Potential of traditional medicines in alleviating COVID-19 symptoms.

This review discusses the prevention and treatment of coronavirus disease 2019 (COVID-19) caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mutations in its spike glycoprotein have driven the emergence of variants with high transmissibility and immune escape capabilities. Some antiviral drugs are ineffective against the BA.2 subvariant at the authorized dose. Recently, 150 natural metabolites have been identified as potential candidates for development of new anti-COVID-19 drugs with higher efficacy and lower toxicity than those of existing therapeutic agents. Botanical drug-derived bioactive molecules have shown promise in dampening the COVID-19 cytokine storm and thus preventing pulmonary fibrosis, as they exert a strong binding affinity for viral proteins and inhibit their activity. The Health Ministry of Thailand has approved Andrographis paniculata (Jap. Senshinren) extracts to treat COVID-19. In China, over 85% of patients infected with SARS-CoV-2 receive treatments based on traditional Chinese medicine. A comprehensive map of the stages and pathogenetic mechanisms related to the disease and effective natural products to treat and prevent COVID-19 are presented. Approximately 10% of patients with COVID-19 are affected by long COVID, and COVID-19 infection impairs mitochondrial DNA. As the number of agents to treat COVID-19 is limited, adjuvant botanical drug treatments including vitamin C and E supplementation may reduce COVID-19 symptoms and inhibit progression to long COVID.

The Roles of Mitochondria in Human Being's Life and Aging.

The universe began 13.8 billion years ago, and Earth was born 4.6 billion years ago. Early traces of life were found as soon as 4.1 billion years ago; then, ~200,000 years ago, the human being was born. The evolution of life on earth was to become individual rather than cellular life. The birth of mitochondria made this possible to be the individual life. Since then, individuals have had a limited time of life. It was 1.4 billion years ago that a bacterial cell began living inside an archaeal host cell, a form of endosymbiosis that is the development of eukaryotic cells, which contain a nucleus and other membrane-bound compartments. The bacterium started to provide its host cell with additional energy, and the interaction eventually resulted in a eukaryotic cell, with both archaeal (the host cell) and bacterial (mitochondrial) origins still having genomes. The cells survived high concentrations of oxygen producing more energy inside the cell. Further, the roles of mitochondria in human being's life and aging will be discussed.

Fourteen-year follow-up results of imatinib therapy in patients with unresectable and metastatic gastrointestinal stromal tumors.

BACKGROUND: Imatinib therapy is the gold standard for the treatment of unresectable and metastatic gastrointestinal stromal tumors (GISTs). However, few studies have reported the long-term outcomes of the treatment. METHODS: Seventy patients who underwent imatinib therapy for unresectable and metastatic GISTs were enrolled between 2001 and 2009, and follow-up data were collected until October 2023. One hundred and sixty-eight months had passed since the final enrollment. The outcome measures were patient survival and the status of GIST and imatinib therapy. The cumulative incidence of disease progression (PD) and the chronological changes in PD hazard rate (HR) were also analyzed. RESULTS: The 5-, 10-, 15-, and 20-year overall survival rates were 64.3%, 30.0%, 16.8%, and 12.2%, respectively. Sixty of the 70 enrolled patients died before the data cutoff date: 47 (78.3%) patients died of GIST progression while the remaining 13 (21.7%) died of diseases other than GISTs. The cumulative incidence of PD logarithmically increased, and PD continued even after 10 years of treatment. PD HR decreased over time to reach the lowest value at 9.6 years after the initiation of treatment (HR 0.00027; 95% CI 0.00007-0.00174) and after that formed a small peak at 13 years (HR 0.00144; 95% CI 0.00043-0.00436). CONCLUSIONS: Imatinib therapy showed high clinical efficacy in terms of long-term survival in GIST patients. However, patients undergoing imatinib therapy were at continuous risk of PD even after the 10-year treatment. Long-term treatment and follow-up beyond 10 years are necessary for unresectable and metastatic GIST patients.

