Next-Generation Therapies for Multiple Myeloma.

Recent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is the combination of Ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere with the integrity of myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors and coactivators that control expression of MM dependency genes. T cell engagers and chimeric antigen receptor T cells redirect patients' own T cells onto defined tumor antigens to kill MM cells. They have induced complete remissions even in end-stage patients. Unfortunately, responses to both conventional therapy and immunotherapy are not durable, and tumor heterogeneity, antigen loss, and lack of T cell fitness lead to therapy resistance and relapse. Novel approaches are under development to target myeloma-specific vulnerabilities, as is the design of multimodality immunological approaches, including and beyond T cells, that simultaneously recognize multiple epitopes to prevent antigen escape and tumor relapse.

A systematic review and meta-analysis on the efficacy of dialectical behavior therapy variants for the treatment of post-traumatic stress disorder.

Background: While there are well-established treatments for post-traumatic stress disorder (PTSD), these interventions appear to be less effective for individuals with comorbid borderline personality disorder (BPD) symptoms. Dialectical Behavior Therapy (DBT) for PTSD and DBT Prolonged Exposure (PE) are both effective interventions for treating these patients, but a comprehensive analysis evaluating the efficacy of these two interventions is lacking.Objective: To determine the effect sizes of PTSD-specific DBT treatments.Methods: We conducted a systematic review and pre-registered meta-analysis of the DBT literature for treating PTSD (osf.io/62rfq). Eligible trials and treatment evaluations published before September 2023 were searched in SCOPUS, PubMed, and the Cochrane Library databases. Thirteen articles were identified, and data were extracted for primary (PTSD symptoms) and secondary outcomes (BPD, depression, dissociation, non-suicidal self-injury [NSSI]). Treatment effects were calculated for randomised controlled trials, controlled clinical trials, and pre-post evaluations.Results: Overall, the studies involved 663 participants. Compared with control groups, PTSD-specific DBT treatments showed moderate effects in reducing PTSD symptom severity g = -0.69 (95% CI -1.03 to -0.34, p < .001) and depression g = -0.62 (95% CI -1.13 to -0.12, p = .016). Moreover, the pre-post changes showed an overall effect size for dissociative symptoms of g = -0.72 (95% CI -1.05 to -0.40, p < .001), for BPD-associated symptoms of g = -0.82 (95% CI -1.06 to -0.59, p < .001), and for NSSI frequency (g = -0.70, 95% CI -1.12 to -0.28, p = .001).Conclusions: Based on the results of our meta-analysis, DBT-PTSD and DBT PE were effective in reducing PTSD symptom severity and comorbid depressive symptoms. Further research on stage-based treatments should focus on systematically assessing NSSI, BPD symptoms, and suicidality.

We conducted the first meta-analysis assessing the efficacy of Dialectical Behavior Therapy for PTSD (DBT-PTSD) and Dialectical Behavior Therapy Prolonged Exposure (DBT PE) for individuals with comorbid PTSD and BPD symptoms.Based on RCTs/CCTs, we found moderately beneficial effects on PTSD symptoms, and depression for both stage-based interventions and large effects on non-suicidal self-injury frequency for DBT PE.DBT-PTSD and DBT PE resulted in pre-post improvements in dissociative symptoms, BPD-associated symptoms, and non-suicidal self-injury frequency.

Unlocking epoxy thermal management capability via hierarchical Ce-MOF@MoS2 hybrid constructed by in-situ growth method.

This study demonstrates the preparation of needle-like Ce-MOF crystals on molybdenum disulfide (MoS2) nanosheets using in-situ growth technology. This hybrid structure significantly enhances the thermal management and mechanical properties of thermosetting epoxy resin (EP). Specifically, EP/Ce-MOF@MoS2-3 exhibits a notable increase in tensile strength (TS) to 50.87 MPa and elongation at break (EB) to 10.84 %. Moreover, Ce-MOF@MoS2 provides synergistic flame retardant benefits, reducing the peak heat release rate (pHRR) and total heat release (THR) of EP/Ce-MOF@MoS2-3 by 38 % and 12.64 %, respectively, compared to EP-0. Additionally, Ce-MOF@MoS2 suppresses smoke and reduces toxic emissions; at a 3 % loading, it decreases CO and CO2 production in EP nanocomposites by 48.8 % and 38.7 %, respectively. Thus, this Ce-MOF@MoS2 hybrid, synthesized via in-situ growth, offers a novel approach for developing EP nanocomposites with superior thermal management and mechanical properties, along with effective flame retardancy and reduced hazardous emissions during thermal events.

