Nuclear ß-catenin expression is positively regulated by JAB1 in human colorectal cancer cells.

Wnt/ß-catenin signaling is important for development and progression of colorectal cancer (CRC). The degradation complex for ß-catenin is functionally impaired in CRC cells, thereby resulting in the accumulation of ß-catenin and its translocation into the nucleus. Nuclear ß-catenin interacts with and co-activates T cell factor4 (TCF4), resulting in ß-catenin/TCF4-dependent transcription. Therefore, nuclear ß-catenin has been categorized as the main driving force in the tumorigenesis of CRC. Recent studies reveal that Jun activation domain-binding protein 1 (JAB1) enhances the degradation of seven in absentia homolog-1 (SIAH-1), a putative E3 ubiquitin ligase of ß-catenin, and positively regulates the expression of total ß-catenin in human CRC cells. An another recent study also shows that nuclear ß-catenin is ubiquitinated and degraded by an E3 ubiquitin ligase, tripartite motif-containing protein 33 (TRIM33). However, the regulatory mechanism for the expression of nuclear ß-catenin remains to be fully understood. In this study, we have demonstrated that JAB1 positively regulates the expression of nuclear ß-catenin, c-MYC as a ß-catenin/TCF4 target, and cell cycle regulators, such as Ki-67 and topoisomerase IIα, in human CRC cells. Taken together, these results suggest that JAB1 is considered as a promising target for novel CRC therapy.

CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.

OBJECTIVE: Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. DESIGN: We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. RESULTS: Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5(neg or low) cell population but was distinct from typical antral Lgr5(high) stem cells. Treatment with progastrin interconverts Lgr5(neg or low) CCK2R+ cells into Lgr5(high) cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. CONCLUSIONS: CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.

Significant role of bone marrow-derived cells in compensatory regenerative lung growth.

BACKGROUND: Extensive studies have attempted to clarify the contribution of bone marrow-derived cells to the regeneration of various organs, but not the lungs. We evaluated the role of bone marrow-derived cells in compensatory regenerative lung growth. METHODS: We induced regenerative lung growth by left pneumonectomy in adult C57BL/6 mice. To evaluate the role of bone marrow-derived cells in lung regenerative growth, green fluorescent protein (GFP)-positive, bone marrow-transplanted chimeric mice underwent inhibition of stromal-cell-derived factor (SDF)-1α/CXCR4 signaling by 7-d continuous administration of a CXCR4 antagonist after pneumonectomy. RESULTS: Left pneumonectomy resulted in a significant increase in lung dry weight, as well as an increase in lung volume, without enlargement of the alveolar air space. We observed GFP-positive cells 2.1-fold more frequently in the lungs of pneumonectomized mice versus sham-operated mice by immunohistochemistry (P = 0.001), although only a proportion of these accumulated cells possessed a pneumocyte-like appearance. Pneumonectomy induced a 1.4-fold increase in the SDF-1α level in the remaining lung at 7 d compared with sham-operated mice (P < 0.05), although pneumonectomy was not accompanied by histopathological lung injury. Blockade of SDF-1α/CXCR4 signaling resulted in a significant reduction in the accumulation of GFP-positive cells in the remaining lung at 7 d and prevented regenerative lung growth, as shown by a 10% reduction in lung dry weight at 14 d compared with control pneumonectomized mice (P < 0.05). CONCLUSIONS: Bone marrow-derived cells have a significant role in compensatory regenerative lung growth in an adult mouse model. Further evaluation to clarify molecular interactions between bone marrow-derived cells and pneumocytes should prove fruitful.

A case of multiple glucagonomas with no clinical manifestations of excess glucagon despite hyperglucagonemia.

