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The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors., IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.

The detection of circulating cell-free DNA (cfDNA) by liquid biopsy is reported to provide prognostic information in colorectal cancer (CRC). Although the frequency of BRAF V600E mutation in CRC is less than 10%, it is associated with poor responses to conventional chemotherapy. We conducted a prospective study to investigate the relationship between the perioperative mutant allele frequency (MAF) of BRAF V600E and tumor recurrence, and to evaluate the possibility of early detection of recurrence. Among 362 patients who underwent radical resection, cfDNA was extracted from the perioperative blood of 11 CRC patients with BRAF V600E mutation and analyzed using the digital polymerase chain reaction (dPCR) system. The median follow-up time was 22 months, and there were four cases of recurrence. Although there was no correlation between recurrence and the perioperative MAF of BRAF V600E, tumor diameter was correlated with the MAF (p = 0.024), and the MAF increased with time in two patients from whom additional samples were obtained prior to recurrence. In this study, we identified a correlation between the pathological tumor diameter and the MAF, but it was difficult to predict recurrence by measuring cfDNA with BRAF V600E mutation in the perioperative period of radical resection of CRC.

In diabetic pathology, insufficiency in β-cell mass, unable to meet peripheral insulin demand, and functional defects of individual β-cells in production of insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of db/db mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic β-cells through deletion of Mek1 and Mek2, glucose intolerance aggravates under high-fat diet–feeding conditions due to insufficient insulin production with lower β-cell proliferation and reduced β-cell mass, while in individual β-cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in β-cells for glucose homeostasis, i.e., in regulating β-cell mass as well as in controlling insulin exocytosis in individual β-cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.

The transanal and transperineal endoscopic approaches are useful advanced surgical options for removing rectal and anorectal cancers. Intraoperative carbon dioxide (CO2 ) embolisms, however, have been increasingly reported as potentially fatal complications associated with surgery employing these approaches. We report our experience with a CO2 embolism that was detected because of a sudden drop in end-tidal CO2 with decreasing saturation of percutaneous arterial oxygen during total pelvic exenteration using the transperineal endoscopic approach under pneumopelvis/pneumoperitoneum. Transesophageal echocardiography confirmed that it was a CO2 embolus. We reversed the pneumopelvis and pneumoperitoneum, which alleviated the cardiopulmonary problems, and the surgery then proceeded to achieve R0 resection. The patient was discharged without severe complications other than the CO2 embolism.

The incidence and time of onset of acute chemotherapy-induced peripheral neuropathy (ACIPN) caused by oxaliplatin remain unclarified. Hence, we investigated the prevalence, onset time, and location of ACIPN symptoms in patients with colorectal cancer (CRC) receiving oxaliplatin without cold stimulation. The study cohort comprised patients receiving oxaliplatin for CRC at our hospital between April 2017 and August 2018. Patients were instructed not to touch and/or drink cold things and were monitored for ACIPN symptoms in the hospital for 24 h after chemotherapy. ACIPN symptoms that appeared > 24 h after chemotherapy were recorded at the next visit. Symptom appearance time was defined as the duration from the administration of chemotherapy until the appearance of paresthesia classified as grade 1 using the Common Terminology Criteria for Adverse Events. Forty-five patients received chemotherapy, comprising 23 men and 22 women, aged 67 years (29–88 years). The location of ACIPN was the fingers in 55.6% of cases, pharynx in 26.7%, perioral region in 24.4%, and feet in 6.7%. The average duration from oxaliplatin administration to symptom development was 182 min (range 62–443 min) for the fingers, 291 min (176–432 min) for the pharynx, 311 min (127–494 min) for the perioral region, and 297 min (234–355 min) for the feet. Pharyngeal symptoms were more common in patients older than 65 years than in those younger than 65 years. The incidence and time of the onset of ACIPN caused by oxaliplatin varies between the body and regions.