Landscape of homologous recombination deficiency in gastric cancer and clinical implications for first-line chemotherapy.

BACKGROUND: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC. METHODS: We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups. RESULTS: Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151-0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy. CONCLUSIONS: Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC.

Combined pancreaticoduodenectomy for advanced gallbladder cancer: Indications, surgical outcomes, and limitations.

BACKGROUND: This study aimed to elucidate the clinical value of combined pancreaticoduodenectomy (PD) for advanced gallbladder cancer according to the mode of cancer spread in the pancreaticoduodenal region. METHODS: Patients who underwent combined PD for advanced gallbladder cancer were retrospectively reviewed. The mode of cancer spread in the pancreaticoduodenal region was defined as involvement of peripancreatic organs/structures alone, peripancreatic nodal metastasis alone, or both. Surgical outcomes were compared among these modes of spread. RESULTS: Fifty-seven patients were included. Rates of severe morbidity and mortality were 52.6% and 3.5%, respectively. The mode of cancer spread was involvement of peripancreatic organs/structures alone in 16 patients, peripancreatic nodal metastasis alone in 17, and both in 24; R0 resection rates differed significantly among the groups (87.5% vs. 94.1% vs. 37.5%; p < 0.001). Overall survival (OS) was significantly worse in patients with both modes of spread (5-year OS, 8.3%) than in those with involvement of peripancreatic organs/structures alone (5-year OS, 37.9%; p < 0.001) and those with peripancreatic nodal metastasis alone (5-year OS, 29.4%; p = 0.011). OS was similar between pM0 patients with both modes of spread and pM1 patients (5-year OS, 16.7% vs. 8.7%; p = 0.605). Multivariate analysis identified mode of cancer spread as an independent prognostic factor (p = 0.006). CONCLUSIONS: Combined PD could be oncologically justified for advanced gallbladder cancer with involvement of peripancreatic organs/structures alone or peripancreatic nodal metastasis alone in the pancreaticoduodenal region. This procedure would not be indicated in patients with both modes of spread.

Heat-treated and/or lysozyme-treated Enterococcus faecalis (FK-23) improves the progression of renal disease in a unilateral ischemia-reperfusion injury rat model.

The prevalence of chronic kidney disease (CKD) is increasing owing to the elderly population. Here, we investigated the effects of heat-treated Enterococcus faecalis (FK-23) and lysozyme-treated FK-23 (LFK) on the progression of CKD in rats. A CKD model was established using male Wistar rats by subjecting them to right nephrectomy (1K), followed by ischemia and reperfusion (IR). FK-23 or LFK was fed ad libitum as a mixed diet after right nephrectomy. Animals subjected to renal ischemia-reperfusion injury (IRI) showed increased plasma creatinine and blood urea nitrogen levels. Furthermore, in the kidneys, collagen accumulation and α-smooth muscle actin, indicative of fibroblast activation and fibrosis-related gene and protein expression, increased 3 weeks after IRI. FK-23 and LFK suppressed the increase in the mRNA levels of some of these genes. The increase in oxidative stress markers, 4-hydroxy-2-nonenal, endothelial nitric oxide synthase, and nitrotyrosine in the kidney, as well as increased plasma uremic toxins after IRI, were also ameliorated by FK-23 and LFK. Metagenomic analysis of fecal samples revealed that gut microbial alteration caused by IRI was also ameliorated by LFK treatment. These results suggest that Enterococcus faecalis ingredients may improve CKD progression by suppressing oxidative stress and correcting the balance of the intestinal microflora.

Clinical application of targeted tumour sequencing tests for detecting ERBB2 amplification and optimizing anti-HER2 therapy in gastric cancer.

