Area postrema syndrome with linear enhancement along the surface of the brainstem and fourth ventricle in autoimmune GFAP astrocytopathy.

BACKGROUND: Glial fibrillary acidic protein (GFAP) astrocytopathy, a novel autoimmune disease of the nervous system, was first defined in 2016. To our knowledge, area postrema syndrome (APS) with linear enhancement along the surface of the brainstem and fourth ventricle is extremely rare in this disorder. CASE PRESENTATION: A Chinese woman presented with intractable nausea and vomiting after onset of flu-like symptoms. Brain magnetic resonance imaging (MRI) disclosed abnormal signal intensities in the dorsal medulla oblongata including area postrema. Besides, linear enhancement surrounding the surface of the brainstem and fourth ventricle was visualized after gadolinium injection. Cerebrospinal fluid (CSF) analysis showed increased cell count and protein. A cell-based assay was positive for anti-GFAP IgG in CSF. She was diagnosed with autoimmune GFAP astrocytopathy and treated with high-dose glucocorticoid. The patient received a quick recovery with entire resolution of the initial abnormalities. CONCLUSIONS: Isolated APS can be the initial manifestation of autoimmune GFAP astrocytopathy. Linear enhancement surrounding the surface of the brainstem and fourth ventricle is another neuroradiological hallmark.

The stroke mechanism, clinical presentation, and radiological feature of bilateral medial medullary infarction.

BACKGROUND: Bilateral medial medullary infarction (BMMI) is a rare type of posterior circulation stroke. The aim of this study is to characterize its stroke mechanisms, clinical manifestations, neuroradiological features, and prognosis. METHODS: From January 2015 to June 2021, a retrospective review of 15 patients diagnosed with BMMI was conducted. The clinical and neuroradiological features were summarized by our experienced neurologists. RESULTS: Fifteen patients (12 male, 3 female), ranging in age from 48 to 72 years, satisfied the inclusion criteria. The common clinical presentations included motor weakness (100%), deep sensory disturbance (93.3%), vertigo/dizziness (80%), dysarthria (93.3%), and dysphagia (66.7%). Vertically, infarct lesions in the rostral medulla were observed in all included patients. Horizontally, "heart appearance," "Y appearance," and "fan appearance" infarcts occurred in 9 cases (60%), 5 cases (33.3%), and 1 (6.7%) case, respectively. Patients (53.3%) had severe stenosis or occlusion in unilateral vertebral artery (VA), and 33.3% had normal findings in the vertebrobasilar artery. Patients (93.3%) achieved poor prognosis. CONCLUSION: BMMI is more frequently located in the rostral medulla and comprises three forms of infarction. The two main stroke etiologies of BMMI are large-artery atherosclerosis (LAA) and small vessel disease (SVD). BMMI is always associated with bad clinical outcome.

Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase.

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B-E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B-E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS-PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

Bilateral symmetrical deep gray matter involvement and leptomeningeal enhancement in a child with MOG-IgG-associated encephalomyelitis.

BACKGROUND: Currently, myelin oligodendrocyte glycoprotein (MOG)-IgG-associated encephalomyelitis (MOG-EM) is regarded as an independent inflammatory demyelinating disease. Magnetic resonance imaging (MRI) abnormalities occur in 44.4% of patients with MOG-EM. However, symmetrical deep gray matter involvement with leptomeningeal enhancement is rarely described in the literature. CASE PRESENTATION: A 3-year-old boy was admitted to our hospital because of acute onset fever, headache, vomiting and disturbance of consciousness. Neurological examination showed somnolence, neck stiffness and positive Kernig's sign. Brain MRI demonstrated bilateral symmetrical lesions in the basal ganglia and thalamus as well as diffuse leptomeningeal enhancement along the sulci of bilateral hemisphere. Cerebrospinal fluid analysis demonstrated increased cell count (7 cells/mm3, mononuclear cells dominant) and protein (1.17 g/L) without glucose and chloride abnormality. Work-up for infectious and autoimmune causes, serum MOG IgG was positive by cell based assay. Therefore, a diagnosis of MOG-EM was established according to the international recommendatory criteria in 2018. He was administrated with intravenous methylprednisolone followed by oral corticosteroids and had recovered completely within 1 week. CONCLUSIONS: In the setting of meningoencephalitis-like clinical presentation with bilateral symmetrical deep gray matter involvement, MOG-EM should be distinguished from other infectious and autoimmune disorders, such as Epstein-Barr virus (EBV) encephalitis, Japanese encephalitis and Anti-NMDA receptor (NMDAR) encephalitis. Besides, aseptic meningitis associated with leptomeningeal enhancement may be an atypical phenotype of MOG-EM.

