Heparin-induced thrombocytopenia with very high antibody titer is associated with slower platelet recovery and higher risk of thrombosis.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by platelet-activating antibodies targeting platelet factor 4 (PF4) and heparin complex. A higher antibody titer is reflected in a higher optical density (OD) by enzyme-linked immunosorbent assay for heparin-PF4 antibodies. This single-institution retrospective study of 116 HIT patients examined the effect of heparin-PF4 OD on time to platelet recovery, vascular thrombosis, and in-hospital mortality. Patients were divided into 3 cohorts based on heparin-PF4 OD: cohort 1 had an OD ≥ 2 and ≤ 2.4, cohort 2 had an OD > 2.4 and ≤ 2.8, and cohort 3 had an OD > 2.8. A higher OD titer was associated with significantly increased time to platelet recovery when compared between cohorts 1 versus 2 (HR = 0.599, p = 0.0221) and 1 versus 3 (HR = 0.515, p = 0.0014), as well as an increased risk of thrombosis (79.4%-cohort 3 vs 53.8%-cohort 2 vs 46.1%-cohort 1, p = 0.04), but had no impact on mortality (2.62-alive vs 2.65-deceased, p = 0.7432). A higher OD titer can inform risk assessment and support decision-making in HIT patients; however, prospective studies are needed to further clarify the impact of heparin-PF4 OD on outcomes.

Sex-related differences regarding headache triggered by low barometric pressure in Japan.

PURPOSE: The prevalence of migraine headache is higher in women. Low barometric pressure is a factor in headache triggering, but sex-related differences have not been identified. The purpose of this study was to examine sex-related differences in headache triggered by low barometric pressure. METHODS: Study subjects aged 20-49 years were randomly selected from a research company's (Macromill, Inc.) web panel. Those with chronic migraine or tension-type headache invited to complete a web-based self-administered questionnaire. Logistic regression analysis was performed with the objective variable as the Headache Impact Test-6 (HIT-6) high scores (56 or more) or headache triggered by low barometric pressure. RESULTS: Participants were 332 women and 337 men in the headache population. HIT-6 high scores were associated with age at headache occurrence 20 years or younger (OR: odds ratio 1.85, 95% CI: confidence interval 1.15-2.99, p = 0.012) and headache triggered by low barometric pressure (OR 2.11, 95%CI 1.51-2.94, p < 0.001). Headache triggered by low barometric pressure was significantly associated with women (OR 2.92, 95%CI 2.12-4.02, p < 0.001). CONCLUSIONS: Headache triggered by low barometric pressure were related to sex-related differences. It was suggested that a sex-specific treatment approach for headache triggering is needed.

Microglial responses to inflammatory challenge in adult rats altered by developmental exposure to polychlorinated biphenyls in a sex-specific manner.

Polychlorinated biphenyls are ubiquitous environmental contaminants linked with peripheral immune and neural dysfunction. Neuroimmune signaling is critical to brain development and later health; however, effects of PCBs on neuroimmune processes are largely undescribed. This study extends our previous work in neonatal or adolescent rats by investigating longer-term effects of perinatal PCB exposure on later neuroimmune responses to an inflammatory challenge in adulthood. Male and female Sprague-Dawley rats were exposed to a low-dose, environmentally relevant, mixture of PCBs (Aroclors 1242, 1248, and 1254, 1:1:1, 20µg / kg dam BW per gestational day) or oil control during gestation and via lactation. Upon reaching adulthood, rats were given a mild inflammatory challenge with lipopolysaccharide (LPS, 50µg / kg BW, ip) or saline control and then euthanized 3hours later for gene expression analysis or 24hours later for immunohistochemical labeling of Iba1+ microglia. PCB exposure did not alter gene expression or microglial morphology independently, but instead interacted with the LPS challenge in brain region- and sex-specific ways. In the female hypothalamus, PCB exposure blunted LPS responses of neuroimmune and neuromodulatory genes without changing microglial morphology. In the female prefrontal cortex, PCBs shifted Iba1+ cells from reactive to hyperramified morphology in response to LPS. Conversely, in the male hypothalamus, PCBs shifted cell phenotypes from hyperramified to reactive morphologies in response to LPS. The results highlight the potential for long-lasting effects of environmental contaminants that are differentially revealed over a lifetime, sometimes only after a secondary challenge. These neuroimmune endpoints are possible mechanisms for PCB effects on a range of neural dysfunction in adulthood, including mental health and neurodegenerative disorders. The findings suggest possible interactions with other environmental challenges that also influence neuroimmune systems.

