Generation of new transgenic SMARCA4-deficient mouse models results in neuromuscular weakness and paralysis of limbs.
Ontology highlight
ABSTRACT:
SUBMITTER: Neyazi S
PROVIDER: S-EPMC10154361 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
Publications
Generation of new transgenic SMARCA4-deficient mouse models results in neuromuscular weakness and paralysis of limbs.
Neyazi Sina S Altendorf Lea L Schwetje Dora D Göbel Carolin C Schoof Melanie M Holdhof Dörthe D Schüller Ulrich U
Brain pathology (Zurich, Switzerland) 20221229 3
Similar Datasets
Project description:BackgroundThoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a distinct clinicopathological entity with an aggressive clinical course. Additionally, SMARCA4/BRG1 deficiency can be observed in a few patients with non-small cell lung cancer (NSCLC). We aimed to compare the clinicopathological, immunohistochemical and prognostic features of SMARCA4-deficient NSCLC (SMARCA4-dNSCLC) with those of thoracic SMARCA4-UT.MethodsPatients with BRG1-deficient tumors in the lung or thorax were enrolled in the study from the Department of Pathology of West China Hospital, Sichuan University, from January 2014 to June 2022. We retrospectively collected the clinicopathological and immunohistochemical features and outcomes of these patients.ResultsSeventy-two patients had tumors in the lung or thorax with BRG1-deficient expression, including 52 patients with SMARCA4-dNSCLC and 20 patients with thoracic SMARCA4-UT. Among the patients with SMARCA4-dNSCLC, 98.1% were male, 85.7% were smokers, and 79.5% (35/44) had tumor-node-metas-tasis (TNM) III-IV tumors. Among the patients with thoracic SMARCA4-UT, all were males who smoked, and 93.75% (15/16) had TNM III-IV tumors. Pure solid architecture and necrosis were the predominant pathological features. Rhabdoid morphology was observed in some SMARCA4-dNSCLCs (10/52, 19.2%) and thoracic SMARCA4-UTs (11/20, 55%). In most patients with thoracic SMARCA4-UT, the tumors exhibited scattered weak expression or negative expression of epithelial markers, and positive expression of CD34 and Syn. Overall survival (OS) and progression-free survival (PFS) were not significantly different between patients with SMARCA4-dNSCLC and patients with thoracic SMARCA4-UT (p = 0.63 and p = 0.20, respectively).ConclusionsThoracic SMARCA4-DTs include SMARCA4-dNSCLC and thoracic SMARCA4-UT. Both have overlapping clinicopathological features and poor prognosis. We hypothesize that thoracic SMARCA4-UT may be the undifferentiated or dedifferentiated form of SMARCA4-dNSCLC. However, further studies with larger cohorts and longer follow-up periods are needed.
| S-EPMC10875988 | biostudies-literature
Project description:Antivenom therapy is currently the standard practice for treating neuromuscular dysfunction in snake envenoming. We reviewed the clinical and experimental evidence-base for the efficacy and effectiveness of antivenom in snakebite neurotoxicity. The main site of snake neurotoxins is the neuromuscular junction, and the majority are either: (1) pre-synaptic neurotoxins irreversibly damaging the presynaptic terminal; or (2) post-synaptic neurotoxins that bind to the nicotinic acetylcholine receptor. Pre-clinical tests of antivenom efficacy for neurotoxicity include rodent lethality tests, which are problematic, and in vitro pharmacological tests such as nerve-muscle preparation studies, that appear to provide more clinically meaningful information. We searched MEDLINE (from 1946) and EMBASE (from 1947) until March 2017 for clinical studies. The search yielded no randomised placebo-controlled trials of antivenom for neuromuscular dysfunction. There were several randomised and non-randomised comparative trials that compared two or more doses of the same or different antivenom, and numerous cohort studies and case reports. The majority of studies available had deficiencies including poor case definition, poor study design, small sample size or no objective measures of paralysis. A number of studies demonstrated the efficacy of antivenom in human envenoming by clearing circulating venom. Studies of snakes with primarily pre-synaptic neurotoxins, such as kraits (Bungarus spp.) and taipans (Oxyuranus spp.) suggest that antivenom does not reverse established neurotoxicity, but early administration may be associated with decreased severity or prevent neurotoxicity. Small studies of snakes with mainly post-synaptic neurotoxins, including some cobra species (Naja spp.), provide preliminary evidence that neurotoxicity may be reversed with antivenom, but placebo controlled studies with objective outcome measures are required to confirm this.
| S-EPMC5408217 | biostudies-literature
Project description:Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) may be effectively managed with immune checkpoint inhibitors; however, the management of posttreatment exacerbations remains uncertain. A 48-year-old man underwent chemotherapy (cisplatin and pemetrexed) along with PD-L1 and CTLA-4 inhibitors, resulting in significant improvement. Subsequently, maintenance therapy was initiated but discontinued because of drug-induced pneumonia. Although prednisone treatment resolved the pneumonia, salvage surgery was performed for exacerbation of an enlarged chest tumor and lymph nodes. No additional postoperative treatment was administered, and the patient has completed 2.5 years of treatment. This case highlights the potential efficacy of salvage surgery in the management of SMARCA4-UT exacerbations.