Spatiotemporal EP4-fibulin-1 expression is associated with vascular intimal hyperplasia.

AIMS: Cyclooxygenase-2-derived prostaglandin E2 (PGE2) is thought to promote vascular intimal hyperplasia (IH). It has been reported that the PGE2 receptor EP4 is upregulated in injured vessels, and that EP4 signaling in vascular smooth muscle cells (VSMCs) promotes IH. In contrast, EP4 in endothelial cells has been demonstrated to restrain IH. We aimed to investigate spatiotemporal expression of EP4 and whether modulating EP4 signaling could be a viable therapeutic strategy. METHODS AND RESULTS: We generated EP4 reporter mice (Ptger4-IRES-nlsLacZ) and found temporary but prominent EP4 expression in VSMCs of the proliferative neointima 2 weeks after femoral artery wire injury. Injury-induced IH was diminished in VSMC-targeted EP4 heterozygous deficient mice (Ptger4fl/+; SM22-Cre) 2 and 4 weeks after vascular injury compared to that in SM22-Cre, whereas injury-induced IH was exacerbated in VSMC-targeted EP4-overexpressing mice (Ptger4-Tg) compared to controls (non-Tg). We then investigated the downstream signaling of EP4 in VSMCs. Stimulation of EP4 increased mRNA and protein levels of the glycoprotein fibulin-1 in Ptger4-Tg VSMCs. Fibulin-1C recombinant proteins increased VSMC proliferation and migration through transforming growth factor (TGF)-ß/Smad3, and EP4-mediated proliferation and migration were attenuated in Fbln1fl/fl; SM22-Cre VSMCs and in CRISPR/Cas9-mediated Fbln1 knockdown in Ptger4-Tg VSMCs. We generated multiple deletion mutants of fibulin-1C and found that EGF-like modules 6-8 appear to be involved in fibulin-1-mediated proliferation. Among binding partners of fibulin-1, extracellular matrix protein 1 (ECM1) was also upregulated by EP4 stimulation, and fibulin-1C and ECM1 proteins additively enhanced VSMC proliferation and migration. Injury-induced IH was attenuated in VSMC-targeted fibulin-1 deletion mice (Fbln1fl/fl; SM22-Cre) compared to Fbln1fl/fl. Furthermore, systemic EP4 antagonist administration reduced injury-induced IH in wild-type mice. CONCLUSIONS: EP4 was upregulated in VSMCs of proliferative IH, and EP4 signaling promoted IH, at least in part through fibulin-1. An EP4 antagonist might be considered as a therapeutic strategy for IH.

Accuracy of the "Surprise Question" in Predicting Long-Term Mortality Among Older Patients Admitted to the Emergency Department: Comparison Between Emergency Physicians and Nurses in a Multicenter Longitudinal Study.

Background: The "surprise question" (SQ) ("Would you be surprised if this patient died in the next 12 months?") is the most frequently used screening tool in emergency departments (EDs) to identify patients with poor prognosis and potential unmet palliative needs. Objective: To test and compare the accuracy of the SQ between emergency nurses (ENs) and emergency physicians (EPs) in predicting long-term mortality among older patients (OP) in the ED. Design and Setting/Subjects: A prospective cohort study of OPs (≥75 years) conducted in two Belgian EDs. EPs and ENs answered the SQ for the patients they cared for. Positive SQ (SQ+) was defined as a "no" answer. One-year mortality was assessed by phone call. Results: EPs and ENs both answered the SQ for 291 OPs (mean age 83.2 ± 5.4, males 42.6%). The SQ was positive in 43% and 40.6%, respectively. Predictive values were similar in both groups: sensitivity, specificity, c-statistics, negative predictive value, and positive predictive value were 0.79 (0.66-0.88), 0.68 (0.62-0.76), 0.69 (0.63-0.75), 0.92 (0.86-0.96), and 0.4 (0.31-0.50), respectively, for EPs and 0.71 (0.57-0.82), 0.69 (0.62-0.75), 0.69 (0.63-0.75), 0.89 (0.83-0.93), and 0.41 (0.31-0.51), respectively, for ENs. SQ + was associated with a higher mortality risk in both group (EPs hazard ratio: 3.2 [1.6-6.7], p = 0.002; ENs hazard ratio: 2.5 [1.3-4.8], p = 0.006). The survival probability was lower when both EPs and ENs agreed on the SQ+ (p < 0.001). Conclusion: The SQ is a simple tool to identify older ED patients at high mortality risk. Concordant responses from EPs and ENs are more predictive than either alone.

