Phosphate uptake restriction, phosphate export, and polyphosphate synthesis contribute synergistically to cellular proliferation and survival.

Phosphate (Pi) is a macronutrient, and Pi homeostasis is essential for life. Pi homeostasis has been intensively studied; however, many questions remain, even at the cellular level. Using Schizosaccharomyces pombe, we sought to better understand cellular Pi homeostasis and showed that three Pi regulators with SPX domains, Xpr1/Spx2, Pqr1, and the VTC complex synergistically contribute to Pi homeostasis to support cell proliferation and survival. SPX domains bind to inositol pyrophosphate and modulate activities of Pi-related proteins. Xpr1 is a plasma membrane protein and its Pi-exporting activity has been demonstrated in metazoan orthologs, but not in fungi. We first found that S. pombe Xpr1 is a Pi exporter, activity of which is regulated and accelerated in the mutants of Pqr1 and the VTC complex. Pqr1 is the ubiquitin ligase downregulating the Pi importers, Pho84 and Pho842. The VTC complex synthesizes polyphosphate in vacuoles. Triple deletion of Xpr1, Pqr1, and Vtc4, the catalytic core of the VTC complex, was nearly lethal in normal medium but survivable at lower [Pi]. All double-deletion mutants of the three genes were viable at normal Pi, but Δpqr1Δxpr1 showed severe viability loss at high [Pi], accompanied by hyper-elevation of cellular total Pi and free Pi. This study suggests that the three cellular processes, restriction of Pi uptake, Pi export, and polyP synthesis, contribute synergistically to cell proliferation through maintenance of Pi homeostasis, leading to the hypothesis that cooperation between Pqr1, Xpr1, and the VTC complex protects the cytoplasm and/or the nucleus from lethal elevation of free Pi.

Analgesic efficacy and safety of percutaneous thermal ablation plus cementoplasty for painful bone metastases: a systematic review and meta-analysis.

PURPOSE: To conduct a systematic review and meta-analysis of publications to evaluate the analgesic efficacy and safety of percutaneous thermal ablation (PTA) plus percutaneous cementoplasty (PCP) (PTA + PCP) for painful bone metastases. METHODS: We searched PubMed, Cochrane Library and Embase for articles published up to October 2022. Outcomes were a 10-point pain scale, morphine equivalents daily dose (MEDD) and complications. A subgroup confined to spinal bone metastases was analyzed. RESULTS: Twenty-one articles were selected for the analysis. The 21 selected articles involved a total of 661 cases. The pooled pain scales at pre-PTA + PCP, 1 day, 1 week and 1-, 3-, and 6 months post-PTA + PCP were 7.60 (95% confidence interval [CI], 7.26-7.95, I2 = 89%), 3.30 (95% CI, 2.25-4.82, I2 = 98%), 2.58 (95% CI, 1.99-3.35, I2 = 94%), 2.02 (95% CI, 1.50-2.71, I2 = 93%), 1.78 (95% CI, 1.26-2.53, I2 = 95%), and 1.62 (95% CI, 1.14-2.31, I2 = 88%), and in the subgroup, 7.97 (95% CI, 7.45-8.52, I2 = 86%), 3.01 (95% CI, 1.43-6.33, I2 = 98%), 2.95 (95% CI, 1.93-4.51, I2 = 95%), 2.34 (95% CI, 1.82-3.01, I2 = 68%), 2.18 (95% CI, 1.57-3.03, I2 = 78%), and 2.01 (95% CI, 1.16-3.48, I2 = 86%). Mean MEDD decreased up to 3 months post-PTA + PCP in 4 articles. The overall pooled major complication rate was 4% (95% CI, 2-6%, I2 = 2%). CONCLUSIONS: The updated systematic review and meta-analysis indicates that PTA + PCP for painful bone metastases is safe, and can lead to rapid and sustained pain reduction.

Clinical impact of diarrhea during enteral feeding after esophagectomy.