BACKGROUND: Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients. METHODS: ERBB2 copy number alteration (CNA) was examined via a targeted tumour sequencing test in 152 formalin-fixed paraffin-embedded (FFPE) GC tissues. ERBB2 CNA was compared to HER2 status evaluated by IHC/FISH in FFPE block sections, which were identical to those subjected to the targeted tumour sequencing test. Treatment outcomes of anti-HER2 therapy in 11 patients with unresectable metastatic GC was evaluated. RESULTS: ERBB2 AMP (≥ 2.5-fold change) was detected by the targeted tumour sequencing test in 15 patients (9.9%), and HER2 positivity (IHC 3 + or IHC 2+/FISH positive) was detected in 21 patients (13.8%). The overall percent agreement, positive percent agreement, negative percent agreement and Cohen's kappa between ERBB2 CNA and HER2 status were 94.7%, 66.7%, 99.2% and 0.75, respectively. Progression-free survival for trastuzumab therapy in patients with ERBB2 AMP was significantly longer than that in patients with no ERBB2 AMP detected by the targeted tumour sequencing test (median 14 months vs. 4 months, P = 0.007). Treatment response to trastuzumab therapy was reduced in patients with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs. One patient with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs achieved a durable response to trastuzumab deruxtecan as fourth-line therapy. CONCLUSIONS: A targeted tumour sequencing test is a reliable modality for identifying HER2-positive GC. ERBB2 AMP and concomitant genetic alterations detected through the targeted tumour sequencing test are potential indicators of treatment response to trastuzumab therapy. The targeted tumour sequencing test has emerged as a plausible candidate for companion diagnostics to determine indications for anti-HER2 therapy in the era of precision medicine for GC.

Prognostic Significance of NQO1 Expression in Non-neoplastic Esophageal Squamous Epithelium for Patients With Esophageal Cancer.

BACKGROUND/AIM: NAD(P)H dehydrogenase [quinone] 1 (NQO1), an antioxidant enzyme, confers resistance to anticancer agents. NQO1 C609T is a single-nucleotide polymorphism associated with reduced protein expression in the non-neoplastic esophageal squamous epithelium (ESE). This study aimed to investigate immunohistochemical NQO1 expression in non-neoplastic ESE and to elucidate its prognostic significance in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant therapy followed by esophagectomy. MATERIALS AND METHODS: NQO1 expression in non-neoplastic ESE was determined in surgical specimens from 83 patients with ESCC using immunohistochemistry. The association between NQO1 expression and clinicopathological factors, and the prognostic significance of NQO1 expression for relapse-free survival (RFS) were statistically evaluated. RESULTS: Patients with complete loss or weak NQO1 expression and patients with moderate or strong NQO1 expression were classified into the NQO1-negative (n=29) and NQO1-positive (n=54) groups, respectively. The downstaging of T classification status after neoadjuvant therapy was significantly more frequent in the NQO1-negative group than in the NQO1-positive group (59% vs. 33%; p=0.036). The NQO1-negative group had significantly more favorable RFS than the NQO1-positive group (p=0.035). Multivariate survival analysis demonstrated that NQO1 negative expression had a favorable prognostic impact on RFS (HR=0.332; 95%CI=0.136-0.812; p=0.016). CONCLUSION: Immunohistochemical evaluation of NQO1 expression in non-neoplastic ESE has clinical utility for predicting patient prognosis after neoadjuvant therapy followed by esophagectomy and might be helpful for selecting candidates for adjuvant therapy to treat ESCC.

Macroscopic type is implicated in the prognostic impact of initial chemotherapy on peritoneal lavage cytology-positive gastric cancer with no other noncurative factors.

