[Therapeutic Effect of Oncolytic Adenovirus on Pancreatic Cancer Stroma].

Pancreatic ductal adenocarcinoma(PDAC)is lethal malignancy with abundant stroma. Cancer-associated fibroblasts (CAFs) exist in the PDAC stroma and contribute to progression of malignant transformation, treatment resistance, and recurrence. However, effective treatment to control PDAC stroma has not been established. We have developed tumor suppressor gene p53-armed oncolytic adenovirus(OBP-702), and have clarified therapeutic effects on PDAC cells. In this study, we investigate the therapeutic effect of OBP-702 on PDAC CAF.

Multiple Hepatolithiasis Following Hepaticojejunostomy Successfully Treated with Left Hemihepatectomy and Double Hepaticojejunostomy Reconstruction.

Surgical intervention for hepatolithiasis following hepaticojejunostomy (HJ) has rarely been reported. Herein, we present a case of post-HJ multiple hepatolithiasis treated with left hemihepatectomy with double HJ reconstruction. A 72-year-old woman who had undergone HJ for iatrogenic bile duct injury developed repeated cholangitis due to complicated hepatolithiasis accompanied by an atrophied left hepatic lobe and HJ stricture. Since endoscopic intervention was unsuccessful, the patient underwent left hemihepatectomy with HJ re-anastomoses of the common hepatic duct and left hepatic duct (double HJ technique). The double HJ technique with hepatectomy can be a useful option for treating complicated hepatolithiasis following HJ.

Left Hemihepatectomy for Hepatocellular Carcinoma Following Esophagectomy with Retrosternal Gastric Tube Reconstruction for Esophageal Cancer.

Approximately 4% of patients with esophageal cancer develop a second primary malignancy in the upper gastrointestinal trunk. However, hepatectomy following esophagectomy for esophageal cancer has rarely been reported. We report the case of a 70-year-old man who underwent an esophagectomy for esophageal cancer with retrosternal gastric tube reconstruction. Nine years later, he developed hepatocellular carcinoma with tumor thrombus involving the left portal vein, and was successfully treated with left hemihepatectomy. Special attention should be paid to avoiding incidental injury of the gastric tube as well as the right gastroepiploic artery during the hepatectomy.

[A Case of Advanced Gastric Cancer with Para-Aortic Lymph Node Dissection after Neoadjuvant Chemotherapy].

The patient was a 49-year-old woman with advanced gastric cancer.CT and PET-CT revealed para-aortic lymph node metastases.She was diagnosed with Stage IV T4aN3M1(LYM)and underwent neoadjuvant chemotherapy with S-1 plus CDDP.After 3 courses, both the tumor and para-aortic lymph node metastases decreased in size.Because radical resection was considered possible, she underwent distal gastrectomy with D3(D2+No.1 6a2-b1)dissection and Roux-en-Y reconstruction. Histopathological findings revealed the cancer was Stage I B(yp T1b N1)with the disappearance of cancer cells in the para-aortic lymph nodes.She was discharged on POD 32.She underwent adjuvant chemotherapy with S-1 and was followed up for 3 years with no recurrence.Para -aortic lymph node metastases are factors predicting a poor outcome; however, when neoadjuvant chemotherapy is effective, long-term survival can be expected from gastrectomy with curative PAND.

[Report of a Case of Long-Term Survival with Mulitidisciplinary Therapy for a Patient with Multiple Liver Metastases from Rectal Cancer].

Multidisciplinary therapy is necessary to prevent recurrence of advanced rectal cancer and advanced cancer with metastases. Here we report a case of long-term survival of a patient with advanced rectal cancer with multiple liver metastases. An 80's woman had previously undergone both Hartmann's operation and a partial hepatectomy for advanced rectal cancer with multiple liver metastases. A year after chemotherapy, a CT scan revealed multiple liver metastases. Thus, we performed partial liver resection. After another round of chemotherapy, a CT scan revealed lung metastases and local recurrence of the rectal cancer; therefore, we performed partial lung resection and a Miles operation. These procedures were conducted 4 years after her first operation. The following year, PET-CT revealed a mediastinum lymph node metastasis; consequently, we performed radiation therapy. New lung metastases and local recurrences of rectal cancer were identified after the radiation therapy; thus, we resumed the therapy, including a molecular targeting drug. Although the patient is in a tumor-bearing state, she is still alive 10 years after her first operation.