Herein we report the case of a patient with multiple glucagonomas that have been precisely described with endoscopic ultrasound. A 36-year-old woman was referred to our hospital for computed tomography investigation of multiple pancreatic masses. Physical examination was unremarkable; on contrast-enhanced computed tomography, mass lesions were evident in the head, body, and tail of the pancreas. The mass in the pancreatic head was poorly demarcated and exhibited a faint contrast effect, the one in the pancreatic body was a cystic lesion, and the one in the pancreatic tail was hypervascular. Blood investigations showed that serum glucagon was abnormally high at 7670 pg/ml; glucose tolerance was not impaired. There was no family history that suggested multiple endocrine neoplasia type 1 or von Hippel-Lindau disease. Endoscopic ultrasound revealed that there were additional masses, which were scattered isoechoic to hyperechoic lesions a few millimeters in size. Ultrasound-guided fine needle biopsy of the lesion in the pancreatic tail resulted in a diagnosis of a neuroendocrine tumor. Based on these pathologic findings, we performed a total pancreatectomy. A large number of nodules with tumor cells were evident in all cut surfaces of the surgical specimen. Immunostaining was positive for chromogranin A and glucagon, and glucagonoma was therefore diagnosed. It is conceivable that attenuated glucagon action could have contributed to the development of the multiple glucagonomas.

Hypoxic preconditioning enhances angiogenic potential of bone marrow cells with aging-related functional impairment.

BACKGROUND: Hypoxic preconditioning of bone marrow cells (BMCs) from young healthy individuals can enhance the cells' therapeutic potential. Considering that the response to hypoxia may differ according to the quality of the cells, we assessed the effect of hypoxic preconditioning on BMCs from aged mice and compared the difference in response between BMCs from aged and young mice. METHODS AND RESULTS: BMCs from young (3 months) and aged (20-22 months) mice were subjected to hypoxic preconditioning by culture for 24 h in 2% O2. Compared with BMCs from young mice, those from aged mice showed significantly fewer CD34- or c-kit-positive stem cells, higher expression of p53, and lower telomerase activity. Adhesion, survival and angiogenic potency were also lower in BMCs from aged mice, indicating an aging-related impairment. Hypoxia-preconditioned BMCs from aged mice showed enhanced adhesion, survival, and angiogenic potency with the in vitro assessments, as well as the in vivo implantation into ischemic hindlimbs. All the enhancements by hypoxic preconditioning were comparable between BMCs from aged and young mice, although the angiogenic potential of BMCs with and without hypoxic preconditioning was lower in old mice compared with young mice. CONCLUSIONS: Similar responses to hypoxia by BMCs from both aged and young mice suggest that hypoxic preconditioning could be a useful method of enhancing the angiogenic potential of BMCs.

Adenoma of the nipple, focusing on the contrast-enhanced magnetic resonance imaging findings: report of a case.

A woman in her 50s was referred to our hospital for an investigation of a right breast tumor. The tumor was palpated below the nipple, but there was no erosion or nipple discharge. Mammography showed a well-defined high-density tumor, measuring 2 cm in diameter, without calcification, and ultrasonography showed a low-echoic mass with a fluid component with posterior echo enhancement and a lateral shadow. Contrast-enhanced magnetic resonance imaging (CE-MRI) demonstrated a 1.3 × 0.8 cm solid component and a gradually increasing time-intensity curve. We performed lumpectomy and the pathological findings were adenoma of the nipple. The pattern of the time-intensity curve might be attributed to moderate fibrosis of the tumor. Contrast-enhanced MRI is therefore considered to be very useful in the diagnosis of breast disease because it can show the nature and extent of the breast lesion; however, we should be aware that various patterns have been observed on CE-MRI for adenoma of the nipple.

Autologous transplantation of multilayered fibroblast sheets prevents postoperative pancreatic fistula by regulating fibrosis and angiogenesis.

