The role of CD98 heavy chain in cancer development.

The glycoprotein CD98, or CD98 heavy chain (CD98hc), encoded by the SLC3A2 gene, plays a crucial role in cancer development and progression. CD98hc, forming heterodimeric complexes with various light chains, regulates neutral amino acid transport across cell membranes. The intricate interplay between CD98hc, integrins, and amino acid transporters shapes the tumor microenvironment and contributes to tumor growth. Elevated expression of CD98hc in various cancers correlates with poor prognosis, making it a potential prognostic marker. In colorectal cancer, CD98hc emerges as a potential therapeutic target, along with its partner LAT1, and inhibitors like JPH203 exhibit promise in preclinical studies. Targeting CD98hc/LAT1, alone or with conventional therapies, shows promise in inhibiting tumor growth. This review focuses on elucidating the multifaceted roles of CD98hc and its partner LAT1 in cancer, particularly its involvement in amino acid transport, signaling pathways, and its prognostic relevance in cancer.

Stable and Highly Active Single Atom Configurations for Photocatalytic H2 Generation.

The employment of single atoms (SAs), especially Pt SAs, as co-catalysts in photocatalytic H2 generation has gained significant attention due to their exceptional efficiency. However, a major challenge in their application is the light-induced agglomeration of these SAs into less active nanosized particles under photocatalytic conditions. This study addresses the stability and reactivity of Pt SAs on TiO2 surfaces by investigating various post-deposition annealing treatments in air, Ar, and Ar-H2 environments at different temperatures. It is described that annealing in an Ar-H2 atmosphere optimally stabilizes SA configurations, forming stable 2D rafts of assembled SAs ≈0.5-1 nm in diameter. These rafts not only resist light-induced agglomeration but also exhibit significantly enhanced H2 production efficiency. The findings reveal a promising approach to maintaining the high reactivity of Pt SAs while overcoming the critical challenge of their stability under photocatalytic conditions.

Long-term impact of weight loss in people with class II obesity on the overall burden of disease: evidence from the national health screening cohort in Korea.

BACKGROUND: Obesity is known to increase overall disease burden but does obesity management actually help reduce disease burden? OBJECTIVES: To investigate the effects of weight loss on disease burden in people with obesity using the National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) in Korea. SETTING: Pure longitudinal observational study using Nationwide cohort database. METHODS: Out of 514,866 NHIS-HEALS cohort, participants with class II obesity in Asia-Pacific region (30 ≤ body mass index [BMI] < 35) who underwent health check-up provided by NHIS during 2003-2004 (index date) were included. All final participants continued to receive a total of 5 biennial health check-ups over the next 10 years without missing. A group-based trajectory model (GBTM) was used to categorize subjects based on 10-year BMI change patterns. The changes of co-morbidities, healthcare resource utilization, and medical cost were analyzed. RESULTS: The final study subjects (9857) were categorized into 3 trajectory clusters based on the pattern of BMI (kg/m2) change: maintenance (57.35%) with an average change of -.02 ± .06, loss (38.65%) with -.04 ± .08, and substantial loss (4.0%) with -.10 ± .18. The annual increases in the number of co-morbidities per subject in each cluster were .18, .18, and .16 (all P < .001), respectively. The increase of healthcare resource utilization over time was lowest for the substantial loss compared to maintenance and loss. With each passing year, the average annual total healthcare cost increased by ₩21,200 ($16.48, P = .034) and ₩10,500 ($8.16, P = .498) in the maintenance and loss, respectively, but decreased by ₩62,500 ($48.59, P = .032) in the substantial loss. CONCLUSIONS: Weight loss in people with obesity was associated with a reduced burden of disease, as evidenced by lower co-morbidity, healthcare resource utilization rate, and decreased medical costs. This study highlights the potential positive long-term impact on Korean society when actively managing weight in individuals with obesity.

Photocatalytic H2 Generation: Controlled and Optimized Dispersion of Single Atom Co-Catalysts Based on Pt-TCPP Planar Adsorption on TiO2.