Genome and metabolome analysis of Bacillus sp. Hex-HIT36: A newly screened functional microorganism for the degradation of 1-hexadecene in industrial wastewater.

1-Hexadecene has been detected at a level of mg/L in both influent and effluent of wastewater treatment plants situated in chemical/pharmaceutical industrial parks, which poses a potential threat to the environment. However, few reports are available on aerobic metabolic pathways and microorganisms involved in 1-Hexadecene degradation. In this study, a new strain of 1-Hexadecene-degrading bacteria, Bacillus sp. Hex-HIT36 (HIT36), was isolated from the activated sludge of a wastewater treatment plants located in an industrial park. The physicochemical properties and degradation efficacy of HIT36 were investigated. HIT36 was cultured on a medium containing 1-Hexadecene as a sole carbon source; it was found to remove ∼67% of total organic carbon as confirmed by mass spectrometric analysis of intermediate metabolites. Metabolomic and genomic analysis showed that HIT36 possesses various enzymes, namely, pyruvate dehydrogenase, dihydropolyhydroxyl dehydrogenase, and 2-oxoglutarate-2-oxoiron oxidoreductase (subunit alpha), which assist in the metabolization of readily available carbon source or long chain hydrocarbons present in the growth medium/vicinity. This suggests that HIT36 has efficient long-chain alkane degradation efficacy, and understanding the alkane degradation mechanism of this strain can help in developing technologies for the degradation of long-chain alkanes present in wastewater, thereby assisting in the bioremediation of environment.

Easily misdiagnosed X-linked adrenoleukodystrophy.

BACKGROUND: Addison's disease and X-linked adrenoleukodystrophy (X-ALD) (Addison's-only) are two diseases that need to be identified. Addison's disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison's-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison's disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD. METHODS: We retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics. RESULTS: Two patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison's disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109_110insGCCA (p.C39Pfs*156), c.1394-2 A > C (NM_000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison's-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum. CONCLUSIONS: Patients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison's disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison's-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy.

The Discovery of GIT1/ß-Pix Inhibitors: Virtual Screening and Biological Evaluation of New Small-molecule Compounds with Anti-invasion Effect in Gastrointestinal Neoplasms.

Background and Objective: GIT1 (G-protein-coupled receptor kinase interacting protein-1) has been found to be highly related with cancer cell invasion and metastasis in many cancer types. ß-Pix (p21-activated kinase-interacting exchange factor) is one of the proteins that interact with GIT1. Targeting GIT1/ß-Pix complex might be a potential therapeutic strategy for interfering cancer metastasis. However, at present, no well-recognized small-molecule inhibitor targeting GIT1/ß-Pix is available. Thus, we aim to discover novel GIT1/ß-Pix inhibitors with simple scaffold, high activity and low toxicity to develop new therapeutic strategies to restrain cancer metastasis. Methods: GIT1/ß-Pix inhibitors were identified from ChemBridge by virtual screening. Briefly, the modeling of GIT1 was performed and the establishment of GIT1/ß-Pix binding pocket enabled the virtual screening to identify the inhibitor. In addition, direct binding of the candidate molecules to GIT1 was detected by biolayer interferometry (BLI) to discover the hit compound. Furthermore, the inhibitory effect on invasion of stomach and colon cancer cells in vitro was carried out by the transwell assay and detection of epithelial-mesenchymal transition (EMT)-related proteins. Finally, the binding mode of hit compound to GIT1 was estimated by molecular dynamics simulation to analyze the key amino residues to guide further optimization. Results: We selected the top 50 compounds from the ChemBridge library by virtual screening. Then, by skeleton similarity analysis nine compounds were selected for further study. Furthermore, the direct interaction of nine compounds to GIT1 was detected by BLI to obtain the best affinitive compound. Finally, 17302836 was successfully identified (KD = 84.1±2.0 µM). In vitro tests on 17302836 showed significant anti-invasion effect on gastric cancer and colorectal cancer. Conclusion: We discovered a new GIT1/ß-Pix inhibitor (17302836) against gastrointestinal cancer invasion and metastasis. This study provides a promising candidate for developing new GIT1/ß-Pix inhibitors for tumor treatment.

