Therapeutic effect of mesenchymal stem cells in an animal model of Alzheimer's disease evaluated by ß-amyloid positron emission tomography imaging.

OBJECTIVE: We evaluated the effects of bone marrow-derived mesenchymal stem cells in a model of Alzheimer's disease using serial [18F]Florbetaben positron emission tomography. METHODS: 3xTg Alzheimer's disease mice were treated with intravenously injected bone marrow-derived mesenchymal stem cells, and animals without stem cell therapy were used as controls. Serial [18F]Florbetaben positron emission tomography was performed after therapy. The standardized uptake value ratio was measured as the cortex standardized uptake value divided by the cerebellum standardized uptake value. Memory function and histological changes were observed using the Barnes maze test and ß-amyloid-reactive cells. RESULTS: Standardized uptake value ratio decreased significantly from day 14 after stem cell administration in the bone marrow-derived mesenchymal stem cells-treated group (n = 28). In contrast, there was no change in the ratio in control mice (n = 25) at any time point. In addition, mice that received bone marrow-derived mesenchymal stem cell therapy also exhibited significantly better memory function and less ß-amyloid-immunopositive plaques compared to controls. CONCLUSION: The therapeutic effect of intravenously injected bone marrow-derived mesenchymal stem cells in a mouse model of Alzheimer's disease was confirmed by ß-amyloid positron emission tomography imaging, memory functional studies and histopathological evaluation.

Abrogation of B-RafV600E induced senescence by FoxM1 expression.

B-RafV600E oncogene mutation occurs in various cancers and is associated with tumor initiation. However, genetic modification of B-RafV600E in cells induces MAPK activation and results in oncogene-induced senescence. Overcoming the oncogene-induced senescence by B-RafV600E requires activation of another oncogene pathway, such as AKT signaling. In the present study, we explored the factors involved in overcoming the senescence program in cells activated by B-RafV600E and AKT signaling. B-RafV600E activation caused a feedback inhibition of AKT phosphorylation and resulted in downregulation of FoxM1, one of the AKT downstream components. AKT activation by PTEN downregulation induced FoxM1 expression, and co-expression of B-RafV600E and FoxM1 overcame the cellular senescence. These observations suggested that FoxM1 is critical downstream gene of AKT and functions to overcome B-RafV600E-induced senescence.

Genomic Common Data Model for Seamless Interoperation of Biomedical Data in Clinical Practice: Retrospective Study.

BACKGROUND: Clinical sequencing data should be shared in order to achieve the sufficient scale and diversity required to provide strong evidence for improving patient care. A distributed research network allows researchers to share this evidence rather than the patient-level data across centers, thereby avoiding privacy issues. The Observational Medical Outcomes Partnership (OMOP) common data model (CDM) used in distributed research networks has low coverage of sequencing data and does not reflect the latest trends of precision medicine. OBJECTIVE: The aim of this study was to develop and evaluate the feasibility of a genomic CDM (G-CDM), as an extension of the OMOP-CDM, for application of genomic data in clinical practice. METHODS: Existing genomic data models and sequencing reports were reviewed to extend the OMOP-CDM to cover genomic data. The Human Genome Organisation Gene Nomenclature Committee and Human Genome Variation Society nomenclature were adopted to standardize the terminology in the model. Sequencing data of 114 and 1060 patients with lung cancer were obtained from the Ajou University School of Medicine database of Ajou University Hospital and The Cancer Genome Atlas, respectively, which were transformed to a format appropriate for the G-CDM. The data were compared with respect to gene name, variant type, and actionable mutations. RESULTS: The G-CDM was extended into four tables linked to tables of the OMOP-CDM. Upon comparison with The Cancer Genome Atlas data, a clinically actionable mutation, p.Leu858Arg, in the EGFR gene was 6.64 times more frequent in the Ajou University School of Medicine database, while the p.Gly12Xaa mutation in the KRAS gene was 2.02 times more frequent in The Cancer Genome Atlas dataset. The data-exploring tool GeneProfiler was further developed to conduct descriptive analyses automatically using the G-CDM, which provides the proportions of genes, variant types, and actionable mutations. GeneProfiler also allows for querying the specific gene name and Human Genome Variation Society nomenclature to calculate the proportion of patients with a given mutation. CONCLUSIONS: We developed the G-CDM for effective integration of genomic data with standardized clinical data, allowing for data sharing across institutes. The feasibility of the G-CDM was validated by assessing the differences in data characteristics between two different genomic databases through the proposed data-exploring tool GeneProfiler. The G-CDM may facilitate analyses of interoperating clinical and genomic datasets across multiple institutions, minimizing privacy issues and enabling researchers to better understand the characteristics of patients and promote personalized medicine in clinical practice.

