Generation of a mouse model of thyroid storm and preliminary investigation of the therapeutic effects of ghrelin.

BACKGROUND: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model. METHODS: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model. RESULTS: Serum IL-6 was increased in patients with TS compared with those with Graves' disease as the diseased control (18.2 vs. 2.85 pg/mL, P < .05, n = 4 each). The dosage for the murine TS model was triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P < .01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine. CONCLUSION: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans.

The Future of Sustainable Neurosurgery: Is a Moonshot Plan for Artificial Intelligence and Robot-Assisted Surgery Possible in Japan?

Japanese neurosurgery faces challenges such as a declining number of neurosurgeons and their concentration in urban areas. Particularly in rural areas, access to neurosurgical care for patients with conditions, such as stroke, is limited, raising concerns about the collapse of regional healthcare. Robot-assisted surgical technologies have advanced in recent years, contributing to the improved precision and safety of deep brain surgery. This study proposes the "Artificial Intelligence (AI) and Robot-Assisted Surgery Moonshot Plan" for Japan, comprising 5 pillars: 1) establishment of regional medical centers, 2) development of remote surgery systems, 3) enhancement of robotic-assisted surgery training programs, 4) integration of AI technologies, and 5) promotion of industry-academia-government collaboration. In addition, strengthening the approach to spinal surgery is expected to revitalize regional medical centers, optimize the number of neurosurgeons, improve surgical skills, and promote minimally invasive surgery. This study analyzed the current status and challenges of Japanese neurosurgery through a literature review and statistical analysis. AI is used in various aspects of neurosurgery, including diagnostic support, surgical planning and navigation, treatment outcome prediction, intraoperative monitoring, robot-assisted surgery, and rehabilitation. However, challenges, such as data bias, ethical issues, costs, and regulations, remain. In Japan, issues such as the uneven distribution and decline of neurosurgeons, collapse of regional healthcare, and increase in the number of patients with spinal disorders due to aging have been highlighted. The "AI and Robot-Assisted Surgery Moonshot Plan" serves as a guide to overcome the challenges of neurosurgery in Japan and establish a sustainable medical system.

C-Mannosyl tryptophan is a novel biomarker for thrombocytosis of myeloproliferative neoplasms.

C-Mannosyl tryptophan (CMW), a unique glycosylated amino acid, is considered to be produced by degradation of C-mannosylated proteins in living organism. Although protein C-mannosylation is involved in the folding and secretion of substrate proteins, the pathophysiological function in the hematological system is still unclear. This study aimed to assess CMW in the human hematological disorders. The serum CMW levels of 94 healthy Japanese workers were quantified using hydrophilic interaction liquid chromatography. Platelet count was positively correlated with serum CMW levels. The clinical significance of CMW in thrombocytosis of myeloproliferative neoplasms (T-MPN) including essential thrombocythemia (ET) were investigated. The serum CMW levels of the 34 patients with T-MPN who presented with thrombocytosis were significantly higher than those of the 52 patients with control who had other hematological disorders. In patients with T-MPN, serum CMW levels were inversely correlated with anemia, which was related to myelofibrosis (MF). Bone marrow biopsy samples were obtained from 18 patients with ET, and serum CMW levels were simultaneously measured. Twelve patients with bone marrow fibrosis had significantly higher CMW levels than 6 patients without bone marrow fibrosis. Collectively, these results suggested that CMW could be a novel biomarker to predict MF progression in T-MPN.

Familial schwannomatosis carrying LZTR1 variant p.R340X with brain tumor: A case report.

Schwannomatosis (SWN) is a rare genetic condition characterized by the risk of developing multiple benign peripheral nerve sheath tumors; however, the risk of developing malignant tumors in patients with SWN remains unclear. This study described the case of a 57-year-old Japanese man diagnosed with SWN whose older brother also had SWN. Whole-exome sequencing identified a heterozygous mutation [c.1018C > T (p.Arg340X)] in the LZTR1 gene, linked to the RAS/MAPK pathway, in the patient and his brother. Moreover, the patient had aphasia and right-sided paralysis because of a brain tumor. RNA sequencing revealed the remarkable upregulation of several genes associated with oxidative stress, such as the reactive oxygen species pathway and oxidative phosphorylation, a downstream effector of the RAS/MAPK pathway, in the the patient and his brother compared with healthy volunteers. The final diagnosis was LZTR1-related familial SWN, and the dysregulated RAS/MAPK pathway in this patient might be associated with brain tumorigenesis.