Accurate preoperative T staging is important when determining the treatment strategy for advanced colorectal cancer. We have previously reported the usefulness of preoperative T staging based on the spatial relationship of tumors and “bordering vessels” by computed tomography colonography (CTC) with multiplanar reconstruction (MPR). The aims of this study were to evaluate the external validity of this method and to determine whether there is a difference in the accuracy of T staging between the mesenteric and antimesenteric sides. The study subjects were 110 patients with colorectal cancer who underwent preoperative CTC and surgical resection from June 2016 to March 2018. Preoperative T stage was determined by CTC based on the relationship between the tumor and the bordering vessels and compared with the pathological T stage. The influence of tumor location, namely, whether the tumor was on the antimesenteric or mesenteric side, on preoperative T staging was assessed in 78 patients with colorectal cancer. Sensitivity, specificity, accuracy, positive, and negative predictive values were respectively, 65%, 91%, 83%, 76%, and 85% for T2 (n = 34); 76%, 82%, 81%, 50%, and 94% for T3 (n = 23); and 77%, 93%, 87%, 86%, and 88% for T4a disease (n = 39). Overall right answer rate was 83.3% (15/18) for the mesenteric side and 65% (39/60) for the antimesenteric side (n = 0.14). Diagnostic criteria based on the bordering vessels seen on CTC images with MPR are useful for T staging of colorectal cancer. However, the accuracy differs between the antimesenteric and mesenteric sides.

Transanal minimally invasive surgery is a combination of single-port surgery and transanal surgery and was initially developed as a treatment for rectal tumors. Recently, this approach has also been used for more advanced or extended pelvic surgery. We present a surgical video of combined laparoscopic and transperineal endoscopic total pelvic exenteration performed in a male patient with recurrent rectal cancer and discuss the pros and cons of this approach. The operating time was 775 min and the operative blood loss was 485 ml. The pathology was recurrent adenocarcinoma invading the prostate and urethra with negative surgical margins. The postoperative course was uneventful except for a urinary tract infection that was treated with antibiotics. The transanal/perineal endoscopic approach may have some benefits for extended pelvic surgery for recurrent rectal cancer.

During insulin resistance, lipid uptake by the liver is promoted with peroxisome proliferator activated protein (PPAR) γ-upregulation, leading to hepatic steatosis. Insulin, however, does not directly regulate adipogenic gene expression in liver, and the mechanisms for their upregulation in obesity remains unclear. Here, we show that the Irs2locus, a critical regulator of insulin actions, encodes an antisense transcript ASIrs2, whose expression increased in obesity or after refeeding in liver, reciprocally to that of Irs2. ASIrs2 regulates hepatic Pparg-expression, and its suppression ameliorates steatosis in obese mice. The human orthologue AL162497.1 shows similar genomic organization like ASIrs2, whose expression being correlated with hepatic PPARG and severity of NASH. We also identified HARS2 as a potential binding protein for ASIrs2, functioning as a regulator of Pparg. Collectively, our data revealed a functional duality of Irs2 gene locus, where reciprocal changes of Irs2 and ASIrs2 in obesity cause insulin resistance and steatosis.

Background/aim Chemoimmunotherapy is a promising treatment for various malignant diseases. In this study, we examined whether first-line chemoimmunotherapy using adoptive immune-cell therapy was effective for metastatic colorectal cancer (mCRC). Patients and methods The therapeutic efficacy and safety of the standard first-line chemoimmunotherapy with adoptive αβ T cell therapy and bevacizumab were assessed using thirty-two patients with mCRC in our hospital. Immunological status after this chemoimmunotherapy was also evaluated. Results The response and disease control rates were 68.8% and 87.5%, respectively. Further, median progression-free and overall survival were 14.2 and 35.3 months. Immunotherapy-associated toxicity was minimal. Significant decrease in the change of monocyte number (p=0.006) and increase in the change of rate of lymphocyte-to-monocyte ratio (p=0.039) were seen in the complete response group. Conclusion First-line chemoimmunotherapy with adoptive αβ T cell therapy may be useful for mCRC.

