Serum exosomal miR-638 is a prognostic marker of HCC via downregulation of VE-cadherin and ZO-1 of endothelial cells.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death. High recurrence rates after curative resection and the lack of specific biomarkers for intrahepatic metastases are major clinical problems. Recently, exosomal microRNAs (miRNAs) have been reported to have a role in the formation of the pre-metastatic niche and as promising biomarkers in patients with malignancy. Here we aimed to clarify the molecular mechanisms of intrahepatic metastasis and to identify a novel biomarker miRNA in patients with HCC. A highly intrahepatic metastatic cell line (HuH-7M) was established by in vivo selection. HuH-7M showed increased proliferative ability and suppression of apoptosis and anoikis. HuH-7M and the parental cell (HuH-7P) showed the similar expression of epithelial-mesenchymal transition markers and cancer stem cell markers. In vivo, mice treated with exosomes derived from HuH-7M showed increased tumorigenesis of liver metastases. Exosomes from HuH-7M downregulated endothelial cell expression of vascular endothelial-cadherin (VE-cadherin) and zonula occludens-1 (ZO-1) in non-cancerous regions of liver and increased the permeability of FITC-dextran through the monolayer of endothelial cells. The miRNAs (miR-638, miR-663a, miR-3648, and miR-4258) could attenuate endothelial junction integrity by inhibiting VE-cadherin and ZO-1 expression. In patients with HCC, higher serum exosomal miR-638 expression was associated with tumor recurrence. In conclusion, the miRNAs secreted from a highly metastatic cancer cell can promote vascular permeability via downregulation of endothelial expression of VE-cadherin and ZO-1. Serum exosomal miR-638 expression holds potential for serving as a significant and independent prognostic marker in HCC.

The blockade of interleukin-33 released by hepatectomy would be a promising treatment option for cholangiocarcinoma.

Interleukin-33 (IL-33), an alarmin released during tissue injury, facilitates the development of cholangiocarcinoma (CCA) in a murine model. However, it is unclear whether IL-33 is associated with human CCA. The aim of this study was to support the following hypothesis: IL-33 is released during hepatectomy for CCA, subsequently facilitating the development of subclinical CCA and eventually leading to recurrent disease. IL-33 expression was assessed in various samples from both humans and mice including resected liver and paired plasma samples collected at hepatectomy and after surgery, and its influences on recurrent disease and patient prognosis were determined. Homogenized human liver samples with high or low IL-33 expression were added to the culture medium of human CCA cells, and the changes in proliferation and migration were evaluated. To examine the effects of inhibiting the IL-33 release induced by hepatectomy, syngraft transplantation of murine CCA cells was performed in C57BL/6J mice with or without IL-33 blockade. The amount of IL-33 released into the plasma during hepatectomy correlated with the background liver expression. High expression of IL-33 in the liver was an independent risk factor for recurrence. Homogenized liver tissue strongly expressing IL-33 increased both the proliferation and migration of tumor cells. Mice who underwent hepatectomy exhibited CCA progression in the remnant liver, whereas blockade of IL-33 during hepatectomy inhibited tumor progression. Thus, we concluded that surgery for CCA with curative intent paradoxically induced IL-33 release, which facilitated CCA recurrence, and anti-IL-33 therapy during hepatectomy might reduce the risk of CCA recurrence.

Endogenous CXCL9 affects prognosis by regulating tumor-infiltrating natural killer cells in intrahepatic cholangiocarcinoma.

CXCL9, an IFN-γ inducible chemokine, has been reported to play versatile roles in tumor-host interrelationships. However, little is known about its role in intrahepatic cholangiocarcinoma (iCCA). Here, we aimed to elucidate the prognostic and biological implications of CXCL9 in iCCA. Endogenous CXCL9 expression and the number of tumor-infiltrating lymphocytes were immunohistochemically assessed in resection specimens. These data were validated in mice treated by silencing CXCL9 with short hairpin RNA. In addition, the induction of endogenous CXCL9 and the effects of CXCL9 on tumor biological behaviors were evaluated in human cholangiocarcinoma cell lines. Immunohistochemical analyses revealed that high CXCL9 expression was closely correlated with prolonged postoperative survival and a large number of tumor-infiltrating natural killer (NK) cells. In fact, due to the trafficking of total and tumor necrosis factor-related apoptosis-inducing ligand-expressing NK cells into tumors, CXCL9-sufficient cells were less tumorigenic in the liver than CXCL9-deficient cells in mice. Although CXCL9 involvement in tumor growth and invasion abilities differed across cell lines, it did not exacerbate these abilities in CXCL9-expressing cell lines. We showed that CXCL9 was useful as a prognostic marker. Our findings also suggested that CXCL9 upregulation might offer a therapeutic strategy for treating CXCL9-expressing iCCA by augmenting anti-tumor immune surveillance.