A stress sensor, IRE1α, is required for bacterial-exotoxin-induced interleukin-1ß production in tissue-resident macrophages.

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1ß (IL-1ß), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarify the roles of inositol-requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1ß production in RPMs. In RPMs, CTB is incorporated into the ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs show a significant impairment of CT- or CTB-induced IL-1ß production, indicating that IRE1α is required for CT- or CTB-induced IL-1ß production in RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.

Functional characterization of variants found in Japanese patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss-of-function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice-site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526-3C > G and c.598C > G in ACVRL1, and c.690-1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase-based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT.

Profiling of Unfolded Protein Response Markers and Effect of IRE1α-specific Inhibitor in Pituitary Neuroendocrine Tumor.

CONTEXT: Inositol-requiring enzyme 1α (IRE1α) and PKR-like ER kinase (PERK), which are endoplasmic reticulum (ER) membrane proteins, regulate the unfolded protein response (UPR). These molecules have recently gained attention as a novel therapeutic target in secretory tumors. The roles of the UPR in pituitary neuroendocrine tumors (PitNETs) are unclear. OBJECTIVE: To clarify UPR profiling of PitNETs and to investigate the effect of pharmacological modulation of UPR by KIRA8, a newly developed IRE1α-specific inhibitor. METHODS: In 131 patients with PitNETs, we evaluated RNA expression of UPR markers in PitNETs and their clinical phenotypes. Using GH3 cells, we examined the effects of KIRA8 and its combination with octreotide on UPR profiling, cell growth, and apoptosis. RESULTS: Cytoprotective adaptive-UPR (A-UPR) markers were more increased in functioning PitNETs (FPitNETs, n = 112) than in nonfunctioning PitNETs (NFPitNETs, n = 19), while there was no difference in proapoptotic terminal-UPR (T-UPR) markers. Similarly, overt somatotroph tumors (STs, acromegaly, n = 11) increased A-UPR compared with silent STs (n = 10). In STs, serum IGF-1 levels were inversely correlated with Txnip mRNA expression, a representative T-UPR marker. KIRA8 inhibited cell growth and facilitated apoptosis in GH3 cells with increased expressions of T-UPR markers, which was enhanced by the combination with octreotide. Octreotide increased mRNA expression of Txnip and Chop, but decreased spliced Xbp1 under ER stress. Octreotide is suggested to inhibit activation of IRE1α but to reciprocally induce T-UPR under PERK. CONCLUSION: UPR markers in FPitNETs are implicated as dominant A-UPR but blunted T-UPR. KIRA8, enhanced with octreotide, unbalances the UPR, leading to antitumor effects. Targeting IRE1α may provide a novel strategy to treat PitNETs.

Validation of Efficacy and Safety of TachoSil ® Tissue Sealant for Vessel Transposition in Microvascular Decompression.

BACKGROUND AND OBJECTIVES: Use of TachoSil ® as the transposition material of microvascular decompression (MVD) for hemifacial spasm (HFS) and trigeminal neuralgia (TN) is easy and safe to perform, but the efficacy and safety of this technique are unknown. This study attempted to validate the efficacy and safety of TachoSil ® as a transposition material of MVD. METHODS: A retrospective study of the surgical results and complications of 63 patients (35 HFS and 28 TN) treated by the TachoSil ® technique between January 2011 and December 2021 was conducted. The efficacy of the treatment was evaluated by Kaplan-Meier survival analysis. Magnetic resonance imaging follow-up study was performed to detect any adverse events including a mass formation. RESULTS: The rate of complete disappearance of HFS was 91.4% at 1 year and estimated to be 85.7% after a 10-year follow-up. The rate of no pain without medication for TN was 85.4% at 1 year and estimated to be 69.0% after a 9-year follow-up. These surgical results are comparable with those previously reported. Flaking of TachoSil ® releasing the offending artery was only recognized in one case (1.6%). Therefore, TachoSil ® can be considered as an effective transposition material for MVD. TachoSil ® did not increase the rate of acute and subacute adverse events such as inflammation and delayed facial palsy. Magnetic resonance imaging follow-up identified no abnormalities including mass that suggested granuloma formation. CONCLUSION: The efficacy of the TachoSil ® technique for HFS and TN and the reliability of TachoSil ® as an adhesive material in MVD were verified. No adverse events associated with TachoSil ® use in MVD were found. We conclude that the TachoSil ® technique has relatively long efficacy and safety for MVD.

