Enhanced expression of the M2 isoform of pyruvate kinase is involved in gastric cancer development by regulating cancer-specific metabolism.

Recent studies have indicated that increased expression of the M2 isoform of pyruvate kinase (PKM2) is involved in glycolysis and tumor development. However, little is known about the role of PKM2 in gastric cancer (GC). Therefore, we examined the expression and function of PKM2 in human GC. We evaluated PKM1 and PKM2 expression by quantitative RT-PCR in gastric tissues from 10 patients who underwent gastric endoscopic submucosal dissection, 80 patients who underwent gastrectomy, and seven healthy volunteers, and analyzed the correlation with clinicopathological variables. To assess the function of PKM2, we generated PKM2-knockdown GC cells, and investigated the phenotypic changes. Furthermore, we examined the induction of PKM2 expression by cytotoxin-associated gene A (CagA), a pathogenic factor of Helicobacter pylori, using CagA-inducible GC cells. We found that PKM2 was predominantly expressed not only in GC lesions but also in the normal gastric regions of GC patients and in the gastric mucosa of healthy volunteers. The PKM2 expression was significantly higher in carcinoma compared to non-cancerous tissue and was associated with venous invasion. Knockdown of PKM2 in GC cells caused significant decreases in cellular proliferation, migration, anchorage-independent growth, and sphere formation in vitro, and in tumor growth and liver metastasis in vivo. The serine concentration-dependent cell proliferation was also inhibited by PKM2 silencing. Furthermore, we found that PKM2 expression was upregulated by CagA by way of the Erk pathway. These results suggested that enhanced PKM2 expression plays a pivotal role in the carcinogenesis and development of GC in part by regulating cancer-specific metabolism.

[An Increase in Cases of Bladder Tamponade Due to Cystitis Among Elderly Women and Clinical Background Factors].

Bladder tamponade is thought to be caused mainly by bladder cancer or radiation cystitis. However, in women, it may often be caused by cystitis in clinical settings. This has not been noted in previous reports of bladder tamponade in Japan. Thus, we retrospectively analyzed the clinical features of 83 male and 41 female patients with bladder tamponade. Seventy-four patients were treated at Nishi-Kobe Medical Center between April 2005 and March 2015, and 50 were treated at Shizuoka City Shizuoka Hospital between November 2008 and March 2015. The patients'median age was 80 years. The cause of bladder tamponade was urological malignancies in 33 of the 83 male patients (40%), benign prostatic hyperplasia in 20 of the 83 male patients (24%), and cystitis in 33 of the 41 female patients (80%). Compared with the men, the women with bladder tamponade were significantly older and the proportion of patients with cerebrovascular disease, diabetes, and dementia was higher. In addition, more women were nursing home residents, with a higher rate of voiding with diapers and antithrombotic use than men. Causative strains of cystitis were diverse, and some were antibiotic resistant. Most of the cases of bladder tamponade in the women occurred in the elderly and were caused by cystitis. In an aging society, increases in the incidences of chronic, complicated cystitis due to impaired independent micturition, dysuria, and systemic diseases such as diabetes, and increased use of antithrombotic drugs may contribute to bladder tamponade in women.

Role for RalA downstream of Rac1 in skeletal muscle insulin signalling.