BACKGROUND: Enteral feeding (EF) is recommended to enhance nutritional status after esophagectomy; however, diarrhea is a common complication of EF. We investigated the clinical and prognostic impact of diarrhea during EF after esophagectomy. METHODS: One hundred and fifty-two patients who underwent transthoracic esophagectomy were enrolled. The King's stool chart was used for stool characterization. The short- and long-term outcomes were compared between a non-diarrhea (Group N) and diarrhea group (Group D). RESULTS: A higher dysphagia score (≥ 1) was observed more frequently in Group D than in Group N (45.7% vs. 19.8%, p = 0.002). Deterioration of serum total protein, serum albumin, serum cholinesterase, and the prognostic nutritional index after esophagectomy was greater in Group D than in Group N (p = 0.003, 0.004, 0.014, and 0.001, respectively). Patients in Group D had significantly worse overall survival (OS) and recurrence-free survival (RFS) than those in Group N (median survival time (MST): OS, 21.9 vs. 30.6 months, p = 0.001; RFS, 12.4 vs. 27.7 months, p < 0.001). In stratified analysis due to age, although there was no difference in OS with or without diarrhea in young patients (MST: 24.1 months in a diarrhea group vs. 33.6 months in a non-diarrhea group, p = 0.218), patients in a diarrhea group had significantly worse OS than those in a non-diarrhea group in elderly patients (MST: 17.8 months vs. 27.9 months, p < 0.001). CONCLUSIONS: Diarrhea during EF can put elderly patients at risk of postoperative malnutrition and a poor prognosis after esophagectomy.

A silicone disc for liver retraction in laparoscopic gastrectomy reduces the postoperative increase in the liver enzyme level.

PURPOSE: To compare changes in liver enzyme levels on postoperative day 1 between patients with and without silicone disc (SD) use during liver retraction in laparoscopic gastrectomy for gastric cancer and laparoscopic gastric mobilization for esophageal cancer. METHODS: This prospective randomized controlled phase II trial was conducted between June 30, 2020, and November 30, 2022, to investigate the benefits of using an SD with a Nathanson liver retractor (NLR) compared with those using an NLR in laparoscopic gastrectomy and gastric mobilization. The primary endpoint was the change in transaminase level on postoperative day 1. RESULTS: A total of 86 patients received randomized assignments and were included in the analysis, with 44 assigned to the SD (-) group and 42 to the SD (+) group. On postoperative day 1, the SD (+) group showed a significantly lower increase in the aspartate aminotransferase levels than the SD (-) group (SD [+], 94.4% vs. SD [-], 179.8%; p = 0.012). Similarly, the SD (+) group showed a significantly lower increase in alanine aminotransferase levels than the SD (-) group (SD [+], 71.6% vs. SD [-], 201.5%; p = 0.014). CONCLUSION: In laparoscopic gastrectomy, the use of an SD combined with an NLR appears to mitigate postoperative liver dysfunction.

Perioperative proximal splenic artery embolization in cirrhotic patients with splenomegaly.

INTRODUCTION: The purpose of this study was to determine the effect of proximal splenic artery embolization (SAE) in cirrhotic patients with splenomegaly who underwent surgical laparotomy. MATERIAL AND METHODS: This retrospective observational study included 8 cirrhotic patients with splenomegaly. They underwent proximal SAE before- (n = 6) or after (n = 2) laparotomy. Vascular plugs or coils were placed in the proximal splenic artery. The diameter of the portal vein and the splenic volume were recorded. Clinical outcome assessments included platelet counts, the model for end-stage liver disease (MELD) score, and complications. RESULTS: After embolization, the portal venous diameter was significantly smaller (pre: 13.6 ± 2.7 mm, post: 12.5 ± 2.3 mm, p = 0.023), the splenic volume was significantly decreased (pre: 463.2 ± 145.7 ml, post: 373.3 ± 108.5 ml, p = 0.008) and the platelet count was significantly higher (pre: 69.6 ± 30.8 × 103/µl, post: 86.8 ± 27.7 × 103/µl, p = 0.035). Before embolization, the median MELD score was 12; after embolization, it was 11 (p = 0.026). No patient developed post-treatment complications after embolization. CONCLUSIONS: The reduction of hypersplenism by perioperative proximal SAE may be safe and reduce the surgical risk in cirrhotic patients with splenomegaly.

Percutaneous splanchnic nerve neurolysis analgesic efficacy and safety for cancer-related pain: a systematic review and meta-analysis.