Erythrocyte Fraction Within Retrieved Thrombi Contributes to Thrombolytic Response in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Recent advent of endovascular thrombectomy (EVT) enables us to provide a new perspective on the use of tPA (tissue-type plasminogen activator) through histological analysis of retrieved thrombus. We investigated the responsiveness of intravenous thrombolysis (IVT) according to the thrombus composition in EVT-attempted patients with acute ischemic stroke. METHODS: We reviewed 92 consecutive patients with anterior circulation stroke who received combined IVT and EVT for 2 years. IVT responsiveness is defined as any decrease in the clot burden from baseline computed tomographic angiography to digital subtraction angiography during EVT. We histologically analyzed the relative fractions of red blood cells (RBCs), congregated fibrin and platelets, and white blood cells in the retrieved thrombi using semiautomated color-based segmentation method. Clinical characteristics according to the RBC fraction were investigated, and associated factors with IVT responsiveness were explored. RESULTS: Fifty-two patients with histological analyses were stratified into lowest, middle, and highest tertiles of RBC fraction. Toward higher RBC fraction, there was more common susceptibility vessel signs on magnetic resonance imaging (50.0% versus 66.7% versus 91.7%; P=0.022) and prevalent IVT responsiveness (25.0% versus 41.7% versus 75.0%; P=0.010). IVT-responsive group (n=23) had higher RBC fraction (45.7±15.5% versus 35.9±12.2%; P=0.010), lower fibrin and platelet (50.4±14.0% versus 58.5±11.1%; P=0.027), and lower white blood cells fraction (3.9±2.1% versus 5.5±3.0%; P=0.027) than IVT-unresponsive group (n=29). After adjusting for potential variables, RBC fraction (odds ratio, 1.05; 95% confidence interval, 1.01-1.10) remained only independent determinant of IVT responsiveness. CONCLUSIONS: In EVT-attempted patients with acute ischemic stroke, IVT responsiveness would be closely associated with RBC fraction.

Improved dopamine transporter binding activity after bone marrow mesenchymal stem cell transplantation in a rat model of Parkinson's disease: small animal positron emission tomography study with F-18 FP-CIT.

OBJECTIVES: We evaluated the effects of bone marrow-derived mesenchymal stem cells (BMSCs) in a model of Parkinson's disease (PD) using serial F-18 fluoropropylcarbomethoxyiodophenylnortropane (FP-CIT) PET. METHODS: Hemiparkinsonian rats were treated with intravenously injected BMSCs, and animals without stem cell therapy were used as the controls. Serial FP-CIT PET was performed after therapy. The ratio of FP-CIT uptake in the lesion side to uptake in the normal side was measured. The changes in FP-CIT uptake were also analyzed using SPM. Behavioural and histological changes were observed using the rotational test and tyrosine hydroxylase (TH)-reactive cells. RESULTS: FP-CIT uptake ratio was significantly different in the BMSCs treated group (n = 28) at each time point. In contrast, there was no difference in the ratio in control rats (n = 25) at any time point. SPM analysis also revealed that dopamine transporter binding activity was enhanced in the right basal ganglia area in only the BMSC therapy group. In addition, rats that received BMSC therapy also exhibited significantly improved rotational behaviour and preservation of TH-positive neurons compared to controls. CONCLUSIONS: The therapeutic effect of intravenously injected BMSCs in a rat model of PD was confirmed by dopamine transporter PET imaging, rotational functional studies, and histopathological evaluation. KEY POINTS: • Mesenchymal stem cells were intravenously injected to treat the PD rats • Dopamine transporter binding activity was improved after stem cell therapy • Stem cell therapy induced functional recovery and preservation of dopaminergic neurons • The effect of stem cells was confirmed by FP-CIT PET.