INTRODUCTION: Postoperative pancreatic fistula (POPF) is a serious complication after gastrointestinal or pancreatic surgery. Despite intensive investigations, the occurrence has not significantly decreased in the past decades. The aims of this study were to clarify the pathophysiology of POPF and establish the preventive measures using multilayered fibroblast sheets. METHODS: We developed a pancreatic fistula (PF) model of rat with transection of the splenic duct and surrounding pancreatic parenchyma. Multilayered fibroblast sheets prepared from tails were autologously transplanted to this model. The preventive effect was biochemically and histologically evaluated by measuring the ascitic levels of pancreatic enzymes and conducting immunohistochemistry and real-time polymerase chain reaction analyses of pancreatic tissue. Findings were compared to those obtained with acellular materials simply sealing the wound. RESULTS: In the PF model, the ascitic levels of pancreatic enzymes were transiently up-regulated. Inflammation and necrosis were histologically observed in a wide range. Islets were damaged even in remote areas. Transplantation of multilayered fibroblast sheets dramatically reduced the ascitic leakage of enzymes, suppressed inflammation, and broadly preserved the islets. Compared with acellular materials, these sheets offered superior prevention of cellular activity through the spaciotemporal regulation of fibrosis and angiogenesis. Notably, the leakage hole appeared to have been plugged with the fibrotic matrix, which might have been the most crucial mechanism minimizing pancreatic damage. CONCLUSIONS: The autologous transplantation of multilayered fibroblast sheets significantly prevented PF and protected the pancreas, underscoring the potential utility of this approach for POPF prevention.

Determination of thymidine phosphorylase expression level facilitates recurrence risk stratification in stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines.

The present study aimed to prospectively clarify the prognostic effect of the expression of several genes that are known to modulate 5-fluorouracil effects in 63 patients who underwent curative resection for stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines between 2008 and 2012. Thymidine phosphorylase (TP) expression in primary tumours was significantly lower in the recurrence group compared with the no-recurrence group (P=0.03), whereas, expression levels of genes that encoded thymidylate synthase, dihydropyrimidine dehydrogenase, folylpolyglutamate synthase, γ-glutamyl hydrolase and dihydrofolate reductase were not statistically different in tumours from the recurrence and no-recurrence groups. In the multivariate analysis using stepwise Cox proportional hazards regression, the following factors were significantly associated with shorter relapse-free survival following adjuvant chemotherapy with oral fluoropyrimidines: Venous invasion [present; hazard ratio (HR)=6.51; 95% confidence interval (CI): 1.55-27.4; P=0.01), Tumour-Node-Metastasis stage (3b; HR=6.18; 95% CI: 1.36-28.2; P=0.02) and TP expression (low; HR=9.61; 95% CI: 1.81-51.0; P=0.04). Patients with two or more risk characteristics had significantly shorter 5-year relapse-free survival compared with patients with one or no risk characteristics (55.8 vs. 91.8%; log-rank P=0.0006). We concluded that low TP expression is an independent predictive factor for poor prognosis in colorectal cancer. Therefore, determining TP expression may help to improve recurrence risk stratification in patients with stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines.

Perioperative variations in indices derived from noninvasive assessments to detect postmastectomy lymphedema.

OBJECTIVE: This study aimed to clarify the variations in indices derived from noninvasive assessments for the early detection of postmastectomy lymphedema (LE) from 1 month preoperatively until 2 years postoperatively. METHODS: In total, 120 patients who underwent surgery for breast cancer in our institution were prospectively followed up with a questionnaire for arm swelling as well as with tape measurements, bioimpedance analysis (BIA), and skin and subcutaneous tissue ultrasound at 1 month before and 3, 6, 12, 18, and 24 months after surgery. RESULTS: Ninety-seven patients completed the study. Among 93 patients who did not present with LE, 9% complained of arm swelling even before surgery, and the incidence peaked at 17% at 6 months after surgery. There were no differences in the circumferences of the upper arm, forearm, and hand between sides throughout the study period. However, the postoperative circumference values of the upper arm only on the operation side were slightly increased compared with the preoperative values. The mean excess fluid in the arm on the operation side compared with the contralateral side, as assessed by BIA, was nearly zero throughout the study period. There were no differences in subcutaneous echogenicity or skin and subcutaneous thicknesses between the sides throughout the study period. However, time-dependent increases in subcutaneous thicknesses were noticed on both sides. Four patients (4.1%) developed LE. In three of these patients, abnormality in the BIA was recorded 6 to 12 months before presentation. Immediately after presentation, the common findings included BIA abnormality and increased subcutaneous echogenicity and skin thickness in the medial forearm. CONCLUSIONS: In this study, a complaint of arm swelling was not sensitive enough for detection of the early onset of LE because a certain number of patients constantly complained of this symptom. Measurements of circumference might help in the diagnosis of LE onset, but this method is not specific enough because these measurements are also affected by various factors. However, BIA and skin and subcutaneous ultrasound were identified as potential tools for the early detection of LE.