Late-onset MELAS syndrome with mtDNA 14453G→A mutation masquerading as an acute encephalitis: a case report.

BACKGROUND: A unique patient with MELAS syndrome, who initially masqueraded as having acute encephalitis and was eventually diagnosed with MELAS syndrome harboring a mtDNA 14453G → A mutation, is described. CASE PRESENTATION: A 74-year-old Japanese man was admitted to another hospital due to acute onset of cognitive impairment and psychosis. After 7 days he was transferred to our hospital with seizures and deteriorating psychosis. The results of primary ancillary tests that included EEG, CSF findings, and brain MRI supported the diagnosis of an acute encephalitis. HSV-DNA and antibodies against neuronal surface antigens in the CSF were all negative. With the assistance of the lactate peak on the brain lesions in the magnetic resonance spectroscopy image and genetic analysis of the biopsied muscle, he was eventually diagnosed with MELAS syndrome harboring mtDNA 14453G → A mutation in the ND6 gene. CONCLUSIONS: This case provides a caveat that MELAS syndrome can manifest in the symptoms and ancillary tests masquerading as an acute encephalitis caused by infection or autoimmunity. This is the first adult patient seen to harbor the mtDNA14453G → A with a unique onset, which broadens the phenotypic spectrum of MELAS syndrome associated with ND6 gene mutation.

A case report of Fontan procedure-related hepatocellular carcinoma: pure laparoscopic approach by low and stable pneumoperitoneum.

BACKGROUND: The Fontan procedure has become the standard operation for patients with single ventricle physiology. Due to cardiac hypokinesis and high central venous pressure, laparoscopic approach, especially in hepatectomy, was considered as controversial after the Fontan procedure. We presented a case of hepatocellular carcinoma (HCC) that was successfully treated by pure laparoscopic hepatectomy with stable pneumoperitoneum after the Fontan procedure. CASE PRESENTATION: An 18-year-old man was referred to our hospital for examination of a hepatic tumor. The patient underwent the Fontan procedure for single ventricle physiology at 6 years of age. Abdominal contrast-enhanced computed tomography (CT) revealed a hypovascular mass in segment 2 and a hypervascular mass in segment 4 of the arterial phase, followed by a delayed washout. CT arteriography revealed that both masses showed hypervascular tumors, and CT during arterial portography showed that both were low-density masses. The patient's general condition was good, and cardiac and respiratory functions were well maintained. Pure laparoscopic hepatectomy was safely performed by keeping the pneumoteritoneum pressure under 6-8 mmHg and monitoring central venous pressure (11-21 mmHg) and end-tidal carbon dioxide. The Pringle maneuver was applied during hepatic resection. The non-anatomical resections were completed without intraoperative complications. The patient was discharged on the 9th postoperative day without postoperative complications. CONCLUSIONS: Our report suggests that treatment of HCC by pure laparoscopic hepatectomy after Fontan circulation can be safely performed in patients under sufficient circulatory management.

The effect of Capacitive and Resistive electric transfer on non-specific chronic low back pain.

The objective of this study was to evaluate the effect of Capacitive and Resistive electric transfer (CRet)-combined exercise therapy for participants with non-specific chronic low back pain (NSCLBP). Twenty-six received only the exercise program (E group, n = 15), or received both CRet and the same exercise program (E+CRet group, n = 11). Pain intensity, functional disability and trunk function were measured pre-, and post-intervention and there was also a 1-month follow-up period. Data analysis was performed for each index using the Mann-Whitney U test for comparisons between two groups at each time point, and the Wilcoxon signed-rank test for comparison between each time point within the group. The results of this study indicate that pain intensity was improved in both groups at post-intervention, also, the effect continued during follow-up period. In addition, functional disability was significantly improved in the E+CRet group at the post-intervention and during the follow-up period. The intervention effect on NSCLBP was higher in the E+CRet group than the E group. CRet, which is a form of deep thermotherapy, combined with exercise have a possibility of more effectiveness than exercise alone.