Background Thyrotoxicosis is common disorder among endocrine dysfunctions. It is not rare that the free thyroid hormone level exceeds the measurement range of immunoassay. Such extreme high concentration of free thyroid hormone is generally considered to be impossible to measure correctly because of changes in the balance between free hormones and binding proteins by dilution of serum. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), however, higher concentrations are able to be determined. Case presentation We present a case of a 21-year-old female with congenital hypothyroidism who had taken a total of 5 mg levothyroxine over three consecutive days following discontinuance of the medication for a month. Immunoassay performed 3 hours after the last ingestion showed that the patient’s free thyroxine (FT4) was over 100 pmol/L and her free triiodothyronine (FT3) was 24.5 pmol/L. With a temporary cessation of levothyroxine, the patient was kept for observation without any other medication. Two days after the last ingestion, FT4 was still over 100 pmol/L and FT3 was increased to 28.8 pmol/L. After an additional 4 days, both FT4 and FT3 levels decreased. Through this period, no thyrotoxic symptom or physical sign had appeared. We also measured FT4 and FT3 levels in her cryopreserved serum by ultrafiltration LC-MS/MS. Her FT4 level measured by ultrafiltration LC-MS/MS on the visiting day and 2 days later were 160.0 and 135.5 pmol/L, respectively, indicating that the toxic dose of levothyroxine was partly changed to T3 during the 2 days. The FT3/FT4 ratios were revealed to be low, accounting for the patient’s benign clinical course despite temporal toxic exposure to levothyroxine. It is implied that prior discontinuation of supplementary levothyroxine increases potential vacant binding sites for thyroid hormone as a buffer to prevent toxic T3 effect. Conclusion It was helpful to clarify the time dependent changes in free thyroid hormone levels by ultrafiltration LC-MS/MS in discussing the clinical course in this case. Though mass spectrometry has a disadvantage in speed for routine laboratory use, its accurate measurement, particularly of levels exceeding the measurable range of the immunoassay, provides valuable information for more appropriate management of extreme thyrotoxicosis.

Background Thyroid ultrasound screening for children aged 0 to 18 years was performed in Fukushima following the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases were detected. To explore the carcinogenic mechanisms of these cancers, we analyzed their clinicopathological and genetic features. Methods We analyzed 138 cases (52 males and 86 females) who had undergone surgery between 2013 and 2016 at Fukushima Medical University Hospital. Postoperative pathological diagnosis revealed 136 (98.6%) cases of papillary thyroid cancer (PTC). Results The BRAFV600E mutation was detected using direct DNA sequencing in 96 (69.6%) of the thyroid cancer cases. In addition, oncogenic rearrangements were detected in 23 cases (16.7%). Regarding chromosomal rearrangements, 8 (5.8%) RET/PTC1, 6 (4.3%) ETV6(ex4)/NTRK3, 2 (1.4%) STRN/ALK, and 1 each of RET/PTC3, AFAP1L2/RET, PPFIBP/RET, KIAA1217/RET, ΔRFP/RET, SQSTM1/NTRK3 and TPR/NTRK1 were detected. Tumor size was smaller in the BRAFV600E mutation cases (12.8 ± 6.8 mm) than in wild-type BRAF cases (20.9 ± 10.5 mm). In the BRAFV600E mutation cases, 83 (86.5%) showed lymph node metastasis, whereas 26 (61.9%) of the wild-type BRAF cases showed lymph node metastasis. Conclusions The BRAFV600E mutation was mainly detected in residents of Fukushima, which was different from post-Chernobyl PTC cases with RET/PTC3 rearrangement. PTC with the BRAFV600E mutation was smaller but was shown in the high rate of central cervical lymph node metastasis than the wild-type BRAF PTC in the young population of Fukushima.

Capecitabine is selectively converted from 5′-DFUR to 5-fluorouracil (5-FU) in tumours by thymidine phosphorylase (TP). We investigated the addition of 5-nitrouracil (5-NU), a TP inhibitor, into blood samples for precise measurements of plasma 5-FU concentrations. The plasma concentration of 5-FU was measured after capecitabine administration. Two samples were obtained at 1 or 2 h after capecitabine administration and 5-NU was added to one of each pair. Samples were stored at room temperature or 4 °C and 5-FU concentrations were measured immediately or 1.5 or 3 h later. The mean plasma 5-FU concentration was significantly higher at room temperature than at 4 °C (p p p

Numbness and pain are currently evaluated using subjective methods such as the visual analogue scale (VAS). PainVision (PV) is an analytical instrument that was designed to quantitatively assess sense perception and nociception in patients. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most important adverse events that renders prolonged chemotherapy difficult. To assess the features of CIPN, we aimed to compare PV methods with existing methods. A total of 73 patients received oxaliplatin for metastatic colorectal cancer. Registered patients included 37 men and 36 women in the range of 37 to 89 years (median 70). CIPN was evaluated a total of 483 times (median per patient six times). Our study examined the correlation between evaluation methods of CIPN using VAS and PV, respectively. The average VAS (hand), VAS (foot) and PV scores of CIPN were 18.4 (range: 0–100), 23.8 (range: 0–100), and 24.7 (range: 0–496), respectively. VAS (hand), VAS (foot), and FACT/GOG-NTX (NTX2, NTX4 and NTX8) were significantly correlated with PV. PV showed no correlation with a Disk-Criminator or the monofilament test used as a quantitative evaluation. The evaluation of CIPN is complex, and further improvement is required for evaluation with PV.