Insulin-stimulated glucose uptake in skeletal muscle is mediated by the translocation of the glucose transporter GLUT4 from intracellular storage sites to the plasma membrane. The small GTPase Rac1 has been implicated in this insulin signalling, but the mechanism whereby Rac1 stimulates GLUT4 translocation remains obscure. In the present study, we examined the role of the small GTPase RalA downstream of Rac1 in skeletal muscle fibres isolated from genetically modified mice. A dominant-negative mutant of RalA, when ectopically overexpressed, significantly reduced GLUT4 translocation in response to insulin or either one of constitutively activated mutants of Rac1 and its upstream regulators, including the guanine-nucleotide-exchange factor FLJ00068, the protein kinase Akt2 and phosphoinositide 3-kinase. Constitutively activated Rac1 also failed to induce GLUT4 translocation in mouse skeletal muscle fibres in which the expression of RalA was abrogated by specific siRNA molecules. Furthermore, we applied a novel approach to detect the activated form of RalA in situ by immunofluorescence microscopy of mouse skeletal muscle fibres, demonstrating that constitutively activated mutants of Rac1 and its upstream regulators as well as insulin indeed cause the activation of RalA. Notably, this RalA activation was remarkably impaired in rac1-deficient skeletal muscle fibres. Taken together, these results provide evidence that RalA is indeed activated and involved in the regulation of GLUT4 translocation in response to insulin downstream of Rac1 in mouse skeletal muscle.

A Japanese case of lymphocytic esophagitis.

We report the case of a 68-year-old Japanese man diagnosed with lymphocytic esophagitis (LE), a rare disease associated with refractory dysphagia. He has had severe dysphagia and heartburn since 2007. Findings of esophagogastroduodenoscopy (EGD) carried out by a local physician in 2010 showed pale mucosa with white exudate and lateral furrows in the esophagus. He was referred to Tohoku University Hospital in 2012, because the symptoms did not improve, despite regular use of a proton pump inhibitor (PPI). At that time, EGD revealed the coexistence of a slight stricture in the upper esophagus, the histopathological findings of which included a predominantly peri-papillary distribution of abundant, infiltrating CD3+ /CD4+ /CD8+ /CD20- lymphocytes without any granulocytes (CD4+  : CD8+  = 3.3:1). These were consistent with a diagnostic criteria of LE. Thereafter, severe dysphagia with food impaction occurred twice a month, despite the long-term use of a PPI, and EGD showed worsened strictures, where endoscopic ultrasonography findings showed marked circumferential thickness of the mucosal and submucosal layers. Then, one session of endoscopic balloon dilatation dramatically improved the dysphagia. Accordingly, LE should be considered an important differential diagnosis of refractory dysphagia based on the characteristic features of endoscopic and pathological findings.

Family history, body mass index and survival in Japanese patients with stomach cancer: a prospective study.

Family history and nutritional status may affect the long-term prognosis of stomach cancer, but evidence is insufficient and inconsistent. To clarify the prognostic factors of stomach cancer, we conducted a prospective study of 1,033 Japanese patients with histologically confirmed stomach cancer who were admitted to a single hospital between 1997 and 2005. Family history of stomach cancer and pretreatment body mass index (BMI) were assessed using a self-administered questionnaire. Clinical data were retrieved from a hospital-based cancer registry. All patients were completely followed up until December, 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated according to family history in parents and siblings and BMI category. During a median follow-up of 5.3 years, 403 all-cause and 279 stomach cancer deaths were documented. Although no association with family history was observed in the patients overall, analysis according to age group found an increased risk of all-cause death associated with a history in first degree relatives (HR = 1.61, 95% CI: 0.93-2.78, p = 0.09) and with a parental history (HR = 1.86, 95% CI: 1.06-3.26) among patients aged under 60 years at diagnosis. BMI was related to all-cause and stomach cancer death among patients aged 60 and over, showing a J-shaped pattern (HR of all-cause death = 2.28 for BMI < 18.5; HR = 1.61 for 25 ≤ vs. ≥ 23.0 to < 25.0 kg/m(2)). A family history of stomach cancer, especially parental history, may affect mortality among younger stomach cancer patients, whereas nutritional status may be a prognostic factor in older patients.

[Cholesterol crystal embolization following urinary diversion: a case report].

