Prostaglandin E2/EP signaling in the tumor microenvironment of colorectal cancer

This article belongs to the Special Issue Molecular and Translational Research on Colorectal CancerThe number of colorectal cancer (CRC) patients is increasing worldwide. Accumulating evidence has shown that the tumor microenvironment (TME), including macrophages, neutrophils, and fibroblasts, plays an important role in the development and progression of CRC. Although targeting the TME could be a promising therapeutic approach, the mechanisms by which inflammatory cells promote CRC tumorigenesis are not well understood. When inflammation occurs in tissues, prostaglandin E2 (PGE2) is generated from arachidonic acid by the enzyme cyclooxygenase-2 (COX-2). PGE2 regulates multiple functions in various immune cells by binding to the downstream receptors EP1, EP2, EP3, and EP4, and plays an important role in the development of CRC. The current therapies targeting PGE2 using non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors have failed due to the global prostanoid suppression resulting in the severe adverse effects despite the fact they could prevent tumorigenesis. Therefore, therapies targeting the specific downstream molecules of PGE2 signaling could be a promising approach. This review highlights the role of each EP receptor in the TME of CRC tumorigenesis and their therapeutic potential

CD56-positive cells with or without synaptophysin expression are recognized in the pancreatic duct epithelium: a study with adult and fetal tissues and specimens from chronic pancreatitis.

We observed the distribution of CD56+ epithelial cells in the pancreatic duct system using 25 fetal, one infantile, 3 normal adult, 4 diabetic, and 8 chronically inflamed pancreatic tissue samples. In the early stage of gestation (12 to 17 weeks), CD56+ cells were commonly seen in the immature tubular structures. They were often continuous to pancreatic islets, and their distribution was similar to that of synaptophysin (Syn)+ cells, suggesting that they are precursors of islet neogenesis. Their number decreased in proportion to gestational age. Instead, from 24 weeks of gestation, luminal cell clusters that were common in interlobular ducts revealed CD56+. These cell clusters were unrelated to islet neogenesis and Syn expression. Similar CD56+ luminal cell clusters were also observed in cases of chronic pancreatitis, whereas they were scarce in normal adult and diabetic tissues. CD56+ cells were also occasionally seen in intralobular ducts, intercalated ducts, and centroacinar cells in cases of chronic pancreatitis. We conclude that there are two types of CD56+ epithelial cells in the pancreatic duct system: CD56+ endocrine cells are numerous during the early stage of gestation, when islet neogenesis appears, while CD56+ luminal cells may represent developmental and regenerative changes of pancreatic ducts.</p

Induction of Ptp2 and Cmp2 protein phosphatases is crucial for the adaptive response to ER stress in Saccharomyces cerevisiae

Expression control of the protein phosphatase is critically involved in crosstalk and feedback of the cellular signaling. In the budding yeast ER stress response, multiple signaling pathways are activated and play key roles in adaptive reactions. However, it remains unclear how the expression level of the protein phosphatase is modulated during ER stress response. Here, we show that ER stress increases expression of Ptp2 tyrosine phosphatase and Cmp2 calcineurin phosphatase. Upregulation of Ptp2 is due to transcriptional activation mediated by Mpk1 MAP kinase and Rlm1 transcription factor. This induction is important for Ptp2 to effectively downregulate the activity of Hog1 MAP kinase. The budding yeast genome possesses two genes, CMP2 and CNA1, encoding the catalytic subunit of calcineurin phosphatase. CMP2 is more important than CNA1 not only in ER stress response, but also in salt stress response. Higher promoter activity of CMP2 contributes to its relative functional significance in ER stress response, but is less important for salt stress response. Thus, our results suggest that expression control of Ptp2 and Cmp2 protein phosphatases at the promoter level is crucial for adaptive responses to ER stress

Influences of small-scale oscillations on growth inhibition and ultrastructural changes of Microcystis cells

