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Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-β/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

Abstract Aim We conducted a multicenter study on classical laparoscopic and endoscopic cooperative surgery (LECS) and LECS‐related procedures to retrospectively clarify the safety, problems, and mid‐term outcomes of these methods after their coverage by the national health insurance. Methods A total of 201 patients who underwent classical LECS/LECS‐related procedures for gastric submucosal tumors (G‐SMTs) in 21 institutions affiliated with the Laparoscopy Endoscopy Cooperative Surgery Study Group from April 2014 to March 2016 were included. Data was retrospectively obtained from the patients' charts. Results The most common surgical procedure was classical LECS (155 patients, 77.1%), non‐exposed endoscopic wall inversion surgery (22 patients, 11.4%), a combination of laparoscopic and endoscopic approaches to neoplasia with non‐exposure technique (16 patients, 8%), and closed LECS (two patients, 1%). Only six (3%) patients underwent LECS with gastrostomy. The mean operative time and blood loss were 188.4 (70–462) minutes and 23.3 (0–793) g, respectively. Ten (5%) patients developed postoperative complications (Clavien–Dindo classification grade II or higher). Two patients needed reoperation due to postoperative bleeding or anastomotic leakage. All tumors were resected with negative margins. A total of 127 (63.2%) patients underwent follow‐up observations for over 36 months, one of whom had a recurrence of peritoneal dissemination and one had poor oral intake. Conclusion Classical LECS and LECS‐related procedures for G‐SMTs have favorable short/mid‐term outcomes.

Background and Aims: GI stromal tumors (GISTs) represent the most common mesenchymal tumors of the GI tract. Guidelines recommend the removal of histologically proven gastric GISTs >2 cm. While the conventional treatment of a gastric GIST involves surgical excision, endoscopic full-thickness resection (EFTR) has been described as an acceptable alternative. We aim to outline how the key steps used in endoscopic submucosal dissection (ESD) can be adapted to the performance of exposed EFTR and discuss the variations in technical aspects between the 2 procedures. Methods: We use a video case illustration with a comprehensive narrative to highlight the similarities and differences in equipment used and techniques in EFTR and ESD. Images and graphical illustrations are also used to describe these techniques. Results: ESD techniques and equipment can be adapted for use in EFTR of gastric GISTs. Principles such as deep mucosal incision, the appropriate use of traction, and identification of vessels for prophylactic coagulation help to ensure a safe and efficient procedure. The main difference in EFTR is the need for general anesthesia, starting the mucosal incision as close to the tumor margin as possible, submucosal dissection around the surface of the tumor capsule, and a strong closure method for the muscle defect. Conclusions: The equipment and techniques in ESD can be adapted to EFTR for gastric GISTs by endoscopists who are familiar with ESD techniques.

Abstract Objectives Individual treatment strategies for esophageal cancer have been investigated based on the anatomical subsite classification. Accurate subsite classification based on these anatomical landmarks is thus important. We investigated the suitability of the existing endoscopic classification and explored alternative landmarks for esophageal subsite classification. Methods Patients who received endoscopic ultrasonography (and computed tomography scans for surveillance of esophageal cancer treatment or esophageal submucosal tumors were included. Distances between anatomical landmarks, including the inferior cricoid cartilage border, superior border of the sternum, and tracheal bifurcation, were measured using a combination of endoscopic ultrasonography, computed tomography, and other information. Results The mean (standard deviation) distances from the superior incisor dentition to the pharynx–esophagus, cervical–upper thoracic esophagus, and upper–middle thoracic esophagus boundaries were 16.9 (1.7), 21.7 (1.9), and 29.0 (1.9) cm, respectively. However, variances in the differences between the mean and individual distances were large (2.8, 3.4, and 3.7, respectively), mainly because of differences in body height. However, variances in the differences between individual distances and novel endoscopic landmarks, including the lower end of the pyriform sinus and lower end of compression of the left main bronchus, were lower (1.7, 1.2, and 0.6, respectively). Conclusions Existing indicators of esophageal subsite boundaries were not consistent with anatomical boundaries. Modification of the distance from the superior incisor dentition based on average distances from anatomical landmarks or the use of alternative endoscopic landmarks is recommended to provide more suitable anatomical boundaries.