Cholesterol crystal embolization (CCE) is a cardiovascular disorder with poor prognosis, causing multiple organ failure. The primary pathological condition of the disease is embolization of cholesterol crystals in peripheral vessels. We report a case of CCE following urinary diversion. The patient is a 82-year-old male with history of hypertention, pneumonectasia, interstitial pneumonia, and heavy smoking. He was afflicted with advanced bladder cancer. He underwent urinary diversion, and had been scheduled for palliative radiotherapy. The next day, he developed thromboembolism of the left lower leg as acomplication of urinary diversion. Thrombectomy by endovascular catheter procedure was performed immediately, and anticoagulant therapy was started. The day after the thrombectomy, his lower legs showed livedo reticularis and toes showed cyanosis (blue toe). Since the laboratory data showed acute deterioration in renal function, hemodialysis was initiated. Three days after the thrombectomy he died of multiple organ failure. At autopsy, diffuse atherosclerosis of the aorta was observed, and cholesterol crystalemboli were found in the skin of the left foot ; and, the diagnosis of CCE was confirmed. This case suggests that tissue examinations for early diagnosis and stopping anticoagulant therapy are preferred when CCE is suspected.

Sterile versus non-sterile gloves during cystoscopy: A randomized prospective single-blind study.

Objective: The objective of this study is to evaluate the need for sterile gloves during cystoscopy by comparing the incidence of UTI symptoms between patients in whom the procedure is performed with non-sterile gloves with those performed with non-sterile gloves. Patients and Methods: This study had a randomized, prospective, single-blind design and included patients aged >20 years who underwent cystoscopy in either of two outpatient clinics between September 2015 and November 2021. The patients were allocated to a sterile group or a non-sterile group. Only the urologists were aware of whether or not the gloves were sterile. The patients were instructed to report any symptoms suggestive of UTI after cystoscopy. Results: A total of 1258 patients were enrolled in the sterile group and 1376 in the non-sterile group. Symptoms of UTI were reported by six patients (0.48%) in the sterile group and six (0.44%) in the non-sterile group. The between-group difference was not statistically significant (p = 0.88). Conclusion: It is not necessary to use sterile gloves during routine cystoscopy.

Durable gelfoams stabilized by compressible nanocomposite microgels.

Although hydrogel microspheres (microgels) are useful as emulsion stabilizers, typical microgels cannot stabilize foams over a prolonged period of time. Here, we found that compressible nanocomposite microgels with solid nanoparticles can overcome undesired desorption of microgels from the air/water interface of bubbles, and form highly durable, microgel-surrounded foams (gelfoams).

[A case of early cystic duct carcinoma concomitant with xanthogranulomatous cholecystitis (XGC)].

We reported a case of early cystic duct carcinoma concomitant with xanthogranulomatous cholecystitis (XGC). This case was a 72-year-old man in whom thickening of the gallbladder wall was pointed out an abdominal ultrasonography and elevation of the CA19-9 level was detected at a local clinic. Endoscopic ultrasonography and CT demonstrated a mass in the cystic duct. Mapping biopsy using peroral cholangioscopy (POCS) revealed a diagnosis of cystic carcinoma with superficial flat growth, therefore a pylorus-preserving pancreatoduodenectomy was performed. Histopathological diagnosis was well differentiated papillotubular adenocarcinoma with superficial flat spread and the thickening of the gallbladder wall was XGC. A case of early cystic duct carcinoma concomitant with XGC is extremely rare.

[Regression of MALT lymphoma of the rectum after Helicobacter pylori eradication therapy in a patient negative for Helicobacter pylori].

A 53-year-old woman was referred to our hospital for further examination of a rectal polypoid lesion. Colonoscopy revealed a submucosal tumor in the rectum (Ra) and a diagnosis of MALT lymphoma was made on the histological examination of the biopsy specimens and Southern blot analysis of the immunoglobulin heavy chain gene rearrangement. Although the patient was negative for Helicobacter pylori, H. pylori eradication therapy was performed. Colonoscopy 3 months after the eradication therapy showed disappearance of the rectal tumor. H. pylori eradication appears to be a useful treatment for not only H. pylori-positive colonic MALT lymphoma but H. pylori-negative colonic MALT lymphoma.