Hypertrophic olivary degeneration concomitant with bilateral middle cerebellar peduncles Wallerian degeneration following unilateral pontine infarction.

BACKGROUND: Wallerian degeneration (WD) can occur in different projecting systems, such as corticospinal tract, dentate-rubro-olivary pathway, and corticopontocerebellar tract. However, the co-occurrence of hypertrophic olivary degeneration (HOD) and middle cerebellar peduncles (MCPs) degeneration secondary to unilateral pontine infarction in a single patient is extremely rare. CASE PRESENTATION: A 71-year-old man presented with acute onset of dizzness, slurred speech, and right-sided weakness. On the next day, his previous neurologic deficits deteriorated. Brain magnetic resonance imaging (MRI) revealed acute ischemic stroke of the left pons. After treatment with thrombolysis, antiplatelets, and rehabilitation training, his speaking and motor function improved moderately. At the 3-month follow-up, the MRI showed hyperintensity in the left medulla oblongata and bilateral MCPs on T2-weighted and FLAIR images, suggesting HOD as well as MCPs degeneration. CONCLUSIONS: It is of great importance for us to know the anatomic knowledge of dentate-rubro-olivary and corticopontocerebellar pathways.

Association between restless legs syndrome and hypertension: a meta-analysis of nine population-based studies.

Previous population-based studies evaluating the association between restless legs syndrome (RLS) and cardiovascular risk factors have showed inconsistent results, especially for the relationship between RLS and hypertension. We, therefore, aimed to meta-analyze to assess the association between RLS and hypertension. PubMed and Embase databases were systematically searched to identify eligible studies. Nine population-based cross-sectional studies were selected for inclusion, involving 102,408 individuals. Overall, the prevalence of hypertension in RLS subjects was higher than those without RLS (OR = 1.36, 95% CI, 1.18-1.57, P = 0.043). Our findings indicate that RLS is associated with increased blood pressure. More large-scale and prospective studies are warranted to further clarify the relationship and its potential mechanism.

Atorvastatin Pretreatment Attenuates Ischemic Brain Edema by Suppressing Aquaporin 4.

BACKGROUND: Cerebral edema, a serious complication of acute cerebral infarction, has a crucial impact on morbidity and mortality in the early stage of cerebral infarction. And aquaporin 4 (AQP4), a bidirectional water transporting protein, plays a pivotal role in edema formation. At experimental model, it has proven that atorvastatin could exert pleiotropic neuroprotection on acute cerebral infarction independent of its cholesterol-lowering action. It was a common protective manifestation that atorvastatin can reduce the infarct volume and cerebral edema. However, little is known about atorvastatin improving ischemic brain edema by regulating AQP4 expression. This study intended to investigate the neuroprotection effects of atorvastatin pretreatment in rats with cerebral ischemia and further explore the potential relationship between atorvastatin and AQP4 expression. METHODS: Fifty-one adult male Sprague Dawley rats were randomly divided into 3 groups: sham, middle cerebral artery occlusion (MCAO), and atorvastatin pretreatment (Ator) group. For Ator group, 20 mg/kg of atorvastatin injectable suspension was administered once for 7days by gavage before operation, whereas the others were administered the same volume of saline matching. Except for sham group, MCAO and Ator groups were subjected to permanent MCAO by modified intraluminal suture method. Infarct volume, neurological deficit, brain water content (BWC), immunohistochemistry, western blot, and polymerase chain reaction (PCR) were measured at 24 hours after MCAO. RESULTS: Compared with sham group, the mNSS, infarct volume, and BWC of ischemic hemisphere were significantly increased (P < 0.001) in MCAO group. Positive cells and protein levels of p-p38MAPK and AQP4 in peri-infarction were significantly increased (P < 0.01). The mRNA levels of p38MAPK and AQP4 were also prominently upregulated (P < 0.01). Interestingly, preadministration of atorvastatin dramatically decreased infarct volume and the BWC of ischemic hemisphere compared with MCAO group (P < 0.05). The overexpressions of p-p38MAPK and AQP4 in peri-infarction were significantly decreased (P < 0.05) and their mRNA levels were downregulated by atorvastatin pretreatment (P < 0.05). Neurological deficits were also dramatically improved (P < 0.001). CONCLUSION: To the best of our knowledge, this is the first study that demonstrates an effect of atorvastatin on expression of AQP4, and we propose that decreased AQP4 expression through a p38MAPK-suppression pathway may be the mechanism of atorvastatin alleviating ischemic cerebral edema.