Esophageal stricture induced by an ultraslim upper endoscope in a novel rabbit model of corrosive injury.

OBJECTIVE: Benign esophageal strictures are regularly encountered problems in clinical practice. The management of refractory benign esophageal stricture, which fails to establish adequate food passage despite multiple dilatation sessions, has been considered challenging. Experimental animal models are essential for the development of effective treatment methods. The aim of this study was to establish a new animal model of benign esophageal stricture using rabbits. MATERIAL AND METHODS: Corrosive injury of the esophagus was induced by administration of 1 ml of 1.5% sodium hydroxide in eight rabbits using an ultraslim upper endoscope equipped with a 5-Fr polytetrafluoroethylene tube and 5-Fr balloon catheter. Two weeks after corrosive injury, endoscopic examination was performed to confirm the state of the injury site. Four weeks after corrosive injury, the esophageal stricture was assessed by endoscopy and esophagography. All animals were then euthanized. RESULTS: Two weeks after corrosive injury, endoscopic examination showed that ulceration had been induced. Four weeks after corrosive injury, endoscopic, radiologic and gross examinations showed that esophageal stricture had been induced without complications in all animals. The esophageal lumen diameter was reduced by an average of 51.8% (range, 48.3%-57.2%), and the mean stricture length was 25.7 mm (range, 20.1-29.3 mm). Microscopic examination revealed focal ulceration and submucosal thickening secondary to fibrosis. CONCLUSIONS: Rabbit esophageal stricture induced by endoscopic delivery of a small amount of low-concentration sodium hydroxide is a relatively simple, safe, and reproducible animal model. This model may be useful in the development of new treatment methods for esophageal stricture.

Cellular senescence is associated with the spatial evolution toward a higher metastatic phenotype in colorectal cancer.

In this study, we explore the dynamic process of colorectal cancer progression, emphasizing the evolution toward a more metastatic phenotype. The term "evolution" as used in this study specifically denotes the phenotypic transition toward a higher metastatic potency from well-formed glandular structures to collective invasion, ultimately resulting in the development of cancer cell buddings at the invasive front. Our findings highlight the spatial correlation of this evolution with tumor cell senescence, revealing distinct types of senescent tumor cells (types I and II) that play different roles in the overall cancer progression. Type I senescent tumor cells (p16INK4A+/CXCL12+/LAMC2-/MMP7-) are identified in the collective invasion region, whereas type II senescent tumor cells (p16INK4A+/CXCL12+/LAMC2+/MMP7+), representing the final evolved form, are prominently located in the partial-EMT region. Importantly, type II senescent tumor cells associate with local invasion and lymph node metastasis in colorectal cancer, potentially affecting patient prognosis.

C-terminus-deleted FoxM1 is expressed in cancer cell lines and induces chromosome instability.

