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A letter to the editor is presented in response to an article about the case of deliberate self-harm.

Background: Compared to minimally invasive brain metastases (MI BrM), highly invasive (HI) lesions form abundant contacts with cells in the peritumoral brain parenchyma and are associated with poor prognosis. Reactive astrocytes (RAs) labeled by phosphorylated STAT3 (pSTAT3) have recently emerged as a promising therapeutic target for BrM. Here, we explore whether the BrM invasion pattern is influenced by pSTAT3+ RAs and may serve as a predictive biomarker for STAT3 inhibition., Methods: We used immunohistochemistry to identify pSTAT3+ RAs in HI and MI human and patient-derived xenograft (PDX) BrM. Using PDX, syngeneic, and transgenic mouse models of HI and MI BrM, we assessed how pharmacological STAT3 inhibition or RA-specific STAT3 genetic ablation affected BrM growth in vivo. Cancer cell invasion was modeled in vitro using a brain slice-tumor co-culture assay. We performed single-cell RNA sequencing of human BrM and adjacent brain tissue., Results: RAs expressing pSTAT3 are situated at the brain-tumor interface and drive BrM invasive growth. HI BrM invasion pattern was associated with delayed growth in the context of STAT3 inhibition or genetic ablation. We demonstrate that pSTAT3+ RAs secrete Chitinase 3-like-1 (CHI3L1), which is a known STAT3 transcriptional target. Furthermore, single-cell RNA sequencing identified CHI3L1-expressing RAs in human HI BrM. STAT3 activation, or recombinant CHI3L1 alone, induced cancer cell invasion into the brain parenchyma using a brain slice-tumor plug co-culture assay., Conclusions: Together, these data reveal that pSTAT3+ RA-derived CHI3L1 is associated with BrM invasion, implicating STAT3 and CHI3L1 as clinically relevant therapeutic targets for the treatment of HI BrM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: Acute megakaryoblastic leukemia (AMKL) is a rare, developmentally restricted, and highly lethal cancer of early childhood. The paucity and hypocellularity (due to myelofibrosis) of primary patient samples hamper the discovery of cell- and genotype-specific treatments. AMKL is driven by mutually exclusive chimeric fusion oncogenes in two-thirds of the cases, with CBFA2T3::GLIS2 (CG2) and NUP98 fusions (NUP98r) representing the highest-fatality subgroups. We established CD34+ cord blood-derived CG2 models (n = 6) that sustain serial transplantation and recapitulate human leukemia regarding immunophenotype, leukemia-initiating cell frequencies, comutational landscape, and gene expression signature, with distinct upregulation of the prosurvival factor B-cell lymphoma 2 (BCL2). Cell membrane proteomic analyses highlighted CG2 surface markers preferentially expressed on leukemic cells compared with CD34+ cells (eg, NCAM1 and CD151). AMKL differentiation block in the mega-erythroid progenitor space was confirmed by single-cell profiling. Although CG2 cells were rather resistant to BCL2 genetic knockdown or selective pharmacological inhibition with venetoclax, they were vulnerable to strategies that target the megakaryocytic prosurvival factor BCL-XL (BCL2L1), including in vitro and in vivo treatment with BCL2/BCL-XL/BCL-W inhibitor navitoclax and DT2216, a selective BCL-XL proteolysis-targeting chimera degrader developed to limit thrombocytopenia in patients. NUP98r AMKL were also sensitive to BCL-XL inhibition but not the NUP98r monocytic leukemia, pointing to a lineage-specific dependency. Navitoclax or DT2216 treatment in combination with low-dose cytarabine further reduced leukemic burden in mice. This work extends the cellular and molecular diversity set of human AMKL models and uncovers BCL-XL as a therapeutic vulnerability in CG2 and NUP98r AMKL., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor mediating the clearance of various molecules from the extracellular matrix. LRP1 also regulates cell surface expression of matrix receptors by modulating both extracellular and intracellular signals, though current knowledge of the underlying mechanisms remains partial in the frame of cancer cells interaction with matricellular substrates. In this study we identified that LRP1 downregulates calpain activity and calpain 2 transcriptional expression in an invasive thyroid carcinoma cell model. LRP1-dependent alleviation of calpain activity limits cell-matrix attachment strength and contributes to FTC133 cells invasive abilities in a modified Boyden chamber assays. In addition, using enzymatic assays and co-immunoprecipitation experiments, we demonstrated that LRP1 exerts post-translational inhibition of calpain activity through PKA-dependent phosphorylation of calpain-2. This LRP-1 dual mode of control of calpain activity fine-tunes carcinoma cell spreading. We showed that LRP1-mediated calpain inhibition participates in talin-positive focal adhesions dissolution and limits β1-integrin expression at carcinoma cell surface. In conclusion, we identified an additional and innovative intracellular mechanism which demonstrates LRP-1 pro-motile action in thyroid cancer cells. LRP-1 ability to specifically control calpain-2 expression and activity highlights a novel facet of its de-adhesion receptor status., Competing Interests: SD is co-founder of Apmonia-Therapeutics and acts as the chair of the Scientific and Clinical Advisory Board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Langlois, Martin, Schneider, Hachet, Terryn, Rioult, Martiny, Théret, Salesse and Dedieu.)