When using single atoms (SAs) as a co-catalyst in photocatalytic H2 generation, achieving a well-dispersed, evenly distributed and adjustable SA surface density on a semiconductor surface is a challenging task. In the present work we use the planar adsorption of tetrakis-(4-carboxyphenyl)-porphyrin (TCPP) and its platinum coordinated analogue, Pt-TCPP, onto anatase TiO2 surfaces to establish a spatially controlled decoration of SAs. We show that the surface Pt SA density can be very well controlled by co-adsorption of Pt-TCPP and TCPP in the planar monolayer regime, and by adjusting the Pt-TCPP to TCPP ratio a desired well dispersed surface density of SAs up to 2.6×105  atoms µm-2 can be established (which is the most effective Pt SA loading for photocatalysis). This distribution and the SA state are maintained after a thermal treatment in air, and an optimized SA density as well as a most active form of Pt for photocatalytic H2 evolution can be established and maintained.

CEACAM5 and TROP2 define metaplastic and dysplastic transitions in human antral gastric precancerous lesions and tumors.

BACKGROUND: Mucosal gastric atrophy and intestinal metaplasia (IM) increase the risk for the development of gastric cancer (GC) as they represent a field for development of dysplasia and intestinal-type gastric adenocarcinoma. METHODS: We have investigated the expression of two dysplasia markers, CEACAM5 and TROP2, in human antral IM and gastric tumors to assess their potential as molecular markers. RESULTS: In the normal antral mucosa, weak CEACAM5 and TROP2 expression was only observed in the foveolar epithelium, while inflamed antrum exhibited increased expression of both markers. Complete IM exhibited weak CEACAM5 expression at the apical surface, but no basolateral TROP2 expression. On the other hand, incomplete IM demonstrated high levels of both CEACAM5 and TROP2 expression. Notably, incomplete IM with dysplastic morphology (dysplastic incomplete IM) exhibited higher levels of CEACAM5 and TROP2 expression compared to incomplete IM without dysplastic features (simple incomplete IM). In addition, dysplastic incomplete IM showed diminished SOX2 and elevated CDX2 expression compared to simple incomplete IM. CEACAM5 and TROP2 positivity in incomplete IM was similar to that of gastric adenomas and GC. Significant association was found between CEACAM5 and TROP2 positivity and histology of GC. CONCLUSIONS: These findings support the concept that incomplete IM is more likely associated with GC development. Overall, our study provides evidence of the heterogeneity of gastric IM and the distinct expression profiles of CEACAM5 and TROP2 in dysplastic incomplete IM. Our findings support the potential use of CEACAM5 and TROP2 as molecular markers for identifying individuals with a higher risk of GC development in the context of incomplete IM.

Oncogenic Fatty Acid Metabolism Rewires Energy Supply Chain in Gastric Carcinogenesis.

BACKGROUND & AIMS: Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells. METHODS: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers. RESULTS: The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers. CONCLUSIONS: Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.

Targeting Stem Cells and Dysplastic Features With Dual MEK/ERK and STAT3 Suppression in Gastric Carcinogenesis.

BACKGROUNDS & AIMS: Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia. METHODS: To assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo. RESULTS: Although pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133+/CD166+ stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways. CONCLUSIONS: Through its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development.

Dynamic tuft cell expansion during gastric metaplasia and dysplasia.

Tuft cells are chemosensory cells associated with luminal homeostasis, immune response, and tumorigenesis in the gastrointestinal tract. We aimed to elucidate alterations in tuft cell populations during gastric atrophy and tumorigenesis in humans with correlative comparison to relevant mouse models. Tuft cell distribution was determined in human stomachs from organ donors and in gastric pathologies including Ménétrier's disease, Helicobacter pylori gastritis, intestinal metaplasia (IM), and gastric tumors. Tuft cell populations were examined in Lrig1-KrasG12D , Mist1-KrasG12D , and MT-TGFα mice. Tuft cells were evenly distributed throughout the entire normal human stomach, primarily concentrated in the isthmal region in the fundus. Ménétrier's disease stomach showed increased tuft cells. Similarly, Lrig1-Kras mice and mice overexpressing TGFα showed marked foveolar hyperplasia and expanded tuft cell populations. Human stomach with IM or dysplasia also showed increased tuft cell numbers. Similarly, Mist1-Kras mice had increased numbers of tuft cells during metaplasia and dysplasia development. In human gastric cancers, tuft cells were rarely observed, but showed positive associations with well-differentiated lesions. In mouse gastric cancer xenografts, tuft cells were restricted to dysplastic well-differentiated mucinous cysts and were lost in less differentiated cancers. Taken together, tuft cell populations increased in atrophic human gastric pathologies, metaplasia, and dysplasia, but were decreased in gastric cancers. Similar findings were observed in mouse models, suggesting that, while tuft cells are associated with precancerous pathologies, their loss is most associated with the progression to invasive cancer.