Association Between Functional Movement Screen Scores and Injuries in Male College Basketball Players.

CONTEXT: The functional movement screen (FMS) is an assessment tool for movement dysfunction, which is used to reduce the risk of injury. Although the relationship between the FMS composite score and injuries has been extensively studied, the association between FMS scores and injuries in only college basketball players remains unknown. OBJECTIVE: To examine the relationship between the FMS score and injuries in basketball players. DESIGN: Cross-sectional study. SETTING: University research laboratory. PARTICIPANTS: Eighty-one male college basketball players (average age 20.1 [1.3] y) participated. MAIN OUTCOME MEASURES: The FMS composite score was calculated from 7 movement tests. The incidence of injuries over a 1-year period prior to the test day was determined based on a questionnaire. Individuals were categorized into 2 groups: injury (with a serious basketball-related injury resulting in the loss of practice and game time for at least 4 wk) and noninjury groups. Mann-Whitney U and chi-square tests were used to evaluate group differences in the composite FMS and 7 movement scores, respectively. Furthermore, the scores significant on univariate analyses were submitted to a multivariate logistic analysis, adjusting for participant characteristics. RESULTS: The composite FMS scores of the 2 groups were not significantly different (P = .38). Among the 7 tasks, only the deep squat and hurdle step showed significant group differences (P = .03 and P = .001, respectively). The multivariate logistic analysis revealed that deep squat (odds ratio, 6.48; 95% confidence interval, 1.23-34.01; P = .03) and hurdle step scores (odds ratio, 25.80; 95% confidence interval, 1.81-368.73; P = .02) were significantly associated with injuries, even after adjustment for participant characteristics. CONCLUSIONS: Deep squat and hurdle step scores may be associated with injuries in basketball players. Further research should be conducted to confirm that these 2 scores can predict the incidence of injuries in basketball players.

Fgf signalling controls diverse aspects of fin regeneration.

Studies have shown that fibroblast growth factor (Fgf) signalling is necessary for appendage regeneration, but its exact function and the ligands involved during regeneration have not yet been elucidated. Here, we performed comprehensive expression analyses and identified fgf20a and fgf3/10a as major Fgf ligands in the wound epidermis and blastema, respectively. To reveal the target cells and processes of Fgf signalling, we performed a transplantation experiment of mesenchymal cells that express the dominant-negative Fgf receptor 1 (dnfgfr1) under control of the heat-shock promoter. This mosaic knockdown analysis suggested that Fgf signalling is directly required for fin ray mesenchyme to form the blastema at the early pre-blastema stage and to activate the regenerative cell proliferation at a later post-blastema stage. These results raised the possibility that the early epidermal Fgf20a and the later blastemal Fgf3/10a could be responsible for these respective processes. We demonstrated by gain-of-function analyses that Fgf20a induces the expression of distal blastema marker junbl, and that Fgf3 promotes blastema cell proliferation. Our study highlights that Fgfs in the wound epidermis and blastema have distinct functions to regulate fin regeneration cooperatively.

Hydrogel Heart Model with Temperature Memory Properties for Surgical Simulation.

The continual development of surgical technology has led to a demand for surgical simulators for evaluating and improving the surgical technique of surgeons. To meet these needs, simulators must incorporate a sensing function into the organ model for evaluating the surgical techniques. However, it is difficult to incorporate a temperature sensor into the conventional cardiac training model. In this study, we propose a heart model for surgical training of cardiac catheter ablation made from hydrogel, which has temperature memory properties. The heart model consists of a photo-crosslinkable hydrogel mixed with an irreversible temperature indicator that exhibits a color change from magenta to colorless at 55 °C. The Young's modulus, electrical resistivity, thermal conductivity, and specific heat capacity of the hydrogel material were evaluated and compared with those of human heart. Furthermore, temperature calibration based on the color of the hydrogel material confirmed that the temperature measurement accuracy of the material is ± 0.18 °C (at 56 °C). A heart model for catheter ablation was fabricated using the hydrogel material and a molding method, and the color change due to temperature change was evaluated.