PURPOSE: To perform a systematic review and meta-analysis of publications to evaluate the analgesic efficacy and safety of percutaneous splanchnic nerve neurolysis (SNN) for cancer-related pain. METHODS: We searched PubMed, Cochrane Library, and Ichushi-Web for English or Japanese articles published up to July 2022 and reporting patients who underwent percutaneous SNN for cancer-related pain. The outcome measures assessed in the systematic review and meta-analysis were the pain measurement scales and morphine equivalents daily dose (MEDD) before and after the intervention and the rate of complications. RESULTS: Pooled pain measurement scores at pre-intervention, 1-2 weeks, and at 1, 2, 3, and 6 months post-intervention were 6.65 (95% confidence interval [CI], 5.77-7.67, I2 = 97%), 2.79 (95% CI, 2.00-3.88, I2 = 88%), 2.82 (95% CI, 2.49-3.20, I2 = 55%), 2.86 (95% CI, 2.64-3.10, I2 = 0%), 2.99 (95% CI, 2.56-3.46, I2 = 82%), and 3.09 (95% CI, 1.44-6.65, I2 = 70%), respectively. Mean MEDD was described in 8 of the 11 included articles. In all 8 articles, MEDD decreased up to 3 months post-intervention. The pooled minor complication rates for diarrhea and hypotension were 28% (95% CI, 13-49%, I2 = 85%) and 31% (95% CI, 16-51%, I2 = 80%), respectively. The pooled major complication rate was 2% (95% CI, 1-2%, I2 = 0%). CONCLUSIONS: Analysis indicates that percutaneous SNN for cancer-related pain can be performed safely with sustained reduction of pain measurement scales while reducing the administration of opioids.

Removal of central venous port-catheter by the combination of interventional radiological procedures.

We encountered a patient with an infection related to an implanted central venous port-catheter that necessitated removal of the system. As the catheter had tightly adhered to the venous wall, removal was impossible with standard methods. After trial and error, we used a guiding catheter that was advanced over the implanted catheter to detach the fibrin sheath on the implanted catheter that had adhered to the vessel wall. At that time, a pull-through technique was used. After we succeeded in detaching the adhesion with the guiding catheter, we were able to withdraw the implanted catheter.

Basal extrusion of single-oncogenic mutant cells induces dome-like structures with altered microenvironments.

At the initial stage of carcinogenesis, oncogenic transformation occurs in single cells within epithelial layers. However, the behavior and fate of the newly emerging transformed cells remain enigmatic. Here, using originally established mouse models, we investigate the fate of RasV12-transformed cells that appear in a mosaic manner within epithelial tissues. In the lung bronchial epithelium, most majority of RasV12-transformed cells are apically extruded, whereas noneliminated RasV12 cells are often basally delaminated leading to various noncell-autonomous changes in surrounding environments; macrophages and activated fibroblasts are accumulated, and normal epithelial cells overlying RasV12 cells overproliferate and form a convex multilayer, which is termed a 'dome-like structure'. In addition, basally extruded RasV12 cells acquire certain features of epithelial-mesenchymal transition (EMT). Furthermore, the expression of COX-2 is profoundly elevated in RasV12 cells in dome-like structures, and treatment with the COX inhibitor ibuprofen suppresses the recruitment of activated fibroblasts and moderately diminishes the formation of dome-like structures. Therefore, basal extrusion of single-oncogenic mutant cells can induce a tumor microenvironment and EMT and generate characteristic precancerous lesions, providing molecular insights into the earlier steps of cancer development.

Development and Validation of the Optimal Circumferential Resection Margin in Pathological T3 Esophageal Cancer: A Multicenter, Retrospective Study.