Efficacy and safety of immune checkpoint inhibitors plus platinum-etoposide vs. platinum-etoposide in the first-line treatment of extensive-stage small cell lung cancer: a systematic review and a meta-analysis.

Background: Currently, immune checkpoint inhibitors (ICIs) combined with platinum-etoposide (EP) are gradually becoming the first-line standard treatment for extensive-stage small cell lung cancer (ES-SCLC). This meta-analysis aims to compare the efficacy and safety of ICIs combined with EP vs. EP alone in the first-line treatment of ES-SCLC. Methods: We searched PubMed, Embase, and Cochrane Library databases for phase II/III randomized controlled trials (RCTs) that met inclusion criteria from January 2016 to November 2023. Outcome measures included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), treatment-related adverse events (TRAEs), treatment-related serious adverse events (TRSAEs), and immune-related adverse events (IRAEs). The effect analysis statistics of the outcome indicators were expressed with hazard ratio (HR) and odds ratio (OR) and their 95% confidence interval (CI). Results: This study included nine RCTs with a total of 4,711 patients. Compared to EP, ICIs plus EP improved patients' PFS (HR =0.71; 95% CI: 0.64-0.79; P<0.001), OS (HR =0.79; 95% CI: 0.74-0.84; P<0.001), and ORR (OR =1.27; 95% CI: 1.12-1.44; P=0.001), but increased the incidence of adverse events (AEs): TRAEs (OR =1.45; 95% CI: 1.20-1.76; P<0.001), IRAEs (OR =3.97; 95% CI: 2.49-6.32; P<0.001), and grade 3-4 IRAEs (OR =6.17; 95% CI: 2.36-16.15; P<0.001). However, there was no significant difference in the incidence of grade 3-4 TRAEs (OR =1.05; P=0.54), TRSAEs (OR =1.40; P=0.13), and grade 3-4 TRSAEs (OR =1.17; P=0.72). Subgroup analysis found that patients with brain metastasis did not benefit from ICIs combined with EP therapy, and patients with programmed cell death ligand 1 (PD-L1) expression ≥1% had poorer survival benefits compared to patients with PD-L1 expression <1%. Conclusions: In the first-line treatment of ES-SCLC, compared to EP chemotherapy, ICIs with EP can benefit patients in terms of PFS, OS, and ORR, but it will increase the occurrence of AEs.

Reasons for gender inequities in invasive electrophysiology: a survey on family issues and career paths of female and male electrophysiology fellows in Germany.

Aims: Female physicians are underrepresented in invasive electrophysiology (EP) for multiple reasons. Despite an increasing focus on the topic, it is unclear what aspects are predominant. Methods and results: We conducted a survey on career paths of current or former EP fellows in Germany to elucidate how gender and family affected their careers. 231 fellows (24.2% female) were invited. 110 participants completed the survey (30.9% female, mean age 41.0 ± 5.0 years, and 79.1% with children). Female and male participants with children reported similar career goals and achievements before parenthood, but afterwards women changed their career paths more often. Major reasons were personal priorities followed by lack of flexibility at work and at home. Women covered the majority of childcare. At the time of the survey, 80.0% of women and 96.4% of men with a former career goal of invasive EP were active in invasive EP. Independent of age, women were in lower-level positions, had accomplished fewer professional achievements, were less satisfied with their work and had fewer children. 56.5% of women did not feel supported by their employers regarding family issues. 82.6% reported there was no satisfactory day care. 69.6% were unable to continue to follow their career during pregnancy, mostly due to restrictions by employers (75.0%). Dedicated policies for pregnant workers or support programmes were scarce. Conclusion: Beside the distribution of childcare at home, lack of flexibility and support by employers as well as working and fluoroscopy restrictions during pregnancy hamper women in EP and should be addressed.

EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells.

Prostaglandin E2 (PGE2) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both α and ß isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.

STAT3 Protein-Protein Interaction Analysis Finds P300 as a Regulator of STAT3 and Histone 3 Lysine 27 Acetylation in Pericytes.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is a member of the cytoplasmic inducible transcription factors and plays an important role in mediating signals from cytokines, chemokines, and growth factors. We and others have found that STAT3 directly regulates pro-fibrotic signaling in the kidney. The STAT3 protein-protein interaction plays an important role in activating its transcriptional activity. It is necessary to identify these interactions to investigate their function in kidney disease. Here, we investigated the protein-protein interaction among three species to find crucial interactions that can be targeted to alleviate kidney disease. METHOD: In this study, we examined common protein-protein interactions leading to the activation or downregulation of STAT3 among three different species: humans (Homo sapiens), mice (Mus musculus), and rabbits (Oryctolagus cuniculus). Further, we chose to investigate the P300 and STAT3 interaction and performed studies of the activation of STAT3 using IL-6 and inhibition of the P300 by its specific inhibitor A-485 in pericytes. Next, we performed immunoprecipitation to confirm whether A-485 inhibits the binding of P300 to STAT3. RESULTS: Using the STRING application from ExPASy, we found that six proteins, including PIAS3, JAK1, JAK2, EGFR, SRC, and EP300, showed highly confident interactions with STAT3 in humans, mice, and rabbits. We also found that IL-6 treatment increased the acetylation of STAT3 and increased histone 3 lysine acetylation (H3K27ac). Furthermore, we found that the disruption of STAT3 and P300 interaction by the P300 inhibitor A-485 decreased STAT3 acetylation and H3K27ac. Finally, we confirmed that the P300 inhibitor A-485 inhibited the binding of STAT3 with P300, which inhibited its transcriptional activity by reducing the expression of Ccnd1 (Cyclin D1). CONCLUSIONS: Targeting the P300 protein interaction with STAT3 may alleviate STAT3-mediated fibrotic signaling in humans and other species.

Rare case of simultaneous occurrence of chronic neutrophil leukemia and T lymphoblastic lymphoma: case report and literature review.

Chronic neutrophil leukemia (CNL) is a rare and life-threatening disease. Cases of CNL combined with lymphoma are rare. Here, we report a case of CNL with T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in a 28-year-old male. After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression.

ERK5 mediates pro-tumorigenic phenotype in non-small lung cancer cells induced by PGE2.

Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) constituting approximately 84 % of all lung cancer cases. The role of inflammation in the initiation and progression of NSCLC tumors has been the focus of extensive research. Among the various inflammatory mediators, prostaglandin E2 (PGE2) plays a pivotal role in promoting the aggressiveness of epithelial tumors through multiple mechanisms, including the stimulation of growth, evasion of apoptosis, invasion, and induction of angiogenesis. The Extracellular signal-Regulated Kinase 5 (ERK5), the last discovered member among conventional mitogen-activated protein kinases (MAPK), is implicated in cancer-associated inflammation. In this study, we explored whether ERK5 is involved in the process of tumorigenesis induced by PGE2. Using A549 and PC9 NSCLC cell lines, we found that PGE2 triggers the activation of ERK5 via the EP1 receptor. Moreover, both genetic and pharmacological inhibition of ERK5 reduced PGE2-induced proliferation, migration, invasion and stemness of A549 and PC9 cells, indicating that ERK5 plays a critical role in PGE2-induced tumorigenesis. In summary, our study underscores the pivotal role of the PGE2/EP1/ERK5 axis in driving the malignancy of NSCLC cells in vitro. Targeting this axis holds promise as a potential avenue for developing novel therapeutic strategies aimed at controlling the advancement of NSCLC.

The surface protein GroEl of lactic acid bacteria mediates its modulation of the intestinal barrier in Penaeus vannamei.