Macrophage-derived exosomes exacerbate postoperative cognitive dysfunction in mice through inflammation.

This study investigated the impact of two-hit inflammation on postoperative cognitive dysfunction (POCD) in mice and the role of macrophage-derived exosomes in regulating this process. Mice models were used to mimic the state of two-hit inflammation, and cognitive function was assessed through behavioral experiments. Proinflammatory cytokine expression levels and blood-brain barrier (BBB)-associated functional proteins were measured using ELISA and Western blot, respectively. An in vitro macrophage inflammation two-hit model was created, and the role of exosomes was examined using the previously mentioned assays. Additionally, exosomes were injected into mice to further understand their impact in the two-hit inflammation model. Mice exposed to two-hit inflammation experienced impaired cognitive function, increased BBB permeability, and elevated levels of proinflammatory cytokines. Macrophages subjected to two-hit inflammation released higher levels of proinflammatory cytokines compared to the control group and other treatment groups. Treatment with an exosome inhibitor GW4869 effectively reduced the expression levels of proinflammatory cytokines in macrophages exposed to two-hit inflammation. Moreover, injection of macrophage-released exosomes into healthy mice induced inflammation, hippocampal damage, and cognitive disorders, which were mitigated by treatment with GW4869. In mice with two-hit inflammation, macrophage-released exosomes worsened cognitive disorders by promoting inflammation in the peripheral blood and central nervous system. However, treatment with GW4869 protected cognitive function by suppressing exosome release. These findings highlight the importance of two-hit inflammation in POCD and emphasize the critical role of exosomes as regulatory factors. This research provides valuable insights into the pathogenesis of POCD and potential intervention strategies.

Real-world evidence from Germany and the United States: Treatment initiation on low-efficacy versus high-efficacy therapies in patients with multiple sclerosis.

BACKGROUND: The hit-hard-and-early (HHAE) strategy where treatment is initiated with high-efficacy therapies opposed to low-efficacy therapies presents a potential paradigm shift in multiple sclerosis (MS) management. This study aimed to assess the adoption of the HHAE strategy in Germany and the United States (US) from 2020 to 2022 based on real-world data. METHODS: The analysis was based on longitudinal, patient-level data from Germany and the US. For Germany, data was extracted from the Permea platform covering approximately 44 % of all German community pharmacy dispensing. For the US, data from the Komodo Healthcare Map™ was utilized, covering medical benefit data from around 88 % of the US patient population. Patients ≥18 years old and who had at least 2 prescriptions for MS-related disease-modifying drugs (DMDs) between January 2020 and December 2022 were included. To approximate therapy beginners, a washout period of one year before treatment start was applied, excluding all patients who had an MS-related DMD prescription or claim in 2019. Cohort entry date was the day of the first MS-related DMD dispense or claim. DMDs were classified as high-efficacy and low-efficacy based on the Multiple Sclerosis Therapy Consensus Group (MSTCG). Group differences were assessed with two-sided χ2-square and t-tests. RESULTS: 29,604 MS therapy beginners were identified in the German and 49,791 MS therapy beginners were identified in the US dataset. 29.6 % of MS therapy beginners in Germany and 61.6 % in the US followed the HHAE strategy. Between 2020 and 2022, a significant 14 % increase in the HHAE strategy was observed in both countries (p < 0.0001). High-efficacy therapy beginners switched from their initially prescribed therapy less frequently than low-efficacy therapy beginners: 6.9 % of high-efficacy vs. 19.5 % of low-efficacy therapy beginners in Germany (p < 0.0001) and 5.5 % of high-efficacy vs. 25.0 % low-efficacy therapy beginners in the US (p < 0.0001) switched from their first prescribed DMD. CONCLUSION: Between 2020 and 2022, the adoption of the HHAE strategy increased in both countries, with the US exhibiting nearly double the adoption rates. High-efficacy therapy beginners were less likely to switch from their initially prescribed medication than low-efficacy therapy beginners. Real world evidence can provide valuable insights into rapidly changing treatment patterns in patients with MS.