BACKGROUND: The clinical significance of circumferential resection margin (CRM) in esophageal squamous cell carcinoma (ESCC) remains unclear. Optimal CRM for predicting the recurrence of pathological T3 ESCC was investigated. METHODS: Seventy-three patients were retrospectively investigated in the development cohort. Patients were divided into CRM-negative and CRM-positive groups, and clinicopathological factors and survival outcomes were compared between the groups. The cutoff value was validated in another validation cohort (n = 99). RESULTS: Receiver operating characteristic analysis in the development cohort showed the cutoff value of CRM was 600 µm. In the validation cohort, patients in the CRM-positive group showed a significantly higher rate of locoregional recurrence (p = 0.006) and worse recurrence-free survival (RFS) (p < 0.001) than those in the CRM-negative group. Multivariate analysis identified positive CRM as an independent predictive factor for poor RFS (hazard ratio, 2.695; 95% confidence interval, 1.492-4.867; p = 0.001). The predictive value of our criteria of positive CRM for RFS was higher than that of the Royal College of Pathologists (RCP) and the College of American Pathologists (CAP) criteria. Stratified analysis in the neoadjuvant chemotherapy groups also revealed that the rate of locoregional recurrence was higher in the CRM-positive group than in the CRM-negative group both in the pathological N0 and N1-3 subgroups. CONCLUSIONS: CRM of 600 µm can be the optimal cutoff value rather than the RCP and CAP criteria for predicting locoregional recurrence after esophagectomy. These results may support the impact of perioperative locoregional control of locally advanced ESCC.

Computed tomography-guided percutaneous biopsy for retroperitoneal lesions: a systematic review and meta-analysis.

The aim of this study is to perform a systematic review and meta-analysis of published studies to evaluate the efficacy and safety of computed tomography (CT)-guided percutaneous biopsy for retroperitoneal lesions. PubMed and the Cochrane Library were searched for English-language articles published up to October 2021 and reporting findings about patients with retroperitoneal lesions who underwent CT-guided percutaneous biopsy. The outcome measures assessed in this systematic review and meta-analysis are accuracy, false negative rate, and rate of minor and major complications. Heterogeneity among studies was evaluated by testing Cochran's Q and the inconsistency index statistics. Seven studies published from 1975 to 2021 were selected for the analysis of accuracy, false negative rates, and rate of major and minor complications. The pooled accuracy of CT-guided percutaneous biopsy for retroperitoneal lesions was 93.6% [95% confidence interval (CI), 88.1-96.6%], with high heterogeneity. The pooled false negative rate was 6.3% (95% CI, 3.3-11.7%) with high heterogeneity. Pooled rates of minor and major complications were 3.7% (95% CI, 1.6-8.6%) with moderate heterogeneity and 0.7% (95% CI, 0.4-1.1%) with low heterogeneity, respectively. CT-guided percutaneous biopsy for retroperitoneal lesions has been reported to have high accuracy with a limited rate of major complications.

Usefulness of wearable fitness tracking devices in patients undergoing esophagectomy.

BACKGROUND: Esophageal cancer surgery requires maintenance and enhancement of perioperative nutritional status and physical function to prevent postoperative complications. Therefore, awareness of the importance of preoperative patient support is increasing. This study examined the usefulness of using a diary in combination with a wearable fitness tracking device (WFT) in patients undergoing surgery for esophageal cancer. METHODS: Ninety-four patients who underwent esophagectomy between February 2019 and April 2021 were included. Physicians, nurses, dietitians, and physical therapists provided diary-based education for the patients. In addition, a WFT was used by some patients. The perioperative outcomes of patients who used both the diary and WFT (WFT group) and those who used the diary alone (non-WFT group) were compared. In addition, propensity score matching was performed to improve comparability between the two groups. RESULTS: After the propensity score matching, the rate of postoperative pneumonia was significantly lower in the WFT group (0% vs. 22.6%, P = 0.005). The postoperative hospital stay was shorter in the WFT group (P = 0.012). Nutritional status indices, such as the prognostic nutritional index, also improved significantly in the WFT group at 1 month after surgery (P = 0.034). The rate of diary entries was significantly higher in the WFT group (72.3% vs. 28.3%, P < 0.001). CONCLUSION: The use of a WFT reduced the incidence of postoperative pneumonia and improved postoperative nutritional status and rates of diary entries after esophagectomy, suggesting that its use may be useful for promoting recovery after esophagectomy.

Survival impact of perioperative changes in prognostic nutritional index levels after esophagectomy.