The molecular chaperone GroEL, commonly found in various bacterial species, exhibits heightened expression levels in response to high temperatures and increased levels of oxygen free radicals. Limited literature currently exists on the probiotic role of GroEL in invertebrates. This study sought to explore how the surface protein GroEL from Lactobacillus plantarum Ep-M17 impacts the intestinal barrier function of Penaeus vannamei. Through pull-down and immunofluorescence assays, the interaction between GroEL and Act1 in the gastrointestinal tract of P. vannamei was confirmed. Results from bacterial binding assays demonstrated that rGroEL can bind to pathogens like Vibrio parahaemolyticus E1 (V. p-E1). In vitro experiments revealed that the administration of rGroEL significantly decreased the levels of inflammatory cytokines induced by pathogens while preserving the integrity of tight junctions between intestinal epithelial cells and reducing bacteria-induced apoptosis. Additionally, rGroEL notably lessened the intestinal loading of V. p-E1 in P. vannamei, downregulated immune-related gene expression, and upregulated BCL/BAX expression in the intestines following V. p-E1 challenge. Mechanistic investigations further showed that rGroEL treatment effectively suppressed the expression and phosphorylation of proteins involved in the NF-κB and PI3K-AKT-mTOR signalling pathways in the intestines of bacteria-infected P. vannamei. Furthermore, GroEL reinforces protection against bacterial infections by enhancing the phagocytic and anti-apoptotic capabilities of P. vannamei hemocytes. These results suggest that GroEL may impede the interaction between pathogens and the intestinal mucosa through its competitive binding characteristics, ultimately reducing bacterial infections.

Similar teleconnection patterns of ENSO-NAO and ENSO-precipitation in Colombia: linear and non-linear relationships.

The Central-Pacific (CP) and Eastern-Pacific (EP) types of El Niño-Southern Oscillation (ENSO) and their ocean-atmosphere effect cause diverse responses in the hydroclimatological patterns of specific regions. Given the impact of ENSO diversity on the North Atlantic Oscillation (NAO), this study aimed to determine the relationship between the ENSO-NAO teleconnection and the ENSO-influenced precipitation patterns in Colombia during the December-February period. Precipitation data from 1981 to 2023, obtained from the Climate Hazards Group (CHIRPS), were analyzed using nine ENSO and NAO indices spanning from 1951 to 2023. Using Pearson's correlation and mutual information (MI) techniques, nine scenarios were devised, encompassing the CP and EP ENSO events, neutral years, and volcanic eruptions. The results suggest a shift in the direction of the ENSO-NAO relationship when distinguishing between the CP and EP events. Higher linear correlations were observed in the CP ENSO scenarios (r > 0.65) using the MEI and BEST indices, while lower correlations were observed when considering EP events along with the Niño 3 and Niño 1.2 indices. MI show difference in relationships based on the event type and the ENSO index used. Notably, an increase in the non-linear relationship was observed for the EP scenarios with respect to correlation. Both teleconnections followed a similar pattern, exhibiting a more substantial impact during CP ENSO events. This highlights the significance of investigating the impacts of ENSO on hydrometeorological variables in the context of adapting to climate change, while acknowledging the intricate diversity inherent to the ENSO phenomenon.

Study on Low-Velocity Impact and Residual Compressive Mechanical Properties of Carbon Fiber-Epoxy Resin Composites.

Room temperature drop hammer impact and compression after impact (CAI) experiments were conducted on carbon fiber-epoxy resin (CF/EP) composites to investigate the variation in impact load and absorbed energy, as well as to determine the residual compressive strength of CF/EP composites following impact damage. Industrial CT scanning was employed to observe the damage morphology after both impact and compression, aiding in the study of impact-damage and compression-failure mechanisms. The results indicate that, under the impact load, the surface of a CF/EP composite exhibits evident cratering as the impact energy increases, while cracks form along the length direction on the back surface. The residual compressive strength exhibits an inverse relationship with the impact energy. Impact damage occurring at an energy lower than 45 J results in end crushing during the compression of CF/EP composites, whereas energy exceeding 45 J leads to the formation of long cracks spanning the entire width of the specimen, primarily distributed symmetrically along the center of the specimen.

Bright New Resources for Syphilis Research: Genetically Encoded Fluorescent Tags for Treponema pallidum and Sf1Ep Cells.