Age-group-specific association of oral health and systemic health on cognitive function: a cross-sectional study of Korean elders.

BACKGROUND: Although the importance of oral and systemic healthcare for elderly people is increasing owing to the rapid ageing of the population in South Korea, studies on the relationship between oral health, systemic health, and cognitive function, as well as on the prediction of cognitive function by oral and systemic health depending upon age groups are lacking. METHODS: We included 5,975 out of 6,488 participants from the 8th wave of the Korean Longitudinal Study of Aging (KLoSA) panel data, divided the participants into three age groups, and performed a hierarchical multiple linear regression analysis to explain cognitive function with four types of predictors: oral health status, sociodemographic factors, objective health status, and subjective health status. RESULTS: Oral health status was positively correlated with systemic health status and cognitive function. Of all ages over 54, cognitive function was significantly predicted by oral health variables, such as the number of functional teeth, masticatory ability, and Geriatric Oral Health Assessment Index (GOHAI); sociodemographic variables, such as age, sex, education level, and residence; and systemic health variables, such as diagnosis of diabetes mellitus, cancer or malignant tumours, cerebrovascular disease and rheumatoid arthritis, depressive symptom, and self-rated health status. Oral health variables explained cognitive function differently by age group; GOHAI appeared important predictor in the group aged < 75 years, whereas the number of functional teeth did in the group aged ≥ 75 years. Educational level, masticatory ability, depressive symptoms, and self-rated health status were pivotal factors age-independently. CONCLUSIONS: The general and age-group-specific association between oral health, systemic health, and cognitive function were confirmed, suggesting that age-group-specific oral healthcare should be emphasized for the effective management of systemic and cognitive health in the elderly group.

Antimicrobial activity of Limosilactobacillus fermentum strains isolated from the human oral cavity against Streptococcus mutans.

Oral probiotics have been recently gaining much attention owing to their potential to inhibit the progression of dental caries by controlling the cariogenic effects of Streptococcus mutans. We isolated and genotypically identified 77 lactic acid bacteria including 12 Limosilactobacillus fermentum probiotic candidates from the oral cavity of healthy volunteers. Among the 12 L. fermentum isolates, nine isolates effectively inhibited the growth of S. mutans via hydrogen peroxide (H2O2) production. The others neither suppressed the growth of S. mutans nor produced H2O2. Eight out of the nine H2O2-producing L. fermentum isolates exhibited strong adherence to oral epithelial KB cells while inhibiting the adherence of S. mutans to KB cells. The eight H2O2-producing isolates were neither haemolytic based on a blood-agar test, cytotoxic according to lactate dehydrogenase assay, nor resistant to eight antibiotics represented by the European Food Safety Authority guideline, indicating that the isolates have potential to suppress the cariogenesis driven by S. mutans while providing general probiotic benefits.

Reactive Deposition Versus Strong Electrostatic Adsorption (SEA): A Key to Highly Active Single Atom Co-Catalysts in Photocatalytic H2 Generation.

In recent years, the use of single atoms (SAs) has become of a rapidly increasing significance in photocatalytic H2 generation; here SA noble metals (mainly Pt SAs) can act as highly effective co-catalysts. The classic strategy to decorate oxide semiconductor surfaces with maximally dispersed SAs relies on "strong electrostatic adsorption" (SEA) of suitable noble metal complexes. In the case of TiO2 - the classic benchmark photocatalyst - SEA calls for adsorption of cationic Pt complexes such as [(NH3 )4 Pt]2+ which then are thermally reacted to surface-bound SAs. While SEA is widely used in literature, in the present work it is shown by a direct comparison that reactive attachment based on the reductive anchoring of SAs, e.g., from hexachloroplatinic(IV) acid (H2 PtCl6 ) leads directly to SAs in a configuration with a significantly higher specific activity than SAs deposited with SEA - and this at a significantly lower Pt loading and without any thermal post-deposition treatments. Overall, the work demonstrates that the reactive deposition strategy is superior to the classic SEA concept as it provides a direct electronically well-connected SA-anchoring and thus leads to highly active single-atom sites in photocatalysis.