BACKGROUND: The correlation between perioperative changes in nutritional status during esophagectomy and prognosis remains unclear. This study aimed to evaluate the impact of changes in prognostic nutritional index levels during the perioperative period on esophageal cancer patient survivals. METHODS: From January 2009 to May 2019, 158 patients with esophageal squamous cell carcinoma were enrolled. From the time-dependent ROC analysis, the cutoff values of preoperative and postoperative prognostic nutritional index levels were 46.9 and 40.9. Patients were divided into preoperative-high group (Group H) and preoperative-low group (Group L). Then, patients in Group L were divided into preoperative-low and postoperative-high group (Group L-H) and preoperative-low and postoperative-low group (Group L-L). Long-term outcomes and prognostic factors were evaluated. RESULTS: Patients in Group L had significantly worse overall survival than those in Group H (p = 0.001). Patients in Group L-L had significantly worse overall survival than those in Group L-H (p = 0.023). However, there was no significant difference in overall survival between Groups H and L-H (p = 0.224). In multivariable analysis, advanced pathological stage (hazard ratio 10.947, 95% confidence interval 2.590-46.268, p = 0.001) and Group L-L (hazard ratio 2.171, 95% confidence interval 1.249-3.775, p = 0.006) were independent predictors of poor overall survival. CONCLUSIONS: Patients in Group L-H had a good prognosis, similar to those in Group H. This result indicated that increasing the postoperative prognostic nutritional index level sufficiently using various intensive perioperative support methods could improve prognosis after esophagectomy in patients with poor preoperative nutritional status.

Fabrication of Gd-DOTA-functionalized carboxylated nanodiamonds for selective MR imaging (MRI) of the lymphatic system.

Magnetic resonance imaging (MRI) contrast agents with the particle diameter of around 3-10 nm hold the potential to be selectively uptaken by lymphatic vessels and be filtered in the kidney for final excretion. However, there are no existing MRI contrast agents based on gadolinium (Gd) complexes within the size of this range, and thus the selective imaging of the lymphatic system has not yet been achieved. In our previous report, we succeeded in fabricating nano-scale MRI contrast agents by complexing ordinary contrast agents (Gd-diethylenetriaminepentaacetic acid (DTPA)) with carboxylated nanodiamond (CND) particles to conquer this problem. However, DTPA has recently been reported to release Gd ions in the course of time, leading to the potential danger of severe side effects in the human body. In this study, we utilized cyclic-chained DOTA as an alternative chelating material for DTPA to fabricate CND-based MRI contrast agents for the selective lymphatic imaging. The newly fabricated contrast agents possessed the diameter ranging from 3 to 10 nm in distilled water and serum, indicating that these particles can be selectively uptaken by lymphatic vessels and effectively filtered in the kidney. Furthermore, the DOTA-applied CND contrast agents exhibited stronger MRI visibility in water and serum compared to DTPA-applied CND contrast agents. These results indicate that DOTA-applied CND contrast agents are promising materials for the selective MR imaging of lymphatic systems.

Snuff box radial access in transcatheter arterial embolization for unruptured renal angiomyolipoma.

OBJECTIVE: We report the first three cases in which the feasibility and safety of the left snuff box radial access in transcatheter arterial embolization (TAE) for unruptured renal angiomyolipoma (AML) were evaluated. MATERIAL AND METHODS: Three patients with unruptured renal AMLs underwent TAE via the left snuff box radial artery. We retrospectively evaluated the characteristics of the AMLs, technical success rate, clinical success rate, and complications. Technical success and clinical success were defined as successful insertions of microballoon catheters selectively via the left distal radial artery into all intended arteries in a treatment session and shrinkage of tumor size as evaluated by CT or MRI after the procedure, respectively. RESULTS: The median size of the renal AMLs was 49 mm. TAE was successfully performed in all cases and all feeding arteries were successfully selected with a microballoon catheter through the left snuff box radial artery. The median amount of the mixture of ethanol and Lipiodol was 1.8 mL. Tumor shrinkage was confirmed in all with a median follow-up period of 6 months. The clinical success rate was 100%. No major complications occurred. CONCLUSION: The left snuff box access in TAE for an unruptured renal AML is safe and feasible.

[A Case of Laparoscopic Gastrojejunal Bypass Surgery for Malignant Stenosis after Chemoradiotherapy for Esophageal Cancer].