BACKGROUND: Initial chemotherapy (Initial-C) followed by surgery is a promising treatment strategy for peritoneal lavage cytology-positive gastric cancer (CY1 GC) with no other noncurative factors. The aim of this study was to investigate the survival advantage of Initial-C compared to initial surgery (Initial-S) for this disease according to the macroscopic type, which was associated with prognosis and the efficacy of chemotherapy in GC. METHODS: One hundred eighty-nine patients who were diagnosed with CY1 GC with no other noncurative factors at four institutions from January 2007 to December 2018 were enrolled. The patients were divided into a macroscopic type 4 group (N = 48) and a non-type 4 group (N = 141). The influence of initial treatment on overall survival (OS) in each group was evaluated. RESULTS: In the type 4 group, the 5-year OS rates of Initial-C (N = 35) and Initial-S (N = 13) were 11.6% and 0%, respectively (P = 0.801). The multivariate analysis could not show the survival advantage of Initial-C. In the non-type 4 group, the 5-year OS rates of Initial-C (N = 41) and Initial-S (N = 100) were 48.4% and 29.0%, respectively (P = 0.020). The multivariate analysis revealed that Initial-C was independently associated with prolonged OS (hazard ratio, 0.591; 95% confidence interval, 0.375-0.933: P = 0.023). CONCLUSIONS: Initial-C improves the prognosis of non-type 4 CY1 GC with no other noncurative factors. On the other hand, further development of effective chemotherapeutic regimens and innovative treatment strategies are required for type 4 CY1 GC.

Malignancy After Living Donor Liver Transplantation.

OBJECTIVES: De novo malignancy (DNM) is a major cause of death in long-term recipients of liver transplantation (LT). We herein report our experience with DNM after living-donor LT (LDLT). PATIENTS AND METHODS: A total of 111 LDLT procedures were performed in our institute from 1999 to 2022. Among them, 70 adult (>13 years old) LDLT recipients who survived for more than 1 year were included in this study. RESULTS: During a median follow-up of 146 (range, 12-285) months, 7 out of 70 recipients developed 8 DNMs, including lung cancer in 4, post-transplant lymphoproliferative disease in 3, and skin cancer in 1. One patient developed metachronal skin cancer and post-transplant lymphoproliferative disease. The pre-LT smoking history rate in patients with DNM was higher than in patients without DNM (P = .004). The survival time after DNM was 6 (1-166) months. Only 2 patients underwent R0 resection. DNM did not recur during follow-up. Other patients who underwent R1 resection and/or chemotherapy and/or radiotherapy all died due to DNMs during the follow-up. The cumulative DNM incidence was 3.5% at 10 years and 18.4% at 20 years after LDLT. The cumulative survival rate in patients with DNM was significantly worse than that in patients without DNM after LDLT (P = .049). CONCLUSION: The survival rate of patients with DNM was lower than that of those without DNM. A pre-LT smoking history is a risk factor for DNM. R0 resection is effective for improving the prognosis of patients with DNM. Regular cancer screening is important for detecting DNM early after LDLT.

Mucin phenotype and genetic alterations in non-V600E BRAF-mutated colorectal cancer.

Colorectal cancer (CRC) is a heterogeneous disease that develops through stepwise accumulation of genetic alterations and progresses via several distinct pathways. However, the tumorigenesis of CRCs with BRAF non-V600E mutations remains unclear. Here, we aimed to elucidate the tumorigenesis of CRCs with BRAF non-V600E mutations, focusing on differences in mucin phenotype and genetic alterations between CRCs with non-V600E and V600E mutations. We investigated 201 patients with CRC and performed panel testing of 415 genes to identify BRAF mutations. Patients were classified into five mucin phenotypes - large-intestinal, small-intestinal, gastric, mixed, and unclassified - using immunohistochemistry for CD10, MUC2, MUC5AC, and MUC6. BRAF mutations were identified in 24 of 201 patients' samples, of which 13 (6.5%) had a V600E mutation (V600E-mutant) and 11 (5.5%) had non-V600E mutations (non-V600E-mutant). MUC5AC expression was significantly associated with V600E mutations (P = 0.040), while CD10 expression was significantly associated with non-V600E mutations (P = 0.010). The small-intestinal mucin phenotype was significantly associated with non-V600E mutations (P = 0.031), while the mixed mucin phenotype was significantly associated with V600E mutations (P = 0.027). Regarding genetic alterations, focusing on the WNT signaling pathway, APC mutation was significantly associated with non-V600E mutations (P < 0.001), while RNF43 mutation was significantly associated with V600E mutations (P = 0.020). Considering the differences in mucin phenotype and genetic alterations, different modes of tumorigenesis are assumed for CRC with BRAF V600E mutation and non-V600E mutations. These findings are important in understanding the biology and treatment strategies for BRAF-mutant CRC.