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.

The authors report three cases--one of them lethal--of intestinal occlusion among 30 patients treated with clozapine between 1991 and 1994 in Châlons-sur-Marne Psychiatric Hospital. The responsibility of clozapine seems to be linked with its potent anticholinergic property. The attention of prescriptors is necessary and the monitoring of the drug should not be limited to the hematologic aspect.

The psychiatric care of the motherhood disorders and of their consequences over the early mother-child relation has become necessary from P.C. Racamier's writings and after studies about maltreated young children. Maltreatment has been defined by us in a broad sense, that is to say from marked cruelties to neglect, including various forms of aggressiveness and rejection. The Maternity Hospital, as a structure, has been considered as a well-suited place because nearly all the future mothers of the department are delivered there. The work undertaken for one year at Charleville-Mézières Maternity Hospital is clinically described, with its advantages and its difficulties, revealing the increasing need of a correctly trained multidisciplinary staff, even specialized, which could ensure psychiatric care over a period long enough to be effective.

Clinical psychiatry, particularly in the case of hospital emergency, begins with the patient's benevolent observation. It goes on with the verbal communication, subordinated itself to linguistic problems. There are now daily cross-cultural practising and education in France. This is the presentation of a standardized inventory and of its instructions for use, created in connection with a multicentric currently analysed survey. The inventory can be used without major difficulty by non clinicians and general practitioners.

Research on suicide risk factors among psychiatric patients has developed considerably over the last 10 years. The methodological problems are numerous. Tentatives of global prediction have been unsuccessful in describing one complete and specific picture of the mentally ill suicide, whereas lawsuits against psychiatrists are frequent after patients' suicides. Through the analysis of 37 publications from 1978 to 1988 the authors review the main suicide risk factors identified among treated psychiatric patients.

The abnormal life--potentially the death--of the cell can be restored by a metalloid--lithium--which is nearly as common as sodium in the mineral world. This established fact grounds indirectly, contrary to apparent and scientific logic, the concept of endogenous brain disease which was until then an abstract concept because of a lack of objective evidence. Seven case reports are described.

Twenty years after the large development of the use of psychotropic drugs and of a psychiatric formation for doctors, 63 subjects with a major depressive episode following the D.S.M. III-R criteria were interviewed in a psychiatric emergency unit about their psychotropic drugs consumption and their medical care preceding a drug self-poisoning. There is a discrepancy between the subjects' depressive pathology and their care consumption. During the depressive episode 3% of the subjects received a treatment considered to be adequate--existence of an antidepressant therapy at sufficient dosage and duration together with a medical psychological follow-up. The results indicate a relative failure of the health care system. The importance of the selection of the sample and the limits of a medical approach are stressed. The usefulness of anti-depressant drugs and the necessity for a psychiatric training for doctors cannot be questioned. Only prospective studies could demonstrate whether a better suited medical action is able to reduce the incidence of suicidal behaviour among depressive patients.

Alcoholism and suicide are two Public Health problems which are linked at the epidemiological and clinical levels. Research over suicide risk factors among alcoholic subjects has developed mainly among medicalized psychiatric populations. Suicide occurs late among alcoholic patients, and affects particularly men and socially isolated subjects. The main risk factors relate to the decrease of the socio-economic status. loss of job and of income-, to the interpersonal loss--i.e. family bereavement or breach of relation, to the existence of a suicidal ideation often communicated or of suicidal antecedents, to a degradation of the physical state or the presence of some affections like gastro-duodenal ulcer. The identified factors are of little specificity. It is difficult to assess their interrelations and their respective true values. The reliable prediction of a later suicide remains presently impossible. Progress in analytic research over the alcoholic patients' suicide could result from the standardization of populations and of studied factors and from the use of multivariate analysis statistical methods.

The ability to demethylate the classical imipraminic antidepressants is a key factor for the immediate and long-term management of long cycles primary unipolar depressions. These are preliminary observations concerning two different cases of a well-demethylating patient, and a badly-demethylating one.