Objective: We evaluated whether the blood parameters before prostate biopsy can diagnose prostate cancer (PCa) and clinically significant PCa (Gleason score [GS] ≥7) in our hospital. Methods: This study included patients with increased prostate-specific antigen (PSA) up to 20 ng/mL. The associations of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) alone or with PSA with PCa and clinically significant PCa were analyzed. Results: We included 365 patients, of whom 52.9% (193) had PCa including 66.8% (129) with GS of ≥7. PSA density (PSAD) and PSA had better the area under the curve (AUC) of 0.722 and 0.585, respectively with p=0.001 for detecting PCa compared with other blood parameters. PSA combined with PLR (PsPLR) and PSA with NLR (PsNLR) had better AUC of 0.608 and 0.610, respectively with p

Cervical auscultation is a simple, noninvasive method for diagnosing dysphagia, although the reliability of the method largely depends on the subjectivity and experience of the evaluator. Recently developed methods for the automatic detection of swallowing sounds facilitate a rough automatic diagnosis of dysphagia, although a reliable method of detection specialized in the peculiar feature patterns of swallowing sounds in actual clinical conditions has not been established. We investigated a novel approach for automatically detecting swallowing sounds by a method wherein basic statistics and dynamic features were extracted based on acoustic features: Mel Frequency Cepstral Coefficients and Mel Frequency Magnitude Coefficients, and an ensemble learning model combining Support Vector Machine and Multi-Layer Perceptron were applied. The evaluation of the effectiveness of the proposed method, based on a swallowing-sounds database synchronized to a video fluorographic swallowing study compiled from 74 advanced-age patients with dysphagia, demonstrated an outstanding performance. It achieved an F1-micro average of approximately 0.92 and an accuracy of 95.20%. The method, proven effective in the current clinical recording database, suggests a significant advancement in the objectivity of cervical auscultation. However, validating its efficacy in other databases is crucial for confirming its broad applicability and potential impact.

Abstract Background and Aim Gastric atrophy is a precancerous lesion. We aimed to clarify whether gastric atrophy determined by artificial intelligence (AI) correlates with the diagnosis made by expert endoscopists using several endoscopic classifications, the Operative Link on Gastritis Assessment (OLGA) classification based on histological findings, and genotypes associated with gastric atrophy and cancer. Methods Two hundred seventy Helicobacter pylori‐positive outpatients were enrolled. All patients' endoscopy data were retrospectively evaluated based on the Kimura‐Takemoto, modified Kyoto, and OLGA classifications. The AI‐trained neural network generated a continuous number between 0 and 1 for gastric atrophy. Nucleotide variance of some candidate genes was confirmed or selectively assessed for a variety of genotypes, including the COX‐21195, IL‐1β 511, and mPGES‐1 genotypes. Results There were significant correlations between determinations of gastric atrophy by AI and by expert endoscopists using not only the Kimura‐Takemoto classification (P

Background and study aims: Diffuse infiltrative gastric cancer can be difficult to diagnose owing to a lack of endoscopic features in the superficial mucosa. Moreover, a forceps biopsy may not reveal a pathological diagnosis. We aimed to evaluate the diagnostic yield and safety of endoscopic mucosal resection (EMR) and 'open-lid submucosal biopsy', a technique wherein EMR followed by biopsy of the ulcer floor is performed for a pathological diagnosis. Patients and methods: This retrospective observational study involved patients with suspected diffuse invasive gastric cancer on endoscopy and cross-sectional imaging in whom endoscopic forceps biopsy did not lead to a pathological diagnosis. Patients who underwent EMR and open-lid submucosal biopsy were included. The primary outcome was the total diagnostic yield. The secondary outcomes were the diagnostic yields of EMR and open-lid submucosal biopsy and incidence of complications. Results: Between June 2011 and February 2022, EMR and open-lid submucosal biopsy for diagnostic purposes were performed on seven patients without complications. EMR was diagnostic in four (57%) cases of diffuse infiltrative gastric cancer. Open-lid submucosal biopsy was diagnostic in five (71%) cases. As the primary endpoint, the combination of EMR and open-lid submucosal biopsy led to a pathological diagnosis in six cases (86%). Secondary analysis revealed gastric adenocarcinoma in 9 of 22 (41%) EMR specimens, while open-lid submucosal biopsies were positive for adenocarcinoma in 14 of 60 specimens (23%). Conclusions: The combination of EMR and open-lid submucosal biopsy was safe and showed good accuracy for the diagnosis of diffuse infiltrative gastric cancer. [ABSTRACT FROM AUTHOR]