Solute carrier (SLC) drug transporters exchange various molecules without energy from adenosine triphosphate hydrolysis, indicating an association with anticancer drug resistance. However, the expression and role of SLC transporters in malignant tumors has not yet been fully elucidated. Therefore, in the current study, the expression of SLC37A family genes was evaluated in patients with colorectal cancer (CRC), and it was revealed that SLC family 37 member 1 (SLC37A1) expression was significantly increased in tumorous tissues compared with that in non-tumorous tissues. The cases with upregulated expression of SLC37A1 by immunohistochemical staining were significantly associated with positive venous invasion and liver metastasis. Furthermore, upregulated SLC37A1 expression was associated with poor overall survival time in the present cohort. These results indicated that SLC37A1 is involved in the hematogenous metastasis of CRC. To investigate whether SLC37A1 is associated with hematogenous metastasis and glycolipid metabolism, SLC37A1 was knocked down in colon cancer cells, and the expression of sialyl Lewis A and sialyl Lewis X was observed to be decreased. In summary, upregulation of SLC37A1 was observed in patients with CRC, and was associated with poor patient outcomes and survival. To the best of our knowledge, the present study is the first to propose a key role of SLC37A1 in CRC, and additional studies are warranted to reveal the functional role of SLC37A1 in CRC development.

Simple Summary In recent years, the incidence of thyroid cancer has been increasing worldwide, mainly due to the widespread use of imaging examination methods, such as ultrasonography. In Japan, the risk of overdiagnosis due to the use of diagnostic imaging has been discussed since the 1990s, and measures have been taken to reduce the risk of overdiagnosis and overtreatment by establishing criteria for the implementation of fine needle aspiration cytology and non-surgical follow-up. This article outlines the diagnostic criteria and management guidelines in Japan in comparison with those published in other countries. Abstract In recent years, the incidence of thyroid cancer has been increasing worldwide, which is believed to be mainly due to the widespread use of imaging examinations, such as ultrasonography. In this context, ultrasonography has become increasingly important because it can evaluate not only the presence or absence of nodules, but also the detailed characteristics of the nodule, making it possible to diagnose benign or malignant nodules before cytology is performed. In Japan, the third edition of the sonographic diagnostic criteria for thyroid nodules is currently widely used, and its content is similar to that of recent meta-analyses and guidelines from medical societies in other countries. In addition, since overdiagnosis of very-low-risk thyroid cancer has recently become an issue, criteria for the implementation of fine needle aspiration cytology (FNAC) have been published by various countries. The Japan Society of Breast and Thyroid Sonology provides guidelines for FNAC implementation for solid and cystic nodules. In the United States, the ATA, NCCA, and ACR have published guidelines, whereas in Europe, the ESMO and ETA have done the same. All of these guidelines used to classify risk are based on nodule size and sonographic findings. This article outlines the diagnostic criteria and management guidelines in Japan in comparison with those published in other countries. Case studies using actual images were also performed to examine the differences in the FNAC guidelines.

Relationships between inflammation and innate immunity in cancer are widely accepted today; however, the precise cell mechanisms mediating these relationships have not yet been elucidated. Interleukin (IL)-17 is a proinflammatory cytokine that has been reported to induce inflammation in patients with autoimmune diseases. Myeloid-derived suppressor cells (MDSC) may contribute to the negative regulation of immune responses during cancer and inflammation. Vascular endothelial growth factor (VEGF) is reported to have multiple biological actions including increasing vascular permeability, neovascularization, and possible inhibition of immune function in malignant diseases. This study investigated the status of systemic inflammation and immune suppression associated with IL-17 and VEGF in patients with breast cancer. IL-17 production and the serum levels of VEGF were also increased in advanced stages of the disease. The production of IL-12, which induces Th1 cells, and the stimulation index (SI), which is a marker of cell-mediated immune function, were both shown to decrease along with disease advancement. Also, the production of IL-17 and the VEGF levels were both positively correlated with the levels of MDSC, the neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and were inversely correlated with IL-12 production and the SI. Nutritional markers, including prealbumin (PA), transferrin (TF), and retinol-binding protein (RBP), were also shown to be significantly lower in patients with high production of IL-17 or high levels of VEGF. These data clearly showed that IL-17 and VEGF, whose levels correlated with each other and with those of MDSC, were significantly associated with disease advancement, systemic inflammation, suppression of cell-mediated immunity including Th1 induction, and malnutrition.