[A case of AFP-producing esophagogastric junction cancer with liver metastases with a good response to chemotherapy].

A 62-year-old man was diagnosed with esophagogastric junction cancer following esophagogastroduodenoscopy in response to hematemesis. Although liver metastasis was detected during surgery, a total gastrectomy and lower esophagus resection for local control was performed. Alpha-fetoprotein(AFP)-producing tumor with hepatoid adenocarcinoma was diagnosed on the basis of the pathological examination. Serum AFP levels remained high postoperatively and multiple liver metastases were detected on computed tomography imaging. After 6 courses of chemotherapy with S-1 and cisplatin (CDDP), a significant reduction in the size of the liver metastases and a decrease of serum AFP levels were achieved. Postoperative 2-year tumor control using S-1 single agent chemotherapy was obtained. AFP-producing esophagogastric junction cancer has a poor prognosis. This case raises the possibility that long-term survival can be obtained by combining surgery for local control with systemic chemotherapy.

Senescent Fibroblasts Potentiate Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells via IL-8-mediated Crosstalk.

BACKGROUND/AIM: Diffuse-type gastric cancer (DGC) often forms peritoneal metastases, leading to poor prognosis. However, the underlying mechanism of DGC-mediated peritoneal metastasis is poorly understood. DGC is characterized by desmoplastic stroma, in which heterogeneous cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) and senescent CAFs (sCAFs), play a crucial role during tumor progression. This study investigated the CAF subtypes induced by GC cells and the role of sCAFs in peritoneal metastasis of DGC cells. MATERIALS AND METHODS: Conditioned medium of human DGC cells (KATOIII, NUGC-4) and human intestinal-type GC (IGC) cells (MKN-7, N87) was used to induce CAFs. CAF subtypes were evaluated by analyzing the expression of α-smooth muscle actin (α-SMA), senescence-associated ß-galactosidase (SA-ß-gal), and p16 in human normal fibroblasts (GF, FEF-3). A cytokine array was used to explore the underlying mechanism of GC-induced CAF subtype development. The role of sCAFs in peritoneal metastasis of DGC cells was analyzed using a peritoneally metastatic DGC tumor model. The relationships between GC subtypes and CAF-related markers were evaluated using publicly available datasets. RESULTS: IGC cells significantly induced α-SMA+ myCAFs by secreting transforming growth factor-ß, whereas DGC cells induced SA-ß-gal+/p16+ sCAFs by secreting interleukin (IL)-8. sCAFs further secreted IL-8 to promote DGC cell migration. In vivo experiments demonstrated that co-inoculation of sCAFs significantly enhanced peritoneal metastasis of NUGC-4 cells, which was attenuated by administration of the IL-8 receptor antagonist navarixin. p16 and IL-8 expression was significantly associated with poor prognosis of DGC patients. CONCLUSION: sCAFs promote peritoneal metastasis of DGC via IL-8-mediated crosstalk.

Impact of cancer-associated fibroblasts on survival of patients with ampullary carcinoma.

Background: Cancer-associated fibroblasts (CAFs) reportedly enhance the progression of gastrointestinal surgery; however, the role of CAFs in ampullary carcinomas remains poorly examined. This study aimed to investigate the effect of CAFs on the survival of patients with ampullary carcinoma. Materials and methods: A retrospective analysis of 67 patients who underwent pancreatoduodenectomy between January 2000 and December 2021 was performed. CAFs were defined as spindle-shaped cells that expressed α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP). The impact of CAFs on survival, including recurrence-free (RFS) and disease-specific survival (DSS), as well as prognostic factors associated with survival, was analyzed. Results: The high-α-SMA group had significantly worse 5-year RFS (47.6% vs. 82.2%, p = 0.003) and 5-year DSS (67.5% vs. 93.3%, p = 0.01) than the low-α-SMA group. RFS (p = 0.04) and DSS (p = 0.02) in the high-FAP group were significantly worse than those in the low-FAP group. Multivariable analyses found that high α-SMA expression was an independent predictor of RFS [hazard ratio (HR): 3.68; 95% confidence intervals (CI): 1.21-12.4; p = 0.02] and DSS (HR: 8.54; 95% CI: 1.21-170; p = 0.03). Conclusions: CAFs, particularly α-SMA, can be useful predictors of survival in patients undergoing radical resection for ampullary carcinomas.

Prognostic Value of the Regional Lymph Node Station in Pancreatoduodenectomy for Ampullary Carcinoma.

BACKGROUND/AIM: The optimal extent of lymph node dissection for ampullary carcinoma is controversial. The aim of this study was to investigate the efficacy of lymph node dissection for ampullary carcinoma. PATIENTS AND METHODS: Between 2000 and 2020, a total of 75 patients undergoing radical resection for ampullary carcinoma were included. The efficacy index (EI) was calculated by multiplication of the frequency of lymph node metastasis (LNM) at the station and the 5-year survival rate of patients with metastasis at the station. RESULTS: Out of 75 patients, 14 had LNM. The EI for the peri-pancreatic head (station 13 and 17) and superior mesenteric artery (station 14) lymph node were 4.4 and 3.5, respectively. Whereas the peri-gastric (station 5 and 6), common hepatic artery (station 8), and liver hilum (station 12) lymph node stations had zero EI. Although the number of patients with the station 16 dissected was small (9%), the para-aortic (station 16) lymph nodes had the highest EI of 14.3 despite being distant lymph nodes. CONCLUSION: We identified the distribution of LNM and survival benefit of lymph node dissection for ampullary carcinoma. Our results suggest that the optimal extent of lymph node dissection for ampullary carcinoma could be reconsidered.

Development of mesenchymal stem cells partially originate from the neural crest.

Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells isolated from many adult tissues. Previous studies reported that MSCs can differentiate to both mesodermal and neural lineages by a phenomenon referred to as ''dedifferentiation'' or ''transdifferentiation''. However, since MSCs have only been defined in vitro, much of their development in vivo is still unknown. Here, we prospectively identified MSCs in the bone marrow from adult transgenic mice encoding neural crest-specific P0-Cre/Floxed-EGFP and Wnt1-Cre/Floxed-EGFP. EGFP-positive MSCs formed spheres that expressed neural crest stem cell genes and differentiated into neurons, glial cells, and myofibroblasts. Interestingly, we observed MSCs both in the GFP(+) and GFP(-) fraction and found that there were no significant differences in the in vitro characteristics between these two populations. Our results suggest that MSCs in adult bone marrow have at least two developmental origins, one of which is the neural crest.

Differentiated astrocytes acquire sensitivity to hydrogen sulfide that is diminished by the transformation into reactive astrocytes.

Hydrogen sulfide (H2S) enhances the induction of hippocampal long-term potentiation (LTP) and induces calcium waves in astrocytes. Based on these observations, H2S has been proposed to be a synaptic modulator in the brain. Here we show that differentiated astrocytes acquire sensitivity to H2S that is diminished by their transformation into reactive astrocytes. Although sodium hydrosulfide hydrate (NaHS), a donor of H2S, did not increase the intracellular concentration of Ca2+ in progenitors, exposure of progenitors to leukemia inhibitory factor (LIF), which induces differentiation into glial fibrillary acidic protein (GFAP)-positive astrocytes, greatly increased the sensitivity to NaHS. In contrast, epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), dibutyryl cyclic AMP (db cAMP) and interleukin-1beta (IL-1beta) induced the conversion to reactive astrocytes with diminished sensitivity to NaHS. This suppressive effect of EGF on the sensitivity to NaHS was inhibited by cycloheximide, indicating that de novo protein synthesis was required for the suppression of H2S sensitivity.

Sclerosing angiomatoid nodular transformation of the spleen presenting rapid growth after adrenalectomy: Report of a case.

INTRODUCTION: Sclerosing angiomatoid nodular transformation (SANT) is a rare benign lesion with an unknown natural history and pathogenesis. So far fewer than 100 cases were documented, but detailed incidence and prevalence are unknown. PRESENTATION OF CASE: We report a case of SANT of the spleen in a 37-year-old man that showed rapid growth after adrenalectomy for primary aldosteronism. Computed tomography showed a nodule in the spleen that increased in size from 2.0cm to 7.0cm during 3 years of observation. DISCUSSION: This case is reported because data regarding growth rates and natural history of these lesions are limited and few cases have been reported to show the rapid growth progression seen in this case. CONCLUSION: Decreases in glucocorticoid concentrations following adrenalectomy may have contributed to the rapid growth of SANT of the spleen, because SANT is considered to be related to immunoglobulin G4-associated disease.

Hydrogen sulfide is produced in response to neuronal excitation.

Although hydrogen sulfide (H2S) is generally thought of in terms of a poisonous gas, it is endogenously produced in the brain. Physiological concentrations of H2S selectively enhance NMDA receptor-mediated responses and alter the induction of hippocampal long-term potentiation (LTP). Here we use cystathionine beta-synthase (CBS) knock-out mice to clearly show that CBS produces endogenous H2S in the brain and that H2S production is greatly enhanced by the excitatory neurotransmitter l-glutamate, as well as by electrical stimulation. This increased CBS activity is regulated by a pathway involving Ca2+/calmodulin. In addition, LTP is altered in CBS knock-out mice. These observations suggest that H2S is produced by CBS in response to neuronal excitation and that it may regulate some aspects of synaptic activity.

Physiological roles of hydrogen sulfide: synaptic modulation, neuroprotection, and smooth muscle relaxation.

Nearly 300 years have passed since the first description of the toxicity of hydrogen sulfide (H(2)S) in 1713. Although many studies have been devoted to its toxicity, very little attention has been paid to understanding its normal physiological function. Relatively high concentrations of endogenous H(2)S, however, have recently been discovered in animal tissues, and its possible function as a biological messenger has been proposed. H(2)S enhances the activity of N-methyl-D-aspartate receptors and facilitates the induction of hippocampal longterm potentiation, a synaptic model for memory. H(2)S also increases intracellular concentrations of Ca(2+) in glia and induces Ca(2+) waves, which mediate glial signal transmission. Based on accumulating evidence for the reciprocal interactions between glia and neurons, it has been suggested that glia modulate synaptic transmission. Therefore, H(2)S may regulate synaptic activity by modulating the activity of both neurons and glia. In addition to a role in the signal transduction, H(2)S protects neurons from oxidative stress and in smooth muscle it may function as a relaxant. H(2)S, the toxic gas, may therefore be used as a multifunctional signaling mechanism under normal physiological conditions.

Hydrogen sulfide induces calcium waves in astrocytes.

Hydrogen sulfide (H2S) modifies hippocampal long-term potentiation (LTP) and functions as a neuromodulator. Here, we show that H2S increases intracellular Ca2+ and induces Ca2+ waves in primary cultures of astrocytes as well as hippocampal slices. H2S increases the influx of Ca2+ and to a lesser extent causes the release from intracellular Ca2+ stores. Ca2+ waves induced by neuronal excitation as well as responses to exogenously applied H2S are potently blocked by La3+ and Gd3+, inhibitors of Ca2+ channels. These observations suggest that H2S induces Ca2+ waves that propagate to neighboring astrocytes.

The splicing regulatory protein p18SRP is down-regulated in Alzheimer's disease brain.

Alzheimer's disease (AD) is the most common neurodegenerative disorder of aging, accounting for an estimated two-thirds of all cases of senile dementia. Using bioinformatics, the yeast two-hybrid-system, reverse transcription polymerase chain reaction, and fluorescence microscopy analysis, we demonstrate here that the new putative splicing regulatory protein p18SRP is a lysine-rich zinc finger domain-containing protein that interacts with the serine-arginine (SR)-rich splicing regulatory protein SRrp86. The additional finding of its down-regulation in the brain of AD subjects points to a possible pivotal role of p18SRP in the control of cellular survival.

The 3' untranslated region of the new rat synaptic vesicle protein 2B mRNA transcript inhibits translational efficiency.

Post-transcriptional regulatory mechanisms have been shown to play a major role in gene expression in eukaryotic cells. Sequences within the 3'-untranslated region (3'UTR) of mRNAs have been described as being important for enhancing or inhibiting message translation. Using fluorescence microscopy, Western blotting and the reverse transcription-polymerase chain reaction (RT-PCR) method, we demonstrate that the 3'UTR of the new rat transcript of synaptic vesicle protein 2B (SV2Bb) mRNA is involved in post-transcriptional regulation of SV2Bb translation. When fused to a reporter gene, this 3'UTR markedly inhibited protein synthesis in transiently transfected cells and this decreased translational efficiency did not occur through changes in mRNA stability. In conclusion, our study gives new insights into unraveling the molecular mechanisms involved in the post-transcriptional regulation of the SV2B gene.

Nerve growth factor (NGF) induces mRNA expression of the new transcription factor protein p48ZnF.

Apoptosis, the cell's intrinsic death program, plays a crucial role in the regulation of tissue homeostasis, and abnormal inhibition of apoptosis is an indicator of cancer and autoimmune diseases, whereas excessive cell death is implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Using cDNA subtraction analysis, we compared p60TRP (p60 transcription regulator protein) expressing cells with control cells during the process of apoptosis and we identified the new zinc-finger protein p48ZnF that is predominantly located in the cytoplasm of the cell. Additionally, we demonstrate here that p48ZnF is up-regulated in rat neuronal PC12 cells upon stimulation with the neurotrophic factor NGF (50 ng/ml). These findings point to a possible pivotal role of p48ZnF in the control of neuronal survival.

APP, NGF & the 'Sunday-driver' in a Trolley on the Road.

Alzheimer's disease (AD) is one of the most common and challenging neurodegenerative diseases in humans and is characterized by: progressive impairment in cognitive function, degeneration of cholinergic neurons of the basal forebrain (CBF), neurofibrillary tangles and amyloid beta-peptide (Abeta) depositions. The amyloid precursor protein (APP) is a transmembrane protein of which abnormal processing produces Abeta that is associated with the pathogenesis of AD. Neurotrophic factors have attracted much attention for their potential as a remedy for neurological disorders. In this regard, nerve growth factor (NGF) has generated a great interest as a potential target for the treatment of AD. This interest is based on the observation that CBF neurons, which provide the major source of cholinergic innervation to the cerebral cortex and hippocampus, undergo selective and severe degeneration in advanced AD and that the survival of CBF neurons depends upon NGF and its receptors, namely, trkA and p75NTR. This review focuses on recent findings about APP, NGF and their potential signaling-connections to the protein encoded by the 'Sunday-driver' (SYD) gene.

Purified mesenchymal stem cells are an efficient source for iPS cell induction.

BACKGROUND: Induced pluripotent stem (iPS) cells are generated from mouse and human somatic cells by the forced expression of defined transcription factors. Although most somatic cells are capable of acquiring pluripotency with minimal gene transduction, the poor efficiency of cell reprogramming and the uneven quality of iPS cells are still important problems. In particular, the choice of cell type most suitable for inducing high-quality iPS cells remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here, we generated iPS cells from PDGFRα+ Sca-1+ (PαS) adult mouse mesenchymal stem cells (MSCs) and PDGFRα⁻ Sca-1⁻ osteo-progenitors (OP cells), and compared the induction efficiency and quality of individual iPS clones. MSCs had a higher reprogramming efficiency compared with OP cells and Tail Tip Fibroblasts (TTFs). The iPS cells induced from MSCs by Oct3/4, Sox2, and Klf4 appeared to be the closest equivalent to ES cells by DNA microarray gene profile and germline-transmission efficiency. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that a purified source of undifferentiated cells from adult tissue can produce high-quality iPS cells. In this context, prospectively enriched MSCs are a promising candidate for the efficient generation of high-quality iPS cells.