Chromothripsis is rare in IDH-mutant gliomas compared to IDH-wild-type glioblastomas whereas whole-genome duplication is equally frequent in both tumor types.

Background: Adult-type diffuse gliomas comprise IDH (isocitrate dehydrogenase)-mutant astrocytomas, IDH-mutant 1p/19q-codeleted oligodendrogliomas (ODG), and IDH-wild-type glioblastomas (GBM). GBM displays genome instability, which may result from 2 genetic events leading to massive chromosome alterations: Chromothripsis (CT) and whole-genome duplication (WGD). These events are scarcely described in IDH-mutant gliomas. The better prognosis of the latter may be related to their genome stability compared to GBM. Methods: Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using the Kaplan-Meier method. Results: At initial diagnosis, 37 GBM (18.7%) displayed CT versus 5 IDH-mutant gliomas (4.7%; P = .0008), the latter were all high-grade (grade 3 or 4) astrocytomas. WGD was detected at initial diagnosis in 18 GBM (9.3%) and 9 IDH-mutant gliomas (5 astrocytomas and 4 oligodendrogliomas, either low- or high-grade; 8.5%). Neither CT nor WGD was associated with overall survival in GBM or in IDH-mutant gliomas. Conclusions: CT is less frequent in IDH-mutant gliomas compared to GBM. The absence of CT in ODG and grade 2 astrocytomas might, in part, explain their genome stability and better prognosis, while CT might underlie aggressive biological behavior in some high-grade astrocytomas. WGD is a rare and early event occurring equally in IDH-mutant gliomas and GBM.

Vascular damage and excessive proliferation compromise liver function after extended hepatectomy in mice.

BACKGROUND AND AIMS: Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of postoperative liver failure, known as the small-for-size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in an SFSS liver remnant initiated early angiogenesis, improving the vascular architecture, safeguarding against liver failure, and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS and their impact on hepatocyte function and subsequent liver failure. APPROACH AND RESULTS: Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered posthepatectomy survival rates. The early proliferation of liver sinusoidal cells, coupled with recruitment of putative endothelial progenitor cells, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of granulocyte colony-stimulating factor in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and endothelial progenitor cell recruitment but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, promoting functional preservation in the regenerating remnant. Injection of Adeno-associated virus serotype 8-thyroxine-binding globulin-hepatocyte nuclear factor 4 alpha virus for hepatocyte-specific overexpression of hepatocyte nuclear factor 4 alpha, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. The combination of hepatocyte nuclear factor 4 alpha overexpression and granulocyte colony-stimulating factor treatment rescued survival after SFSS-setting hepatectomy. CONCLUSIONS: In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To improve survival following SFSS hepatectomy, it is essential to adopt a 2-pronged strategy aimed at preserving the function of proliferating parenchymal cells and simultaneously attenuating vascular damage.

[Neuroepithelial tumor with PATZ1 fusion - case report and focus on an ill-defined entity]. / Tumeur neuroépithéliale avec fusion PATZ1 ­ à propos d'un cas et mise au point sur une entité mal définie.

The neuroepithelial tumor with PATZ1 fusion is a recently described tumor type, at the border between central nervous system and mesenchymal tumors. The histopathological diagnosis of this neoplasm, not recognized by the 2021 WHO classification, is challenging due to its varied and non-specific morphologic features. Most cases are densely cellular with monomorphous nuclei. Perivascular pseudo-rosettes of the ependymal type and astroblastic features are frequent. Blood vessels may be hyalinized. The tumor may display low- or high-grade features. OLIG2 and GFAP are variably expressed. Guided by DNA methylation profiling, a pathologist aware of this tumor type will search for a fusion involving PATZ1 and EWSR1 or MN1. The physiopathology of neuroepithelial tumor with PATZ1 fusion is not fully understood. The prognosis appears to align with that of intermediate-grade tumors but follow-up data are scarce. The therapeutic management is often similar to that of high-grade neoplasms. Nonetheless, PATZ1 fusion is a potential therapeutic avenue that may lead to personalized and less aggressive treatments.

Keratinocytes activated by IL-4/IL-13 express IL-2Rγ with consequences on epidermal barrier function.