We investigated the effects of small-scale oscillation (SSO) on toxic Microcystis cells. The oscillating device was made of silicon with two axes that had a diameter of similar to 40 mm, and a frequency of 2.5 Hz was observed at 150 rpm. The SSO was effective in inhibiting Microcystis growth. Microcystin release was not observed, whereas cell density barely increased in the oscillating group. Cell size and morphology of the oscillating group were no different from the control group. However, cell quotas of chl.a and microcystin in the oscillating group were half the level of the control group. Crucially, a number of large-sized holes were observed and layered long linear thylakoids were rarely observed in the oscillating group. Therefore, SSO was found to be very effective in Microcystis growth inhibition, and it caused ultrastructural changes without damage to the cell membrane and subsequent microcystin release.ArticleJournal of Environmental Science and Health, Part A.53(13):1161-1166(2018)journal articl

Pathoetiology and prevention of NIDDM Lessons from the OLETF rat *

The OLETF rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the β-cell proliferation per se is the primary pathogenetic event in this model rat. To clarify this matter, we used partially pancreatectomized rats as a model. Male rats of 6weeks of age were allocated at random to two groups:70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into 4 subgroups by the date of sacrifice after surgery. Sustained hyperglycemia was evident in the Px OLETF rats after surgery. This was associated with insufficient proliferation of β-cells, characterized by a decrease in β-cell labeling with 5-bromo-2'deoxyuridine in proportion to a decrease in β-cell mass and reduction in insulin content in the remnant pancreas. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing β-cell proliferation. These findings suggest that OLETF rats have a poor capacity for proliferation of pancreatic β-cells, and that this change may be the critical pathogenetic event prior to the onset of overt diabetes. OLETF rats following long-term caloric restriction and spontaneous exercise training show normal glucose tolerance accompanied by an increase in GIR as shown by a euglycemic clamp. Both exercise training and caloric restriction normalize the abnormalities in the pancreas such as marked hypertrophy of islets and hyperplasia of connective tissues in islets. It is particularly noteworthy that exercise training significantly elevated the β-cell mass / body weight ratio. This evidence obtained from OLETF rats may be of value when the mechanism of diet and exercise effects on diabetic patients are considered

Disseminated Nontuberculous Mycobacterial Infection in a Patient with Anti-IFN-γ Autoantibodies

We treated a 72-year-old Japanese female with sustained high fever and overall body exhaustion. An infectious liver cyst and right lung pneumonia were suspected causes. Hepatic cystectomy and various antibiotics did not resolve symptoms. Pneumonia exacerbation and ascitic fluid retention, left lumbar spinal osteomyelitis, and peri-gastric lymph node abscess penetrating the stomach were observed. Mycobacterium avium was identified in sputum, ascites, vertebral body abscess puncture specimen, and pus mucus secretion in the stomach. We diagnosed a disseminated nontuberculous mycobacterial infection. She seemed immunocompetent, without signs of AIDS or hematological malignancy. Serum anti-IFN-γ autoantibodies tested positive and were suspected to be involved in the illness onset

Optimal Place for Precordial Stethoscope Attachment in Nonintubated Children under Two Years of Age: An Observational Trial

Background: The precordial stethoscope is a non-invasive monitoring method in pediatric anesthesia. We previously investigated optimal place for its attachment among intubated children under two years old. Now we also did in nonintubated children under two years old. Methods: Twenty-five patients who underwent general anesthesia in our institution were involved in this study. Lung and heart sounds via precordial stethoscope were recorded (MP3 format) at the six places: Site A (paratracheal region), B (suprasternal notch), C (between place of the nipple and clavicle on the left midclavicular line), D (between place of the costal arch and nipple on the left midclavicular line), E (horizontal level of Site D on the left midaxillary line), and F (epigastric fossa). Two blinded evaluators scored random sorted lung and heart sounds on a 10-point scale (0: cannot hear at all and 10: can hear clearly) individually. Results: Statistically significant differences were observed between Sites A: 10.0 (8.5–10.0), B: 9.0 (2.5–9.5), C: 8.0 (6.5-9.0) and D: 1.5 (1.0–6.5), E: 4.5 (1.5–7.0), F: 1.0 (0.0–4.5) for lung sounds and between Sites B: 9.0 (5.0–10.0), C: 9.5 (8.0–10.0), D: 9.0 (4.5–9.5) and A: 0.0 (0.0–0.0), E: 0.5 (0.0–2.5), F: 0.5 (0.0–0.5) for heart sounds. Conclusion: Site C is the optimal place for precordial stethoscope attachment for children under two years of age during general anesthesia