Risk factors for death from other diseases after curative gastrectomy and lymph node dissection for gastric cancer.

BACKGROUND: Recent advances in treatment are expected to bring a cure to more patients with gastric cancer (GC). Focusing on the risk of death from other diseases (DOD) has become a crucial issue in patients cured of GC. The aim of this study was to elucidate the risk factors for DOD in patients who underwent curative gastrectomy with lymph node dissection for GC. METHODS: We enrolled 810 patients who underwent curative gastrectomy with lymph node dissection for GC from January 1990 to December 2014 and had no recurrence or death of GC until December 2019. We investigated the risk factors for DOD defined as death excluding death from a malignant neoplasm, accident, or suicide after gastrectomy, focusing on the perioperative characteristics at gastrectomy. RESULTS: Among 315 deaths from any cause, 210 died from diseases other than malignancy, accidents and suicide. The leading cause of DOD was pneumonia in 54 patients (25.7%). The actual survival period in 167 patients (79.5%) with DOD was shorter than their estimated life expectancy at gastrectomy. Multivariate analysis revealed that a high Charlson Comorbidity Index score (score 1-2: hazard ratio [HR] 2.192, 95% confidence interval [CI] 1.713-2.804, P < 0.001 and score ≥ 3: HR 4.813, 95% CI 3.022-7.668, P < 0.001), total gastrectomy (HR 1.620, 95% CI 1.195-2.197, P = 0.002) and the presence of postoperative complications (HR 1.402, 95% CI 1.024-1.919, P = 0.035) were significant independent risk factors for DOD after gastrectomy for GC, in addition to age of 70 years or higher, performance status of one or higher and body mass index less than 22.0 at gastrectomy. CONCLUSIONS: Pneumonia is a leading cause of DOD after curative gastrectomy and lymph node dissection for GC. Paying attention to comorbidities, minimizing the choice of total gastrectomy and avoiding postoperative complications are essential to maintain the long-term prognosis after gastrectomy.

[Long-Term Survival after Liver and Pulmonary Metastasectomy Following Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma-A Case Report].

The patient was a 61-year-old man with a diagnosis of carcinoma of the pancreatic head. Abdominal computed tomography( CT)showed no distant metastasis, and he underwent subtotal stomach-preserving pancreatoduodenectomy. Immediately after surgery, he received liver perfusion chemotherapy with 5-fluorouracil followed by systemic gemcitabine. Eighteen months after surgery, CT revealed liver metastasis in the S6 segment, and partial hepatectomy was performed. The pathological diagnosis was liver metastasis of pancreatic cancer. Postoperatively, the patient was treated with gemcitabine and S-1 therapy for 1 year and then switched to S-1 monotherapy for about 6 months. Four years after the initial surgery, CT showed 2 metastases in the right lung. After 2 months of S-1 monotherapy, wedge resection of the upper and lower lobes of the right lung was performed. Gemcitabine and nab-paclitaxel therapy were administered, after the metastasectomy, but pleural dissemination appeared on CT 5 years after the initial surgery. Modified FOLFIRINOX therapy was started and continued for 8 months, but CT revealed further disseminated lesions in the diaphragm. Palliative irradiation was provided, but the disease gradually progressed. After multidisciplinary treatment, the patient survived for 6 years and 3 months after the initial surgery.

Mitochondria Play Essential Roles in Intracellular Protection against Oxidative Stress-Which Molecules among the ROS Generated in the Mitochondria Can Escape the Mitochondria and Contribute to Signal Activation in Cytosol?

