarkably, both genetic and pharmacological inhibition of EGR1, using the MEK1/2 inhibitor Trametinib, significantly reduced the proliferation of 2D and 3D cultures of cells displaying constitutive activation of TFEB, including those from a patient with Birt-Hogg-Dubé (BHD) syndrome, a TFEB-driven inherited cancer condition. Overall, we uncover an additional layer of TFEB regulation consisting in modulating its transcription via EGR1 and propose that interfering with the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A.B. is a cofounder of Casma Therapeutics and an advisory board member of Next Generation Diagnostic srl, Avilar Therapeutics and Coave Therapeutics. Davide Cacchiarelli is Co-Founder, Shareholder and Consultant of Next Generation Diagnostic srl., (Copyright: © 2023 Cesana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: The purpose of the study is to evaluate the diagnostic value of tridimensional endoanal ultrasound (3D-EAUS) and magnetic resonance (MR) in the preoperative assessment of both simple and complex anorectal fistulas., Methods: All the patients referred for the treatment of anal fistulas were enrolled in this study and underwent, as preoperative assessment, anamnestic evaluation, clinical examination, and unenhanced and H2O2-enhanced 3D-EAUS and MR. The results of imaging evaluation were compared with surgical findings, considered as reference standard., Results: During the study period, 124 patients operated on for anal fistulas underwent complete preoperative imaging assessment. Perfect agreement between 3D-EAUS and surgery in the anal fistulas' severity grading was found (K = 1). The fistulas were classified as simple in 68/126 (53.9%) and complex in 58/126 (46.03%) cases, according to fistulas' Parks' classification and the most recent American Guidelines. In both simple and complex anal fistulas, 3D-EAUS did not show a significantly higher accuracy in the evaluation of internal openings, if compared with MR (P = 0.47; McNemar's Chi-square test). In the complex anal fistulas, MR showed a significantly higher accuracy in the evaluation of secondary extensions if compared with 3D-EAUS (P = 0.041; McNemar's Chi-square test), whereas in the simple anal fistulas, no significant difference was found., Conclusion: In the preoperative work-up of patients with anorectal fistulas, 3D-EAUS may represent the first-line diagnostic tool. In cases of fistulas classified as complex by 3D-EAUS, MR may be indicated as adjunctive diagnostic imaging examination, to more carefully describe the fistulas' complete anatomy.

A correct surgical approach to rectal cancer today has to make due allowance for both improved overall survival with local control of disease and preservation of the sphincter and urinary and genital functions. Increased understanding of the natural history, the importance of preoperative accurate staging and new surgical techniques may influence future treatment strategies. The aim of this study was to review and make a reappraisal of the role of sphincter-preserving surgery in the treatment of carcinomas of the lower third of the rectum. From January 1999 to June 2004, 63 consecutive total rectal resections were performed at our surgical department. Thirty-five of these patients, who underwent surgery for a primary adenocarcinoma of the distal rectum (3.5 to 8 cm from the anal verge), were reviewed retrospectively. The preoperative clinical assessment was based largely on T staging, tumor size, fixation and distance from the anal verge. Patient stratification, based on the definitive pathological report, was 3 Dukes' stage A (T1 N0), 21 stage B (T2 N0) and 11 stage C (T2-3-4 N+). The distance from the anal verge was > 5 cm in 30 patients and < 5 cm in 5. Sphincter-saving procedures were performed in 28/35 patients (80%); 7 (20%) had abdominoperineal resections of the rectum for very distal, locally extensive tumours or local recurrence (2 patients). The overall recurrence rate was 11.4%. Postoperative morbidity related to the procedures was low: anastomotic leakage occurred in 10.7% (3/28). Perfect continence was documented in 86.3%. The minimum follow-up time is 12 months. Our data, in agreement with the findings of other Authors, appear to bear out the validity of sphincter-saving procedures in the treatment of cancer of the lower third of the rectum. This approach is possible for the majority of patients. Functional results are good, using an accurate nerve-sparing technique, and may be improved by employing a colonic reservoir in selected cases.

Interferon (IFN)-alpha with or without ribavirin is the treatment of choice for patients with chronic HCV-related hepatitis. Cough and dyspnea during IFN therapy are often regarded as a side effect and not as a possible sign of the onset of a pulmonary interstitial disease. It may therefore be claimed that the likelihood that patients treated with IFN develop sarcoidosis is being underestimated. Although they are not conventionally classified as etiopathologic agents of sarcoidosis, the IFNs have been proven to be capable of triggering macrophages and of promoting the expression of class II HLA antigens. It is therefore possible that IFN-alpha treatment could trigger macrophages and promote the polarization of the immune response towards Th1 in the presence of particular susceptibility conditions, thus starting the series of events that lead to the onset of sarcoidosis. We describe a case of pulmonary sarcoidosis in a 33-year-old patient treated with IFN-alpha2b and ribavirin for chronic HCV-related hepatitis after 6 months of therapy. The case we report here brings forth the issue of a possible underestimation of the real incidence of sarcoidosis during IFN therapy and highlights the need for more attention to and a more careful evaluation of respiratory symptoms manifesting in treated patients.

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

Polyps occur throughout the gastrointestinal tract in Peutz-Jeghers syndrome, but the most serious problems are encountered in the management of small bowel polyposis. We report here on a case of Peutz-Jeghers syndrome admitted to hospital for intestinal obstruction and anaemia. The patient was submitted to colonoscopy, oesophagogastro-duodenoscopy and small bowel enema. At laparotomy, multiple intussusceptions were found and we conducted a combined surgical-endoscopic approach. Most of the polyps were identified and removed endoscopically (snare polypectomy). Five enterotomies were performed to remove 18 very large polyps (> 3 cm). Finally, a limited portion of the jejunal tract (20 cm) was resected owing to the presence of multiple, large, obstructive polyps. None of the polyps showed cancerous transformation. The shortcomings of the traditional surgical approach include repeated small bowel resections and often early reoperation to manage complications caused by polyps missed at the time of previous surgery. If surgical intervention is required, intraoperative endoscopy is always indicated. Conservative surgical management, the role of intraoperative endoscopy, planned medical follow-up and the need for a national registration system are stressed.

Orthodeoxia-platypnea is a rare but increasingly recognized syndrome of upright hypoxemia usually associated to breathlessness relieved by recumbency. We report the case of isolated orthodeoxia discovered in a military recruit who referred only fatigability as the clinical symptom after a forced march. Transesophageal echocardiography demonstrated the presence of interatrial defect ostium secundum type with the persistence of left superior vena cava draining into coronary sinus. Right-to-left shunt was visualized by peripheral saline contrast infusion, despite normal right hemodynamics at heart catheterization. Hypoxemia recovered after the percutaneous closure of the interatrial defect. Orthodeoxia and platypnea could occur as separate disease manifestations, the latter probably being a rarer acute event, whereas orthodeoxia was underestimated and potentially earlier screenable., (Copyright 2003 S. Karger AG, Basel)

The Authors report a small series (three cases) of Spigelian hernias and underline the rarity of this pathology (0.2% in their series of hernias of the abdominal wall). They determine the anatomical features of the region, recall clinical features and discuss the most interesting points differential diagnosis and therapy.

A case of primary mucinous carcinoid of the ovary observed in a 52-year-old woman is reported after some remarks on the various histogenetic theories. The observation of this extremely rare cancer was fortuitous during surgery carried out for benign pathology in the contralateral organ. Careful postoperative controls absolutely excluded the possibility of a metastatic tumour. The patient was treated by combining surgery with chemotherapy and eight months after operation is apparently free of cancer.