We report a case of malignant stenosis due to recurrence of lymph node metastasis treated with laparoscopic gastrojejunal bypass. A 83-year-old man who underwent chemoradiotherapy for esophageal cancer(cT3N2M0). About 3 and half years after chemoradiotherapy, he was referred to hospital for vomiting. As a result of the examination, we diagnosed malignant stenosis of descending part of duodenum due to retroperitoneum lymph node recurrence of esophageal cancer. We performed laparoscopic gastrojejunal bypass operation because we suggested self-expandable metallic stent make easy to migrate into anal side of the duodenum. The postoperative course was good. He was enrolled in oncology department on the 21 days after the operation. Gastroduodenal stenosis is common pathology by malignant tumor. Gastrojejunostomy and placement of self-expandable metallic stent is commonly performed for malignant gastroduodenal obstruction. Endoscopic metallic stent placement is minimally invasive treatment for malignant stenosis of the intestine, however sometime the stent placement will make easy to migrate by extra compression. Gastrojejunostomy mat be more safety than endoscopic stent placement for the malignant gastroduodenal obstruction.

Early detection of anastomotic leakage after esophagectomy using drain amylase levels.

BACKGROUND: Early diagnosis of anastomotic leakage (AL) after esophagectomy is essential to minimize postoperative complications. In this study, we hypothesized that drain amylase levels may be useful for early AL detection, and measuring drain amylase levels could reduce severe postoperative AL incidence. We, therefore, analyzed the usefulness of measuring drain fluid amylase levels after esophagectomy, in esophageal cancer patients. METHODS: From January 2016 to March 2020, 134 patients with esophageal cancer who underwent surgical resection with esophagogastric anastomosis in the cervical region were included. The patients were divided into a group whose cervical drain fluid amylase levels were not measured (No-AMY Group) and a group whose cervical drain fluid amylase levels were measured daily until postoperative day (POD) 7 (AMY Group). The incidence of severe AL was compared between groups. In the AMY Group, we also investigated the association between AL and drain amylase levels. RESULTS: Drain amylase levels were significantly higher in AL-positive cases than in AL-negative cases (P < 0.001). Receiver operating characteristic curve analysis revealed the drain amylase level cut-off value for AL diagnosis was 1800 U/L on POD 2 (Area under the curve = 0.835; P = 0.027). The incidence of ≥ grade III AL was significantly lower in the AMY Group than in the No-AMY Group (2 vs. 10%, P = 0.047). CONCLUSIONS: Cervical drain fluid amylase levels can be a useful screening method for early detection of AL after esophagectomy for esophageal cancer and may help reduce incidence of severe postoperative AL.

The RHEB-mTOR axis regulates expression of Tf2 transposons in fission yeast.

The human TSC2 gene, mutations in which predispose individuals to the disease tuberous sclerosis complex (TSC), encodes a GTPase-activating protein for the GTPase RHEB. Loss of TSC2 results in constitutive activation of RHEB and its target mammalian target of rapamycin (mTOR). We have previously reported that fission yeast (Schizosaccharomyces pombe) Tf2 retrotransposons (hereafter Tf2s) are abnormally induced upon nitrogen starvation in cells lacking the tsc2+ gene (Δtsc2), a homolog of the human TSC2 gene, and in cells with a dominant-active mutation in the fission yeast RHEB GTPase (rhb1-DA4). We report here that induction of Tf2s in these mutants is suppressed upon overexpression of the cgs2+ gene, which encodes a cAMP-specific phosphodiesterase, or upon deletion of components in the glucose/cAMP signaling pathway, namely Cyr1, Pka1, Tor1 and the stress-activated transcription factor Atf1. The results suggest that the glucose/cAMP signaling pathway is downregulated when cells are starved for nitrogen. We also show that Tf2 proteins are degraded via autophagy, which is under control of Tor2, a homolog of human mTOR. It appears that failure in the two processes, downregulation of the glucose/cAMP signaling pathway and induction of autophagy, allows abnormal induction of Tf2s upon nitrogen starvation in Δtsc2 and rhb1-DA4 cells.

The mechanism of Tyk2 deficiency-induced immunosuppression in mice involves robust IL-10 production in macrophages.

Macrophages are highly plastic in their pro-inflammatory/anti-inflammatory roles. Type I and II interferons (IFNs) are known to modulate macrophage activation. Tyrosine kinase 2 (Tyk2) has an intimate relationship with type I and II IFN signaling. Animal studies have shown that Tyk2 knock-out (KO) in mice is associated with reduced inflammatory responses in various mouse models of diseases. To investigate the role of Tyk2 in inflammation in more detail, we intraperitoneally injected heat-killed Propionibacterium acnes (P. acnes) to Tyk2 KO mice. P. acnes-induced acute peritoneal inflammation, assessed by neutrophil infiltration, was reduced in Tyk2 KO mice. The reduction was accompanied with diminished productions of inflammatory cytokines and an enhanced production of anti-inflammatory IL-10. Unexpectedly, pre-treatment of wild-type mice with the neutralizing antibodies for IFNs did not affect P. acnes-induced neutrophil infiltration. A neutralizing antibody for the IL-10 receptor in Tyk2 KO mice restored P. acnes-induced peritoneal inflammation. Enhanced production of IL-10 from Tyk2 KO peritoneal cells was suppressed by either the cyclooxygenase inhibitor diclofenac or protein kinase A inhibitor H-89. The level of prostaglandin E2 (PGE2) in the steady-state peritoneal cavity in Tyk2 KO mice was higher than that in wild-type mice. Tyk2 KO macrophages showed an enhanced CREB phosphorylation induced by P. acnes plus PGE2. Taken together, these results showed that Tyk2 deficiency potentiates the PGE2-protein kinase A-IL-10 pathway in macrophages, and thereby contributes to potentiation of the immunosuppressive phenotype.

Preventive effects of low-intensity exercise on cancer cachexia-induced muscle atrophy.

We hypothesized that low-intensity endurance exercise might be more effective in preventing cancer cachexia-induced muscle atrophy through both an increase in protein synthesis and a decrease in protein degradation. The purpose of present study was to evaluate the effects and to clarify the mechanism of low-intensity endurance exercise on cancer cachexia-induced muscle atrophy. Twenty-four male Wistar rats were randomly divided into 4 groups: control (Cont), Cont plus exercise (Ex), AH130-induced cancer cachexia (AH130), and AH130 plus Ex. Cancer cachexia was induced by intraperitoneal injections with AH130 Yoshida ascites hepatoma cells; we analyzed the changes in muscle mass and the gene and protein expression levels of major regulators or indicators of skeletal muscle protein degradation and synthesis pathway in the soleus muscles. Low-intensity exercise inhibited the muscle mass loss through a suppression of the ubiquitin-proteasome pathway, increased hypoxia-inducible factor- 1α and phosphorylated AMPK, and inhibited the deactivation of mammalian target of rapamycin pathway in the soleus muscle, which contributed to the prevention of cancer cachexia-induced muscle atrophy. These results suggest that low-intensity exercise has the potential to become an effective therapeutic intervention for the prevention of cancer cachexia-induced muscle atrophy.-Tanaka, M., Sugimoto, K., Fujimoto, T., Xie, K., Takahashi, T., Akasaka, H., Kurinami, H., Yasunobe, Y., Matsumoto, T., Fujino, H., Rakugi, H. Preventive effects of low-intensity exercise on cancer cachexia-induced muscle atrophy.

The approach of scratch-imprint cytology: Is it an alternative to frozen section for intraoperative assessment of pulmonary lesions?

To address the diagnostic performance of scratch-imprint cytology (SIC), in this study we compared intraoperative diagnoses of pulmonary lesions between SIC and frozen section histology (FSH) for accuracy with respect to the final pathological diagnosis. We histologically divided 206 pulmonary lesions (resected surgically) into two groups (benign and malignant) and compared each intraoperative diagnosis by SIC and FSH with the final pathological diagnoses. We also examined the radiological existence of pure ground-glass opacity (GGO) nodules in each group. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 91.5%, 100%, 100%, 63.6%, and 92.6%, respectively for SIC, and 98.2%, 100%, 100%, 92.1% and 98.5%, respectively, for FSH. Thus, we concluded that diagnosis by SIC is reliable for malignancy, but not for benign lesions. All pure GGO nodules (19; 9.2%) were noninfectious and malignant with a high accuracy of FSH diagnosis (100%), in comparison with those of low accuracy with a SIC diagnosis (57.9%). SIC can be an appropriate intraoperative diagnostic tool where multiple cytotechnologists observe intraoperative SIC preparations scratched evenly across the whole lesion including the peripheral area of the mass.