Establishment of a Screening Method for Epstein-Barr Virus-Associated Gastric Carcinoma by Droplet Digital PCR.

BACKGROUND: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is classified as one of the molecular subtypes of gastric cancer. We used droplet digital polymerase chain reaction (ddPCR) to enable highly sensitive and quantitative detection of EBV. METHODS: EBV-DNA load was calculated based on the copy number of the BamH1-W fragment of EBV by ddPCR, and the cut-off value of EBV-DNA load was set. We conducted both ddPCR and EBER1 ISH to examine whether their results coincided in 158 gastric cancer specimens of unknown EBV status. We prepared 26 biopsy specimens and 49 serum samples including EBVaGC and assayed them by ddPCR. RESULTS: The median values of EBV-DNA load for EBVaGC and EBV-negative control were 17.0 and 0.00308, respectively. A cut-off value of 0.032 was determined for which the sensitivity was 1. Among the 158 gastric cancer specimens, 14 lesions were judged as EBV-positive by the 0.032 cut-off value determined by ddPCR. The results of ddPCR and EBER1 ISH were in complete agreement. Even when using a biopsy specimen as a sample for ddPCR, the EBV-DNA load of all EBVaGCs was larger than the cut-off value. CONCLUSIONS: We established a new method of diagnosing EBVaGC from tissue samples by ddPCR.

Loss of skeletal muscle mass after curative gastrectomy is a poor prognostic factor.

Sarcopenia has been reported to relate to poor prognosis in various malignant cancer types. The present study aimed to clarify the prognostic impact of skeletal muscle mass (SMM) loss after curative gastrectomy in patients with gastric cancer. A total of 119 patients who underwent curative gastrectomy for gastric cancer between 2009 and 2016 were analyzed. The SMM loss at 6 months postoperatively compared with the SMM prior to surgery was calculated using the hospital records. The median loss of SMM was 3.8%. Multivariate logistic regression analysis demonstrated that total gastrectomy was a significant and independent risk factor for SMM loss of ≥5% (odds ratio=2.58; P=0.02). Results from multivariate analysis using stepwise Cox proportional hazards regression indicated that the following factors were significantly associated with shorter overall survival after curative gastrectomy: Age [>70 years; hazard ratio (HR)=2.46, P=0.04], TNM stage (≥2; HR=2.65, P=0.04) and loss of SMM (≥5%; HR=2.57, P=0.03). The present findings suggested that loss of SMM after curative gastrectomy for gastric cancer is an independent predictive factor for poor prognosis.

Laparoscopic low anterior resection for rectal cancer after Whitehead's hemorrhoidectomy: A case report.

A 65-year-old man presented with bloody stool. Colonoscopy revealed a raised tumor in the rectum, above the peritoneal reflection. He underwent endoscopic mucosal resection, but the pathological findings suggested the possibility of residual cancer. We performed laparoscopic low anterior resection using a circular stapling instrument for additional curative surgery. However, we could not insert the shaft of the endoscopic circular stapler from the anus because of anal stenosis due to Whitehead's hemorrhoidectomy the patient had undergone 20 years earlier. Therefore, we planned to use a linear stapler to insert an anvil into the rectum. The cartridge-carrying instrument was inserted from the sigmoidal side, and we performed a side-to-end anastomosis. The patient was discharged without anastomotic leakage or defecation disorder. We present this case because laparoscopic low anterior resection for rectal cancer with anal stenosis has not been previously reported.

Dclk1 Inhibition Cancels 5-FU-induced Cell-cycle Arrest and Decreases Cell Survival in Colorectal Cancer.

