BACKGROUND: Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study.
METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines\'s interaction with key genes.
RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines.
CONCLUSIONS: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.

Anthracyclines, including doxorubicin, idarubicin, and epirubicin, are common antitumor drugs as well as well-known cardiotoxic agents. This study analyzed the proteomics alteration in cardiac tissues caused by these 3 anthracyclines analogs. The in vitro human cardiac microtissues were exposed to drugs in 2 weeks; the proteomic data were measured at 7 time points. The heart biopsy data were collected from heart failure patients, in which some patients underwent anthracycline treatment. The anthracyclines-affected proteins were separately identified in the in vitro and in vivo dataset using the WGCNA method. These proteins engage in different cellular pathways including translation, metabolism, mitochondrial function, muscle contraction, and signaling pathways. From proteins detected in 2 datasets, a protein-protein network was established with 4 hub proteins, and 7 weighted proteins from both cardiac microtissue and human biopsies data. These 11 proteins, which involve in mitochondrial functions and the NF-κB signaling pathway, could provide insights into the anthracycline toxic mechanism. Some of them, such as HSPA5, BAG3, and SH3BGRL, are cardiac therapy targets or cardiotoxicity biomarkers. Other proteins, such as ATP5F1B and EEF1D, showed similar responses in both the in vitro and in vivo data. This suggests that the in vitro outcomes could link to clinical phenomena in proteomic analysis.

BACKGROUND: Initial clinical manifestations of NMOSD may rarely overlap with MS. Fingolimod may trigger severe attacks in patients with NMOSD previously misdiagnosed as MS. These cases are rare and their pathophysiology remains elusive.
METHODS: We recruited all NMOSD patients treated by fingolimod in a single-center cohort of Afro-Caribbean neuro-inflammatory patients in Fort-de-France (French West Indies). Six patients were collected from the literature.
RESULTS: Among 622 patients followed locally for MS, 101 received fingolimod and two suffered severe attacks revealing a typical NMOSD presentation. These two patients were found to have AQP4-IgG. The risk of misdiagnosed NMOSD in MS in our high-risk Afro-Caribbean patients was estimated to be 1.9% (0 to 4.7%). Among the whole cohort, relapses occurred within a month after fingolimod initiation in five patients. All attacks were severe and contrasted with previously benign attacks, suggesting a shift to a more severe disorder. An unusual finding in these patients was large brain lesions.
CONCLUSIONS: AQP4-IgG should be obtained before initiation of fingolimod in high-risk patients, especially in those from areas of high NMOSD prevalence.

OBJECTIVE: Bullous pemphigoid (BP) might be drug-induced. The present study evaluated the relationship between BP and dipeptidyl peptidase-4 inhibitors (DPP4Is).
METHODS: We recruited patients diagnosed with BP at Ogaki Municipal Hospital from 1 December 2009 through 31 December 2017. We retrospectively collected data from medical records and divided patients into two groups based on whether they received DPP4Is. Additionally, we determined the incidence of BP in patients who were first prescribed DPP4Is at our hospital during the study period.
RESULTS: Of 168 patients diagnosed with BP, 133 (79.1%) were positive for anti-BP180NC16a antibody. A total of 32 (19.0%) patients had been prescribed a DPP4I, 21 of whom (65.6%) were positive for anti-BP180NC16a antibody; this rate was lower than that in patients not receiving a DPP4I (82.3%; P = 0.0360). A total of 16 patients with type 2 diabetes mellitus had not been prescribed a DPP4I; only one (6.3%) was positive for anti-BP180NC16a antibody (P = 0.0339). During the study period, 9,304 patients were prescribed DPP4Is, eight of whom developed BP; six (75.0%) had non-inflammatory BP, and five of the six (83.3%) were negative for anti-BP180NC16a antibody.
CONCLUSIONS: The positive rate of anti-BP180NC16a antibody was lower in BP patients with DPP4I than without DPP4I, regardless of type 2 diabetes mellitus. The antibody titer was low in both the overall and type 2 diabetes mellitus populations. The prevalence of BP in 9,304 patients receiving DPP4Is was 0.0859%, which is higher than that in the general population. As DPP4Is are common diabetes treatments, we must be aware of the risk of BP.

Detecting similar ligand-binding sites in globally unrelated proteins has a wide range of applications in modern drug discovery, including drug repurposing, the prediction of side effects, and drug-target interactions. Although a number of techniques to compare binding pockets have been developed, this problem still poses significant challenges.
We evaluate the performance of three algorithms to calculate similarities between ligand-binding sites, APoc, SiteEngine, and G-LoSA. Our assessment considers not only the capabilities to identify similar pockets and to construct accurate local alignments, but also the dependence of these alignments on the sequence order. We point out certain drawbacks of previously compiled datasets, such as the inclusion of structurally similar proteins, leading to an overestimated performance. To address these issues, a rigorous procedure to prepare unbiased, high-quality benchmarking sets is proposed. Further, we conduct a comparative assessment of techniques directly aligning binding pockets to indirect strategies employing structure-based virtual screening with AutoDock Vina and rDock.
Thorough benchmarks reveal that G-LoSA offers a fairly robust overall performance, whereas the accuracy of APoc and SiteEngine is satisfactory only against easy datasets. Moreover, combining various algorithms into a meta-predictor improves the performance of existing methods to detect similar binding sites in unrelated proteins by 5-10%. All data reported in this paper are freely available at https://osf.io/6ngbs/ .

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Transient lesions of the splenium of the corpus callosum are characterized by MRI findings. The lesions are very rare, but significant from a clinical standpoint as differential diagnoses include serious conditions such as encephalitis, meningitis, and neuroleptic malignant syndrome. In addition, it is reported that some are attributed to the withdrawal of antiepileptic drugs. Here, we present a case of transient lesions of the splenium of the corpus callosum following rapid withdrawal of levetiracetam alone. To the best of our knowledge, this is the first report of such a case. Moreover, it is reported that cases of incidental transient lesions of the splenium of the corpus callosum are detected in Japan more often than in other countries, and as a result are prone to over-triage. Taking this into consideration, in the event of transient lesions of the splenium of the corpus callosum, the utmost attention must be paid to clinical symptoms and history relating to any of the aforementioned serious conditions.

Some therapeutic side-effects result from simultaneous activation of homolog receptors by the same ligand. Tropomyosin receptor kinases (TrkA, TrkB and TrkC) play a major role in the development and biology of neurons through neurotrophin signaling. The wide range of cross-interactions between Trk receptors and neurotrophins vary in selectivity, affinity and function. In this study, we discuss new perspectives to the manipulation of side-effects via a better understanding of the cross-interactions at the molecular level, derived by computational methods. Available crystal structures of Trk receptors and neurotrophins are a valuable resource for exploitation via molecular mechanics (MM) and dynamics (MD). The study of the energetics and dynamics of neurotrophins or neurotrophic peptides interacting with Trk receptors will provide insight to structural regions that may be candidates for drug targeting and signaling pathway selection.