The recently discovered methodologies to cultivate and genetically manipulate Treponema pallidum subsp. pallidum (T. pallidum) have significantly helped syphilis research, allowing the in vitro evaluation of antibiotic efficacy, performance of controlled studies to assess differential treponemal gene expression, and generation of loss-of-function mutants to evaluate the contribution of specific genetic loci to T. pallidum virulence. Building on this progress, we engineered the T. pallidum SS14 strain to express a red-shifted green fluorescent protein (GFP) and Sf1Ep cells to express mCherry and blue fluorescent protein (BFP) for enhanced visualization. These new resources improve microscopy- and cell sorting-based applications for T. pallidum, better capturing the physical interaction between the host and pathogen, among other possibilities. Continued efforts to develop and share new tools and resources are required to help our overall knowledge of T. pallidum biology and syphilis pathogenesis reach that of other bacterial pathogens, including spirochetes.

Mouse brain contains age-dependent extraparenchymal granular structures and astrocytes, both reactive to natural IgM antibodies, linked to the fissura magna.

BACKGROUND: Mouse brains can contain specific polyglucosan aggregates known as Periodic Acid-Schiff (PAS)-granules. Generated in astrocytes, these granules increase with age and exhibit neo-epitopes of carbohydrate nature that are recognized by natural IgM antibodies (IgMs). The existence of neoepitopes on PAS granules suggests the presence of neoepitopes in other brain structures, and this is investigated here. To this end, brain sections from SAMP8 and ICR-CD1 mice were examined at different ages. RESULTS: We have identified two novel structures that, apart from PAS granules, are recognized by natural IgMs. On one side, IgM reactive (IgM+) granular structures which are placed in the longitudinal fissure, the quadrigeminal cistern, and a region that extends from the quadrigeminal cistern to the interpeduncular cistern. This last region, located between the telencephalon and both the mesencephalon and diencephalon, is designated henceforth as the fissura magna, as it is indeed a fissure and the largest in the brain. As all these regions are extraparenchymal (EP), the IgM+ granules found in these zones have been named EP granules. These EP granules are mainly associated with fibroblasts and are not stained with PAS. On the other side, some IgM+ astrocytes have been found in the glia limitans, near the above-mentioned fissures. Remarkably, EP granules are more prevalent at younger ages, while the number of IgM+ astrocytes increases with age, similarly to the already described evolution of PAS granules. CONCLUSIONS: The present work reports the presence of two brain-related structures that, apart from PAS granules, contain neo-epitopes of carbohydrate nature, namely EP granules and IgM+ astrocytes. We suggest that EP granules, associated to fibroblasts, may be part of a physiological function in brain clearance or brain-CSF immune surveillance, while both PAS granules and IgM+ astrocytes may be related to the increasing accumulation of harmful materials that occurs with age and linked to brain protective mechanisms. Moreover, the specific localisation of these EP granules and IgM+ astrocytes suggest the importance of the fissura magna in these brain-related cleaning and immune functions. The overall results reinforce the possible link between the fissura magna and the functioning of the glymphatic system.

Delayed Aspiration of Cerebrospinal Fluid From a Thoracic Epidural Catheter After Difficult Placement: A Case Report.

A 69-year-old female with Crohn's disease was admitted for open ileocecectomy with lysis of adhesions. The plan was to proceed with general endotracheal anesthesia and a thoracic epidural catheter for perioperative analgesia. Epidural access was attempted at the T10-11 and T11-12 interspaces, both of which resulted in accidental dural punctures. On the third attempt, the epidural catheter was inserted at the T9-10 interspace. Both the aspiration and test dose were negative. Thirty minutes later, after induction of general anesthesia, the catheter was again aspirated before the epidural pump was connected. Freely flowing, glucose-positive fluid was obtained, and the catheter was removed for the patient's safety. This case suggests that accidental dural puncture may be a risk factor for inappropriate communication with the subarachnoid space. This can be assumed to increase the risk of unanticipated high or total spinal block and its life-threatening sequelae.

Analysis of Intervertebral Disc Degeneration Induced by Endplate Drilling or Needle Puncture in Complement C6-Sufficient and C6-Deficient Rabbits.