Myc rearrangement redefines the stratification of high-risk multiple myeloma.

BACKGROUND: Myc rearrangement (Myc-R) is a controversial factor linked to adverse outcomes in newly diagnosed multiple myeloma (NDMM). AIMS: This study aimed to evaluate the impact of Myc-R on the prognosis of NDMM patients and its role in risk stratification compared with traditional high-risk cytogenetic abnormalities (HRCAs). MATERIALS & METHODS: A total of 417 NDMM patients enrolled from May 2009 to September 2022 were included. Fluorescence in situ hybridization (FISH) was used to detect Myc-R and other Myc abnormalities (Myc-OA). Median progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and log-rank tests. Multivariate Cox regression analysis was used to identify independent risk factors. RESULTS: Myc-R was identified in 13.7% of patients, while 14.6% had Myc-OA. Patients with Myc-R had significantly shorter median PFS (15.9 months) and OS (25.1 months) compared with those with Myc-OA (24.5 months PFS; 29.8 months OS) and Myc-negative (Myc-N) status (29.8 months PFS, 29.8 months OS). Myc-R was independently associated with worse PFS and OS compared to Myc-OA. Patients with Myc-R alone had inferior median PFS (15.9 months vs. 28.1 months, p = 0.032) and OS (25.1 months vs. 61.2 months, p = 0.04) compared to those with traditional single HRCA. DISCUSSION: The study suggests that traditional single HRCA may not significantly impact survival in NDMM patients. However, incorporating Myc rearrangement or traditional double/triple-hit HRCAs into the risk stratification model improves its predictive value, highlighting the importance of Myc rearrangement in risk assessment. CONCLUSION: Myc rearrangement is an independent adverse prognostic factor in NDMM. The incorporation of Myc rearrangement or multiple HRCAs into risk stratification models improves their prognostic value, providing a novel perspective on high-risk factors in NDMM.

Well-differentiated G1 and G2 pancreatic neuroendocrine tumors: a meta-analysis of published expanded DNA sequencing data.

Introduction: Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in MEN1 as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs. Methods: A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020. A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25th of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package. Results: Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was MEN1, with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in MEN1, VHL, CHEK2, BRCA2, PTEN, CDKN1B, and/or MUTYH) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The MEN1 point mutations/indels were distributed throughout MEN1. Overall, DAXX (16%, 37/225) and ATRX-variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. DAXX mutations occurred more frequently in PNETs with MEN1 mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways. Discussion: The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).

Vestibular evaluation with video head impulse test in pediatric cochlear implant patients.