Questions about which reactive oxygen species (ROS) or reactive nitrogen species (RNS) can escape from the mitochondria and activate signals must be addressed. In this study, two parameters, the calculated dipole moment (debye, D) and permeability coefficient (Pm) (cm s-1), are listed for hydrogen peroxide (H2O2), hydroxyl radical (•OH), superoxide (O2•-), hydroperoxyl radical (HO2•), nitric oxide (•NO), nitrogen dioxide (•NO2), peroxynitrite (ONOO-), and peroxynitrous acid (ONOOH) in comparison to those for water (H2O). O2•- is generated from the mitochondrial electron transport chain (ETC), and several other ROS and RNS can be generated subsequently. The candidates which pass through the mitochondrial membrane include ROS with a small number of dipoles, i.e., H2O2, HO2•, ONOOH, •OH, and •NO. The results show that the dipole moment of •NO2 is 0.35 D, indicating permeability; however, •NO2 can be eliminated quickly. The dipole moments of •OH (1.67 D) and ONOOH (1.77 D) indicate that they might be permeable. This study also suggests that the mitochondria play a central role in protecting against further oxidative stress in cells. The amounts, the long half-life, the diffusion distance, the Pm, the one-electron reduction potential, the pKa, and the rate constants for the reaction with ascorbate and glutathione are listed for various ROS/RNS, •OH, singlet oxygen (1O2), H2O2, O2•-, HO2•, •NO, •NO2, ONOO-, and ONOOH, and compared with those for H2O and oxygen (O2). Molecules with negative electrical charges cannot directly diffuse through the phospholipid bilayer of the mitochondrial membranes. Short-lived molecules, such as •OH, would be difficult to contribute to intracellular signaling. Finally, HO2• and ONOOH were selected as candidates for the ROS/RNS that pass through the mitochondrial membrane.

Allometric scaling of skin weight and thickness to body weight in relation to taxonomic orders and habitats in mammals.

Skin is the largest organ in a mammal body, and it exhibits most significant range of adaptations to different habitats. It is a complex, biological composite structure, consisting of epidermis, dermis and subcutaneous tissues and is used for the therapeutic application of medical devices to improve healthcare. Extensive studies have been performed on the roles of the skin; however, little is known on its physiological characteristics in relation to body size among different species. The purpose of this study was therefore to evaluate the allometric scaling of skin weight (SW) and thickness (ST) to body weight (BW) in relation to genetics and habitats. Also analysed the relationship of BW to thicknesses of epidermis, dermis and subcutaneous tissues. This study used 249 adult animals of both sexes, belonging to 144 species, clustered in 18 taxonomic orders and five types of habitats. The animals were obtained from various sources in Japan. SW and BW were weighed, and ST was measured using a calliper followed by data analysis. Results showed that SW and ST were related to BW [log SW = 0.969 × logBW - 0636, adjust. R2 : 0.975]. The BW increased with increasing skin dermal thickness (y = 0.3916x + 1.5253, adjust. R2 : 0.6921), slightly with epidermal thickness (y = 0.2495x + 0.3984, adjust. R2 : 0.3402), but not all with the thickness of subcutaneous tissues (y = 0.1454x + 2.2437, adjust. R2 : 0.0752). The ratio of SW to BW (SW/BW) distributed over a large range from 0.06 to 0.64 values and varied among animal taxonomic orders and their dwelling habitats. Close relationship of BW to SW/BW was observed in species weighing ≥200 g but not in species weighing <200 g. In conclusion, SW and ST in mammals are determined by BW. The SW/BW varies based on BW, taxonomic orders and habitat and is large in small mammals weighing ≥200 g to provide a mechanism used for survival strategy.

Three types of university students with subthreshold depression characterized by distinctive cognitive behavioral skills.