Complete mesocolic excision with central vascular ligation is a standard advanced technique for achieving favorable long-term oncological outcomes in colon cancer surgery. Clinical evidence abounds demonstrating the safety of high ligation of the inferior mesenteric artery (IMA) for sigmoid colon cancer but is scarce for descending colon cancer. A major concern is the blood supply to the remnant distal sigmoid colon, especially for cases with a long sigmoid colon. We sought to clarify the safety and feasibility of high ligation of the IMA in surgery for descending colon cancer using indocyanine green (ICG) fluorescence imaging. In this prospective single-center pilot study, we examined 20 patients with descending colon cancer who underwent laparoscopic colectomy between April 2018 and September 2019. Following full mobilization and division of the proximal colonic mesentery, we temporarily clamped the root of the IMA and performed ICG fluorescence imaging of the blood flow to the sigmoid colon. The postoperative anastomosis-related complications (primary endpoint) and length of viable remnant colon, and the number of lymph nodes retrieved (secondary endpoints) were evaluated and compared with historical controls who underwent conventional IMA-preserving surgery (n = 20). Blood flow reached 40 (17–66) cm retrograde from the peritoneal reflection, even after IMA clamping. Accordingly, IMA high ligation was performed in all cases. No anastomotic anastomosis-related complications occurred in each group. Retrieved total lymph nodes were higher in number in the ICG-guided group than in the conventional group (p = 0.035). Specifically, more principal nodes were retrieved in the ICG-guided group, compared with the conventional group (p = 0.023). However, the distal margin was not as long compared with the conventional group. We demonstrated the safety and feasibility of high ligation of the IMA for descending colon cancer without sacrificing additional distal colon using fluorescence evaluation of blood flow in the remnant colon.

In abdominoperineal resection (APR) in male patients with rectal cancer, high margin involvement and urethral injury have been reported to result from difficulty in dissecting the anterior anorectum. Recently, the efficacy of an endoscopic down-to-up rectal dissection was reported. Here, we present a safe and simple technique for anterior dissection using a simultaneous laparoscopic and transperineal endoscopic approach. We perform transperineal APR (TpAPR) using both the laparoscopic and transperineal approach (a 2-team approach). Anterior dissection commences just behind the superficial transverse perineal muscle. Next, the striated muscle complex surrounding the rectum (levator ani and puborectalis muscle) is divided. At this point, it is difficult to identify the dissection plane between the membranous urethra and anterior rectum; thus, dissection along the lateral aspect of neurovascular bundle from the lateral to anterior side with the assistance of the laparoscopic team is helpful in identifying the posterior surface of the prostate. Once the prostate is identified, it is relatively easy to divide the rectourethralis muscles. The key steps of our procedure are shown in the video. Between April 2016 and July 2019, we performed 14 TpAPR procedures in male patients with rectal cancer without distant metastasis. Extended surgery was performed in 8 patients, including pelvic sidewall dissection and combined resection of adjacent organs. Median operative time was 453 min and median blood loss was 46 g. There was 1 (7.1%) circumferential-positive case, but no cases of urethral injury or rectal perforation. The 2-team TpAPR procedure is beneficial for appropriate dissection of the anterior side during APR surgery.