Radical resection of intracavernous chondrosarcoma using an intradural keyhole approach: how I do it.

BACKGROUND: Skull base chondrosarcoma is rare, arising from the clivus or petroclival junction, and usually presents as ocular motility disorders. Endonasal transsphenoidal surgery may be performed in some cases of midline clivus chondrosarcoma. Chondrosarcoma is located within the cavernous sinus and presents a softer/gelatinous mass and can be removed with suctions and curettage. We have been using a simple intradural keyhole transcavernous approach, avoiding a complex extradural transcavernous dissection. METHODS: The intracavernous chondrosarcoma was removed via a 5 mm keyhole opening over the Parkinson's triangle using a standard frontotemporal intradural approach. CONCLUSION: Minimally invasive keyhole surgical resection can be performed to eradicate skull base chondrosarcomas, avoiding complex extradural cranial base approaches.

Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric and Adult Japanese Patients with Moyamoya Disease.

It is unclear how rare RNF213 variants, other than the p.R4810K founder variant, affect the clinical phenotype or the function of RNF213 in moyamoya disease (MMD). This study included 151 Japanese patients with MMD. After performing targeted resequencing for all coding exons in RNF213, we investigated the clinical phenotype and statistically analyzed the genotype-phenotype correlation. We mapped RNF213 variants on a three-dimensional (3D) model of human RNF213 and analyzed the structural changes due to variants. The RNF213 p.R4810K homozygous variant, p.R4810K heterozygous variant, and wild type were detected in 10 (6.6%), 111 (73.5%), and 30 (19.9%) MMD patients, respectively. In addition, 15 rare variants were detected in 16 (10.6%) patients. In addition to the influence of the p.R4810K homozygous variant, the frequency of cerebral infarction at disease onset was higher in pediatric patients with other rare variants (3/6, 50.0%, P = 0.006) than in those with only the p.R4810K heterozygous variant or with no variants (2/51, 3.9%). Furthermore, on 3D modelling of RNF213, the majority of rare variants found in pediatric patients were located in the E3 module and associated with salt bridge loss, contrary to the results for adult patients. The clinical phenotype of rare RNF213 variants, mapped mutation position, and their predicted structural change differed between pediatric and adult patients with MMD. Rare RNF213 variants, in addition to the founder p.R4810K homozygous variant, can influence MMD clinical phenotypes or structural change which may contribute to the destabilization of RNF213.

Renoprotective potential of concomittant medications with SGLT2 inhibitors and renin-angiotensin system inhibitors in diabetic nephropathy without albuminuria: a retrospective cohort study.

The renal protective effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors and renin-angiotensin system (RAS) inhibitors on diabetic nephropathy without albuminuria have not been fully investigated. This retrospective cohort study focused on patients with type 2 diabetes mellitus who had a baseline estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m2, and a urinary albumin-to-creatinine ratio < 30 mg/gCr. After propensity score matching, using covariates such as age, body mass index, systolic blood pressure, hemoglobin A1c levels, and prescription history of RAS inhibitors, we established a cohort of 58 patients: the SGLT2 inhibitor group (n = 28) and the control group (n = 28). In this cohort, we compared the annual eGFR decline rate between the two groups. The SGLT2 inhibitor group exhibited a significantly smaller eGFR change than the control group (- 1.15 vs. - 2.18 mL/min/1.73 m2/year). Within the SGLT2 inhibitor group, patients prescribed RAS inhibitors had demonstrated an even smaller eGFR change (- 0.70 mL/min/1.73 m2/year). In conclusion, SGLT2 inhibitors also have safeguarding effects in the stage of diabetic nephropathy without albuminuria, and the combined use of a SGLT2 inhibitor and a RAS inhibitor appears to be more effective than the single use of each.

Thyroid function, glycemic control, and diabetic nephropathy in patients with type 2 diabetes over 24 months: prospective observational study.