Acute effects of capacitive and resistive electric transfer (CRet) on the Achilles tendon.

This study aimed to investigate the acute effects of capacitive and resistive electric transfer (CRet) on Achilles tendon elongation during muscle contraction, as well as the circulation in the peritendinous region. Sixteen healthy men participated in this study. All 16 participants underwent 2 interventions: (1) CRet trial and (2) CRet without power (sham trial). Tendon elongation was measured four times. Using near-infrared spectroscopy, the blood circulation (volume of total-hemoglobin (Hb), oxygenated hemoglobin (oxy-Hb), and deoxygenated hemoglobin (deoxy-Hb)) was measured for 5 min before the intervention and for 30 min after the intervention. The differences between the measurements obtained before and after intervention were compared between the two interventions. The changes in tendon elongation and deoxy-Hb were not significantly different between the interventions. Total- and oxy-Hb were significantly increased in the CRet trial compared with the sham trial. In addition, the increases in total-Hb and oxy-Hb lasted for 30 min after the CRet intervention (CRet vs. sham: oxy-Hb: F = 8.063, p = 0.001, total-Hb: F = 4.564, p = 0.011). In conclusion, CRet significantly improved blood circulation in the peritendinous region.

[A Case Report of SOX Treatment for Primary Duodenal Carcinoma with Liver Metastasis].

We report a case of effective S-1 plus oxaliplatin (SOX) treatment for duodenal cancer with liver metastases. The patient was a 70-year-old female diagnosed with duodenal carcinoma that was unresectable because of liver metastasis(cT4N1M1, cStage IV in UICC 7th). She received SOX treatment(100mg/m / 2 of oxaliplatin on day 1 combined with 40 mg/day of S-1 twice daily on days 1-14, was repeated every 3 weeks). After 4 courses, a partial response was confirmed by computed tomography and no severe adverse events were observed. However, during the 5th courses, several new liver metastases were observed, so we changed to weekly paclitaxel treatment. This case suggests that SOX treatment may be an effective chemotherapy for advanced primary duodenal carcinoma.

[A Case of Intrahepatic Cholangiocarcinoma with Tumor Thrombus in the Left Portal Branch].

A 63-year-old man was referred to our hospital for detailed examinations and treatment of a hepatic tumor. Abdominal contrast-enhanced CT examination showed a huge mass measuring 12 cm in diameter with ring enhancement in the left liver lobe. The liver tumor was accompanied by a macroscopic tumor thrombus in the left portal branch. Under preoperative diagnosis of intrahepatic cholangiocarcinoma with portal vein tumor thrombus, left liver lobectomy, removal of the tumor thrombus, extrahepatic bile duct excision, and lymph node dissection were performed. Histopathological examination of the resected specimens revealed moderately differentiated adenocarcinoma concomitant with tumor thrombus in the left portal branch. Adjuvant chemotherapy with S-1 was administered. However, 3 months after the surgery, CT examination revealed postoperative recurrences in the liver, lung, and bone. Systemic chemotherapy with gemcitabine and cisplatin was administered with radiotherapy for the bone metastasis. However, the chemotherapy was not effective, and 6 months after surgery, he died of the cancer. There have been few reports of cases with ICC accompanied by a macroscopic portal vein tumor thrombus. Based on the reported cases and the present case, prognosis of the disease seems very poor.

[A Resected Case of Lymph Node Metastasis at the Splenic Hilum from Lung Cancer Invading the Pancreas and Spleen].

A 72-year-old man received chemoradiotherapy for lung squamous cell carcinoma(T4N2M0, Stage Ⅲb). Nine months after the start of chemoradiotherapy, a 60 mm sized mass was identified in the spleen on abdominal CT. FDG-PET/CT examination revealed abnormal FDG accumulation in the tumor, and no obvious accumulation was observed in other sites. By endoscopic ultrasound-guided fine needle aspiration cytology, the tumor was diagnosed as splenic metastasis from lung cancer. Since the primary lung tumor was well controlled by the chemoradiotherapy and no metastatic lesions were found except in the spleen, laparoscopic excision of the splenic metastasis was planned. Since the tumor was suspected to have infiltrated the tail of the pancreas, laparoscopic distal pancreatectomy and splenectomy were performed. There were no severe postoperative complications. The resected tumor was histopathologically diagnosed as not splenic metastasis, but lymph node metastasis at the splenic hilum from lung cancer invading the pancreas and spleen. Brain metastasis and bone metastasis were observed 3 months postoperatively. He did not undergo any treatments for the metastatic lesions, and he died because of the cancer 11 months after the operation. This case suggests the clinical significance of surgical treatment for distant metastatic lesions from lung cancer.

