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Abstract Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance of METI on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. We also conduct a quantitative comparison of METI with existing clustering and cell deconvolution tools, demonstrating METI’s robust and consistent performance.

While technological advances have made implants a good treatment option with a good long-term prognosis, peri-implantitis, which results in alveolar bone resorption around implants, has been observed in some cases. Micromotion at the implant abutment connection can cause peri-implantitis. However, the temporal progression of micromotion upon loading remains unclear. Therefore, we aimed to longitudinally measure micromotion upon loading application on an implant. Implants with Morse-tapered connections were prepared. Custom titanium abutments were fabricated and tightened onto implant bodies at 35 N. A 100 N vertical load was applied for 200,000 cycles. Micromotion was measured when the load was applied, as was the total implant length and removal torque before and after loading. The micromotion was measured from the position data of the jig of the testing machine during loading. The average removal torque was 30.67 N after 10 min of tightening and 27.95 N after loading, indicating a decrease due to loading. The implant length reduced by 3.6 μm under the load. The average micromotion was 0.018 mm at 2 cycles, 0.016 mm at 100,000 cycles, and 0.0157 mm at 200,000 cycles, indicating implant length reduction under the load but not reaching 0. The micromotion between the implant and abutment under a cyclic load decreased over time but did not completely cease. These results highlight the relationship between micromotion and loading, underscoring the importance of careful monitoring and management to mitigate potential complications, such as peri-implantitis, and ensure optimal performance and durability of the implant.

Background & Aims: Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined. Methods: We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15-Pgdh+/− mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC. Results: PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC. Conclusions: 15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC. Impact and implications: The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC.

PurposeTo establish a fast and accurate detection method for interspecies contaminations in the patient-derived xenograft (PDX) models and cell lines, and to elucidate possible mechanisms if interspecies oncogenic transformation is detected.MethodsA fast and highly sensitive intronic qPCR method detecting Gapdh intronic genomic copies was developed to quantify if cells were human or murine or a mixture. By this method, we documented that murine stromal cells were abundant in the PDXs; we also authenticated our cell lines to be human or murine.ResultsIn one mouse model, GA0825-PDX transformed murine stromal cells into a malignant tumorigenic murine P0825 cell line. We traced the timeline of this transformation and discovered three subpopulations descended from the same GA0825-PDX model: epithelium-like human H0825, fibroblast-like murine M0825, and main passaged murine P0825 displayed differences in tumorigenic capability in vivo. P0825 was the most aggressive and H0825 was weakly tumorigenic. Immunofluorescence (IF) staining revealed that P0825 cells highly expressed several oncogenic and cancer stem cell markers. Whole exosome sequencing (WES) analysis revealed that TP53 mutation in the human ascites IP116-generated GA0825-PDX may have played a role in the human-to-murine oncogenic transformation.ConclusionThis intronic qPCR is able to quantify human/mouse genomic copies with high sensitivity and within a time frame of a few hours. We are the first to use intronic genomic qPCR for authentication and quantification of biosamples. Human ascites transformed murine stroma into malignancy in a PDX model.

We propose a new laser injection attack Redshift that manipulates signal propagation delay, allowing for precise control of oscillator frequencies and other behaviors in delay-sensitive circuits. The target circuits have a significant sensitivity to light, and a low-power continuous-wave laser, similar to a laser pointer, is sufficient for the attack. This is in contrast to previous fault injection attacks that use highpowered laser pulses to flip digital bits. This significantly reduces the cost of the attack and extends the range of possible attackers. Moreover, the attack potentially evades sensor-based countermeasures configured for conventional pulse lasers. To demonstrate Redshift, we target ring-oscillator and arbiter PUFs that are used in cryptographic applications. By precisely controlling signal propagation delays within these circuits, an attacker can control the output of a PUF to perform a state-recovery attack and reveal a secret key. We finally discuss the physical causality of the attack and potential countermeasures.

Gastroesophageal cancers are a group of aggressive malignancies that are inherently heterogeneous with poor prognosis. Esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, and gastric adenocarcinoma all have distinct underlying molecular biology, which can impact available targets and treatment response. Multimodality therapy is needed in the localized setting and treatment decisions require multidisciplinary discussions. Systemic therapies for treatment of advanced/metastatic disease should be biomarker-driven, when appropriate. Current FDA approved treatments include HER2-targeted therapy, immunotherapy, and chemotherapy. However, novel therapeutic targets are under development and future treatments will be personalized based on molecular profiling. Herein, we review the current treatment approaches and discuss promising advances in targeted therapies for gastroesophageal cancers.