BACKGROUND: The higher prevalence of thyroid dysfunction in type 1 diabetes patients has been well established, whereas it is a matter of debate whether that is also observed in type 2 diabetes patients. This study was conducted to reveal whether higher prevalence of thyroid dysfunction is observed in patients with type 2 diabetes. METHODS: We examined thyroid functions and thyroid autoantibodies in 200 patients with type 2 diabetes and 225 controls, with 24 months follow up for those with type 2 diabetes. RESULTS: Serum free triiodothyronine (fT3) levels and fT3/free thyroxine (fT4) ratio were significantly lower, while fT4 levels were significantly higher in patients with type 2 diabetes. The number of patients with thyroid dysfunction or patients positive for thyroid autoantibodies were not different between the two groups. The fT3/fT4 ratio was positively and negatively correlated with serum c-peptide and HbA1c levels, respectively, suggesting that the difference can be attributable to insulin resistance and diabetic control. In the follow-up observation, we found no significant correlation between basal thyrotropin (TSH), fT3, fT4 or fT3/fT4 ratio with the amounts of changes of HbA1c levels at 12 or 24 months after the basal measurements. There was a negative relationship between TSH levels and eGFR at baseline measurements, but TSH levels did not seem to predict future decline of eGFR levels. No relationship was observed between urine albumin/ g‧cre levels and thyroid function. CONCLUSION: Thyroid dysfunction and thyroid autoantibodies were not different in prevalence between patients with type 2 diabetes and controls, although in patients with type 2 diabetes, the fT3/fT4 ratio was decreased. Basal thyroid function did not predict future diabetes control or renal function within 24 months of follow-up.

Supraorbital keyhole approach for paraclinoid aneurysms clipping: A case series with literature review.

Background: Paraclinoid aneurysms (PcAs) are challenging aneurysms due to the complexity of their relation to the surrounding bony and neurovascular structures. Although over the past decade, their management strategy has shifted from transcranial to endovascular approaches; here, we try to revolve around a subcategory to which minimal invasive supraorbital keyhole (SOK) surgery is feasible depending on specific radiological criteria with a literature review. Methods: A group of unruptured PcAs was managed surgically, with a subset that was clipped through the SOK approach. They were selected by preoperative simulation images using 3D computed tomography (CT) angiography (CTA). We also conducted an extensive literature review based on a database available on PubMed and Google Scholar, the yielded cases from the literature review plus our cases were analyzed according to six parameters including their size, location, dome direction, need for clinoidectomy and proximal cervical control, and surgical outcome. Results: From February 2009 to August 2022, 49 cases of unruptured PcAs were managed by clipping, and of these, four cases were clipped by the SOK approach, in addition, four cases were yielded through the literature review. The sizes of the PcAs ranged from 3 to 8 mm. Their location fluctuated from anterior to the superomedial wall and their domes pointed superiorly except for one which points posteriorly. Six of eight cases required anterior clinoidectomy, the outcome was uneventful. Conclusion: A subset of unruptured PcAs are amenable to SOK with criteria such as unruptured small aneurysm (<10 mm) and projected superiorly. These characteristics can be determined preoperatively using CTA.

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors.

Introduction: Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear. Methods: We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules. Results and Discussion: Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

Traumatic rupture of intracranial dermoid cyst with continuous fat droplet migration.

Background: The intracranial dermoid cyst (ICD) can be complicated by rupture and spilling of its contents with potentially dreadful consequences. Head trauma as a predisposing element for this phenomenon is extremely rare. Few reports address the diagnosis and management of trauma-related rupture of ICD. However, there is a pronounced knowledge gap related to the long-term follow-up and the fate of the leaking contents. Here, we present a unique case of traumatic rupture of ICD complicated by continuous fat particle migration within the subarachnoid space with its surgical implications and outcome. Case Description: A 14-year-old girl had an ICD rupture following a vehicle collision. The cyst was located near the foramen ovale with intra and extradural extensions. Initially, we opted to follow the patient clinically and radiologically as she had no symptoms, and the imaging showed no red flags. Over the next 24 months, the patient remained asymptomatic. However, the sequential brain magnetic resonance imaging revealed significant continuous migration of the fat within the subarachnoid space, with the droplets noticed to increase in the third ventricle. That is considered an alarming sign of potentially serious complications impacting the patient's outcome. Based on the above, the ICD was completely resected through an uncomplicated microsurgical procedure. On follow-up, the patient is well, with no new radiological findings. Conclusion: Trauma-related ruptured ICD may have critical consequences. Persistent migration of dermoid fat can be managed with surgical evacuation as a viable option to prevent those potential complications such as obstructive hydrocephalus, seizures, and meningitis.