Addition of Cladribine to Idarubicin and Cytarabine during Induction Increases the Overall Efficacy Rate in Adult Patients with Acute Myeloid Leukemia: A Matched-Pair Retrospective Comparison.

OBJECTIVES: The aims of this study were to evaluate a novel induction regimen composed of idarubicin (IDA), cytarabine (Ara-C) and cladribine (IAC regimen) for acute myeloid leukemia (AML) patients, and to identify the prognostic factors affecting treatment outcomes. METHODS: The clinical data of 27 untreated AML patients who received the IAC regimen as primary induction therapy in our hospital between April and November 2014 were analyzed retrospectively. The treatment outcomes of the IAC regimen were compared with two IA (IDA + Ara-C) regimens (IDA 10 mg/m² and IDA 12 mg/m²) in a pair-matched analysis. RESULTS: The complete remission (CR) rate in the IAC arm was higher compared to the IA(L) arm (p = 0.002) as was the overall efficacy rate (p = 0.017). There was no significant difference in outcomes between the IAC and IA(H) (Ara-C with high-dose IDA) arms. The IAC arm contained significantly higher CR rates than the IA(L) (Ara-C with low-dose IDA) arm in both the intermediate group (p = 0.050) and the unfavorable group (p = 0.013). Toxicity did not differ between the IAC group and the other two arms. High WBC at diagnosis (p = 0.022) and an unfavorable karyotype (p = 0.026) were related to a poorer response. The IAC regimen (p = 0.013) had greater superiority over the IAL regimen on efficacy than over the IA(H) regimen (p = 0.041). CONCLUSIONS: The IAC regimen achieved a more significant advantage over the IA(L) regimen without increasing the risk of adverse events. The efficacy of induction therapy is associated with WBC at diagnosis, karyotype and induction regimen.

Concomitant rapidly growing aneurysm of intracavernous carotid artery and cavernous sinus thrombosis: Case report and review of the literature.

RATIONALE: Intracavernous infectious aneurysm (ICIA), represents a rare entity that is always described in the form of case reports in the literature. The coexistence of ICIA and cavernous sinus thrombosis (CST) is extremely rare and poorly understood. PATIENT CONCERNS: A 53-year-old female patient presented to our hospital with headache, nausea and fatigue for 3 weeks. She complained of blurry vision and drooping eyelids before admission. Neurological examination revealed bilateral decreased visual acuity, limitation of extraocular movements and decreased sensation of forehead. Brain magnetic resonance imaging (MRI) showed mixed signal intensities in both cavernous sinuses and expansion of right superior ophthalmic vein, suggesting the formation of CST. One month later, computed tomography angiography (CTA) confirmed a large aneurysm was attached to the left intracavernous carotid artery (ICCA). DIAGNOESE: This patient was diagnosed with ICIA and CST. INTERVENTIONS: She was administered with intravenous meropenem and vancomycin and subcutaneous injection of low molecular heparin for 4 weeks. OUTCOMES: One month later, her extraocular movement had significantly improved, without ptosis and conjunctival congestion. At 1-year follow-up, her ophthalmoplegia fully recovered. Fortunately, such large aneurysm did not rupture in spite of slight broadening. LESSONS: The coexistence of ICIA and CST is extremely rare. Contiguous infection from adjacent tissues is the foremost cause of ICIA. A repeated angiographic examination is recommended under enough anti-infective treatment due to the characteristics of rapid emergence and fast growth of infectious aneurysms.

Exploring the substrate stereoselectivity and catalytic mechanism of nonribosomal peptide macrocyclization in surugamides biosynthesis.