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for 30% of non‐Hodgkin lymphomas. Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by Spi1, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non‐germinal center B‐cell‐like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in vivo, we generated conditional Spi1 knockout mice using Cγ1‐Cre mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B‐cell lymphomas. In contrast, no wild‐type mice developed B‐cell lymphoma. In addition, RNA‐seq analysis of lymphoma cells from Cγ1‐Cre Spi1F/F mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3 weeks. Lentiviral‐transduced Spi1 rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B‐cell lymphoma development. [ABSTRACT FROM AUTHOR]

Abstract There remains an unmet clinical need to identify which patients with diffuse large B‐cell lymphoma (DLBCL) would benefit from central nervous system (CNS) prophylaxis, due to the low positive predictive value (PPV; 10%–15%) of the currently available predictive models. To stratify patients at high risk of developing CNS relapse, we retrospectively analyzed 182 patients with DLBCL initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP), or a R‐CHOP‐like regimen. Among them, 17 patients relapsed with CNS involvement, and the 2‐year rate of CNS relapse was 7.9%. Upon carrying out multivariate analysis, ≥3 extranodal sites and elevated soluble interleukin‐2 receptor (sIL‐2R) levels at diagnosis were identified as independent risk factors for CNS relapse. The 2‐year and 3.5‐year rates of CNS relapse were 57.1% and 78.6%, respectively, in patients with both elevated sIL‐2R and ≥3 extranodal sites. Furthermore, combined use of these risk factors of both elevated sIL‐2R and ≥3 extranodal sites resulted in a high PPV (71.4%), negative predictive value (93.1%), and overall accuracy (92.3%) for undergoing CNS relapse. In conclusion, we propose a simple and valuable tool to predict patients with DLBCL at very high risk of CNS relapse.

IntroductionCerebral small vessel disease (SVD) is one of the leading causes of stroke; each neuroimaging marker of SVD is correlated with vascular risk factors and associated with poor prognosis after stroke. However, longitudinal studies investigating the association between comprehensive SVD burden scoring system, “total SVD score” – which encompasses the established neuroimaging markers of lacunae, cerebral microbleeds (CMBs), white matter hyperintensities (WMH) including periventricular hyperintensities, and perivascular spaces in basal ganglia– and clinical outcomes are limited. The aim of this study is to determine the association between SVD burden and long-term prognosis in patients with ischemic stroke.Methods and designThis prospective, single-center, observational study enrolled patients with acute ischemic stroke, including cerebral infarction and transient ischemic attack. Magnetic resonance imaging scans were performed, and then total SVD score (range, 0–4) was calculated. We recorded baseline characteristics and evaluated the relationships of long-term outcomes to SVD neuroimaging markers and total SVD score. Stroke recurrence was thought as primary outcome. Hazard ratios (HRs) of events during follow-up were calculated using Cox proportional hazards modeling with adjustments for age, sex, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and smoking. Cumulative event rates were estimated using the Kaplan–Meier method.ResultsConsecutive 564 acute ischemic stroke patients were enrolled according to inclusion and exclusion criteria. A total of 467 participants with first-ever ischemic stroke were analyzed (median age 75.0 [interquartile range, 64.0–83.0] years, 59.3% male). Total SVD score was 0 point in 47 individuals (12.0%), 1 point in 83 (21.2%), 2 points in 103 (26.3%), 3 points in 85 (21.7%), and 4 points in 73 (18.7%). Twenty-eight recurrent stroke events were identified during follow-up. Total SVD score ≥ 2, presence of CMBs, and moderate-to-severe WMH were associated with increased risk of recurrent stroke events (HR 9.31, 95% confidence interval [CI] 2.33–64.23; HR 2.81, 95% CI 1.08–7.30; HR 2.90, 95% CI 1.22–6.88, respectively).ConclusionThe accumulation of SVD biomarkers as determined by total SVD score offered a reliable predictor of stroke recurrence. This study established a firm understanding of SVD prognosis in clinical settings.