Overexpression of the transcriptional coregulator Cited2 protects against glucocorticoid-induced atrophy of C2C12 myotubes.

In patients with various catabolic conditions, glucocorticoid excess induces skeletal muscle wasting by accelerating protein degradation via the ubiquitin-proteasome pathway. Although the transcriptional coactivator p300 has been implicated in this pathological process, regulatory mechanisms and molecular targets of its action remain unclear. Here we show that CREB-binding protein (CBP)/p300-interacting transactivator with ED-rich tail 2 (Cited2), which binds to the cysteine-histidine-rich region 1 of p300 and CBP, regulates muscle mass in vitro. Adenovirus-mediated overexpression of wild-type Cited2 significantly blocked morphological alterations of C2C12 myotubes with a concomitant decrease in myosin heavy chain protein in response to synthetic glucocorticoid dexamethasone, which were attributable to the reduced induction of atrophy-related ubiquitin ligases MuRF1 and MAFbx. These myotube-sparing effects were less pronounced, however, with a carboxyl-terminally truncated mutant of Cited2 that lacked the ability to bind p300. These results suggest that the gain of Cited2 function counteracts glucocorticoid-induced muscle atrophy through inhibition of proteolysis mediated by p300-dependent gene transcription.

Identification and characterization of an alternative promoter of the human PGC-1alpha gene.

The transcriptional regulator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) controls mitochondrial biogenesis and energy homeostasis. Although physical exercise induces PGC-1alpha expression in muscle, the underlying mechanism of this effect has remained incompletely understood. We recently identified a novel muscle-enriched isoform of PGC-1alpha transcript (designated PGC-1alpha-b) that is derived from a previously unidentified first exon. We have now cloned and characterized the human PGC-1alpha-b promoter. The muscle-specific transcription factors MyoD and MRF4 transactivated this promoter through interaction with a proximal E-box motif. Furthermore, either forced expression of Ca(2+)- and calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A, or the p38 mitogen-activated protein kinase (p38 MAPK) kinase MKK6 or the intracellular accumulation of cAMP activated the PGC-1alpha-b promoter in cultured myoblasts through recruitment of cAMP response element (CRE)-binding protein (CREB) to a putative CRE located downstream of the E-box. Our results thus reveal a potential molecular basis for isoform-specific regulation of PGC-1alpha expression in contracting muscle.

SHPS-1/SIRP1alpha contributes to interleukin-6 signalling.

The transmembrane glycoprotein signal regulatory protein/SHP2-substrate (SIRP1alpha/SHPS-1) has been implicated in growth factor- and cell adhesion-induced signalling. Here we report on the contribution of SIRP1alpha to IL-6 type cytokine signalling. SIRP1alpha binds the protein tyrosine phosphatase SHP2 upon treatment with interleukin-6 in a stimulation-dependent manner. Mouse embryonic fibroblasts expressing a SIRP1alpha protein which lacks the intracellular part show enhanced SHP2 phosphorylation and ERK1/2 activation in response to IL-6, suggesting that SIRP1alpha affects IL-6-signalling through SHP2. Whereas SHP2 phosphorylation is enhanced in SIRP1alpha-deficient cells STAT3 activation is delayed and STAT3-dependent gene induction is reduced which correlates with reduced STAT3 serine phosphorylation. Our results indicate that SIRP1alpha contributes to IL-6 signalling by counteracting SHP2 phosphorylation which consequently affects ERK-activation and STAT3-dependent transactivation as well as target gene expression. Our observations will help to understand the tight balance of MAPK- and STAT3-activation in response to IL-6 which was found to be misbalanced in many autoimmune diseases, inflammatory proliferative diseases and cancer.

[A case of pancreatic endocrine tumor developing from intraductal papillary mucinous neoplasm (IPMN)].