Background/aim TAS-102 has led to a significant improvement in overall survival (OS) and progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC). Neutropenia is the most common adverse event and an important factor impacting chemotherapy continuation. In this retrospective study, factors associated with grade ≥3 neutropenia, that is frequently observed in TAS-102-treated patients, were examined. Patients and methods The medical records of 41 patients with CRC who received TAS-102 between October 2014 and June 2017 at the Fukuoka University Hospital were retrospectively reviewed. Response rate, PFS, OS, and adverse events were analyzed using KRAS mutation, administration method, concomitant drug administration, neutrophil-to-lymphocyte ratio (NLR), and Onodera's prognostic nutritional index (Onodera's index) as a stratification factors. Results Both PFS and OS were significantly higher with TAS-102 plus bevacizumab combination therapy. Biweekly administration (7.1%) was associated with significantly less neutropenia compared to normal administration (44.4%). DCR with biweekly administration was better than that with normal administration, although without statistical significance. No significant difference was observed in OS rates between the biweekly and normal administration regimens; however, the biweekly regimen was associated with significantly prolonged PFS. By multivariate analysis, a significant difference was noted in the Onodera's index for OS and in the administration method and NLR for PFS. Conclusion Biweekly administration without a change in the drug dose intensity was associated with reduced neutropenia in patients with mCRC. The effects and adverse events of TAS-102 were associated with concomitant drug administration, administration method, and nutritional status.

Homeobox A (HOXA) cluster genes, members of the HOX family, perform an important role in normal organ development. It has previously been reported that HOXA gene expression in various types of cancer is associated with poor patient outcomes. However, the role of HOXA genes, as well as their expression, in colorectal cancers (CRC) remains unknown. Therefore, the present study investigated HOXA gene expression in patients with CRC and revealed that HOXA9 expression was significantly increased in tumor tissues compared with non-tumor tissues. Additionally, the functional role of HOXA9 was assessed by knocking down the HOXA9 gene in CRC cells and by evaluating cell growth. Regarding gene expression, cases with positive HOXA9 expression (as detected by immunohistochemical staining) were significantly associated with higher TNM stage and positive lymph node metastasis, although no association was observed between increased HOXA9 levels and the rate of overall survival in the present cohort. Regarding the functional role, HOXA9 expression was demonstrated to be upregulated in patients with CRC and was associated with lymph node metastasis.

Kinesin family member 4A (KIF4A) is a member of the kinesin 4 subfamily of kinesin-related proteins and serves an important role in cell division. The expression levels of KIF4A have been investigated in numerous types of cancer, including cervical, lung, oral, and breast cancer, and are established to be associated with poor patient prognosis. However, the role of KIF4A, as well as its expression in colorectal cancer (CRC), remains to be elucidated. Therefore, the current study investigated KIF4A expression levels in patients with CRC and demonstrated that its levels were increased in tumor tissues compared with non-tumor tissues. To investigate the functional role of KIF4A, KIF4A was knocked down in CRC cells and cell viability was evaluated. CRC cells with KIF4A knockdown exhibited lower cell proliferation compared with control cells. In addition, KIF4A expression levels, as determined by immunohistochemistry, were compared with the expression of Ki-67, but no significant associations were observed in the patients with CRC. Therefore, KIF4A was found to be upregulated in patients with CRC and downregulation of KIF4A reduced cell proliferation in CRC cells. These results suggest that KIF4A may be a potential therapeutic target, which may improve the outcomes of patients with CRC.

Myeloid-derived suppressor cells (MDSCs) have been identified in the majority of patients and experimental mice with tumors by their suppression of T cell activation. MDSCs have also been reported to be associated with chronic inflammation. In advanced cancer, the T helper (Th) cell balance tends to shift from Th1 to Th2 predominance, and immune function, including cell-mediated immunity, is impaired by cytokines produced by Th2 cells. The present study examined the correlations between MDSC levels and inflammation, immune suppression, malnutrition, and poor prognosis in 155 patients with breast cancer. The levels of MDSCs in preoperative patients and in patients with recurrent breast cancer were significantly higher compared with postoperative patients, patients with recurrent breast cancer who received chemotherapy and healthy volunteers. The MDSC levels of preoperative patients were significantly positively correlated with interleukin (IL)-6 production by peripheral blood mononuclear cells (PBMCs), the neutrophil/lymphocyte ratio and C-reactive protein, and were negatively correlated with the production of interferon-γ and IL-12, serum concentration of rapid turnover protein, and the stimulation index. These patients were divided into two groups based on the levels of MDSCs. In preoperative patients with MDSC levels >1.0% of total PBMCs, the overall survival of patients with stage IV disease was significantly shorter compared with other disease stages, and was also significantly shorter compared with patients with MDSC levels