BACKGROUND: The cochlear implant (CI) is effective for rehabilitating patients with severe to profound sensorineural hearing loss. However, its placement and use have been associated with various complications, such as those affecting the vestibular system. The objective of this study was to compare vestibular function using the video head impulse test (vHIT) in pediatric patients before and after CI placement. METHODS: A descriptive and retrospective study was conducted. The outcomes of 11 pediatric patients of both sexes with a history of profound hearing loss were evaluated. The results of vestibular-ocular reflex (VOR) gain, saccades, asymmetry, Pérez Rey (PR) index, and VOR/saccade ratio for both ears obtained by the vHIT test before and after CI placement were compared. RESULTS: Of the 11 patients evaluated, the VOR gain showed that 81.8% had normal function, 18.2% had hypofunction, and no patients had hyperfunction before implantation. No statistically significant differences were found when compared with post-implant off and post-implant on conditions (p > 0.05). The extracted variables, asymmetry, PR index, and the VOR/saccades ratio also showed no statistically significant differences between the pre- and post-implant conditions, whether off or on. CONCLUSIONS: The vestibular function of pediatric patients did not show significant changes before and after CI placement. The vHIT test is a valuable tool for assessing vestibular function and could be considered a criterion for surgical and rehabilitation decisions in patients undergoing CI placement.

INTRODUCCIÓN: El implante coclear es un dispositivo eficaz para la rehabilitación de pacientes con hipoacusia neurosensorial severa a profunda. Sin embargo, su colocación y uso se ha asociado a diversas complicaciones, entre ellas a nivel del sistema vestibular. El objetivo del presente estudio fue comparar la función vestibular mediante la prueba de videoimpulso cefálico (vHIT) de pacientes pediátricos antes y después de la colocación del implante coclear. MÉTODOS: Se llevó a cabo un estudio descriptivo y retrospectivo. Se evaluaron los resultados de 11 pacientes pediátricos de ambos sexos con antecedente de hipoacusia profunda. Se compararon los resultados de ganancia del VOR, sacadas, asimetría, índice PR así como la relación VOR/sacadas para ambos oídos obtenidos mediante la prueba vHIT antes y después de la colocación del implante coclear. RESULTADOS: De los 11 pacientes evaluados, la ganancia del VOR mostró que el 81.8% tenía normofunción, 18.2% hipofunción y ningún paciente hiperfunción antes del implante. Al compararlo con la ganancia post implante apagado y post implante encendido no se encontraron diferencias estadísticamente significativas (p > 0.05). Las variables sacadas, asimetría, índice PR así como la relación VOR/sacadas tampoco mostraron diferencias estadísticamente significativas entre las condiciones pre y pos implante ya sea apagado o encendido. CONCLUSIONES: La función vestibular de pacientes pediátricos no mostró cambios significativos previo y posterior a la colocación del implante coclear. La prueba vHIT es una herramienta útil que permite evaluar la función vestibular y que podría considerarse como criterio para tomar decisiones quirúrgicas en pacientes que se encuentran en protocolo para implante coclear.

Heparin-induced thrombocytopenia in extracorporeal membrane oxygenation-supported patients: a systematic review and meta-analysis.

BACKGROUND: In recent years, extracorporeal membrane oxygenation (ECMO) has been increasingly used in critically ill patients with respiratory or cardiac failure. Heparin is usually used as anticoagulation therapy during ECMO support. However, heparin-induced thrombocytopenia (HIT) in ECMO-supported patients, which results in considerable morbidity and mortality, has not yet been well described. This meta-analysis and systematic review aimed to thoroughly report the incidence of HIT on ECMO, as well as the characteristics and outcomes of HIT patients. METHODS: We searched the PubMed, Embase, Cochrane Library, and Scopus databases for studies investigating HIT in adult patients supported by ECMO. All studies conforming to the inclusion criteria were screened from 1975 to August 2023. Nineteen studies from a total of 1,625 abstracts were selected. The primary outcomes were the incidence of HIT and suspected HIT. RESULTS: The pooled incidence of HIT in ECMO-supported patients was 4.2% (95% CI: 2.7-5.6; 18 studies). A total of 15.9% (95% CI: 9.0-22.8; 12 studies) of patients on ECMO were suspected of having HIT. Enzyme-linked immunosorbent assay (ELISA) is the most commonly used immunoassay. The median optical density (OD) of the ELISA in HIT-confirmed patients ranged from 1.08 to 2.10. In most studies, the serotonin release assay (SRA) was performed as a HIT-confirming test. According to the subgroup analysis, the pooled incidence of HIT in ECMO patients was 2.7% in studies whose diagnostic mode was functional assays, which is significantly lower than the incidence in studies in which the patients were diagnosed by immunoassay (14.5%). Argatroban was most commonly used as an alternative anticoagulation agent after the withdrawal of heparin. Among confirmed HIT patients, 45.5% (95% CI: 28.8-62.6) experienced thrombotic events, while 50.1% (95% CI: 24.9-75.4) experienced bleeding events. Overall, 46.6% (95% CI: 30.4-63.1) of patients on ECMO with HIT died. CONCLUSION: According to our study, the pooled incidence of HIT in ECMO-supported patients is 4.2%, and it contributes to adverse outcomes. Inappropriate diagnostic methods can easily lead to misdiagnosis of HIT. Further research and development of diagnostic algorithms and laboratory assays are warranted.