Abstract Aim Many studies have shown that patients with mental disorders are less likely than non‐psychiatric patients to be diagnosed with or treated for various types of cancers because of their low awareness and understanding of the disease as well as reduced ability to cooperate with medical staff. We analyzed the clinical features of patients with colorectal cancer (CRC) and preexisting mental illness. Methods All patients underwent primary tumor resection for CRC. We reviewed the records of 68 patients who were diagnosed with mental disorders. The patients' clinicopathological information was compared with that of a control group of 893 CRC patients. Results There was no significant difference in the overall disease stage at the time of surgery between the groups. However, disease‐free survival, cancer‐specific survival, and overall survival were significantly worse in the mental disorder group than in the control group (P

Abstract Cancer immunotherapy has caused a paradigm shift from conventional therapies that directly target cancer cells to innovative therapies that utilize the host immune system. In particular, programmed cell death‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) inhibitors have achieved an impressive breakthrough and been approved for clinical use in several types of cancer including gastrointestinal (GI) cancer. To identify and develop predictive biomarkers for PD‐1 inhibitors is of great concern in clinical practice. Although PD‐L1 expression is considered a logical biomarker as PD‐L1 is a substantial target of the immune checkpoint inhibitors, its clinical significance in GI cancer remains unclear. In this review, we summarize the current evidence for PD‐L1 expression as a prognostic and predictive biomarker for PD‐1/PD‐L1 inhibitors in GI cancer from recent publications, and emerging evidence from recent key clinical trials on the efficacy of PD‐1/PD‐L1 inhibitors. Challenging clinical issues for PD‐L1 assessment are then discussed from the viewpoint of the methodology for PD‐L1 evaluation including the differences in PD‐L1 detection assays and evaluation criteria for PD‐L1 positivity. Moreover, we highlight the biological features of PD‐L1 expression in terms of tumor spatial and temporal heterogeneity, which suggests important implications for biomarker analysis. Finally, we describe future perspectives using liquid biopsy for better assessment of PD‐L1 status. This new information should improve our understanding of the clinical significance of PD‐L1 in GI cancer, leading to optimal patient selection and treatment strategy for the clinical use of PD‐1/PD‐L1 inhibitors in patients with GI cancer.

Abstract Background IgG4-related disease (IgG4-RD) is an immune-mediated disorder in which abundant IgG4-positive plasma cells infiltrate affected organs. There have been reported four cases of probable IgG4-RD presenting as a submucosal tumor of the stomach. We herein report the first case of definite IgG4-RD presenting as a submucosal tumor of the stomach resected with laparoscopic endoscopic cooperative surgery (LECS). Case presentation A 70-year-old woman with a 6-year history of autoimmune pancreatitis was referred to our department because a 15-mm submucosal tumor in the greater curvature of the lower part of the stomach had been identified via upper gastrointestinal endoscopy. Endoscopic ultrasonography showed a 10-mm low-echoic lesion derived from the submucosal layer of the stomach. A fine-needle aspiration biopsy was attempted, but the tumor was too hard for sampling. F-fluorodeoxyglucose (FDG) positron emission tomography showed an FDG uptake, suggesting a possibility of malignant disease. As the diagnosis could not be confirmed, LECS for both the diagnosis and curative treatment was performed. A histopathological examination showed a tumor with IgG4-positive lymphoplasmacytic infiltration and fibrosis. The ratio of IgG4+/IgG+ lymphoplasmacytic cells was > 80%. A laboratory examination showed elevation of the serum IgG4 levels preoperatively. Thus, the final diagnosis was IgG4-RD of the stomach. No recurrence was observed within 1 year after surgery. Conclusions We encountered a case of definite IgG4-RD presenting as a gastric SMT in which a correct diagnosis was achieved by a minimally invasive LECS technique. IgG4-RD may present as a gastric lesion and should be taken into consideration as a differential diagnosis.