Forkhead Box M1 (FoxM1) protein is a transcription factor and regulates cell cycle. It is commonly upregulated in human cancer tissue and correlated with poor prognosis, suggesting that the overexpression of FoxM1 plays a critical role in carcinogenesis. In this study, we report the identification and characterization of a new variant of FoxM1, which was first isolated from our laboratory in hepatoma cell lines. Compared with wild-type FoxM1, the new variant lacks of C-terminus of FoxM1 (FoxM1ΔC), which is a transactivation domain. Reverse transcription-polymerase chain reaction and western blot analysis demonstrated that FoxM1ΔC was highly expressed in a variety of cancer cell lines such as HepG2, HeLa, A549, MB231, EJ, U2OS, Hep3B and MCF7, but not expressed in normal human dermal fibroblast (HDF). Immunoprecipitation assay revealed that FoxM1ΔC interacted with wild-type FoxM1. Furthermore, FoxM1ΔC bound to FoxM1 targeted gene promoter region and correlated with dysregulation of wild-type FoxM1. FoxM1ΔC delayed G2/M to G1 progression of cell cycle, decreased Aurora B(T232) phosphorylation and increased chromosome centromere interspace. Finally, FoxM1ΔC induced instability of chromosome and formation of aneuploid cells within 1 month when expressed in HDF. In conclusion, FoxM1ΔC is expressed in cancer cells and dysregulates normal cell cycle and induces chromosome instability.

Valproic acid sensitizes TRAIL-resistant anaplastic thyroid carcinoma cells to apoptotic cell death.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is an aggressive human tumor associated with a median survival of 2-6 months. TRAIL, as a ligand of death receptors, is known to induce apoptotic cell death in several cancer cells. However, TRAIL treatment alone is not effective against TRAIL-resistant cancer cells. This study was designed to investigate whether valproic acid (VPA) enhances apoptotic cell death of TRAIL-resistant ATC cells and to identify the mechanism of cell death of ATC cells by combination treatment with VPA and TRAIL. METHODS: To evaluate the cytotoxic effect of TRAIL and/or VPA on ATC cells, we used the MTT assay. The effects of VPA and TRAIL on apoptosis were assessed using FACS analysis (Annexin-V/PI stain) and Western blotting. RESULTS: The combination of VPA with TRAIL significantly induced apoptotic cell death compared with 8505C and ARO cells treated with TRAIL alone. The protein levels of cleaved caspase-8, -3, and PARP were increased in VPA and TRAIL co-treated ARO cells. The combination induced the activation of JNK and the phosphorylation of FADD and c-Jun but not p38. However, pretreatment with caspase inhibitors reduced the expression of cleaved caspase-8, -3, and PARP in co-treated ARO cells. SP600125 remarkably reduced the expression of cleaved caspase-8, -3, and PARP and the phosphorylation of FADD and c-Jun, as well as apoptotic cell death. CONCLUSIONS: VPA sensitized TRAIL-resistant ATC cells to apoptotic cell death through involvement of the JNK pathway. Thus, the combination of VPA and TRAIL may be a promising therapy for ATC.

Gankyrin is frequently overexpressed in breast cancer and is associated with ErbB2 expression.

Gankyrin is a subunit of the 26S proteasome, and has been known to degrade p53 and retinoblastoma protein and promote the tumorigenicity and metastasis in some malignancies. However, the role of gankyrin in breast cancer has not been explored. In this study, we investigated the expression of gankyrin in breast cancer and evaluated its effect on breast cancer. Representative cancer tissues including normal breasts from 60 patients with breast cancer were stained immunohistochemically for gankyrin, estrogen receptor, progesterone receptor, and ErbB2. We evaluated the relationship between gankyrin expression and clinicopathologic parameters or prognostic markers. We also attempted to clarify the mechanism of gankyrin involved in breast carcinogenesis by using MCF7 breast cancer cells. Gankyrin was weakly expressed in normal breast epithelial cells, however, tumor regions of 37/60 (61.7%) cases showed an overexpression of gankyrin. Gankyrin overexpression was associated with extensive intraductal carcinoma (p=0.014) and ErbB2 positivity (p=0.031) in invasive ductal carcinoma. In MCF7 breast cancer cells, downregulation of gankyrin was associated with a reduction of cell proliferation and tumorigenicity. In conclusion, gankyrin was identified in normal breasts and overexpressed in invasive breast cancers. The overexpression of gankyrin was associated with extensive intraductal carcinoma and ErbB2 expression in breast cancer.

Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats.

Tofacitinib, an inhibitor of Janus kinases (JAKs) 1 and 3, has been shown to be effective in the treatment of rheumatoid arthritis. The incidence of hyperlipidemia has been found to be higher in patients with rheumatoid arthritis. The present study therefore investigated the pharmacokinetics of tofacitinib after its intravenous (10 mg/kg) or oral (20 mg/kg) administration in poloxamer-407-induced hyperlipidemic (PHL) rats. The area under the plasma concentration-time curve from zero to infinity (AUC0-∞) after intravenous administration of tofacitinib was 73.5% higher in PHL than in control rats, owing to slower time-averaged nonrenal clearance (CLNR) in the former. Evaluation of in vitro metabolism showed that the intrinsic clearance (CLint) of tofacitinib was 38.6% lower in PHL than in control rats, owing to the decreased protein expression of hepatic cytochrome P450 (CYP) 3A1/2 and CYP2C11 in PHL rats. Similar results were observed in PHL rats after oral administration of tofacitinib. These results were likely due to the decreased CLNR, CLint, and P-glycoprotein (P-gp) expression in the intestines of PHL compared to control rats. Overall, these findings indicated that hyperlipidemia slowed the metabolism of tofacitinib, increasing its plasma concentrations, and that this reduced metabolism was due to alterations in expression of the proteins CYP3A1/2, CYP2C11, and P-gp in the liver and/or intestines of PHL rats.

p15INK4B is an alternative marker of senescent tumor cells in colorectal cancer.

Senescent tumor cells are nonproliferating tumor cells which are closely related to cancer progression by secreting senescence-related molecules, called senescence-associated secreting phenotypes. Therefore, the presence of senescent tumor cells is considered a prognostic factor in various cancer types. Although senescence-associated ß-galactosidase staining is considered the best marker for detection of senescent tumor cells, it can only be performed in fresh-frozen tissues. p16INK4A, a cyclin-dependent inhibitor, has been used as an alternative marker to detect senescent tumor cells in formalin-fixed paraffin-embedded tissues. However, other reliable markers to detect senescent tumor cells is still lacking. In the present study, using public single-cell RNA-sequencing data, we found that p15INK4B, a cyclin-dependent kinase inhibitor, is a novel marker for detection of senescent tumor cells. Moreover, p15INK4B expression was positively correlated with that of p16INK4A in colorectal cancer tissues. In in vitro studies, mRNA expression of p15INK4B was increased together with that of p16INK4A in H2O2- and therapy-induced cancer senescence models. However, the mRNA level of p15INK4B did not increase in the oncogene-induced senescence model in primary colonic epithelial cells. In conclusion, p15INK4B is a potential alternative marker for detection of senescent tumor cells together with conventional markers in advanced stages of colorectal cancer.

Senescent tumor cells in colorectal cancer are characterized by elevated enzymatic activity of complexes 1 and 2 in oxidative phosphorylation.

BACKGROUND: Cellular senescence is defined as an irreversible cell cycle arrest caused by various internal and external insults. While the metabolic dysfunction of senescent cells in normal tissue is relatively well-established, there is a lack of information regarding the metabolic features of senescent tumor cells. METHODS: Publicly available single-cell RNA-sequencing data from the GSE166555 and GSE178341 datasets were utilized to investigate the metabolic features of senescent tumor cells. To validate the single-cell RNA-sequencing data, we performed senescence-associated ß-galactosidase (SA-ß-Gal) staining to identify senescent tumor cells in fresh frozen colorectal cancer tissue. We also evaluated nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase (NADH-TR) and succinate dehydrogenase (SDH) activity using enzyme histochemical methods and compared the staining with SA-ß-Gal staining. MTT assay was performed to reveal the complex 1 activity of the respiratory chain in in-vitro senescence model. RESULTS: Single-cell RNA-sequencing data revealed an upregulation in the activity of complexes 1 and 2 in oxidative phosphorylation, despite overall mitochondrial dysfunction in senescent tumor cells. Both SA-ß-Gal and enzyme histochemical staining using fresh frozen colorectal cancer tissues indicated a high correlation between SA-ß-Gal positivity and NADH-TR/SDH staining positivity. MTT assay showed that senescent colorectal cancer cells exhibit higher absorbance in 600 nm wavelength. CONCLUSIONS: Senescent tumor cells exhibit distinct metabolic features, characterized by upregulation of complexes 1 and 2 in the oxidative phosphorylation pathway. NADH-TR and SDH staining represent efficient methods for detecting senescent tumor cells in colorectal cancer.