Subthreshold depression impairs young people's quality of life and places them at greater risk of developing major depression. Cognitive behavioral therapy (CBT) is an evidence-based approach for addressing such depressive states. This study identified subtypes of university students with subthreshold depression and revealed discrete profiles of five CBT skills: self-monitoring, cognitive restructuring, behavioral activation, assertive communication, and problem solving. Using data from the Healthy Campus Trial (registration number: UMINCTR-000031307), a hierarchical clustering analysis categorized 1,080 students into three clusters: Reflective Low-skilled, Non-reflective High-skilled, and Non-reflective Low-skilled students. Non-reflective Low-skilled students were significantly more depressed than other students (p < .001). The severity of depression seemed to be related to the combination of self-monitoring skills and other CBT skills. Considering the high prevalence of poor self-monitoring skills in persons with autism, the most severe depression was observed in the significant association between Non-reflective Low-skilled students and autistic traits (p = .008). These findings suggest that subthreshold depression can be categorized into three subtypes based on CBT skill profiles. The assessment of autistic traits is also suggested when we provide CBT interventions for Non-reflective Low-skilled students.

Axillary cutaneous metastasis of colon cancer with microsatellite instability-high and BRAF V600E mutation treated with curative-intent surgery: a case report.

BACKGROUND: Colorectal cancer (CRC) metastasizes to various organs, while cutaneous metastases are rare. Although there have been several previous reports of axillary cutaneous metastases with other metastases of CRC, there has never been a report of axillary cutaneous metastasis of CRC that could be treated with curative-intent surgery. CASE PRESENTATION: A 68-year-old female was diagnosed with an axillary cutaneous tumor and ascending colon cancer with invasion to the duodenum. Histopathological and immunohistochemical analysis revealed that the axillary cutaneous tumor showed adenocarcinoma and the same expression pattern for cytokeratin 7, cytokeratin 20, and CDX2 as the ascending colon cancer, and that proved to be KRAS-NRAS wild type, MSI-H, and with a BRAF V600E mutation. The patient underwent a two-stage resection with curative intent after receiving neoadjuvant chemotherapy which consisted of one cycle of modified FOLFOX6 followed by two cycles of FOLFOXIRI. During and after the two operations, the patient received a total of nine cycles of modified FOLFOX6 as adjuvant chemotherapy. Two years after the initial surgery, and 1 year and 8 months after the second surgery, the patient is alive without recurrence. CONCLUSIONS: To the best of our knowledge, this is the first report of axillary cutaneous metastasis of CRC with microsatellite instability-high and BRAF V600E mutation that could be treated with curative-intent surgery. It is important to recognize the presence of such cases for the accurate diagnosis and treatment of CRC with cutaneous metastasis.

Oral Administration of Glucosylceramide Suppresses Tumor Growth by Affecting the Ceramide/Sphingosine-1-Phosphate Balance in Breast Cancer Tissue.

Background: Ceramide and sphingosine-1-phosphate (S1P) play opposing roles in cell death and survival, and maintain a dynamic balance called the sphingolipid rheostat. Glucosylceramide is a substrate to generate ceramide but its effect on breast cancer by oral administration was never tested. The purpose of this study was to reveal the anticancer activity of glucosylceramide and its potential as a new therapeutic agent in breast cancer. Methods: E0771 cells were inoculated into the breast tissue of female C57BL/6NJcl mice. Glucosylceramide was administered orally to the mice for nine consecutive days. The concentrations of sphingolipid mediators including ceramide, glucosylceramide, and S1P in tumor tissues and serum were determined by mass spectrometry. Results: Oral administration of glucosylceramide significantly suppressed E0771 tumor growth compared with the control group (P = 0.006). There were no significant differences in the serum concentrations of sphingolipid mediators including ceramide and S1P between the mice treated with glucosylceramide and control-treated mice. The ceramide concentration was significantly lower in tumor tissues (P = 0.026), and the S1P concentration was significantly higher than that in paired non-tumor tissues (P = 0.009). The S1P concentration in tumor tissues was significantly lower in mice treated with glucosylceramide than in control-treated mice (P = 0.001). The ceramide-to-S1P concentration ratio in tumor tissues was significantly higher in mice treated with glucosylceramide than in control-treated mice (P = 0.034). Conclusions: Breast tumors could enhance their survival by increasing S1P conversion from ceramide. Oral administration of glucosylceramide suppressed tumor growth by affecting the ceramide/S1P balance. Oral administration of glucosylceramide is a promising basis for a new therapeutic approach.