Forefoot transverse arch height asymmetry is associated with foot injuries in athletes participating in college track events.

[Purpose] The association between foot injuries and foot alignment, including the transverse arch height (TAH) and asymmetry, was examined in athletes participating in college track events. [Participants and Methods] This study included 55 male athletes participating in a college track and field club. Data including demographic information and the incidence of foot injuries within a year prior to participation in this study were obtained via questionnaires. TAH and the medial longitudinal arch height during 10 and 90% loading, leg-heel alignment, and the heel angle were measured before calculating the asymmetry of each alignment parameter measured. Participants were categorized into an injury or a normal group. Unpaired t-tests were used to perform between-group comparisons for each alignment parameter measured and asymmetry. Additionally, logistic regression analysis was performed to identify factors associated with foot injuries after adjustment for demographic data. [Results] TAH asymmetry during 10 and 90% loading was significantly greater in the injury group. Further logistic regression analysis performed showed that only TAH asymmetry during 90% loading was significantly associated with foot injuries after adjustment for demographic data. [Conclusion] With regard to track events, a greater asymmetry of forefoot TAH in a weight-bearing position was observed to be associated with foot injuries.

Relationship between agility and lower limb muscle strength, targeting university badminton players.

[Purpose] Targeting university badminton players, this study investigated the relationship between agility, which is associated with performance in badminton, and lower limb muscle strength, and examined which muscles influence agility. [Subjects and Methods] A total of 23 male university badminton players were evaluated for side-shuffle test scores and lower limb strength. The relationships between agility, lower limb strength, and duration of experience playing badminton were evaluated using a correlation analysis. Moreover, the relationship between agility and lower limb strength was evaluated by partial correlation analysis, adjusting for the effects of experience of each badminton player. [Results] The agility score correlated with hip extension and ankle plantar flexion strength, with adjustment for badminton experience. [Conclusion] This study suggests that hip extension training and improvement in ankle plantar flexion strength may improve agility.

Effect of Capacitive and Resistive electric transfer on changes in muscle flexibility and lumbopelvic alignment after fatiguing exercise.

[Purpose] This study aimed to clarify the effects of Capacitive and Resistive electric transfer (CRet) on changes in muscle flexibility and lumbopelvic alignment after fatiguing exercise. [Subjects and Methods] Twenty-two healthy males were assigned into either the CRet (n=11) or control (n=11) group. Fatiguing exercise and CRet intervention were applied at the quadriceps muscle of the participants' dominant legs. The Ely test, pelvic tilt, lumbar lordosis, and superficial temperature were measured before and after exercise and for 30 minutes after intervention. Statistical analysis was performed using one-way analysis of variance, with Tukey's post-hoc multiple comparison test to clarify within-group changes and Student's t-test to clarify between-group differences. [Results] The Ely test and pelvic tilt were significantly different in both groups after exercise, but there was no difference in the CRet group after intervention. Superficial temperature significantly increased in the CRet group for 30 minutes after intervention, in contrast to after the exercise and intervention in the control group. There was no significant between-group difference at any timepoint, except in superficial temperature. [Conclusion] CRet could effectively improve muscle flexibility and lumbopelvic alignment after fatiguing exercise.

Relationship between transverse arch height and foot muscles evaluated by ultrasound imaging device.