In March, 2004, a 64-year-old man was given a diagnosis of IPMN of the pancreas in postoperative CT of left shoulder blade chondrosarcoma. In October, 2007, because a tumor in the pancreas body was found, distal pancreatectomy was performed a diagnosis of the poorly differentiated adenocarcinoma. Histopathologic diagnosis revealed as pancreatic endocrine tumor and immunity dyeing was useful for differential diagnosis. A case of pancreatic endocrine tumor developing from IPMN has a possibility not rare for frequency, but few reports are available so far.

[A case of primary gastric mantle cell lymphoma].

Endoscopic examination of a 60-year-old man revealed multiple erosions in the gastric antrum. After 6 months, erosions also formed in the duodenal bulb and systemic lymph nodes become enlarged. After 20 months, the gastroduodenal erosions developed into mucosal ulcers, and the systemic lymph node swelling progressed. Histological examination of the neck lymph node showed mantle cell lymphoma (MCL). This result agreed with the results of the gastroduodenal biopsy. This case was diagnosed as recurrent primary gastric MCL in other areas, with systemic lymph node metastasis and bone marrow invasion. Hyper-CVAD (cyclophosphamide, doxorubicin, vincristine, and dexamethasone), high-dose methotrexate and cytarabine in combination with Rituximab and stem cell transplantation was performed. The gastroduodenal lesions and atypical cells in the bone marrow disappeared after 2 cycles of the chemotherapy. Metastatic lymph node swelling regressed after stem cell transplantation. We have had no evidence of recurrence for 50 months. Primary gastric MCL is very rare and cyclin D1 immunohistochemistry and FISH assay were very useful for the diagnosis of MCL.

Risk factors for cervical lymph node metastasis in endoscopically resected superficial hypopharyngeal cancers.

OBJECTIVE: Hypopharyngeal cancer is a head and neck cancer with a poor prognosis, and most cases show metastases on diagnosis. Cervical lymph node (LN) metastasis is a poor prognostic factor in hypopharyngeal cancer patients. The identification of risk factors for LN metastasis can help guide surgical treatment strategies for these patients. METHODS: This retrospective study included 93 superficial hypopharyngeal cancer patients with 109 histopathologically examined lesions treated by endoscopic resection between January 2007 and December 2017. Tumor thickness quantification, quantification of budding nests, immunostaining and other histopathological analyses in paraffin-embedded, formalin-fixed tissue sections (3-µm) of surgical specimens were performed by a certified pathologist. RESULTS: Cervical LN metastasis was positive in 18 out of 93 cases (19.3%) and 18 out of 109 lesions (16.5%). No differences were detected in patient characteristics between LN-positive and LN-negative cases, except for tumor thickness, which was significantly larger in LN-positive cases (3119.4±602.2µm vs. 1015.5±129.6µm, respectively; p<0.0001). Univariate analysis showed that tumor thickness ≥1000µm (odds ratio: 5.559, p=0.003), lesions with high budding grade (odds ratio: 5.188, p=0.01) and vascular invasion (odds ratio: 12.710, p=0.007) were significantly associated with cervical LN metastasis. Multivariate analysis revealed tumor thickness≥1000µm as the most significant risk factor for cervical LN metastasis in superficial hypopharyngeal cancer (odds ratio: 3.639, p=0.04). CONCLUSIONS: We demonstrate for the first time that high budding grade may serve as powerful predictors of LN metastasis and tumor thickness ≥1000µm is a significant risk factor for LN metastasis of superficial hypopharyngeal cancer. These results should be further examined in future larger scale studies.

Enhanced expression of semaphorin 3E is involved in the gastric cancer development.