Extent of regional lymphadenectomy and number-based nodal classification for non-ampullary duodenal adenocarcinoma.

BACKGROUND: This study aimed to evaluate the adequate extent of regional lymphadenectomy according to tumor location and the impact of number-based nodal classification on survival in patients with non-ampullary duodenal adenocarcinoma (NADAC). METHODS: A total of 85 patients with NADAC who underwent surgery were enrolled. The frequency of metastasis was calculated for each node group in the respective tumor locations for 63 patients who underwent lymphadenectomy for pT2-pT4 tumor. RESULTS: The frequency of metastasis in the pancreaticoduodenal (nos. 13 and 17) and superior mesenteric artery (no. 14) nodes was high (16.7 %-52.3 %) regardless of tumor location. Metastasis in the perigastric (nos. 3 and 4d) and right celiac artery (no. 9) nodes was not uncommon (14.3 %-22.2 %) for tumors in the first portion. The frequency of metastasis in the pyloric (nos. 5 and 6) and the other peripancreaticoduodenal (nos. 8 and 12) nodes varied depending on tumor location but could not be ignored for staging. When these nodes were classified as regional nodes, the 5-year survival in patients with pN0, pN1 (1-2 positive nodes), and pN2 (≥3 positive nodes) were 82.9 %, 51.7 %, and 19.2 %, respectively (p < 0.001). pN classification independently predicted survival (pN1, p = 0.022; pN2, p < 0.001). CONCLUSIONS: Nos. 5, 6, 8, 12, 13, 14, and 17 nodes in all advanced NADAC and nos. 3, 4d, and 9 nodes in advanced NADAC in the first portion should be considered as regional nodes for accurate staging. The number-based nodal classification allows good patients' prognostic stratification.

Clinical Significance of Phosphorylated Sphingosine Kinase 1 Expression in Pancreatic Ductal Adenocarcinoma.

BACKGROUND/AIM: Sphingosine-1-phosphate (S1P) is a pleiotropic, bioactive, lipid mediator, produced by sphingosine kinase 1 (SphK1). In this study, we evaluated the expression of phosphorylated SphK1 (pSphK1) in patients with pancreatic ductal adenocarcinoma (PDAC) and investigated its clinical significance. MATERIALS AND METHODS: A total of 111 patients who underwent curative-intent resection for PDAC were enrolled. We investigated pSphK1 (Ser-225) expression in surgically resected specimens of PDAC using immunohistochemistry. The patients were divided into two groups according to pSphK1 immunoreactive expression: a pSphK1-high group (n=63) and a pSphK1-low group (n=48). RESULTS: Logistic regression analyses revealed that lymphatic invasion (p=0.007) was a significantly independent factor associated with high pSphK1 immunoreactive expression. The pSphK1-high group showed significantly worse disease-specific survival (DSS) than the pSphK1-low group (5-year DSS rate, 19.6% vs. 58.7%; p=0.001). High pSphK1 immunoreactive expression (hazard ratio=2.547; 95% confidence interval= 1.434-4.527; p=0.001) was an independent prognostic factor for DSS. CONCLUSION: High pSphK1 expression is independently associated with lymphatic invasion and unfavorable prognosis in PDAC patients. Thus, the SphK1-S1P axis may be important in mechanisms of tumor progression, such as lymphatic invasion, in PDAC patients.