Atomic-scale observation of premelting at 2D lattice defects inside oxide crystals.

Since two major criteria for melting were proposed by Lindemann and Born in the early 1900s, many simulations and observations have been carried out to elucidate the premelting phenomena largely at the crystal surfaces and grain boundaries below the bulk melting point. Although dislocations and clusters of vacancies and interstitials were predicted as possible origins to trigger the melting, experimental direct observations demonstrating the correlation of premelting with lattice defects inside a crystal remain elusive. Using atomic-column-resolved imaging with scanning transmission electron microscopy in polycrystalline BaCeO3, here we clarify the initiation of melting at two-dimensional faults inside the crystals below the melting temperature. In particular, melting in a layer-by-layer manner rather than random nucleation at the early stage was identified as a notable finding. Emphasizing the value of direct atomistic observation, our study suggests that lattice defects inside crystals should not be overlooked as preferential nucleation sites for phase transformation including melting.

Investigation of canine caudal articular process dysplasia of thoracic vertebrae using computed tomography: Prevalence and characteristics.

Caudal articular process (CAP) dysplasia is a congenital vertebral malformation that results from the failure of ossification center of articular process located in vertebrae, which includes aplasia or hypoplasia. In previous studies, it was reported to be common in small and chondrodystrophic dogs however, investigated in limited breeds. So we aimed to confirm the prevalence and the characteristics of CAP dysplasia in various breeds, and also to investigate the association of CAP dysplasia and spinal cord myelopathy in neurologically abnormal dogs. In this multicenter, retrospective study, the clinical records and thoracic vertebral column computed tomographic (CT) images of 717 dogs between February 2016 and August 2021 were included and 119 dogs which also underwent magnetic resonance imaging (MRI) examination were evaluated. Overall, 337 of 717 dogs (47.0%) had at least one thoracic CAP dysplasia and the prevalence of CAP dysplasia was significantly higher in dogs with a lower body weight (P < 0.0001). A total of 66.4% of toy breeds, 39.0% of small breeds, 20.2% of medium breeds, and 6.0% of large breeds were affected by at least one CAP dysplasia. The most affected vertebra was T4 in toy (48.1%) and small breeds (20.8%), and T5 in medium (20.8%) and large breeds (5.0%). In all groups, prevalence of CAP dysplasia between T1 and T9 was higher than post-diaphragmatic vertebrae (T10-T13). Fifty nine of 119 dogs which underwent both CT and MRI examination had symptoms of spinal cord myelopathy of T3-L3 and twenty-five of 59 dogs (42.3%) had at least one thoracic CAP dysplasia. In that 25 neurologically abnormal dogs, 41 sites of intervertebral disc disease (IVDD) were detected. However, only one dog had both CAP dysplasia and herniated disc at the same level. Also, CAP dysplasia associated non-compressive spinal myelopathy at the same level was found in the other dog. Association CAP dysplasia with spinal myelopathy is speculated but is not confirmed by this study.

A multicomponent equimolar proton-conducting quadruple hexagonal perovskite-related oxide system.

Since the high configurational entropy-driven structural stability of multicomponent oxide system was proposed Rost et al. in 2015, many experiments and simulations have been done to develop new multicomponent oxides. Although many notable findings have shown unique physical and chemical properties, high configurational entropy oxide systems that have more than 3 distinct cation sites are yet to be developed. By utilizing atomic-scale direct imaging with scanning transmission electron microscopy and AC-impedance spectroscopy analysis, we demonstrated for the first time that a multicomponent equimolar proton-conducting quadruple hexagonal perovskite-related Ba5RE2Al2ZrO13 (RE = rare earth elements) oxide system can be synthesized even when adding eight different rare earth elements. In particular, as the number of added elements was increased, i.e., as the configurational entropy was increased, we confirmed that the chemical stability toward CO2 was improved without a significant decrement of the proton conductivity. The findings in this work broaden the use of the crystal structure to which the multicomponent model can be applied, and a systematic study on the correlation between the configurational entropy and proton conductivity and/or chemical stability is noteworthy.

Twelve-Year Trajectory of Disease Burden and Mortality by Obesity Level in Korea: Analysis of the National Health Insurance Service Database.