BACKGROUND/AIM: 5-Fluorouracil (5-FU) is frequently used in colorectal cancer treatment, but with limited success. The aim of the present study was to explore the cytotoxic effects of 5-FU, in combination with inhibition of doublecortin-like kinase 1 (Dclk1), a tumor stem cell marker that regulates pro-survival signaling in colorectal cancer cells, in the human colon cancer cell line, COLO-320. MATERIALS AND METHODS: The effects of 5-FU treatment plus Dclk1 inhibition on the phosphorylation of checkpoint kinase 1 (Chk1), cell cycle, DNA damage, apoptosis, and cell survival in COLO-320 cells were evaluated. RESULTS: Combined treatment with 5-FU and a Dclk1 inhibitor, LRRK2-IN-1 (LRRK), decreased 5-FU-induced phosphorylation of Chk1 and canceled 5-FU-induced cell-cycle arrest at the S phase. Combined treatment with 5-FU and LRRK failed to induce poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, but tended to decrease cell survival compared to individual treatment with 5-FU or LRRK. CONCLUSION: These results indicate that a combination of 5-FU and LRRK may be an effective, novel approach for colorectal cancer therapy.

Early laparoscopic cholecystectomy for acute gangrenous cholecystitis.

Treatment of severe acute cholecystitis by laparoscopic cholecystectomy remains controversial because of technical difficulties and high rates of complications and conversion to open cholecystectomy. We investigated whether early laparoscopic cholecystectomy is appropriate for acute gangrenous cholecystitis. Pathologic diagnoses and outcomes were analyzed in patients who underwent laparoscopic or open cholecystectomy at our hospital, January 2002 to September 2005. Of 30 patients with acute gangrenous cholecystitis, 16 underwent early laparoscopic cholecystectomy, 10 underwent open cholecystectomy, and 4 were converted to open cholecystectomy (conversion rate, 20.0%). There was no significant difference in operation time or intraoperative bleeding. The requirement for postoperative analgesics was significantly lower (6.4+/-7.3 vs. 1.5+/-1.2 doses, P<0.05) and hospital stay significantly shorter (8.6+/-2.1 vs. 15.6+/-6.3 d, P<0.01) after laparoscopic cholecystectomy. There were no postoperative complications in either group. Thus, early laparoscopic cholecystectomy seems appropriate for acute gangrenous cholecystitis. Conversion to open cholecystectomy may be required in difficult cases with complications.

JAB1-STAT3 activation loop is associated with recurrence following 5-fluorouracil-based adjuvant chemotherapy in human colorectal cancer.

Jun activation domain-binding protein 1 (JAB1) has been shown to have multiple roles in tumorigenesis, including the degradation of tumor suppressor proteins such as p53, Smad7, Runx3 and the cyclin-dependent kinase inhibitor p27Kip1, and the activation of oncogenic transcription factors, such as c-Jun and hypoxia-inducible factor-1α. In addition, our previous study revealed that JAB1 positively regulates signal transducer and activator of transcription 3 (STAT3) DNA-binding activity in human colon cancer cells. In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop. Furthermore, high JAB1 expression is associated with a poor prognosis in numerous malignant carcinomas. However, the association between JAB1 expression and prognosis in colorectal cancer remains unclear. The aim of the present study was to elucidate the association between JAB1 and STAT3 expression and recurrence in colorectal cancer. In the present study, it was found that high JAB1 expression in primary colorectal cancer tissues is an independent predictor of recurrence following 5-fluorouracil (5-FU)-based adjuvant chemotherapy in colorectal cancer patients, and that high expression of both JAB1 and STAT3 in primary colorectal cancer tissues is associated with a lower recurrence-free survival rate following 5-FU-based adjuvant chemotherapy compared to high expression of only JAB1 or STAT3. Overall, these results suggest that JAB1 is a novel predictive marker of recurrence following 5-FU-based adjuvant chemotherapy in colorectal cancer patients, and that the JAB1-STAT3 activation loop may be a potential therapeutic target in recurrent colorectal cancer following 5-FU-based adjuvant chemotherapy.

Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells.