Previous studies indicate an implication of the terminal complement complex (TCC) in disc degeneration (DD). To investigate the functional role of TCC in trauma-induced DD in vivo, the model of endplate (EP) drilling was first applied in rabbits using a C6-deficient rabbit strain in which no TCC formation was possible. In parallel the model of needle puncture was investigated. Using a minimally invasive surgical intervention, lumbar rabbit intervertebral discs (IVDs) were treated with EP drilling or needle puncture. Degenerative effects of both surgical interventions were assessed by Pfirrmann grading and T2 quantification of the IVDs based on high-resolution MRI (11.7 T), as well as radiographic determination of disc height index. Pfirrmann grading indicated significant degenerative effects after EP drilling. Contrary to our assumption, no evidence was found that the absence of TCC formation in C6-deficient rabbits reduces the development of DD compared to C6-sufficient animals. EP drilling was proven to be suitable for application in rabbits. However, results of the present study do not provide clear evidence of a central functional role of TCC within DD and suggest that TCC deposition in DD patients may be primarily considered as a marker of complement activation during DD progression.

Establishment of CRISPR-Cas9 ribonucleoprotein mediated MSTN gene edited pregnancy in buffalo: Compare cells transfection and zygotes electroporation.

Genome editing is recognized as a powerful tool in agriculture and research, enhancing our understanding of genetic function, diseases, and productivity. However, its progress in buffaloes has lagged behind other mammals due to several challenges, including long gestational periods, single pregnancies, and high raising costs. In this study, we aimed to generate MSTN-edited buffaloes, known for their distinctive double-muscling phenotype, as a proof of concept. To meet our goal, we used somatic cell nuclear transfer (SCNT) and zygotic electroporation (CRISPR-EP) technique. For this, we firstly identified the best transfection method for introduction of RNP complex into fibroblast which was further used for SCNT. For this, we compared the transfection, cleavage efficiency and cell viability of nucleofection and lipofection in adult fibroblasts. The cleavage, transfection efficiency and cell viability of nucleofection group was found to be significantly (P ≤ 0.05) higher than lipofection group. Four MSTN edited colony were generated using nucleofection, out of which three colonies was found to be biallelic and one was monoallelic. Further, we compared the efficacy, embryonic developmental potential and subsequent pregnancy outcome of SCNT and zygotic electroporation. The blastocyst rate of electroporated group was found to be significantly (P ≤ 0.05) higher than SCNT group. However, the zygotic electroporation group resulted into two pregnancies which were confirmed to be MSTN edited. Since, the zygotic electroporation does not require complex micromanipulation techniques associated with SCNT, it has potential for facilitating the genetic modification in large livestock such as buffaloes. The present study lays the basis for inducing genetic alternation with practical or biological significance.

Neurosurgical Management of Rubinstein-Taybi Syndrome: An Institutional Experience.

INTRODUCTION: Rubinstein-Taybi syndrome (RTS) is a rare genetic condition with a distinctive set of physical features. This case series reports a single institutional experience of RTS cases, highlighting the role of neurosurgery in the comprehensive management of RTS patients. METHODS: A retrospective review of patients with genetically confirmed RTS presenting between 2010 and 2023 at Children's Hospital of Pittsburgh was performed. Patient demographics, genetic profile, clinical symptoms, radiographic characteristics, and neurosurgical management were recorded for all patients. RESULTS: Twenty-one patients (13 females, 8 males) aged 0 to 22 years presented for formal genetic counseling and diagnosis. Twenty patients (95%) had CREBBP pathogenic variants (RTS type 1), and 1 patient (5%) had EP300 pathogenic variants (RTS type 2). Ten patients (48%) had a low-lying conus medullaris, and 3 patients (30%) underwent subsequent spinal cord detethering. Four patients (19%) had a Chiari malformation, and three (75%) underwent Chiari decompression surgeries. One patient (5%) had Chiari-associated syringomyelia. CONCLUSIONS: RTS patients have an increased rate of tethered cord syndrome requiring detethering. The incidence of symptomatic Chiari I malformation requiring decompression has not been previously reported. The RTS series presented here demonstrates a high incidence of symptomatic Chiari I malformation in addition to tethered cord syndrome.