| S-EPMC11910827 | biostudies-literature
Project description:Acute neuromuscular paralysis (ANMP) is a clinical syndrome characterized by rapid onset muscle weakness progressing to maximum severity within several days to weeks (less than 4 wk). Bulbar and respiratory muscle weakness may or may not be present. It is a common neurological emergency which requires immediate and careful investigations to determine the etiology because accurate diagnosis has significant impact on therapy and prognosis. Respiratory failure caused by neuromuscular weakness is considered as more critical than lung disease because its development may be insidious or subtle until sudden decompensation leads to life threatening hypoxia. Also, the arterial blood gas finding of severe hypoxemia, hypercapnia, and acidosis may not be apparent until respiratory failure is profound. Hence, the requirement for respiratory assistance should also be intensively and promptly investigated in all patients with neuromuscular disease. The disorder is classified based on the site of defect in motor unit pathway, i.e., anterior horn cells, nerve root, peripheral nerve, neuromuscular junction or muscle. Identification of the cause is primarily based on a good medical history and detailed clinical examination supplemented with neurophysiologic investigations and sometimes few specific laboratory tests. Medical history and neurological examination should be focused on the onset, progression, pattern and severity of muscle weakness as well as cranial nerves testing and tests for autonomic dysfunction. Associated non neurological features like fever, rash or other skin lesions etc. should also be noted. Globally, Guillain-Barré syndrome is the most frequent cause of ANMP and accounts for the majority of cases of respiratory muscles weakness associated with neuromuscular disorders. Newly acquired neuromuscular weakness in intensive care unit patients consist of critical illness polyneuropathy, critical illness myopathy and drug induced neuromuscular weakness which may arise as a consequence of sepsis, multi-organ failure, and exposure to certain medications like intravenous corticosteroids and neuromuscular blocking agents.
| S-EPMC5535318 | biostudies-other
Project description:IntroductionAlthough alterations in SMARCA4-deficient occur in non-small cell lung carcinoma (SD-NSCLC), thoracic SMARCA4-deficient undifferentiated tumor (TSDUT) is recognized as a distinct entity in the 2021 World Health Organization Classification of Thoracic Tumors because of unique morphologic, immunophenotypic and molecular features, and worse survival compared with SD-NSCLC. Cytologic diagnosis of TSDUT is clinically important because of its aggressive behavior and because it is often diagnosed by fine-needle aspiration because TSDUTs are usually unresectable at presentation. Here, we identify cytologic features that can be used for recognition of TSDUT and distinction from SD-NSCLC.Materials and methodsCytomorphologic features were investigated in cytology specimens from patients with TSDUT (n = 11) and compared with a control group of patients with SD-NSCLC (n = 20).ResultsThe presence of classic rhabdoid morphology, at least focally, was entirely specific for TSDUT (n = 6, 55%) compared with SD-NSCLC (n = 0) in this study. TSDUT more frequently showed tumor necrosis (n = 11, 100% vs. n = 8, 40%; p = .001), dominant single-cell pattern on aspirate smears or touch preparation slides (n = 8 [of 9], 80% vs. n = 3, 15%; p = .010), nuclear molding (n = 5, 45% vs. n = 1, 5%; p = .013), and indistinct cell borders (n = 11, 100% vs. n = 5, 25%; P < .001) compared with SD-NSCLC, respectively.ConclusionsCytomorphologic features occurring more frequently in TSDUT include tumor necrosis, dominant single-cell pattern, nuclear molding indistinct cell borders, and focal rhabdoid cells. Presence of these features in a cytology specimen of an undifferentiated tumor, particularly in a patient with a thoracic mass, should raise suspicion for TSDUT and prompt appropriate ancillary workup.
| S-EPMC11037264 | biostudies-literature
Project description:A large, highly prolific swine farm in Hungary had a 2-year history of neurologic disease among newly weaned (25- to 35-day-old) pigs, with clinical signs of posterior paraplegia and a high mortality rate. Affected pigs that were necropsied had encephalomyelitis and neural necrosis. Porcine astrovirus type 3 was identified by reverse transcription PCR and in situ hybridization in brain and spinal cord samples in 6 animals from this farm. Among tissues tested by quantitative RT-PCR, the highest viral loads were detected in brain stem and spinal cord. Similar porcine astrovirus type 3 was also detected in archived brain and spinal cord samples from another 2 geographically distant farms. Viral RNA was predominantly restricted to neurons, particularly in the brain stem, cerebellum (Purkinje cells), and cervical spinal cord. Astrovirus was generally undetectable in feces but present in respiratory samples, indicating a possible respiratory infection. Astrovirus could cause common, neuroinvasive epidemic disease.
| S-EPMC5708238 | biostudies-literature
Project description:PurposeSMARCA4-deficient thoracic tumors, characterized by distinct clinicopathological, morphological, immunohistochemical, and genetic features, differ significantly from conventional non-small-cell lung carcinomas (NSCLCs). This group encompasses both SMARCA4-deficient NSCLCs (SMARCA4-NSCLCs) and SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs). The efficacy of PD-1 inhibitors in treating SMARCA4-deficient thoracic tumors remains uncertain.MethodsMedical records of 36 patients diagnosed with stage IIIB, IIIC, or IV SMARCA4-deficient thoracic tumors were analyzed. We assessed the clinical, pathological, and genetic features of these patients through immunohistochemistry (IHC) and a 68-gene panel next-generation sequencing (NGS). We compared the differences between SMARCA4-NSCLCs and SMARCA4-UTs, and evaluated the impact of chemotherapy and immunotherapy on patient outcomes.ResultsThe majority of patients with SMARCA4-deficient thoracic tumors were heavy-smoking males, averaging 64.6 years in age. IHC predominantly showed weak or negative staining for markers such as TTF-1, CK5/6, p40, synaptophysin, chromogranin A, and CD56, which are often associated with adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumors. The most common genetic mutations identified via NGS included TP53, CDKN2A, KRAS, STK11, NF1, and PTEN. No significant overall survival (OS) difference was observed between SMARCA4-NSCLCs and SMARCA4-UTs (p = 0.366). The median OS for patients treated with chemotherapy (n = 9) was 447 days, while the median OS for patients undergoing PD-1-inhibitor-based therapy (n = 16) was not reached (p = 0.105).ConclusionSMARCA4-deficient thoracic tumors exhibit distinct characteristics from conventional NSCLCs, and PD-1 inhibitors show promise in treating advanced SMARCA4-deficient thoracic tumors.
| S-EPMC10807565 | biostudies-literature
Project description:(1) Background: SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) is a rare and aggressive cancer that urgently requires novel therapeutic strategies. Despite the proven efficacy of immunotherapy in various cancer types, its application in SDUS remains largely unexplored. This study aims to investigate the immune microenvironment of SDUS to evaluate the feasibility of utilizing immunotherapy. (2) Methods: Multiplex immunofluorescence (mIF) was employed to examine the immune microenvironment in two cases of SDUS in comparison to other subtypes of endometrial stromal sarcomas (ESSs). This research involved a comprehensive evaluation of immune cell infiltration, cellular interactions, and spatial organization within the tumor immune microenvironment (TiME). Statistical analysis was performed to assess differences in immune cell densities and interactions between SDUS and other ESSs. (3) Results: SDUS exhibited a significantly higher density of cytotoxic T lymphocytes (CTLs), T helper (Th) cells, B cells, and macrophages compared to other ESSs. Notable cellular interactions included Th-CTL and Th-B cell interactions, which were more prominent in SDUS. The spatial analysis revealed distinct immune niches characterized by lymphocyte aggregation and a vascular-rich environment, suggesting an active and engaged immune microenvironment in SDUS. (4) Conclusions: The results suggest that SDUS exhibits a highly immunogenic TiME, characterized by substantial lymphocyte infiltration and dynamic cellular interactions. These findings highlight the potential of immunotherapy as an effective treatment approach for SDUS. However, given the small number of samples evaluated, these conclusions should be drawn with caution. This study underscores the importance of additional investigation into immune-targeted therapies for this challenging cancer subtype, with a larger sample size to validate and expand upon these preliminary findings.
| S-EPMC11352696 | biostudies-literature
Project description:Intensive care unit-acquired weakness (ICU-AW) causes significant morbidity and impairment in critically ill patients. Recent advances in neuromuscular ultrasound (NMUS) allow evaluation of neuromuscular pathology early in critical illness. Here we review application of ultrasound in ICU-AW. MEDLINE-indexed articles were searched for terms relevant to ultrasound and critical illness. Two reviewers evaluated the resulting abstracts (n = 218) and completed full-text review (n = 13). Twelve studies and 1 case report were included. Ten studies evaluated muscle thickness or cross-sectional area (CSA): 8 reported a decrease, and 2 reported no change. Two studies reported preservation of muscle thickness in response to neuromuscular electrical stimulation, and 1 found no preservation. One study found decreases in gray-scale standard deviation, but no change in echogenicity. One study described increases in echogenicity and fasciculations. Ultrasound reliability in ICU-AW is not fully established. Further investigation is needed to identify ultrasound measures that reliably predict clinical, electrodiagnostic, and pathologic findings of ICU-AW.
| S-EPMC4596754 | biostudies-literature
Project description:ObjectivesTo investigate the effect of endogenous Cas9 on genome editing efficiency in transgenic zebrafish.ResultsHere we have constructed a transgenic zebrafish strain that can be screened by pigment deficiency. Compared with the traditional CRISPR injection method, the transgenic zebrafish can improve the efficiency of genome editing significantly. At the same time, we first observed that the phenotype of vertebral malformation in early embryonic development of zebrafish after ZFERV knockout.ConclusionsThe transgenic zebrafish with expressed Cas9, is more efficient in genome editing. And the results of ZFERV knockout indicated that ERV may affect the vertebral development by Notch1/Delta D signal pathway.
| S-EPMC6223727 | biostudies-literature