Although gemcitabine (GEM) is frequently used in the treatment of pancreatic cancer, the effects are limited. To increase the inhibitory effect of GEM, the identification of a molecular target is needed. Recent studies have revealed that doublecortin-like kinase 1 (Dclk1) positively regulates tumor growth, invasion, metastasis, factors related to epithelial-mesenchymal transition (EMT), pluripotency, angiogenesis, and anti-apoptosis in pancreatic cancer cells. Therefore, Dclk1 is a potential therapeutic target for pancreatic cancer. However, the Dclk1-signaling pathway including its substrate proteins remains to be elucidated. To identify the candidate substrate proteins phosphorylated by Dclk1, we performed a cancer-related phosphorylated protein microarray using Dclk1-inhibited MIA Paca2 cells. Expression levels of phosphorylated cdc25A (p-cdc25A) and phosphorylated Chk1 (p-Chk1), belonging to the ATR pathway, were decreased by treatment with Dclk1 inhibitor LRRK2-IN-1 (LRRK), indicating Dclk1 involvement in the ATR pathway. Consistent with this finding, the GEM-induced p-Chk1 expression was significantly decreased by treatment with LRRK. Notably, combined treatment with GEM and LRRK allowed cell cycle progression without arresting at S phase, while individual treatment with GEM induced cell cycle arrest at S phase. In addition, combined treatment with GEM and LRRK increased the number of γ-H2AX-positive cells compared with that upon individual treatments. Moreover, LRRK alone, and combined treatment with GEM and LRRK, induced caspase-3 activation and PARP1 cleavage, in contrast to treatment with GEM alone. Finally, combined treatment with GEM and LRRK significantly reduced cell survival compared to individual treatment with GEM. These results indicate that Dclk1 inhibition in combination with GEM treatment offers a novel approach to treat pancreatic cancer cells.

Histidine decarboxylase (HDC)-expressing granulocytic myeloid cells induce and recruit Foxp3+ regulatory T cells in murine colon cancer.

The colorectal tumor microenvironment contains a diverse population of myeloid cells that are recruited and converted to immunosuppressive cells, thus facilitating tumor escape from immunoediting. We have identified a genetically and functionally distinct subset of dynamic bone marrow myeloid cells that are characterized by histidine decarboxylase (HDC) expression. Lineage tracing in Hdc-CreERT2;R26-LSL-tdTomato mice revealed that in homeostasis, there is a strong bias by HDC+ myeloid cells toward the CD11b+Ly6Ghi granulocytic lineage, which was accelerated during azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colonic carcinogenesis. More importantly, HDC+ myeloid cells strongly promoted colonic tumorigenesis, and colon tumor progression was profoundly suppressed by diphtheria toxin A (DTA)-mediated depletion of HDC+ granulocytic myeloid cells. In addition, tumor infiltration by Foxp3+ regulatory T cells (Tregs) was markedly impaired following HDC+ myeloid cell depletion. We identified an HDC+ myeloid-derived Cxcl13/Cxcr5 axis that mediated Foxp3 expression and Treg proliferation. Ablation of HDC+ myeloid cells or disruption of the Cxcl13/Cxcr5 axis by gene knockdown impaired the production and recruitment of Tregs. Cxcl13 induction of Foxp3 expression in Tregs during tumorigenesis was associated with Stat3 phosphorylation. Overall, HDC+ granulocytic myeloid cells affect CD8+ T cells directly and indirectly through the modulation of Tregs and thus appear to play key roles in suppressing tumoricidal immunity.

Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis.

The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

[All-trans retinoic acid-induced erythema nodosum in acute promyelocytic leukemia].

A 24-year-old woman with acute promyelocytic leukemia was treated with all-trans retinoic acid (ATRA) as a remission induction therapy. After pneumonia in the neutropenic period was successfully treated with antibiotic treatment, there was recurrence of high fever alone, followed by the appearance of erythema nodosum with pain in her upper limbs on day 25 of ATRA therapy. Skin biopsy neither revealed infiltration of leukemic cells nor suggested Sweet's syndrome. We considered the eruptions to be associated with ATRA, and prednisolone (30 mg/day for 5 days) was administered. Although the administration of ATRA was continued until complete remission of the leukemia, the erythema nodosum rapidly disappeared following short-term steroid therapy and no recurrence was observed. ATRA-induced erythema nodosum is rare, however it should be recognized as a possible adverse effect in ATRA therapy.

Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche.

The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.