Mid-old cells are a potential target for anti-aging interventions in the elderly.

The biological process of aging is thought to result in part from accumulation of senescent cells in organs. However, the present study identified a subset of fibroblasts and smooth muscle cells which are the major constituents of organ stroma neither proliferative nor senescent in tissues of the elderly, which we termed "mid-old status" cells. Upregulation of pro-inflammatory genes (IL1B and SAA1) and downregulation of anti-inflammatory genes (SLIT2 and CXCL12) were detected in mid-old cells. In the stroma, SAA1 promotes development of the inflammatory microenvironment via upregulation of MMP9, which decreases the stability of epithelial cells present on the basement membrane, decreasing epithelial cell function. Remarkably, the microenvironmental change and the functional decline of mid-old cells could be reversed by a young cell-originated protein, SLIT2. Our data identify functional reversion of mid-old cells as a potential method to prevent or ameliorate aspects of aging-related tissue dysfunction.

Helicobacter pylori infection as an independent prognostic factor for locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection.

A few studies reported the association between negative Helicobacter pylori infection and poor clinical outcome in resected gastric cancer patients. We investigated the H. pylori infection status and its association with the clinical outcome in 274 locally advanced gastric cancer patients (American Joint Committee on Cancer stage IB: 25, II: 82, IIIA: 80, IIIB: 39 and IV: 48) who underwent adjuvant chemotherapy after curative resection (≥ D2 dissection). H. pylori infection status in hematoxylin and eosin stained corporal and antral mucosa of non-tumor tissue was graded according to the updated Sydney System and categorized as H. pylori negative (normal or mild infection) and H. pylori positive (moderate or marked infection). Eighty-one patients received 5-fluorouracil (5-FU) and doxorubicin-based chemotherapy, while 193 patients underwent 5-FU, mitomycin-C and polysaccharide-K chemotherapy. The median follow-up duration of survivors was 144 (120-184) months. In univariate analysis, patients with H. pylori negative status (108 patients) demonstrated significantly poor 10-year overall survival (OS) compared to those with H. pylori-positive status (166 patients; 21.3% vs. 71.1%, p < 0.0001). H. pylori negative status was associated with poor outcome in all stages except stage IIIB. In multivariate analysis, H. pylori-negative status was the most significant independent prognostic factor of poor OS (hazard ratio: 3.45, 95% confidence interval: 2.43-4.89, p < 0.0001) followed by old age (>54 years, p < 0.0001), advanced stage (stage III or IV, p = 0.001), and Borrmann type IV (p = 0.027). H. pylori infection status seems to have strong prognostic significance in locally advanced gastric cancer. H. pylori-negative patients may need careful follow-up after curative resection.

Good interobserver and intraobserver agreement in the evaluation of the new ILAE classification of focal cortical dysplasias.

PURPOSE: An International League Against Epilepsy (ILAE) consensus classification system for focal cortical dysplasias (FCDs) has been published in 2011 specifying clinicopathologic FCD variants. The aim of the present work was to microscopically assess interobserver agreement and intraobserver reproducibility for FCD categories among an international group of neuropathologists with different levels of experience and access to epilepsy surgery tissue. METHODS: Surgical FCD specimens covering a broad histopathology spectrum were retrieved from 22 patients with epilepsy. Three surgical nonepilepsy specimens served as controls. A total of 188 slides with routine or immunohistochemical stainings were digitalized with a slide scanner to allow Internet-based microscopy review. Nine experienced neuropathologists were invited to review these cases twice at a time gap of 3 months and different orders of case presentation. The 2011 ILAE FCD consensus classification served as instruction. Kappa analysis was calculated to estimate interobserver and intraobserver agreement levels. In a third evaluation round, 21 additional neuropathologists with different experience and access to epilepsy surgery reviewed the same case series. KEY FINDINGS: Interobserver agreement was good (κ = 0.6360), with 84% consensus of diagnoses during the first evaluation (21 of 25 cases). Kappa values increased to 0.6532 after reevaluation, and consensus was obtained in 24 (96%) of 25 cases. Overall intraobserver reproducibility was also good (κ = 0.7824, ranging from 0.4991 to 1.000). Fewest changes in the classification were made in the FCD type II group (2.2% of 225 original diagnoses), whereas the majority of changes occurred in FCD type III (13.7% of 225 original diagnoses). In the third evaluation round, interobserver agreement was reflected by the level of experience of each neuropathologist, with κ values ranging from moderate (0.5056; high level of experience >40 cases/year) to low (0.3265; low level of experience <10 cases/year). SIGNIFICANCE: Our study achieved a good and reliable interobserver agreement among the group of expert neuropathologists originally involved in the ILAE FCD consensus classification system. Intraobserver reproducibility in this group was even more robust. These results showed considerable improvement compared to a previous study evaluating the 2004 Palmini FCD classification. Agreement levels were lower in our second group of neuropathologists and were related to their level of access and experience with epilepsy surgery specimens. These results suggested that the more precise ILAE definition of FCD histopathology patterns improves operational procedures in the diagnosis of FCDs. On the other hand, microscopic assessment of FCD is a challenge and requires sustained experience and teaching. The virtual slide review system allowed testing of this hypothesis and reached a widespread group of participating colleagues from different centers all over the world. We propose to further use this tool as a teaching device and also to address other epilepsy-associated entities still difficult to classify such as hippocampal sclerosis, long-term epilepsy-associated tumors, or mild malformations of cortical development (mMCDs), which were not yet covered by current ILAE classification systems.

Bax predicts outcome in gastric cancer patients treated with 5-fluorouracil, leucovorin, and oxaliplatin palliative chemotherapy.

BACKGROUND: Platinum and 5-fluorouracil (5-FU)-based regimens have been used the most frequently in palliative chemotherapy for gastric cancer. The present study evaluated the prognostic significance of Bax, excision repair cross-complementation group 1 (ERCC1), and thymidylate synthase (TS) in advanced gastric cancer patients treated with 5-FU, leucovorin, and oxaliplatin (FOLFOX) palliative chemotherapy. METHODS: Seventy-two patients with metastatic or recurrent gastric cancer were treated with FOLFOX regimen. Pretreatment tumor biopsy specimens were analyzed for Bax, ERCC1, and TS expression by immunohistochemistry. RESULTS: High expression of Bax, ERCC1, and TS was observed in 31 (43%), 33 (46%), and 35 (49%) patients, respectively. The median overall survival (OS) of patients was 12 months. Low expression of Bax was associated with poor OS (median, 9 months vs. 18 months; 2-year, 10% vs. 48%; p=0.0005) in univariate analysis, while expression of ERCC1 and TS was not correlated with patient outcome. In multivariate analysis, low expression of Bax was a significant independent predictor of poor OS (p=0.028). Low expression of Bax was significantly associated with poor survival of patients with metastatic or recurrent gastric cancer treated with FOLFOX chemotherapy. CONCLUSIONS: Immunohistochemical staining for Bax with pretreatment biopsy specimen may be useful in selecting FOLFOX regimen as a treatment option for advanced gastric cancer patients.

Role of corticotrophin-releasing factor in the stress-induced dilation of esophageal intercellular spaces.

Corticotrophin-releasing factor (CRF) plays a major role in coordinating stress responses. We aimed to test whether blocking endogenous CRF activity can prevent the stress-induced dilation of intercellular spaces in esophageal mucosa. Eighteen adult male rats were divided into 3 groups: 1) a non-stressed group (the non-stressed group), 2) a saline-pretreated stressed group (the stressed group), 3) and an astressin-pretreated stressed group (the astressin group). Immediately after completing the experiments according to the protocol, distal esophageal segments were obtained. Intercellular space diameters of esophageal mucosa were measured by transmission electron microscopy. Blood was sampled for the measurement of plasma cortisol levels. Mucosal intercellular spaces were significantly greater in the stressed group than in the non-stressed group. Mucosal intercellular spaces of the astressin group were significantly smaller than those of the stressed group. Plasma cortisol levels in the stressed group were significantly higher than in the non-stressed group. Pretreatment with astressin tended to decrease plasma cortisol levels. Acute stress in rats enlarges esophageal intercellular spaces, and this stress-induced alteration appears to be mediated by CRF. Our results suggest that CRF may play a role in the pathophysiology of reflux-induced symptoms or mucosal damage.

Senescent tumor cells: an overlooked adversary in the battle against cancer.

Senescent cells in cancer tissue, including senescent fibroblasts and macrophages, have been reported to increase the malignant potency of cancer cells by secreting senescence-associated secretory phenotype (SASP). Otherwise, Senescence of tumor cells has been believed to inhibit tumor growth by halting the massive proliferation and increasing the chances of immune clearance. In particular, senescent tumor cells (STCs) have been thought that they rarely exist in carcinomas because oncogene-induced senescence needs to be overcome for protumorigenic cells to become malignant. However, recent studies have revealed that a considerable number of STCs are present in cancer tissue, even in metastatic sites. In fact, STCs are widely involved in cancer progression by leading to collective invasion and building a cytokine barrier to protect nonsenescent tumor cells from immune attack. Furthermore, therapy-induced STCs can induce tumor progression and recurrence by increasing stemness. However, obscure causative factors and their heterogeneity in various cancers make it difficult to establish the physiological role of STCs. Here, we summarize and review the current knowledge of the pathophysiology and role of STCs. We also outline the current status of therapeutic strategies for directly removing STCs or modulating the SASPs to maximize the positive functions of STCs while suppressing the negative functions.

Correlation Between 18F-FDG Uptake and Immune Cell Infiltration in Metastatic Brain Lesions.

BACKGROUND: The purpose of this study was to investigate the correlation between 18F-fluorodeoxyglucose (FDG) uptake and infiltrating immune cells in metastatic brain lesions. METHODS: This retrospective study included 34 patients with metastatic brain lesions who underwent brain 18F-FDG positron emission tomography (PET)/computed tomography (CT) followed by surgery. 18F-FDG uptake ratio was calculated by dividing the standardized uptake value (SUV) of the metastatic brain lesion by the contralateral normal white matter uptake value. We investigated the clinicopathological characteristics of the patients and analyzed the correlation between 18F-FDG uptake and infiltration of various immune cells. In addition, we evaluated immune-expression levels of glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and Ki-67 in metastatic brain lesions. RESULTS: The degree of 18F-FDG uptake of metastatic brain lesions was not significantly correlated with clinical parameters. There was no significant relationship between the 18F-FDG uptake and degree of immune cell infiltration in brain metastasis. Furthermore, other markers, such as GLUT1, HK2, and Ki-67, were not correlated with degree of 18F-FDG uptake. In metastatic brain lesions that originated from breast cancer, a higher degree of 18F-FDG uptake was observed in those with high expression of CD68. CONCLUSIONS: In metastatic brain lesions, the degree of 18F-FDG uptake was not significantly associated with infiltration of immune cells. The 18F-FDG uptake of metastatic brain lesions from breast cancer, however, might be associated with macrophage activity.