Purpose An autoantibody against aquaporin-4 (AQP4 Ab) is highly specific for neuromyelitis optica spectrum disorder and plays a pathogenic role in this disease. The purpose of this study was to investigate the impact of AQP4 Ab on inner retinal structure, function, and the structure−function relationships in eyes with optic neuritis. Methods Thirty five eyes from 25 cases who had received visual function tests and RTVue optical coherence tomography (OCT) measurement at least six months after the latest episode of optic neuritis were enrolled. Patients with multiple sclerosis were excluded. AQP4 Ab was measured using a cell-based assay. Visual acuity, mean deviation (MD) of the Humphrey visual field SITA standard 30–2 tests, retinal nerve fiber layer (RNFL), ganglion cell complex (GCC) thicknesses, and other clinical variables were compared between the AQP4 Ab-positive and -negative groups. Parameters associated with visual functions were evaluated by generalized estimating equation (GEE) models. Results The AQP4 Ab-positive group (20 eyes from 12 cases) had a higher proportion of bilateral involvement and longer duration of follow-up than the AQP4 Ab-negative group (15 eyes from 13 cases). Linear mixed effect models revealed worse MD and visual acuity in AQP4 Ab-positive eyes than those in AQP4 Ab-negative eyes after adjusting for within-patient inter-eye dependence, whereas there were no differences in RNFL and GCC thickness between the two groups. In seropositive eyes, GEE regression analyses revealed that depending on age and the number of recurrences of ON episodes, OCT parameters correlated strongly with MD and more weakly with visual acuity. Conclusions Reductions in RNFL and GCC thickness were proportional to the visual field defect in eyes with AQP4 Ab but not in eyes without AQP4 Ab. The presence of AQP4 Ab probably plays a critical role in retinal ganglion cell loss in optic neuritis.

To measure changes in axial length before and after trabeculectomy with noncontact, partial coherence laser interferometry and identify patient factors that lead to the development of hypotony maculopathy and axial length shortening in 25 eyes with intraocular pressure (IOP) ≤6 mmHg at 4 weeks after mitomycin C-augmented trabeculectomy. A retrospective comparative case series. Hypotony maculopathy was identified with both ophthalmoscopy and spectral-domain optical coherence tomography. Axial length and IOP were serially measured pre- and postoperatively. Logistic regression analysis was performed to identify factors associated with the presence of hypotony maculopathy at 4 weeks after trabeculectomy and multiple regression analysis to identify factors associated with axial length changes. Ten eyes exhibited hypotony maculopathy, whereas the remaining 15 did not. Patients with hypotony maculopathy were significantly younger (47.7 ± 6.2 years) compared with those without it (63.3 ± 9.6 years, P = 0.0002, unpaired t test). The percent reduction of axial length after trabeculectomy was significantly larger in the former group (5.91 ± 2.76 %) compared with the latter group (1.51 ± 0.91 %) (P = 0.0001, Mann–Whitney U test). Multivariate analyses showed that only age was associated with the presence of hypotony maculopathy, with an odds ratio of 0.82 (P = 0.0075), when age, sex, type of glaucoma, lens status, percent changes in axial length and IOP before and after trabeculectomy, and central corneal thickness were included as independent variables (R 2 = 0.543, P = 0.003). Age-dependent axial length reduction is a risk factor for the development of hypotony maculopathy after trabeculectomy.

Neuromyelitis optica (NMO) is an autoimmune inflammatory, neurodestructive disease primarily targeting the optic nerve and spinal cord. An autoantibody against water channel protein aquaporin-4 (AQP4), which is expressed at endofeet of astrocytes has been implicated in the pathogenesis of NMO. We evaluated the impact of sera of seropositive patients with NMO spectrum disorders (NMOSDs) on the rodent optic nerve and retina. Serum was obtained either from patients with seropositive NMOSD (AQP4+), seronegative patient with idiopathic optic neuritis (AQP4-), and healthy volunteers (control). Anti-AQP4 antibody in a serum was measured by a previously established cell-based assay. The patients' sera were applied on the optic nerve after de-sheathed. Immunohistochemistry showed that at 7 days after the treatment, the area of the optic nerve exposed to the AQP4+ sera lost expression of both AQP4 and glial fibrillary acidic protein. Also, Human-IgG immunoreactivity and marked invasion of inflammation cells were observed in the optic nerve treated with AQP4+ serum. