Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas.

Pancreatic stellate cells (PSCs) are stromal cells in the pancreas that play an important role in pancreatic pathology. In chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), PSCs are known to get activated to form myofibroblasts or cancer-associated fibroblasts (CAFs) that promote stromal fibroinflammatory reactions. However, previous studies on PSCs were mainly based on the findings obtained using ex vivo expanded PSCs, with few studies that addressed the significance of in situ tissue-resident PSCs using animal models. Their contributions to fibrotic reactions in CP and PDAC are also lesser-known. These limitations in our understanding of PSC biology have been attributed to the lack of specific molecular markers of PSCs. Herein, we established Meflin (Islr), a glycosylphosphatidylinositol-anchored membrane protein, as a PSC-specific marker in both mouse and human by using human pancreatic tissue samples and Meflin reporter mice. Meflin-positive (Meflin+ ) cells contain lipid droplets and express the conventional PSC marker Desmin in normal mouse pancreas, with some cells also positive for Gli1, the marker of pancreatic tissue-resident fibroblasts. Three-dimensional analysis of the cleared pancreas of Meflin reporter mice showed that Meflin+ PSCs have long and thin cytoplasmic protrusions, and are localised on the abluminal side of vessels in the normal pancreas. Lineage tracing experiments revealed that Meflin+ PSCs constitute one of the origins of fibroblasts and CAFs in CP and PDAC, respectively. In these diseases, Meflin+ PSC-derived fibroblasts showed a distinctive morphology and distribution from Meflin+ PSCs in the normal pancreas. Furthermore, we showed that the genetic depletion of Meflin+ PSCs accelerated fibrosis and attenuated epithelial regeneration and stromal R-spondin 3 expression, thereby implying that Meflin+ PSCs and their lineage cells may support tissue recovery and Wnt/R-spondin signalling after pancreatic injury and PDAC development. Together, these data indicate that Meflin may be a marker specific to tissue-resident PSCs and useful for studying their biology in both health and disease. © 2023 The Pathological Society of Great Britain and Ireland.

Seawater fish use an electrogenic boric acid transporter, Slc4a11A, for boric acid excretion by the kidney.

Boric acid is a vital micronutrient in animals; however, excess amounts are toxic to them. Little is known about whole-body boric acid homeostasis in animals. Seawater (SW) contains 0.4 mM boric acid, and since marine fish drink SW, their urinary system was used here as a model of the boric acid excretion system. We determined that the bladder urine of a euryhaline pufferfish (river pufferfish, Takifugu obscurus) acclimated to fresh water and SW contained 0.020 and 19 mM of boric acid, respectively (a 950-fold difference), indicating the presence of a powerful excretory renal system for boric acid. Slc4a11 is a potential animal homolog of the plant boron transporter BOR1; however, mammalian Slc4a11 mediates H+ (OH-) conductance but does not transport boric acid. We found that renal expression of the pufferfish paralog of Slc4a11, Slc4a11A, was markedly induced after transfer from fresh water to SW, and Slc4a11A was localized to the apical membrane of kidney tubules. When pufferfish Slc4a11A was expressed in Xenopus oocytes, exposure to media containing boric acid and a voltage clamp elicited whole-cell outward currents, a marked increase in pHi, and increased boron content. In addition, the activity of Slc4a11A was independent of extracellular Na+. These results indicate that pufferfish Slc4a11A is an electrogenic boric acid transporter that functions as a B(OH)4- uniporter, B(OH)3-OH- cotransporter, or B(OH)3/H+ exchanger. These observations suggest that Slc4a11A is involved in the kidney tubular secretion of boric acid in SW fish, probably induced by the negative membrane potential and low pH of urine.

The role of Na+-coupled bicarbonate transporters (NCBT) in health and disease.

Cellular and organism survival depends upon the regulation of pH, which is regulated by highly specialized cell membrane transporters, the solute carriers (SLC) (For a comprehensive list of the solute carrier family members, see: https://www.bioparadigms.org/slc/ ). The SLC4 family of bicarbonate (HCO3-) transporters consists of ten members, sorted by their coupling to either sodium (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE), chloride (AE1, AE2, AE3), or borate (BTR1). The ionic coupling of SLC4A9 (AE4) remains controversial. These SLC4 bicarbonate transporters may be controlled by cellular ionic gradients, cellular membrane voltage, and signaling molecules to maintain critical cellular and systemic pH (acid-base) balance. There are profound consequences when blood pH deviates even a small amount outside the normal range (7.35-7.45). Chiefly, Na+-coupled bicarbonate transporters (NCBT) control intracellular pH in nearly every living cell, maintaining the biological pH required for life. Additionally, NCBTs have important roles to regulate cell volume and maintain salt balance as well as absorption and secretion of acid-base equivalents. Due to their varied tissue expression, NCBTs have roles in pathophysiology, which become apparent in physiologic responses when their expression is reduced or genetically deleted. Variations in physiological pH are seen in a wide variety of conditions, from canonically acid-base related conditions to pathologies not necessarily associated with acid-base dysfunction such as cancer, glaucoma, or various neurological diseases. The membranous location of the SLC4 transporters as well as recent advances in discovering their structural biology makes them accessible and attractive as a druggable target in a disease context. The role of sodium-coupled bicarbonate transporters in such a large array of conditions illustrates the potential of treating a wide range of disease states by modifying function of these transporters, whether that be through inhibition or enhancement.

Electroneutral Na+/Cl- cotransport activity of zebrafish Slc12a10.1 expressed in Xenopus oocytes.

Na+/Cl- cotransporter 2 (Ncc2 or Slc12a10), is a membrane transport protein that belongs to the electroneutral cation-chloride cotransporter family. The Slc12a10 gene (slc12a10) is widely present in bony vertebrates but is deleted or pseudogenized in birds, some bony fishes, and most mammals. Slc12a10 is highly homologous to Ncc (Slc12a3 or Ncc1); however, there are only a few reports measuring the activity of Slc12a10. In this study, we focused on zebrafish Slc12a10.1 (zSlc12a10.1) and analyzed its activity using Xenopus oocyte electrophysiology. Analysis using Na+-selective microelectrodes showed that intracellular sodium activity (aNai) in zSlc12a10.1 oocytes was significantly decreased in Na+- or Cl--free medium and recovered when Na+ or Cl- was readded to the medium. Similar analysis using a Cl--selective microelectrode showed that intracellular chloride activity (aCli) in zSlc12a10.1 oocytes significantly decreased in Na+- or Cl--free medium and recovered when Na+ or Cl- was readded to the medium. When a similar experiment was performed with a voltage clamp, the membrane current did not change when aNai of zSlc12a10.1 oocytes were decreased in Na+-free medium. Molecular phylogenetic and synteny analyses suggest that gene duplication between slc12a10.2 and slc12a10.3 in zebrafish, is a relatively recent event, whereas gene duplication between slc12a10.1 and the ancestral gene of slc12a10.2/slc12a10.3 occurred at least about 2 million years ago. slc12a10 deficiency was observed in species belonging to Ictaluridae, Salmoniformes, Osmeriformes, Batrachoididae, Syngnathiformes, Gobiesociformes, Labriformes, and Tetraodontiformes. These results indicate that zebrafish Slc12a10.1 is an electroneutral Na+/Cl-cotransporter and establish its evolutionary position among various teleost slc12a10 paralogs.

[A Case of Transverse Colon Cancer with Gastrointestinal Amyloidosis Prevented from Anastomotic Leakage by Multidimensional Approach].

The patient was a 68-year-old woman who was on hemodialysis due to systemic amyloidosis and nephrotic syndrome. Biopsy revealed amyloid deposition in the stomach, duodenum, and colon. A transverse colon tumor was found on a follow- up CT after the aortic dissection surgery. We performed lower gastrointestinal endoscopy and contrast-enhanced CT and diagnosed transverse colon cancer with gastric wall infiltration(cStage Ⅲc). We considered that transverse colon resection was oncologically sufficient. However, due to concurrent gastrointestinal amyloidosis, which increased the risk of anastomotic leakage we performed laparoscopic extended right hemicolectomy to avoid colon-colon anastomosis with partial gastrectomy. Additionally intraoperative indocyanine green(ICG)fluorescence imaging showed that the fluorescence signal in the small intestinal wall was satisfactory, while it was weak in the colon wall. As a result, we suspected of impaired blood flow of colon wall due to an amyloidosis, so we additionally created a loop ileostomy. It is said that gastrointestinal amyloidosis raises the risk of anastomotic leakage. A case of transverse colon cancer complicated by gastrointestinal amyloidosis in which we successfully prevented anastomotic leakage through a multidimensional evaluation and approach is reported, along with a literature review.

Na+/Cl- cotransporter 2 is not fish-specific and is widely found in amphibians, non-avian reptiles, and select mammals.

Solute carrier 12 (Slc12) is a family of electroneutral cation-coupled chloride (Cl-) cotransporters. Na+/K+/2Cl- (Nkcc) and Na+/Cl- cotransporters (Ncc) belong to the Nkcc/Ncc subfamily. Human and mouse possess one gene for the Na+/Cl- cotransporter (ncc gene: slc12a3), whereas teleost fishes possess multiple ncc genes, slc12a3 (ncc1) and slc12a10 (ncc2), in addition to their species-specific paralogs. Amphibians and squamates have two ncc genes: slc12a3 (ncc1) and ncc3. However, the evolutionary relationship between slc12a10 and ncc3 remains unresolved, and the presence of slc12a10 (ncc2) in mammals has not been clarified. Synteny and phylogenetic analyses of vertebrate genome databases showed that ncc3 is the ortholog of slc12a10, and slc12a10 is present in most ray-finned fishes, coelacanths, amphibians, reptiles, and a few mammals (e.g., platypus and horse) but pseudogenized or deleted in birds, most mammals, and some ray-finned fishes (pufferfishes). This shows that slc12a10 is widely present among bony vertebrates and pseudogenized or deleted independently in multiple lineages. Notably, as compared with some fish that show varied slc12a10 tissue expression profile, spotted gar, African clawed frog, red-eared slider turtle, and horse express slc12a10 in the ovaries or premature gonads. In horse tissues, an unexpectedly large number of splicing variants for Slc12a10 have been cloned, many of which encode truncated forms of Slc12a10, suggesting that the functional constraints of horse slc12a10 are weakened, which may be in the process of becoming a pseudogene. Our results elaborate on the evolution of Nkcc/Ncc subfamily of Slc12 in vertebrates.NEW & NOTEWORTHY slc12a10 is not a fish-specific gene and is present in a few mammals (e.g., platypus and horse), non-avian reptiles, amphibians, but was pseudogenized or deleted in most mammals (e.g., human, mouse, cat, cow, and rhinoceros), birds, and some ray-finned fishes (pufferfishes).

Placental Mammals Acquired Functional Sequences in NRK for Regulating the CK2-PTEN-AKT Pathway and Placental Cell Proliferation.

The molecular evolution processes underlying the acquisition of the placenta in eutherian ancestors are not fully understood. Mouse NCK-interacting kinase (NIK)-related kinase (NRK) is expressed highly in the placenta and plays a role in preventing placental hyperplasia. Here, we show the molecular evolution of NRK, which confers its function for inhibiting placental cell proliferation. Comparative genome analysis identified NRK orthologs across vertebrates, which share the kinase and citron homology (CNH) domains. Evolutionary analysis revealed that NRK underwent extensive amino acid substitutions in the ancestor of placental mammals and has been since conserved. Biochemical analysis of mouse NRK revealed that the CNH domain binds to phospholipids, and a region in NRK binds to and inhibits casein kinase-2 (CK2), which we named the CK2-inhibitory region (CIR). Cell culture experiments suggest the following: 1) Mouse NRK is localized at the plasma membrane via the CNH domain, where the CIR inhibits CK2. 2) This mitigates CK2-dependent phosphorylation and inhibition of PTEN and 3) leads to the inhibition of AKT signaling and cell proliferation. Nrk deficiency increased phosphorylation levels of PTEN and AKT in mouse placenta, supporting our hypothesis. Unlike mouse NRK, chicken NRK did not bind to phospholipids and CK2, decrease phosphorylation of AKT, or inhibit cell proliferation. Both the CNH domain and CIR have evolved under purifying selection in placental mammals. Taken together, our study suggests that placental mammals acquired the phospholipid-binding CNH domain and CIR in NRK for regulating the CK2-PTEN-AKT pathway and placental cell proliferation.

Oral Dysfunction in Patients with Oral Cancer Could Occur Before Treatment and Require Early Nutritional Improvement: A Cross-Sectional Study.

Patients with oral cancer have poor nutritional status before treatment. However, there have been no reports of the detailed evaluation of preoperative oral function in patients with oral squamous cell carcinoma (OSCC). Therefore, this study aimed to evaluate the preoperative oral function of patients with OSCC and examine the relationship with nutritional status. Oral function measurements (microorganisms, oral dryness, occlusal force, tongue pressure, masticatory function, Eating Assessment Tool, and Postoperative Oral Dysfunction Scale) and Mini Nutritional Assessment-Short Form (MNA-SF) data were collected from 51 patients with OSCC (men: 37, women: 14, mean age: 72.1 years) who visited the Shimane University Hospital, Department of Oral and Maxillofacial Surgery, from September 2019 to September 2021. The tongue was the most prevalent primary gingiva site [22 patients (43.1%)], and 36 patients (70.6%) had advanced cancer. Comparisons between nutritional status and each related factor revealed significant differences in the number of individuals in the household, cancer stage, presence of pulmonary disease, number of teeth, microorganisms (grade), and masticatory function (mg/dL) (p < 0.05). Multiple regression analysis using the total MNA-SF score as the dependent variable with adjustment for confounding factors showed significant association between oral dryness and tongue pressure (p < 0.05). No significant association was found for the Eating Assessment Tool or Postoperative Oral Dysfunction scale. Patients with OSCC may have decreased oral function because of the tumor at the time of diagnosis, which causes a decline in nutritional status. Preoperative interventions are necessary to improve nutrition based on the state of oral function.

Matrix remodeling-associated protein 8 is a marker of a subset of cancer-associated fibroblasts in pancreatic cancer.

Cancer-associated fibroblasts (CAFs), a compartment of the tumor microenvironment, were previously thought to be a uniform cell population that promotes cancer progression. However, recent studies have shown that CAFs are heterogeneous and that there are at least two types of CAFs, that is, cancer-promoting and -restraining CAFs. We previously identified Meflin as a candidate marker of cancer-restraining CAFs (rCAFs) in pancreatic ductal adenocarcinoma (PDAC). The precise nature of rCAFs, however, has remained elusive owing to a lack of understanding of their comprehensive gene signatures. Here, we screened genes whose expression correlated with Meflin in single-cell transcriptomic analyses of human cancers. Among the identified genes, we identified matrix remodeling-associated protein 8 (MXRA8), which encodes a type I transmembrane protein with unknown molecular function. Analysis of MXRA8 expression in human PDAC samples showed that MXRA8 was differentially co-expressed with other CAF markers. Moreover, in patients with PDAC or syngeneic tumors developed in MXRA8-knockout mice, MXRA8 expression did not affect the roles of CAFs in cancer progression, and the biological importance of MXRA8+ CAFs is still unclear. Overall, we identified MXRA8 as a new CAF marker; further studies are needed to determine the relevance of this marker.

Continuous intradialytic amino acid infusion from the start of dialysis is better to avoid catabolism under the high-volume pre-dilution on-line HDF.

It was reported that amino acid infusion during hemodialysis is useful for improving nutritional status. The optimal administration method of amino acid infusion under the high-volume pre-dilution on-line HDF (HVPO-HDF) was analyzed in this study. Subjects were 10 patients on maintenance dialysis at our clinic. We performed high-volume pre-dilution on-line HDF. We investigated two methods for administration of Neoamiyu® 200-ml total amino acid (TAA) infusion for patients with renal failure: (1) continuous infusion into the dialysis circuit for 4 h from the start of dialysis to its completion (infusion rate 50 ml/h) and (2) continuous infusion started 1 h before completion of dialysis (infusion rate 200 ml/h), and compared pre- and post-dialysis blood concentrations and leakage of TAA, essential amino acids (EAA), and nonessential amino acids (NEAA) between these methods. Pre-dialysis blood concentrations of amino acids showed no difference between both the groups. Post-dialysis blood concentrations of amino acids were higher in all concentrations were significantly higher with continuous infusion starting 1 h before completion of dialysis. Leakage of amino acids showed no difference between both the groups. The continuous intradialytic amino acid infusion from the start of dialysis is better to avoid catabolism under high-volume pre-dilution on-line HDF.

[A Case of Lower Gingival Carcinoma Treated Surgically Using Computer-Assisted Patient-Specific Cutting Guide and Mandibular Reconstruction Plate].

We report a case of advanced lower gingival carcinoma treated with a computer-assisted custom-made surgical guide and reconstruction plate system(TruMatch®)in combination with a pectoralis major myocutaneous flap. In a 74-year-old male patient, a neoplastic lesion with a 30×30 mm periapical induration was observed around an extraction socket of left mandibular third molar. After various examinations, we diagnosed lower gingival carcinoma(cT4aN2bM0, Stage ⅣA). The patient was a paraplegic with a spinal cord injury, and reconstruction of mandible with free flap was not indicated, requiring minimally invasive surgery. Therefore, a surgical guide and reconstruction plate were prepared preoperatively using the Tru- Match® system. Under general anesthesia, the patient underwent tracheostomy, left modified radical neck dissection, segmental mandibulectomy, and reconstruction of the mandible using this system in combination with a pectoralis major myocutaneous flap. Postoperatively, the patient had minimal dysfunction. Currently, at 18 months follow up postoperatively, good prognosis was observed. In conclusion, this is a useful surgical system with accurate and less invasive surgery for segmental mandibulectomy of advanced lower gingival carcinoma.

Lack of GD3 synthase (St8sia1) attenuates malignant properties of gliomas in genetically engineered mouse model.

High expression of gangliosides GD3 and GD2 is observed in human gliomas. The functions of GD3 and GD2 in malignant properties have been reported in glioma cells in vitro, but those functions have not yet been investigated in vivo. In this study, we showed that deficiency of GD3 synthase (GD3S, St8sia1) attenuated glioma progression and clinical and pathological features in a platelet-derived growth factor B-driven murine glioma model. Lack of GD3S resulted in the prolonged lifespan of glioma-bearing mice and low-grade pathology in generated gliomas. Correspondingly, they showed reduced phosphorylation levels of Akt, Erks, and Src family kinases in glioma tissues. A DNA microarray study revealed marked alteration in the expression of various genes, particularly in MMP family genes, in GD3S-deficient gliomas. Re-expression of GD3S restored expression of MMP9 in primary-cultured glioma cells. We also identified a transcription factor, Ap2α, expressed in parallel with GD3S expression, and showed that Ap2α was critical for the induction of MMP9 by transfection of its cDNA and luciferase reporter genes, and a ChIP assay. These findings suggest that GD3S enhances the progression of gliomas by enhancement of the Ap2α-MMP9 axis. This is the first report to describe the tumor-enhancing functions of GD3S in vivo.

Noneffectiveness of scopolamine for facilitating detection of upper gastrointestinal neoplasia during screening esophagogastroduodenoscopy: propensity score-matched study.

BACKGROUND: Antispasmodics, such as scopolamine, are widely used in several countries prior to diagnostic and screening esophagogastroduodenoscopy (EGD), with the goal of optimizing the detection of minute lesions, typically early gastric cancer (T1 lesions). The aim of this study was to determine whether scopolamine facilitates detection of gastric cancer in the screening setting. METHODS: A propensity score-matched retrospective study was conducted in a tertiary referral medical center in Tokyo, Japan. Consecutive individuals (n = 40 776) underwent screening EGD between January 2011 and May 2016. All outcome lesions were diagnosed with histopathological confirmation. Detection of esophageal cancer, gastric adenoma, duodenal adenoma, and upper gastrointestinal neoplasia (UGIN) were investigated as secondary outcomes. RESULTS: Scopolamine was used in 31 130 patients (76.3 %) and propensity score matching yielded 6625 pairs. Bivariate analysis revealed no significant association between possible confounders (age, sex, overweight, atrophic gastritis, alcohol history, smoking history, midazolam use, endoscopist biopsy rate grade, and gastric cancer in first-degree relatives) and scopolamine use. Lesions detected were 18 gastric cancers, 11 esophageal cancers, 19 gastric adenomas, 6 duodenal adenomas, and 54 UGINs, with no significant association between scopolamine use and lesion detection. CONCLUSIONS: Scopolamine use did not appear to effectively facilitate detection of gastric or esophageal cancer, gastric or duodenal adenoma, and UGIN during screening EGD. Scopolamine should be avoided until its efficacy is confirmed by a randomized controlled trial.

Materials informatics approach to understand aluminum alloys.

The relations between the mechanical properties, heat treatment, and compositions of elements in aluminum alloys are extracted by a materials informatics technique. In our strategy, a machine learning model is first trained by a prepared database to predict the properties of materials. The dependence of the predicted properties on explanatory variables, that is, the type of heat treatment and element composition, is searched using a Markov chain Monte Carlo method. From the dependencies, a factor to obtain the desired properties is investigated. Using targets of 5000, 6000, and 7000 series aluminum alloys, we extracted relations that are difficult to find via simple correlation analysis. Our method is also used to design an experimental plan to optimize the materials properties while promoting the understanding of target materials.

Cloning, function, and localization of human, canine, and Drosophila ZIP10 (SLC39A10), a Zn2+ transporter.

Zinc (Zn2+) is the second most abundant trace element, but is considered a micronutrient, as it is a cofactor for many enzymes and transcription factors. Whereas Zn2+ deficiency can cause cognitive immune or metabolic dysfunction and infertility, excess Zn2+ is nephrotoxic. As for other ions and solutes, Zn2+ is moved into and out of cells by specific membrane transporters: ZnT, Zip, and NRAMP/DMT proteins. ZIP10 is reported to be localized at the apical membrane of renal proximal tubules in rats, where it is believed to play a role in Zn2+ import. Renal regulation of Zn2+ is of particular interest in light of growing evidence that Zn2+ may play a role in kidney stone formation. The objective of this study was to show that ZIP10 homologs transport Zn2+, as well as ZIP10, kidney localization across species. We cloned ZIP10 from dog, human, and Drosophila ( CG10006), tested clones for Zn2+ uptake in Xenopus oocytes and localized the protein in renal structures. CG10006, rather than foi (fear-of-intimacy, CG6817) is the primary ZIP10 homolog found in Drosophila Malpighian tubules. The ZIP10 antibody recognizes recombinant dog, human, and Drosophila ZIP10 proteins. Immunohistochemistry reveals that ZIP10 in higher mammals is found not only in the proximal tubule, but also in the collecting duct system. These ZIP10 proteins show Zn2+ transport. Together, these studies reveal ZIP10 kidney localization, a role in renal Zn2+ transport, and indicates that CG10006 is a Drosophila homolog of ZIP10.

High Incidence of Renal Stones in Severely Disabled Children with Epilepsy Treated with Topiramate.

PURPOSE: This study was aimed to assess the accurate incidence of renal stones in severely disabled children treated with topiramate (TPM). METHOD: We reviewed the medical records of severely disabled children with epilepsy under 15 years old who underwent radiological examinations to investigate urinary stones. The study enrolled 26 patients who were divided into two groups. One group had been treated with TPM for at least 1 year and the other had not been treated with TPM, zonisamide, acetazolamide, or other diuretic drugs. We collected parameters from the medical records and compared the groups. RESULTS: All participants were evaluated radiologically, with computed tomography (CT) in two patients, ultrasonography in 22 patients, and both in two. No patient had any morphological abnormality of the kidneys and history of urinary tract infection. There were no significant differences in sex, age, body weight, or feeding manner between the groups, while the incidence of renal stones or calcifications was significantly higher in the TPM-treated group (60 vs. 0%; p = 0.00241). CONCLUSION: There is a high incidence of renal stone formation in severely disabled children treated with TPM.

[A Case of Colostomy-Free and Long-Term Survival with 5-FU/CDDP for Local Recurrence of Anal Cancer after Chemoradiation Therapy].

We report a case of colostomy-free, long-term survival following 5-FU/CDDP for the local recurrence of anal cancer after chemoradiation therapy(CRT). The patient was a 48-year-old woman who was diagnosed with cStage ⅢA anal cancer. She was treated with CRT(5-FU/MMC plus 59 Gy)and achieved a complete response upon treatment completion. A local recurrence was detected on the left-side wall of her rectum after 6 months. We recommended abdominoperineal resection but the patient refused operation. The patient was treated with chemotherapy consisting of 5-FU(1,000mg/m / 2/day)on days 1-5 and CDDP(100mg/m / 2/day)on day 2. Grade 3 peripheral neuropathy appeared following the completion of 5 courses. Therefore, the dose was reduced to 60%. Twenty-five courses of this treatment were continued and chemotherapy was completed. The patient has been alive with no sign of recurrence for 6 years and 8 months from the initial treatment. CRT for anal cancer is becoming a standard therapy but local recurrence is possible. In these cases, abdominoperineal resection is required. Chemotherapy with 5-FU/CDDP in cases of recurrence can be a colostomy-free option.

[A Case of Resected Pancreatic Metastasis of Rectal Cancer after Multiple Resections of Metastatic Lesions].

A 71-year-old man underwent low anterior resection for rectal cancer 10 years prior. He underwent resection of liver metastasis once and that of lung metastases multiple times after the primary surgery. Computed tomography revealed a mass measuring 22mm in size in the pancreatic body 10 years after the rectal resection. We inspected it before surgery by performing EUS-FNA. On suspicion of metastasis of rectal cancer or primary pancreatic cancer, we performed distal pancreatectomy. The pancreatic tumor was diagnosed as metastasis of the rectal cancer. There were multiple metastases in the resected specimen that we were unable to indicate at the preoperative inspection. Resectable pancreatic metastasis from colorectal cancer is rare, but some patients with long-term survival have been reported. If a patient is tolerant to pancreatectomy and has no metastasis in other organs, the patient should be considered as a good candidate for pancreatectomy.

Significance of perivascular tumour cells defined by CD109 expression in progression of glioma.

In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Transport proteins NHA1 and NHA2 are essential for survival, but have distinct transport modalities.

The cation/proton antiporter (CPA) family includes the well-known sodium/proton exchanger (NHE; SLC9A) family of Na(+)/H(+) exchangers, and the more recently discovered and less well understood CPA2s (SLC9B), found widely in living organisms. In Drosophila, as in humans, they are represented by two genes, Nha1 (Slc9b1) and Nha2 (Slc9b2), which are enriched and functionally significant in renal tubules. The importance of their role in organismal survival has not been investigated in animals, however. Here we show that single RNAi knockdowns of either Nha1 or Nha2 reduce survival and in combination are lethal. Knockdown of either gene alone results in up-regulation of the other, suggesting functional complementation of the two genes. Under salt stress, knockdown of either gene decreases survival, demonstrating a key role for the CPA2 family in ion homeostasis. This is specific to Na(+) stress; survival on K(+) intoxication is not affected by sodium/hydrogen antiporter (NHA) knockdown. A direct functional assay in Xenopus oocytes shows that Nha2 acts as a Na(+)/H(+) exchanger. In contrast, Nha1 expressed in Xenopus oocytes shows strong Cl(-) conductance and acts as a H(+)-Cl(-) cotransporter. The activity of Nha1 is inhibited by chloride-binding competitors 4,4'-diiso-thiocyano-2,2'-disulfonic acid stilbene and 4,4'-dibenzamido-2,2'-stilbenedisulphonate. Salt stress induces a massive up-regulation of NHA gene expression not in the major osmoregulatory tissues of the alimentary canal, but in the crop, cuticle, and associated tissues. Thus, it is necessary to revise the classical view of the coordination of different tissues in the coordination of the response to osmoregulatory stress.