[Purpose] Few studies on the transverse arch (TA) in the forefoot have been conducted. The forefoot is where pains occur most frequently and is related to walking and balance; hence, paying attention to TA is vital. However, the relationship between TA and foot muscles has not been investigated. Therefore, this study aims to investigate muscles related to TA. [Subjects and Methods] Nineteen healthy young males were included. Measurements of their feet, excluding one foot with recent foot pain (n=37), were obtained. The height of TA (TAH) was measured in two ways: during 10% and 90% loading of body weight. The cross-sectional area and thickness of five muscles were measured: flexor digitorum longus, peroneus longus and brevis, flexor hallucis brevis, flexor digitorum brevis (FDB) and abductor hallucis (ABH). All measurements were performed with an ultrasound device. [Results] FDB and ABH were correlated with TAH during 10% and 90% loading after removing the effect of body mass index and age. The greater FDB and ABH, the higher TAH. [Conclusion] As FDB becomes larger, the second, third and fourth metatarsal heads are raised more. Furthermore, the height of the first metatarsal head is lowered by a larger ABH. These mechanisms may increase TAH.

Effect of Capacitive and Resistive electric transfer on haemoglobin saturation and tissue temperature.

PURPOSE: This study aims to evaluate the effects of Capacitive and Resistive electric transfer (CRet) and hotpack (HP) on haemoglobin saturation and tissue temperature. MATERIALS AND METHODS: The participants were 13 healthy males (mean age 24.5 ± 3.0). They underwent three interventions on different days: (1) CRet (CRet group), (2) HP (HP group) and (3) CRet without power (sham group). The intervention and measurement were applied at the lower paraspinal muscle. Indiba® active ProRecovery HCR902 was used in the CRet group, and the moist heat method was used in the HP group. Oxygenated, deoxygenated and total haemoglobin (oxy-Hb, deoxy-Hb, total-Hb) counts were measured before and after the 15-min interventions, together with the temperature at the skin surface, and at depths of 10 mm and 20 mm (ST, 10mmDT and 20mmDT, respectively). The haemoglobin saturation and tissue temperature were measured until 30 min after the intervention and were collected at 5-min intervals. Statistical analysis was performed for each index by using the Mann-Whitney U test for comparisons between all groups at each time point. RESULTS: Total-Hb and oxy-Hb were significantly higher in the CRet group than in the HP group continuously for 30 min after the intervention. The 10mmDT and 20mmDT were significantly higher in the CRet group than in the HP group from 10- to 30 min after intervention. CONCLUSIONS: The effect on haemoglobin saturation was higher in the CRet group than in the HP group. In addition, the CRet intervention warmed deep tissue more effectively than HP intervention.

Stable but reactive perfluoroalkylzinc reagents: application in ligand-free copper-catalyzed perfluoroalkylation of aryl iodides.

The aromatic perfluoroalkylation catalyzed by a copper(I) salt with bis(perfluoroalkyl)zinc reagents Zn(RF)2(DMPU)2, which were prepared and then isolated as a stable white powder from perfluoroalkyl iodide and diethylzinc, was accomplished to provide the perfluoroalkylated products in good-to-excellent yields. The advantages of this reliable and practical catalytic reaction are 1) air-stable and easy-to-handle bis(perfluoroalkyl)zinc reagents can be utilized, 2) the reagent is reactive and hence the operation without activators and ligands is simple, and 3) not only trifluoromethylation but also perfluoroalkylation can be attained.

Susceptibility to male infertility: replication study in Japanese men looking for an association with four GWAS-derived loci identified in European men.

PURPOSE: A previous genome-wide association study in European men identified four single nucleotide polymorphism (SNP) loci associated with male infertility. Our aim was to replicate, if possible, the association of these SNPs with Japanese male infertility. METHODS: We genotyped four SNPs (rs5911500, rs10246939, rs2059807, and rs11204546) in 517 Japanese patients with male infertility and 369 fertile controls using SNP-specific real-time polymerase chain reaction TaqMan assays. Subsequently, we divided patients with male infertility into azoospermia (n = 417) and oligospermia subgroups (n = 70). RESULTS: The four SNPs previously identified in European men showed no significant association with collective male infertility in our Japanese cohort. However, allele frequency analysis did indicate a significantly higher frequency of the rs11204546 C allele of the OR2W3 gene in the oligospermia subset of infertility patients compared with controls (p = 0.0037; odds ratio = 1.74; 95 % confidence interval, 1.21-2.53). CONCLUSIONS: Although this study was somewhat limited by overall sample size, the OR2W3 gene polymorphism rs11204546 was significantly associated with oligospermia in Japanese men, suggesting that OR2W3 might be involved in genetic susceptibility to Japanese male infertility as well as in European males.