Semaphorins and their receptors are abnormally expressed in various cancers, but little is known about the expression and function of semaphorin 3E (SEMA3E) and its receptor, plexin D1 (PLXND1), in gastric cancer development or metastasis. We evaluated SEMA3E and PLXND1 expression by quantitative RT-PCR in gastric tissues from 62 patients who underwent gastrectomy and analyzed the correlation between their expression and clinicopathological variables. To assess the function of SEMA3E, we generated human gastric cancer cell lines with suppressed or increased SEMA3E expression. The expression level of SEMA3E, but not PLXND1, was correlated with lymph node involvement and metastatic progression in gastric cancer. A significant association was observed between a high level of SEMA3E expression and poor differentiation or poor survival in the intestinal type of gastric cancer. SEMA3E knockdown in gastric cancer cells attenuated cell proliferation and metastatic ability in vitro and in vivo. Moreover, SEMA3E caused cell proliferation and anchorage-independent cell growth in the intestinal type of gastric cancer. These results suggested that SEMA3E is likely to be involved in the development of gastric cancer and might also be a therapeutic target for its treatment.

Downregulation of stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1) in advanced human hepatocellular carcinoma.

SAP-1 (stomach cancer-associated protein tyrosine phosphatase-1) is a transmembrane-type protein tyrosine phosphatase that has been implicated as a negative regulator of integrin-mediated signaling. The potential role of this enzyme in hepatocarcinogenesis has now been investigated by examining its expression in 32 surgically excised human hepatocellular carcinoma (HCC) specimens. Both immunohistochemical and immunoblot analyses revealed that normal liver tissue, as well as tissue affected by chronic hepatitis or cirrhosis, contained substantial amounts of SAP-1. The expression level of SAP-1 in 75% of well-differentiated HCCs was similar to or higher than that observed in the surrounding noncancerous tissue. In contrast, the abundance of SAP-1 in 85.7% of moderately differentiated HCCs and in all poorly differentiated HCCs was greatly reduced compared with that in the adjacent tissue. Indeed, SAP-1 was almost undetectable in 83.3% of poorly differentiated HCCs. Furthermore, expression of recombinant SAP-1 in two highly motile human HCC cell lines resulted in a change in morphology and a marked reduction in both migratory activity and growth rate. In conclusion, these results indicate that SAP-1 expression is downregulated during the dedifferentiation of human HCC, and that this downregulation may play a causal role in disease progression.

Mucinous cystic neoplasm in a young male patient.

A 25-year-old Japanese man was admitted to our hospital with a history of recurrent pancreatitis and a pseudocyst of the pancreas. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) revealed an encapsulated multilocular cystic mass 5 cm in diameter in the pancreatic tail. Endoscopic ultrasonography demonstrated a mural nodule, and endoscopic retrograde pancreatography showed a communication of the lesion with the main pancreatic duct. A neoplastic cystic tumor was suspected, and a resection of the body tail of the pancreas was performed. The lesion was a multilocular cyst having a common fibrous capsule and viscous content. Histologically, the cystic lesion was lined with a single layer of columnar cells with low-grade atypia. Ovarian-type stroma (OS) was confirmed, and it showed positive for antiestrogen receptor and antiprogesteron receptor staining. Based on these findings, the lesion was diagnosed as mucinous cystic neoplasm (MCN), an adenoma that shows extraordinarily high prevalence in women. Further study on the pathogenesis of MCN in male patients should be undertaken to elucidate the process of development.

Alternate-day Treatment with Crizotinib for Drug-induced Esophagitis and Liver Damage in a Patient with EML4-ALK Fusion Gene-positive Lung Adenocarcinoma.

A 44-year-old woman who was diagnosed with anaplastic lymphoma kinase-positive lung adenocarcinoma developed brain metastases, multiple spinal metastases and meningeal dissemination. Crizotinib was administered after the failure of first-line chemotherapy. Esophagitis and liver damage were induced by the twice-daily administration of crizotinib at 250 mg and 200 mg, respectively. The alternate-day administration of crizotinib (250 mg, twice daily) was able to control disease progression without any adverse effects for several months. We evaluated the relationship between the serum concentration of crizotinib and the development of esophagitis and liver damage. The alternate-day administration of crizotinib is one of the strategies for managing the severe toxicity of crizotinib.