Effect of SARS-CoV-2 BNT162b2 mRNA vaccine on thyroid autoimmunity: A twelve-month follow-up study.

Objectives: Graves' disease (GD) has been highlighted as a possible adverse effect of the respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. However, it is unknown if the SARS-CoV-2 vaccine disrupts thyroid autoimmunity. We aimed to present long-term follow-up of thyroid autoimmunity after the SARS-CoV-2 BNT162b2 mRNA vaccine. Methods: Serum samples collected from seventy Japanese healthcare workers at baseline, 32 weeks after the second dose (pre-third dose), and 4 weeks after the third dose of the vaccine were analyzed. The time courses of anti-SARS-CoV-2 spike immunoglobulin G (IgG) antibody, thyroid-stimulating hormone receptor antibody (TRAb), and thyroid function were evaluated. Anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were additionally evaluated in thirty-three participants. Results: The median age was 50 (IQR, 38-54) years and 69% were female. The median anti-spike IgG antibody titer was 17627 (IQR, 10898-24175) U/mL 4 weeks after the third dose. The mean TRAb was significantly increased from 0.81 (SD, 0.05) IU/L at baseline to 0.97 (SD, 0.30) IU/L 4 weeks after the third dose without functional changes. An increase in TRAb was positively associated with female sex (ß = 0.32, P = 0.008) and low basal FT4 (ß = -0.29, P = 0.02) and FT3 (ß = -0.33, P = 0.004). TgAb was increased by the third dose. Increase in TgAb was associated with history of the thyroid diseases (ß = 0.55, P <0.001). Conclusions: SARS-CoV-2 BNT162b2 mRNA vaccine can disrupt thyroid autoimmunity. Clinicians should consider the possibility that the SARS-CoV-2 vaccine may disrupt thyroid autoimmunity.

Pheochromocytoma Multisystem Crisis Complicated by Severe Acute Pancreatitis.

A 43-year-old man developed headache, dizziness, abdominal pain, and vomiting. His blood pressure was 203/121 mmHg, heart rate 122 beats/min, body temperature 39.1°C, and respiratory rate 24/min. He had elevated levels of creatinine at 2.95 mg/dL and lipase at 1,364 U/L as well as an extremely low calcium level at 5.2 mg/dL. Hypertriglyceridemia and hyperglycemia were seen. Chest and abdominal computed tomography showed interstitial pneumonia, severe pancreatitis, and a right adrenal tumor. The patient also developed vertebral artery dissection and medullary infarction. After right adrenalectomy, the patient was diagnosed with pheochromocytoma multisystem crisis (PMC). Acute pancreatitis might augment numerous life-threatening manifestations of PMC.

Glioependymal cyst in the medulla oblongata - A case report.

Background: Glioependymal cysts (GECs) are rare benign lesions that can be found anywhere along the neuroaxis, with most of the reports denoting supratentorial location. Here, we introduce a rare case of successfully treated glioependymal cysts lying in an uncommon location, namely medulla oblongata. Case Description: A 69-year-old lady presented with progressive unsteadiness and swallowing disturbances, and brain magnetic resonance imaging showed a dorsally located lesion within the medulla oblongata; based on the presentation and radiological features, surgical intervention was deemed mandatory. The suboccipital midline approach was used to perform marsupialization of the cyst with shunting through a syringosubarachnoid shunt to prevent future recurrence, and the patient outcome was improved. Conclusion: Medulla Oblongata's location for glioependymal cysts proposed unique diagnostic and operative challenges that may require highlighting for practicing neurosurgeons.

Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.

Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic ß cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced XBP1 mRNA splicing in primary human myeloma cells and myeloma cell lines. RNA sequencing identified the induction of UPR- and apoptosis-related genes by asciminib. Asciminib re-localized c-Abl to the endoplasmic reticulum, and its combination with a specific IRE1α inhibitor, KIRA8, enhanced cell death with the reciprocal induction of CHOP mRNA expression. Together, the allosteric inhibition of c-Abl-activated UPR with anti-myeloma effects; this could be a novel therapeutic target for multiple myeloma.