Mycophenolate mofetil for immune checkpoint inhibitor‐related hepatotoxicity relapsing during dose reduction of corticosteroid: A report of two cases and literature review

[Background] Immune checkpoint inhibitors (ICIs) sometimes cause immune-related liver injury, which can lead to cessation of treatment, hospitalization, and even mortality. Although high-dose corticosteroids are usually effective in treatment of ICI-related liver injury, one fifth of affected patients require additional immunosuppressive therapy. It remains uncertain how best to treat ICI-related liver injury that relapses under corticosteroid therapy after temporary remission. [Case] Here we report two cases of ICI-related liver injury successfully treated with mycophenolate mofetil (MMF). In the first case, a 74-year-old man with stage IIIA lung cancer underwent curative chemoradiotherapy. After the second infusion of durvalumab, grade 3 ICI-related liver injury (mixed pattern) developed. In the second case, a 46-year-old man with stage IVB lung cancer received pembrolizumab-containing chemotherapy. After the first cycle, grade 2 ICI-related hepatitis developed. In the both cases, liver injury improved with high-dose prednisolone but relapsed during tapering of the drug. After liver biopsy was performed to confirm the diagnosis of ICI-related liver injury, MMF (2000 mg/day) was added. MMF was effective for both patients and permitted discontinuation or reduction of prednisolone. [Conclusion] MMF appears to be an appropriate treatment option for ICI-related liver injury that respond to high-dose corticosteroids but relapse during steroid tapering

Strangulated small bowel obstruction caused by isolated obturator nerve and pelvic vessels after pelvic lymphadenectomy in gynecologic surgery: two case reports

[Background] Although small bowel obstruction (SBO) is a major complication occurring after abdominal surgery, few reports have described strangulated SBO after pelvic lymphadenectomy (PL). This report describes two cases of strangulated SBO caused by a skeletonized obturator nerve and pelvic vessels after laparoscopic PL during gynecologic surgery. [Case presentation] Case 1: A 57-year-old woman with endometrial cancer underwent a laparoscopic semi-radical total hysterectomy with PL. Nine months after the operation, she visited our emergency room complaining about subacute pain spreading in the right groin, right buttock, and dorsal part of the right thigh. She had no abdominal pain. Although her symptoms were not typical, computed tomography (CT) revealed strangulated SBO in the right pelvis. Laparoscopic surgery revealed that the small bowel was ischemic. Then we converted to open surgery. We transected the right obturator nerve and umbilical artery, which constructed an internal hernia orifice in the right pelvis, followed by resection of the ischemic small bowel. Fortunately, during 6-month follow-up, she showed only slight difficulty in walking as a postoperative complication. Case 2: A 62-year-old woman with cervical cancer underwent laparoscopic radical hysterectomy with PL. Six months after the operation, she visited our hospital emergently because of sudden onset of abdominal pain and vomiting. CT showed strangulated SBO. Urgent laparoscopic surgery exhibited the incarcerated small bowel at the right pelvis. Consequently, we converted to open surgery. The terminal ileum was detained into the space constructed by the right umbilical artery. We cut the umbilical artery and performed ileocecal resection. After the surgery, she was discharged with no complication or sequela. [Conclusion] When examining a patient after PL who complains of severe pain or symptoms, one should consider the possibility of PL-related SBO, even if the pain is apparently atypical for SBO