INTRODUCTION: Despite increases in obesity prevalence, awareness of obesity as a disease requiring active treatment remains lacking in Korea. We investigated differences in medical problems and expenditures and mortality across obesity categories using 12-year data from the National Health Insurance Service. MATERIALS AND METHODS: Individuals aged 40-79 years who underwent medical examinations during 2003-2004 (n = 415,201) were divided based on Asian body mass index (kg/m2) criteria: normal weight (18.5 to < 23.0, 36.4%), overweight (23.0 to < 25.0, 28.3%), obesity (25.0 to < 30.0, 32.5%), and severe obesity (≥ 30.0, 2.8%). Medical problems and expenditures were fitted to linear mixed models. Mortality was analyzed via Cox proportional-hazards model. RESULTS: More severe obesity was associated with a higher rate of medical problems, relative to normal weight: coefficient = 0.31 (95% confidence interval [CI], 0.30-0.32) for overweight, 0.61 (0.60-0.61) for obesity, and 1.07 (1.04-1.09) for severe obesity. A similar association was observed for medical expenditure: coefficient = 8.85 (95%CI, 6.80-10.89) for overweight, 20.04 (18.07-22.01) for obesity, and 48.76 (43.66-53.86) for severe obesity. Relative to overweight participants, those with normal weight and severe obesity exhibited a higher mortality risk (hazard ratio [HR] 1.21 [95%CI, 1.18-1.25] for normal; 1.27 [1.19-1.36] for severe obesity). In age-specific analyses, mortality risk was the highest for participants with severe obesity, aged < 60 years (HR, 1.58 [95%CI, 1.41-1.77]). CONCLUSION: Disease burden including medical problems and expenditure, and mortality in middle-aged adults, increased proportionally to the degrees of obesity. Health policies and medical systems aimed at reducing the burden of obesity may help reduce the burden of disease on society.

Complete Genome Sequence of Hydrogen Peroxide-Producing Limosilactobacillus fermentum DM072 Isolated from the Human Oral Cavity.

The complete genome of hydrogen peroxide (H2O2)-producing Limosilactobacillus fermentum strain DM072, isolated from the oral cavity of healthy volunteers in South Korea, was sequenced by long-read sequencing and was subsequently corroborated by short-read sequencing. The genome comprises one circular chromosome and one plasmid and lacks antimicrobial resistance genes.

Complete Genome Sequence of Lacticaseibacillus rhamnosus DM065, Isolated from the Human Oral Cavity.

The 3.0-Mb complete genome of Lacticaseibacillus rhamnosus strain DM065, which was isolated from the oral cavity of healthy volunteers in South Korea, was sequenced using a combination of PacBio and Illumina technologies. The genome consists of one circular chromosome and two plasmids and lacks antimicrobial resistance genes.

Whole-Genome Sequence of Limosilactobacillus fermentum Strain DM075, Isolated from the Human Oral Cavity.

Here, we report the complete genome sequence of nitric oxide (NO)-producing Limosilactobacillus fermentum strain DM075, which was isolated from human tongue coating samples from healthy donors in South Korea. The complete genome sequence of DM075 comprises a single circular 2,204,022-bp genome, with a GC content of 51.0%, and lacks antimicrobial resistance genes.

Determination of Blood NOTCH3 Extracellular Domain and Jagged-1 Levels in Healthy Subjects.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic disorder among those responsible for hereditary strokes, and it is caused by a mutation in the NOTCH3 gene on chromosome 19. Blood biomarkers related to the Notch signaling pathway have not been investigated extensively in CADASIL. In this study, we measured the serum and plasma levels of NOTCH3 extracellular domain (N3ECD) and its ligand, Jagged-1, in 279 healthy subjects. The levels of N3ECD and Jagged-1 showed significant correlations in both serum (p < 0.0001, r = 0.2681) and plasma (p < 0.0001, r = 0.4065). The N3ECD levels were significantly higher in the serum than in plasma and tend to increase with age. In contrast, there was no significant difference between the serum and plasma levels of Jagged-1 levels. To summarize, we were able to measure N3ECD and Jagged-1 protein levels in healthy human serum and plasma. Taken together, our findings provide the basis for further studies investigating the clinical use of blood N3ECD and Jagged-1 levels for CADASIL and other Notch signaling-related diseases.