SurE, the first reported penicillin-binding protein-like thioesterase (PBP-like TE), is known as a new off-loading cyclase, which catalyzes heterochiral coupling in nonribosomal peptides (NRPs). However, the structural rationale for substrate stereoselectivity and enzymatic mechanism remains mysterious. Here, computational models, integrating MD simulations and QM/MM methods, unveiled SurE's substrate recognition and catalytic process. An oxyanion hole stabilized the C-terminal D-residue during recognition. Residue R446 anchored the substrate for macrocyclization. A vital hydrogen-bonding network (Y154, K66, N156), verified by mutation results, was responsible for the recognition of N-terminal L-residue and involvement in catalytic process with a calculated 19.4 kcal/mol energy barrier. Four novel-designed peptide precursors were effectively cyclized into cyclopeptides by SurE based on computational analysis. Our results provide a comprehensive understanding of SurE's catalytic mechanism and guiding design of versatile PBP-like TEs for novel macrocyclic NRPs.

Bilateral thalamic and brainstem anaplastic astrocytoma: A case report.

RATIONALE: Bilateral thalamic glioma is extremely rare and characterized by strictly limited involvement of bilateral thalami. To investigate its clinical and neuroimaging features, we herein reported a rare case of anaplastic astrocytoma (AA) involving both thalami and the brainstem and reviewed the literature. PATIENT CONCERNS: A-33-year-old Chinese woman was referred to our department owing to persistent headache and nausea and vomiting. Neurological examination showed mild cognitive impairment and positive Kernig sign. DIAGNOSIS: Brain magnetic resonance imaging (MRI) demonstrated asymmetrical and swollen lesions involving both thalami, midbrain and pontine tegmentum, without restricted diffusion or enhancement. On day 7 after admission, she was transferred to the department of neurosurgery and underwent a stereotactic brain biopsy of the right thalamic lesion. Histopathological features and immunohistochemistry were consistent with AA, IDH wild-type, World Health Organization grade III. INTERVENTIONS: She was administrated with mannitol and glycerin fructose for decreasing intracranial pressure. OUTCOMES: In spite of receiving chemotherapy, she died on 2-month after her initial diagnosis. LESSONS: AA involving in both thalami and brainstem is a rare entity with poor prognosis. The clinicians and radiologists should deepen their awareness of the specific MRI feature of bilateral thalamic involvement. When MRI alone is insufficient, the utility of stereotactic biopsy is essential for making a definitive diagnosis.

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer.

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/ß-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/ß-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APCmin/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Reduced-dose chemotherapy and blinatumomab as induction treatment for newly diagnosed Ph-negative B-cell precursor acute lymphoblastic leukemia: a phase 2 trial.

Blinatumomab has emerged as a promising component of first-line therapy for acute B-cell precursor lymphoblastic leukemia (BCP-ALL), bolstering treatment efficacy. To mitigate CD19 selection pressure and reduce the incidence of blinatumomab-associated toxicities, pre-treatment chemotherapy is recommended before administering blinatumomab. From September 2022 to December 2023, we conducted a single-arm, multicenter, phase 2 trial (NCT05557110) in newly diagnosed Philadelphia chromosome-negative BCP-ALL (Ph-negative BCP-ALL) patients. Participants received induction treatment with reduced-dose chemotherapy (RDC), comprising idarubicin, vindesine, and dexamethasone over 7 days, followed by 2 weeks of blinatumomab. Those failing to achieve composite complete remission (CRc) received an additional 2 weeks of blinatumomab. The primary endpoint was the CRc rate post initial induction treatment. Of the 35 enrolled patients, 33 (94%) achieved CRc after 2 weeks of blinatumomab, with 30 (86%) achieving measurable residual disease (MRD) negativity. Two patients extended blinatumomab to 4 weeks. With either 2 or 4 weeks of blinatumomab treatment, all patients achieved CR (35/35) and 89% (31/35) were MRD negativity. The median time to CR was 22 days. Immune effector cell-associated neurotoxicity syndrome was limited (14%, all grade 1). Non-hematological adverse events of grade 3 or higher included pneumonia (17%), sepsis (6%), and cytokine release syndrome (9%). With a median follow-up of 11.5 months, estimated 1-year overall survival and 1-year progression-free survival rates were 97.1% and 82.2%, respectively. These findings affirm that RDC followed by blinatumomab is an effective and well-tolerated induction regimen for newly diagnosed Ph-negative BCP-ALL, supporting a shift towards less intensive and more targeted therapeutic approaches. Trial registration: https://www.clinicaltrials.Gov . Identifier NCT05557110.