Long-term Environmental Enrichment Normalizes Schizophrenia-like Abnormalities and Promotes Hippocampal Slc6a4 Promoter Demethylation in Mice Submitted to a Two-hit Model.

Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5-7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.

Discovery of novel CXCR4 inhibitors for the treatment of inflammation by virtual screening and biological evaluation.

C-X-C chemokine receptor type 4 (CXCR4) exerts considerable influence on the pathogenesis of inflammatory disorders and offers a potent avenue for drug intervention. This research utilizes a hybrid virtual screening methodology constructed using computer-aided drug design to discover novel CXCR4 inhibitors for the treatment of inflammation. First, a compound library was screened by Lipinski's five rules and adsorption, distribution, metabolism, excretion and toxicity properties. Second, the HypoGen algorithm was used in constructing a 3D-QSAR pharmacophore model and verify it layer by layer, and the obtained optimal pharmacophore 1 (Hypo 1) was used as a 3D query for compound screening. Then, hit compounds were obtained through molecular docking (Libdock and CDOCKER). The toxicity of the compounds to MDA-MB-231 cells was evaluated in vitro, and their binding affinity to the target was evaluated according to how they compete with 12G5 antibody for CXCR4 on the surfaces of the MDA-MB-231 cells. Compound Hit14 showed the strongest binding affinity among the hit compounds and inhibited cell migration and invasion in Matrigel invasion and wound healing assay at a concentration of 100 nM, demonstrating a better effect than AMD3100. Western Blot experiments further showed that Hit14 blocked the CXCR4/CXCL12-mediated phosphorylation of Akt. Meanwhile, cellular thermal displacement assay analysis showed that CXCR4 protein bound to Hit14 had high thermal stability. Finally, through in vivo experiments, we found that Hit14 inhibited mouse ear inflammation and reduced ear swelling and damage. Therefore, Hit14 is a promising drug for the further development of CXCR4 inhibitors for inflammation treatment.

Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents.

An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl fragment of hit 1, a compound with low micromolar activity against Plasmodium falciparum discovered by high-throughput screening. After confirming the crucial role played by this aryl fragment in the antiplasmodial activity, the replacement of the ortho-methyl substituent of 1 by halogenated ones led to an improvement for four analogs, either in terms of potency, expected pharmacokinetics profile, or both. Further introduction of endocyclic nitrogens in this fragment identified two more optimized compounds, 20 and 23, which are expected to be much more metabolically stable than 1. Additional assessment of the cytotoxicity, Ligand Lipophilic Efficiency, potency against the chloroquine-resistant Dd2 strain and in silico ADMET predictions revealed a satisfactory profile for most compounds, ultimately identifying the four optimized compounds 7, 9, 20 and 23 as promising compounds for further lead optimization of this series against Plasmodium falciparum.

A Rare Case of Argatroban-Induced Anaphylaxis in a Patient With Intermediate-High Risk Pulmonary Embolism.

Heparin-induced thrombocytopenia is a rare and potentially devastating complication of heparin therapy. Patients with an absolute indication for anticoagulation, such as those with significant pulmonary embolism, must be switched to a different anticoagulant, such as argatroban, a direct thrombin inhibitor. We report a case of anaphylaxis to argatroban in a patient who was initially on heparin for intermediate-high risk pulmonary embolism but developed suspected type II heparin-induced thrombocytopenia. This case highlights the significance of recognizing and treating anaphylactic reactions and the diagnostic challenges associated with heparin-induced thrombocytopenia.