Double expressor lymphoma (DEL), defined as overexpression of BCL2 and MYC, is an aggressive subtype of diffuse large B cell lymphoma (DLBCL). Here we report a case of a 64-year-old female diagnosed with abdominal DEL transformed from jejunum follicular lymphoma (FL). 18F-fluorodeoxyglucose (FDG)-positron emission tomography showed diffuse accumulation of FDG into the peritoneum and small bowel wall. Double balloon-assisted enteroscopy revealed whitish submucosal tumors in the proximal jejunum. Aggregation of atypical lymphocytes positive for CD20, CD79a, and BCL2 was seen in the jejunal biopsy samples. These atypical lymphocytes were monoclonal since cell surface expression of Ig light chains was limited to κ chain by flow-cytometry. Thus, immunohistochemical and flowcytometric analyses data were consistent with FL of the jejunum. Neoplastic lymphocytes obtained from ascites were positive for CD10, CD20, CD79a, BCL2, and BCL6. Fluorescence in situ hybridization (FISH) showed formation of BCL2/IgH fusion gene and extra copies of MYC, the former of which is a characteristic chromosomal abnormality of FL. These genetic alterations and protein expression profiles of ascitic fluid cells were consistent with those of DEL transformed from FL. Given that a significant population of patients with indolent FL of the gastrointestinal tract developed into aggressive DLBCL, it is likely that primary FL of the jejunum transformed into the abdominal aggressive DEL in this case. This case is unique in that concurrent occurrence of FL and DEL was confirmed by immunohistochemical and FISH analyses and that abdominal DEL transformed from jejunal FL was highly suspected.

Esophageal cancer (EC) is an aggressive malignancy with an increasing incidence and a poor prognosis. EC is histologically divided into two major categories: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). EAC and ESCC are molecularly different and therefore treatments should reflect the respective histological subtype. Combined modality therapy is needed for localized EC. When EC is advanced (stage 4), systemic therapy is the mainstay treatment for palliation. For localized EC, several strategies are considered standard, and more trials are necessary to determine a unified and more effective approach. The management for advanced EC is slowly evolving as immunotherapy is showing some promise for ESCC, but more data from ongoing studies are anticipated. Treatment advances will be based on high-definition genomic investigation of individual tumors. Herein, we review the contemporary trends in diagnosing and treating EAC and ESCC.

The nuclear receptor, REV-ERBα, has a key role in circadian rhythms and requires heme as its ligand. The present study determined whether the heme precursor, 5-aminolevulinic acid (ALA), affects REV-ERBα and its target genes. When exposed to ALA, the human lung diploid cell line, WI-38, exhibited activation of REV-ERBα and repression of the transcription of REV-ERBα target genes, including BMAL1, an essential component of the circadian oscillator. Moreover, co-incubation of sodium ferrous citrate (SFC) and ALA also activated REV-ERBα and repressed the transcription of REV-ERBα target genes. These results indicate that ALA regulates human circadian rhythms via REV-ERBα.

Carbon nanomaterials, including fullerenes, carbon nanohorns, and carbon nanotubes, are increasingly being used in various fields owing to these materials’ unique, size-dependent functions and physicochemical properties. Recently, because of their high variability and stability, carbon nanomaterials have been explored as a novel tool for the delivery of therapeutic molecules including peptide and nucleic acid cancer drugs. However, insufficient information is available regarding the safety of carbon nanomaterials for human health, even though such information is vital for the development of safe and effective nanomedicine technologies. In this review, we discuss currently available information regarding the safety of carbon nanomaterials in nanomedicine applications, including information obtained from our own studies; and we discuss types of carbon nanomaterials that demonstrate particular promise for safe nanomedicine technologies.

The fastening mechanics of prosthetic screws under various conditions is crucial to the maintenance of dental implants. This study comprehensively explores the prosthetic screw rupture in titanium (Ti) and zirconia (ZrO2) superstructures under wet and dry conditions. Superstructures were fabricated using digital technology and subjected to tightening torque trials. Experimental results suggested that the implications of the conventionally recommended torque of 15 N•cm differ significantly between dry and wet environments. Both Ti and ZrO2 exhibited preloads of >30 N•cm under dry conditions; however, differences emerged under wet conditions. In addition, screw rupture posed a prominent clinical challenge —particularly during long-term cyclic loading. Notably, the ZrO2 superstructures exhibited a greater resistance to breaking torque than that of Ti. This study underscores the importance of reevaluating torque recommendations with consideration to the distinct characteristics of Ti and ZrO2 in diverse environments. [ABSTRACT FROM AUTHOR]