Atopic dermatitis (AD) is a Th2-type inflammatory disease characterized by an alteration of epidermal barrier following the release of IL-4 and IL-13. These cytokines activate type II IL-4Rα/IL-13Rα1 receptors in the keratinocyte. Whilst IL-2Rγ, that forms type I receptor for IL-4, is only expressed in haematopoietic cells, recent studies suggest its induction in keratinocytes, which questions about its role. We studied expression of IL-2Rγ in keratinocytes and its role in alteration of keratinocyte function and epidermal barrier. IL-2Rγ expression in keratinocytes was studied using both reconstructed human epidermis (RHE) exposed to IL-4/IL-13 and AD skin. IL-2Rγ induction by type II receptor has been analyzed using JAK inhibitors and RHE knockout (KO) for IL13RA1. IL-2Rγ function was investigated in RHE KO for IL2RG. In RHE, IL-4/IL-13 induce expression of IL-2Rγ at the mRNA and protein levels. Its mRNA expression is also visualized in keratinocytes of lesional AD skin. IL-2Rγ expression is low in RHE treated with JAK inhibitors and absent in RHE KO for IL13RA1. Exposure to IL-4/IL-13 alters epidermal barrier, but this alteration is absent in RHE KO for IL2RG. A more important induction of IL-13Rα2 is reported in RHE KO for IL2RG than in not edited RHE. These results demonstrate IL-2Rγ induction in keratinocytes through activation of type II receptor. IL-2Rγ is involved in the alteration of the epidermal barrier and in the regulation of IL-13Rα2 expression. Observation of IL-2Rγ expression by keratinocytes inside AD lesional skin suggests a role for this receptor subunit in the disease.

Interplay between Prostate Cancer and Adipose Microenvironment: A Complex and Flexible Scenario.

Adipose tissue is part of the prostate cancer (PCa) microenvironment not only in the periprostatic area, but also in the most frequent metastatic sites, such as bone marrow and pelvic lymph nodes. The involvement of periprostatic adipose tissue (PPAT) in the aggressiveness of PCa is strongly suggested by numerous studies. Many molecules play a role in the reciprocal interaction between adipocytes and PCa cells, including adipokines, hormones, lipids, and also lipophilic pollutants stored in adipocytes. The crosstalk has consequences not only on cancer cell growth and metastatic potential, but also on adipocytes. Although most of the molecules released by PPAT are likely to promote tumor growth and the migration of cancer cells, others, such as the adipokine adiponectin and the n-6 or n-3 polyunsaturated fatty acids (PUFAs), have been shown to have anti-tumor properties. The effects of PPAT on PCa cells might therefore depend on the balance between the pro- and anti-tumor components of PPAT. In addition, genetic and environmental factors involved in the risk and/or aggressiveness of PCa, including obesity and diet, are able to modulate the interactions between PPAT and cancer cells and their consequences on the growth and the metastatic potential of PCa.

Lipophagy and prostate cancer: association with disease aggressiveness and proximity to periprostatic adipose tissue.

The prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is believed to play a role in prostate cancer (PCa) progression. Cancer cells can take up lipids from the microenvironment and store them in lipid droplets (LDs). Fatty acids released from LDs are used by PCa cells as preferential metabolic fuels to provide energy and promote cancer progression. Recently, fatty acids have been associated with autophagy, a cellular recycling pathway. Lipophagy is a selective form of autophagy involved in LD degradation, the role of which in PCa progression remains unknown. Here, we explored markers of autophagy and lipophagy in human PCa tissues in correlation with factors of aggressiveness, and we evaluated the influence of PPAT adipocytes on autophagy and lipophagy. We analyzed markers of autophagy (p62, LC3), lipid droplets (PLIN and Oil Red O), androgen receptor (AR), proliferation (Ki67), and epithelial-mesenchymal transition (Zeb1) on 465 PCa samples. Co-cultures of PCa cell lines PC3 and 22RV1 with adipocytes isolated from patients' PPAT were used to analyze the influence of PPAT on autophagy and lipophagy in vitro. In human PCa tissues, we observed a correlation between markers of LD and those of autophagy, which are associated with clinical and biological factors of disease aggressiveness. In addition, PLIN staining was associated with AR expression. In locally advanced PCa, p62, LC3, and PLIN were increased in extraprostatic areas where cancer cells are in contact with PPAT. Co-culture of PCa cell lines with adipocytes decreased autophagy activity and increased LD flux in PC3 cells. These results suggest an active process of lipophagy in PCa, linked to disease aggressiveness, to the proximity of PPAT, and induced in vitro in co-culture with adipocytes. Lipophagy is therefore likely to be a crucial player in PCa progression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.