A Service-Caching Strategy Assisted by Double DQN in LEO Satellite Networks.

Satellite fog computing (SFC) achieves computation, caching, and other functionalities through collaboration among fog nodes. Satellites can provide real-time and reliable satellite-to-ground fusion services by pre-caching content that users may request in advance. However, due to the high-speed mobility of satellites, the complexity of user-access conditions poses a new challenge in selecting optimal caching locations and improving caching efficiency. Motivated by this, in this paper, we propose a real-time caching scheme based on a Double Deep Q-Network (Double DQN). The overarching objective is to enhance the cache hit rate. The simulation results demonstrate that the algorithm proposed in this paper improves the data hit rate by approximately 13% compared to methods without reinforcement learning assistance.

Molecular characterization of a rare case of high-grade B-cell lymphoma with MYC, BCL2, BCL6, and CCND1 rearrangements.

Quadruple-hit lymphomas are extremely rare non-Hodgkin lymphomas with a reported dismal prognosis in the few reported cases. A "quadruple hit" has been defined by the presence of concurrent MYC, BCL2, BCL6, and CCND1 chromosomal rearrangements. We report a new case of a quadruple hit lymphoma in a 73-year-old Hispanic man who presented with an enlarging left-sided neck mass. Computed tomography showed a 1.9-cm mass in left the tonsil with bulky cervical lymphadenopathy. The presence of all four chromosomal rearrangements can reportedly occur with disease progression in both diffuse large B-cell lymphomas and mantle cell lymphomas. Further characterization of the tumor by next-generation sequencing may be of benefit to delineate between these two possibilities. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing were used to confirm and classify the diagnosis. Histologic sections of the cervical lymph node demonstrated an atypical lymphoid infiltrate with large and pleomorphic cells, which were positive for CD20, CD10, BCL1 (Cyclin D1), BCL2, BCL6, and cMYC and negative for CD5 and SOX11 on immunohistochemistry with a Ki-67 proliferative index of 70%. FISH demonstrated MYC, BCL2, BCL6, and CCND1 rearrangements and the diagnosis of high-grade B-cell lymphoma with MYC, BCL2, BCL6, and CCND1 was rendered. Our patient was treated with dose adjusted etoposide, doxorubicin, cyclophosphamide, prednisone, and rituximab chemotherapy and has been in remission for 20 months.

Therapy-related myeloid neoplasms with single-hit TP53 mutations share the clinical, molecular, and survival characteristics of their multi-hit counterparts.

Recent updates in the classification of myeloid neoplasms (MNs) recognize the poor prognostic impact of TP53 mutations, with particular emphasis on the TP53 allele status. Studies on the effect of TP53 allele status exclusively in therapy-related MNs (t-MNs) are lacking. We compared the clinicopathologic and survival characteristics of t-MNs with single-hit (SH) and multi-hit (MH) TP53 mutations. A total of 71 TP53-mutated t-MNs were included, including 56 (78.9%) MH and 15 (21.1%) SH. Both groups showed comparable genetic profiles with an excess of high-risk karyotypes and a paucity of other co-mutated genes. TP53 was the sole detectable mutation in 73.3% of SH and 75.0% of MH cases. The overall survival (OS) of SH TP53-mutated t-MNs was not significantly different from MH cases (median survival: 233 vs.273 days, p = 0.70). Our findings suggest that t-MNs with SH TP53 mutations share the poor prognostic and biologic profile of their MH counterparts.

Performance of MYC, BCL2, and BCL6 break-apart FISH in small biopsies with large B-cell lymphoma: a retrospective Cytopathology Hematopathology Interinstitutional Consortium study.

Introduction: Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies. Methods: We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens. Results: FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement. Discussion: FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing.