Traction Devices May Not Affect the Vertical Margin Distance in the Endoscopic Submucosal Dissection of Rectal Neuroendocrine Tumors.

Introduction The usefulness of traction devices (TDs) in endoscopic submucosal dissection (ESD) for rectal neuroendocrine tumors (NETs) has not been reported. The aim of this study was to investigate the impact of using a TD on the vertical margin (VM) distance in the ESD of rectal NETs. Methods In this single-center, retrospective study, we included patients with rectal NETs who were treated with ESD during 2013-2023. They were divided into TD and non-TD groups. One pathologist remeasured the VM distance (primary outcome) and the depth of submucosal invasion (SM depth). Secondary outcomes were margins, resection time, delayed bleeding, and perforation. First, we performed propensity score matching (PSM) to assess the usefulness of TD for VM distance. Then, we used multiple regression analysis to identify factors affecting the VM distance. Results The TD and non-TD groups comprised 24 and 117 lesions, respectively. Patients in the TD group were significantly younger than those in the non-TD group (P = 0.003). In the TD and non-TD groups, the VM distance was 150 µm and 100 µm, respectively (P = 0.70). Only resection time significantly differed between groups, shorter in the TD group (P = 0.005). Twenty-two cases in each group were matched after PSM, yielding no significant differences in VM distance. The use of a TD was not an independent predictor of VM distance (P = 0.65), but age (P < 0.001) and SM depth (P = 0.003) were. Conclusion Using a TD does not seem to affect the VM distance in ESD for rectal NETs.

The combination of hydrogen gas and hydrogen-rich solution does not protect against ischemic spinal cord injury in rabbits.

PURPOSE: This study aimed to determine whether the combination of H2 gas inhalation and administration of hydrogen-rich acetated Ringer's solution (HS) could protect against ischemic spinal cord injury in rabbits. METHODS: In Experiment 1, rabbits were randomly assigned to a 1.2% H2 gas group, HS group, 1.2% H2 gas + HS group (combination group), or control group (n = 6 per group). The H2 concentration of HS was 0.65 mM. H2 was inhaled for 60 min, starting 5 min before reperfusion. HS (20 mL/kg) was divided into six bolus injections at 10-min intervals, starting 5 min before reperfusion. Spinal cord ischemia was produced by occluding the abdominal aorta for 15 min. Neurologic and histopathologic evaluations were performed 7 days after reperfusion. In Experiment 2, H2 concentrations in spinal cord tissue according to the administration of 1.2% H2 gas or HS were compared by measuring the electric current through a platinum needle electrode (n = 2). In Experiment 3, rabbits were assigned to a 2% H2 gas group or control group (n = 6 per group). Spinal cord ischemia was produced and neurologic and histopathologic evaluations were performed as in Experiment 1. RESULTS: There were no significant differences among the groups in the neurologic and histopathologic outcomes in Experiments 1 and 3. Bolus administration of HS (10 mL) transiently increased the current to only 1/30th and 1/27th of the plateau current with 1.2% H2 gas inhalation in two animals. CONCLUSION: These results suggest that the combination of 1.2% H2 gas inhalation and administration of a hydrogen-rich solution does not protect against ischemic spinal cord injury and that the increase in H2 concentration in spinal cord tissue after administration of HS is very low compared to 1.2% H2 gas inhalation.

Severe induction of aberrant DNA methylation by nodular gastritis in adults.

BACKGROUND: Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG. METHODS: Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively. RESULTS: Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13/CXCR5 and CXCL12/CXCR4, had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1, had only half the expression in NG. CONCLUSIONS: Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.

Gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder after kidney transplantation: A case report.

We report on a 53-year-old Japanese man diagnosed with gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder (B-PTLD) after endoscopy for gastric discomfort 28 months after the patient underwent renal transplantation in Ethiopia. Serum Epstein-Barr virus (EBV) tests were negative before transplantation, but the tumor cells collected from a gastric biopsy showed positive EBV-encoded small RNAs (EBER) at B-PTLD onset. Intensive treatment started with R(rituximab)-CHOP therapy and continued with DA-EPOCH-R therapy has been effective, and relapse has not yet occurred. Burkitt lymphoma has a poor prognosis, but B-PTLD may be effectively treated with high-dose chemotherapy. This is a rare case of gastric B-PTLD in a Japanese patient.

Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation.

OBJECTIVE: The presence of intestinal metaplasia (IM) is a risk factor for gastric cancer. However, it is still controversial whether IM itself is precancerous or paracancerous. Here, we aimed to explore the precancerous nature of IM by analysing epigenetic alterations. DESIGN: Genome-wide DNA methylation analysis was conducted by EPIC BeadArray using IM crypts isolated by Alcian blue staining. Chromatin immunoprecipitation sequencing for H3K27ac and single-cell assay for transposase-accessible chromatin by sequencing were conducted using IM mucosa. NOS2 was induced using Tet-on gene expression system in normal cells. RESULTS: IM crypts had a methylation profile unique from non-IM crypts, showing extensive DNA hypermethylation in promoter CpG islands, including those of tumour-suppressor genes. Also, the IM-specific methylation profile, namely epigenetic footprint, was present in a fraction of gastric cancers with a higher frequency than expected, and suggested to be associated with good overall survival. IM organoids had remarkably high NOS2 expression, and NOS2 induction in normal cells led to accelerated induction of aberrant DNA methylation, namely epigenetic instability, by increasing DNA methyltransferase activity. IM mucosa showed dynamic enhancer reprogramming, including the regions involved in higher NOS2 expression. NOS2 had open chromatin in IM cells but not in gastric cells, and IM cells had frequent closed chromatin of tumour-suppressor genes, indicating their methylation-silencing. NOS2 expression in IM-derived organoids was upregulated by interleukin-17A, a cytokine secreted by extracellular bacterial infection. CONCLUSIONS: IM cells were considered to have a precancerous nature potentially with an increased chance of converting into cancer cells, and an accelerated DNA methylation induction due to abnormal NOS2 expression.

DNA Methylation Aberrations in Dimethylarsinic Acid-Induced Bladder Carcinogenesis.

Arsenic is a known human urinary bladder carcinogen. While arsenic is known to cause aberrant DNA methylation, the mechanism of arsenic-triggered bladder carcinogenesis is not fully understood. The goal of this study was to identify aberrant DNA methylation in rat bladder urothelial carcinoma (UC) induced by dimethylarsinic acid (DMAV), a major organic metabolite of arsenic. We performed genome-wide DNA methylation and microarray gene expression analyses of DMAV-induced rat UCs and the urothelium of rats treated for 4 weeks with DMAV. We identified 40 genes that were both hypermethylated and downregulated in DMAV-induced rat UCs. Notably, four genes (CPXM1, OPCML, TBX20, and KCND3) also showed reduced expression in the bladder urothelium after 4 weeks of exposure to DMAV. We also found that CPXM1 is aberrantly methylated and downregulated in human bladder cancers and human bladder cancer cells. Genes with aberrant DNA methylation and downregulated expression in DMAV-exposed bladder urothelium and in DMAV-induced UCs in rats, suggest that these alterations occurred in the early stages of arsenic-induced bladder carcinogenesis. Further study to evaluate the functions of these genes will advance our understanding of the role of aberrant DNA methylation in arsenic bladder carcinogenesis, and will also facilitate the identification of new therapeutic targets for arsenic-related bladder cancers.

Validity of Endoscopic Submucosal Dissection for Gastric Cancer Diagnosed as Differentiated Adenocarcinoma Before Treatment Regardless of Lesion Size.

BACKGROUND/AIMS: We investigated the validity and safety of endoscopic submucosal dissection for gastric tumors by examining shortand long-term outcomes by tumor diameter. MATERIALS AND METHODS: Endoscopic submucosal dissection for gastric tumor was performed on 4259 lesions at our hospital between January 2005 and June 2021. [Study 1] Patients were divided into 5 tumor diameter groups: 3751 lesions, ≤30 mm; 366 lesions, 31-50 mm; 106 lesions, 51-75 mm; 24 lesions, 76-100 mm; and 12 lesions, ≥101 mm. Short-term gastric endoscopic submucosal dissection outcomes were investigated. [Study 2] Long-term outcomes (delayed gastric emptying and prognosis) were investigated in 508 cases with tumor diameter ≥31 mm. RESULTS: [Study 1] Perforation rate (%) was 1.2, 3.6, 3.8, 12.5, and 25.0 for lesions with tumor diameter ≤30 mm, in the range 31-50 mm, 51-75 mm, and 76-100 mm, and ≥101 mm, respectively. Postoperative bleeding rate (%) was 4.8, 9.0, 6.6, 20.8, and 33.3, respectively, R0 resection rate (%) was 96.8, 90.2, 89.6, 70.8, and 66.6, respectively, and curative resection rate (%) was 92.0, 61.2, 63.2, 45.8, and 8.3, respectively. [Study 2] There were 7 cases of delayed gastric emptying after wide resection, with 3 patients requiring balloon dilatation, 1 of whom subsequently underwent distal gastrectomy. Among 205 cases of noncurative resection, 110 underwent additional surgery, residual cancer was present in 11 cases, and lymph node metastasis was observed in 7 cases (1 patient died of disease). To date, 1 of the 95 patients being followed up has died of disease (mean follow-up: 2042 days). CONCLUSION: Even with a tumor diameter ≥31 mm, curative resection was achieved in about 60% of cases in which intramucosal lesions were considered possible preoperatively, but the rate was low at 8.3% for tumor diameter ≥101 mm. Long-term outcomes appear favorable, with only 0.4% of the patients dying of disease but delayed gastric emptying observed in 1.7% of cases.

Diagnostic Performance of Endoscopic Ultrasonography with Water-Filled Balloon Method for Superficial Esophageal Squamous Cell Carcinoma.

BACKGROUND: Endoscopic ultrasonography (EUS) is a commonly used tool for preoperative depth diagnosis of superficial esophageal squamous cell carcinoma (ESCC). Probing EUS using the water-filled balloon method is a simple and safe examination. AIM: The aim of this study was to clarify the diagnostic performance of EUS with the water-filled balloon method for superficial ESCC compared to magnifying narrow-band imaging (ME-NBI). METHODS: We retrospectively examined 403 lesions in 393 consecutive patients diagnosed with ESCC and evaluated them with ME-NBI and EUS. Clinicopathological findings were collected, and the accuracy of the preoperative diagnosis was compared between ME-NBI and EUS-B. EUS examiners were not blinded to prior ME-NBI results, and EUS results may have been influenced by ME-NBI results. RESULTS: The pathological tumor depth of the EP/LPM in 152 lesions, MM/SM1 in 130 lesions, and deep submucosa (SM2/SM3) in 121 lesions was examined. The proportion of total lesions with an accurate diagnosis was significantly higher in EUS than in ME-NBI (67.7% versus 62.0%, P = 0.015). When analyzed by clinical depth diagnosis using ME-NBI, the proportion of lesions with an accurate diagnosis was significantly higher for EUS in MM/SM1 (55.7% versus 46.1%, P = 0.033). The sensitivity was significantly higher in EUS for SM2/SM3 lesions (76.0% versus 54.5%, P < 0.001). The accuracy and specificity of EUS, which differentiate MM/SM1 from EP/LPM or SM2/SM3, were significantly higher than those of ME-NBI. The median endoscopic ultrasonography procedure time was approximately 6.5 min. CONCLUSIONS: EUS with the water-filled balloon method is a safe and straightforward method that can be performed on lesions clinically diagnosed as MM/SM1 using ME-NBI. We retrospectively reviewed lesions in patients diagnosed with ESCC and evaluated them using magnifying endoscopy with narrow-band imaging (ME-NBI) and endoscopic ultrasound using the water-filled balloon method (EUS-B). We conclude that EUS-B can increase the diagnostic accuracy.

Pathogenic role of anti-cN1A autoantibodies in sporadic inclusion body myositis.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is an intractable muscle disease that frequently affects elderly people. Autoantibodies recognising cytosolic 5'-nucleotidase 1A (cN1A) were found in the sera of patients with sIBM. However, the pathogenic role of the autoantibodies remained unknown. This study investigated the pathogenic properties of the autoantibodies using active cN1A peptides immunisation. METHODS: Wild-type C57BL6 mice were injected with three different mouse cN1A peptides corresponding to the previously reported epitope sequences of human cN1A. After confirming the production of autoantibodies to the corresponding cN1A peptides in each group, changes in body weight, exercise capacity by treadmill test and histological changes in mice injected with cN1A peptides or controls were investigated. RESULTS: Autoantibodies against cN1A were detected in serum samples from mice injected with cN1A peptide. Some groups of mice injected with cN1A peptide showed significant weight loss and decreased motor activity. The number of myofibres with internal nuclei increased in all the peptide-injected groups, with surrounding or invading CD8-positive T cells into myofibres, abnormal protein aggregates and overexpression of p62 and LC3. CONCLUSIONS: Active cN1A peptide immunisation partially reproduced the clinical and histological aspects of sIBM in wild-type mice. The murine model demonstrates the pathogenic properties of anti-cN1A autoantibodies to cause sIBM-like histological changes.

[Sporadic Inclusion Body Myositis].

Inclusion body myositis (IBM) is an idiopathic inflammatory muscle disease that predominantly affects elderly men over the age of 50 years, and the number of patients is rapidly increasing in Japan. Generally, muscle weakness and atrophy occur asymmetrically in the flexor muscles of the fingers and wrists and the quadriceps muscles. Invasive muscle biopsy is essential for the diagnosis of IBM. Although its pathogenesis is not yet understood, both inflammatory as well as degenerative mechanisms are postulated to be involved. In particular, degeneration of the IBM muscle may be associated with the IFN-II secretion by highly differentiated CD8+ T lymphocytes. Cytoplasmic 5'-nucleotidase 1A (cN1A) antibody has been detected in the blood samples of approximately half of the patients with IBM. While there are positive opinions about the diagnostic significance of the antibody, its usefulness for the diagnosis of IBM is limited. The results of passive immunization support its etiologic significance; however, more detailed verification, including active immunization, is needed in the future.

HSD17B4 methylation enhances glucose dependence of BT-474 breast cancer cells and increases lapatinib sensitivity.

PURPOSE: HER2-positive breast cancer has a high chance of achieving pathological complete response when HSD17B4, responsible for peroxisomal ß-oxidation of very long-chain fatty acids (VLCFA) and estradiol, is methylation-silenced. Here, we aimed to identify the underlying molecular mechanism. METHODS: Using a HER2-positive breast cancer cell line, BT-474, control and knock-out (KO) clones were obtained. Metabolic characteristics were analyzed using a Seahorse Flux analyzer. RESULTS: HSD17B4 KO suppressed cellular proliferation, and enhanced sensitivity to lapatinib approximately tenfold. The KO led to accumulation of VLCFA and a decrease of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and arachidonic acid. HSD17B4 KO increased Akt phosphorylation, possibly via decreased DHA, and genes involved in oxidative phosphorylation (OxPhos) and electron transport chain (ETC) were upregulated. Increased mitochondrial ATP production in the KO cells was confirmed by extracellular flux analyzer. Increased OxPhos led to severe dependence of the KO cells on pyruvate from glycolysis. Suppression of glycolysis by lapatinib led to severe delayed suppression of OxPhos in KO cells. CONCLUSION: HSD17B4 KO in BT-474 cells caused a decrease of PUFAs, increased Akt phosphorylation, enhanced glucose dependence of OxPhos, and increased sensitivity to inhibition of HER2, upstream of Akt. This mechanism may be applicable to other HER2-positive glucose-dependent breast cancer cells with HSD17B4 silencing.

Long-term outcome of cervical lymph node metastasis in superficial pharyngeal squamous cell carcinoma after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Superficial pharyngeal squamous cell carcinoma (PSCC) has received increasing attention as a therapeutic target in the GI field with recent innovations in endoscopic submucosal dissection (ESD). However, there are currently no defined criteria for the application of ESD to superficial PSCC. One of the problems encountered during follow-up after ESD is cervical lymph node metastasis (LNM). Identifying the clinicopathologic predictors of cervical LNM can help to provide a basis for the refinement of therapeutic strategies for superficial PSCC. METHODS: The risk of cervical LNM was evaluated in 331 patients with superficial PSCC who underwent initial ESD between 2008 and 2021. Since tumor size, rather than depth, is the dominant factor in the current TNM classification for PSCC, the correlation between tumor size and thickness was investigated. RESULTS: The median follow-up period was 4.8 years. The cumulative 5-year cervical LNM rate was 6.1%. Multivariate Cox proportional hazards regression analysis identified tumor thickness ≥1000 µm and lymphatic invasion as significant independent predictors. Among 204 cases with subepithelial invasion, both factors were also revealed to be significant independent predictors, suggesting that tumor thickness was superior to tumor size in predicting cervical LNM. Despite the positive correlation between tumor thickness and size, there was noticeable variability in the values (R = .20), and the current staging was inadequate to identify groups at high risk for cervical LNM. CONCLUSIONS: Tumor thickness and lymphatic invasion are validated as significant independent predictors for cervical LNM and can be useful indicators to optimize the therapeutic strategies for superficial PSCC.

Metachronous Multiple Gastric Cancer Discovered as Endoscopic Curability C2 during Regular Follow-Up after Gastric Endoscopic Submucosal Dissection.

INTRODUCTION: The objective of this study was to clarify characteristics of metachronous endoscopic curability C2 (eCura C2) cancer during post-endoscopic submucosal dissection (ESD) follow-up. METHODS: Of 4,355 gastric lesions treated by ESD at our hospital during 2005-2021, 657 were metachronous. After excluding lesions found ≥2 years since the prior examination or in the gastric remnant, the remaining 515 were analyzed. Study 1: We compared 35 eCura C2 cancers and 480 eCura A-C1 cancers. Study 2: Endoscopic findings of the 35 lesions were examined to determine why they had been missed. RESULTS: Mean tumor size was larger (34.0 mm vs. 12.1 mm, p < 0.01) and the proportions of mixed-type and poorly differentiated cancers were higher (highly:mixed:poorly, 34.3:57.1:8.6 vs. 94.2:5.0:0.8, p < 0.01) in the eCura C2 group. Study 2: At the prior examination, 4 lesions were noticed but considered benign, 2 lacked sufficient imaging, 19 were detectable on imaging but missed, and 10 were not detectable on imaging. Over half the lesions that were detectable but missed at the prior examination were in the lesser curvature, many being type IIa-IIb lesions with color similar to the background mucosa. All lesions not detectable on imaging at the prior examination were mixed-type or poorly differentiated type. DISCUSSION: Metachronous cancer detected as eCura C2 cancers was significantly larger, and a significantly higher proportion was mixed-type or poorly differentiated cancers, compared with eCura A-C1 cancers. Possible reasons why these lesions were missed include rapid progression of mixed-type and poorly differentiated cancers, and poor recognition that lesions showing only slight color changes may be present at the lesser curvature.

Safety of Cold Snare Polypectomy during Continuous Use of Antithrombotic Drugs for Delayed Post-Polypectomy Bleeding: A Pilot Study.

BACKGROUND: Cold snare polypectomy is a high-risk endoscopic procedure with a low delayed post-polypectomy bleeding rate. However, it is unclear whether delayed post-polypectomy bleeding rates increase during continuous antithrombotic treatment. This study aimed to determine the safety of cold snare polypectomy during continuous antithrombotic treatment. METHODS: This single-center, retrospective cohort study enrolled patients who underwent cold snare polypectomy during antithrombotic treatment between January 2015 and December 2021. Patients were divided into continuation and withdrawal groups based on whether they continued with antithrombotic drugs or not. Propensity score matching was performed using age, sex, Charlson comorbidity index, hospitalization, scheduled treatment, type of antithrombotic drugs used, multiple medications used, indication for antithrombotic drugs, and gastrointestinal endoscopist qualifications. The delayed polypectomy bleeding rates were compared between the groups. Delayed polypectomy bleeding was defined as the presence of blood in stools and requiring endoscopic treatment or a decrease in hemoglobin level by 2 g/dL or more. RESULTS: The continuation and withdrawal groups included 134 and 294 patients, respectively. Delayed polypectomy bleeding was observed in 2 patients (1.5%) and 1 patient (0.3%) in the continuation and withdrawal groups, respectively (p = 0.23), before propensity score matching, with no significant difference. After propensity score matching, delayed polypectomy bleeding was observed in 1 patient (0.9%) in the continuation group but not in the withdrawal group, with no significant difference. CONCLUSION: Cold snare polypectomy during continuous antithrombotic treatment did not significantly increase delayed post-polypectomy bleeding rates. Therefore, this procedure may be safe during continuous antithrombotic treatment.

PD-L1 and HLA-class I expression status and their therapeutic implication in oesophageal small-cell carcinoma.

AIMS: Oesophageal small-cell carcinoma is a rare and highly aggressive subtype of oesophageal cancer with a dismal prognosis. To explore the potential applicability of immunotherapy, we investigated the expression status of programmed death ligand 1 (PD-L1) and human leukocyte antigen (HLA)-class I and the degree of tumour-infiltrating lymphocytes (TILs) in oesophageal small-cell carcinoma. METHODS AND RESULTS: PD-L1 and HLA-class I expression levels were evaluated in 10 pure small-cell carcinomas and five mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). The combined positive score (CPS) and tumour proportion score (TPS) were used for PD-L1 assessment. Immunohistochemistry for mismatch repair (MMR) proteins was also performed. PD-L1 immunohistochemistry demonstrated CPS ≥1 in nine (60%), CPS ≥10 in five (33%), and TPS ≥1 in five (33%) cases. Overall survival was significantly longer in patients with CPS ≥1 than in those with CPS <1. HLA-class I deficiency (>50% tumour cells) was noted in five cases (33%), with no significant correlation with PD-L1 expression status. Among the five MiNENs, HLA-class I expression was decreased in the small-cell carcinoma component of three cases. HLA-class I deficiency was significantly associated with higher TNM stage and reduced TIL levels. MMR deficiency was not observed in any case. CONCLUSION: Given that a significant subset (40%) exhibited PD-L1 CPS ≥1 with preserved HLA-class I expression and high levels of TIL, the PD-1/PD-L1 pathway is a potential therapeutic target for oesophageal small-cell carcinoma.

Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1-4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I-III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.

Myopathic changes caused by protein aggregates in adult-onset spinal muscular atrophy.

Spinal muscular atrophy (SMA), an autosomal-recessive lower motor neuron disease, causes progressive proximal muscle waste and weakness. It remains unclear whether myopathic changes are involved in pathogenesis. We encountered a patient with adult-onset SMA caused by a homozygous deletion in exon 7 of the survival motor neuron 1 (SMN1) gene who had had four copies of SMN2 exon 7. Muscle biopsy showed neurogenic features of groups of atrophic fibers, fiber-type grouping, and pyknotic nuclear clumps associated with fibers with rimmed vacuoles. Immunohistochemistry revealed sarcoplasmic aggregates of phosphorylated TDP-43 and p62 but not SMN. This study demonstrated myopathic changes with the accumulation of phosphorylated p62 and TDP-43 in the muscles of a patient with SMA, suggesting that abnormal protein aggregation may be involved in myopathic pathology.

The Role of Autophagy in the Female Reproduction System: For Beginners to Experts in This Field.

Autophagy is a fundamental process involved in regulating cellular homeostasis. Autophagy has been classically discovered as a cellular process that degrades cytoplasmic components non-selectively to produce energy. Over the past few decades, this process has been shown to work in energy production, as well as in the reduction of excessive proteins, damaged organelles, and membrane trafficking. It contributes to many human diseases, such as neurodegenerative diseases, carcinogenesis, diabetes mellitus, development, longevity, and reproduction. In this review, we provide important information for interpreting results related to autophagic experiments and present the role of autophagy in this field.

Characteristics and varieties of gases enclathrated in natural gas hydrates retrieved at Lake Baikal.

Molecular and stable isotope compositions of hydrate-bound gases collected from 59 hydrate-bearing sites between 2005 to 2019 in the southern and central sub-basins of Lake Baikal are reported. The δ2H of the hydrate-bound methane is distributed between - 310‰ and - 270‰, approximately 120‰ lower than its value in the marine environment, due to the difference in δ2H between the lake water and seawater. Hydrate-bound gases originate from microbial (primary and secondary), thermogenic, and mixed gas sources. Gas hydrates with microbial ethane (δ13C: - 60‰, δ2H: between - 310‰ and - 250‰) were retrieved at approximately one-third of the total sites, and their stable isotope compositions were lower than those of thermogenic ethane (δ13C: - 25‰, δ2H: - 210‰). The low δ2H of ethane, which has rarely been reported, suggests for the first time that lake water with low hydrogen isotope ratios affects the formation process of microbial ethane as well as methane. Structure II hydrates containing enclathrated methane and ethane were collected from eight sites. In thermogenic gas, hydrocarbons heavier than ethane are biodegraded, resulting in a unique system of mixed methane-ethane gases. The decomposition and recrystallization of the hydrates that enclathrate methane and ethane resulted in the formation of structure II hydrates due to the enrichment of ethane.

Macroglossia in rapidly progressive inclusion body myositis.

Inclusion body myositis (IBM) is a refractory muscle disease characterized by inflammatory and degenerative features in myofibers. Macroglossia is common in systemic amyloid light chain amyloidosis; however, no reports have been published on patients with IBM. We encountered a female patient with clinicopathologically defined IBM who exhibited relatively rapid progression of dysphagia, gait disturbance, and macroglossia. Muscle biopsy demonstrated endomysial mononuclear inflammatory infiltrates, fiber necrosis and regeneration with rimmed vacuoles, and sarcoplasmic inclusions of p62. Tongue biopsy demonstrated fiber degeneration with fatty replacement and fibrosis, nonnecrotic fibers surrounded and invaded by mononuclear cells, and sarcoplasmic dotlike inclusions of p62. Based on the parotid gland, lip, and muscle biopsy, she was diagnosed as having IBM with Sjögren's syndrome. She was treated with steroid pulse and intravenous immunoglobulin therapy followed by oral administration of prednisolone, which resulted in temporary clinical improvement. Macroglossia might be an indicator of immunotherapy effectiveness.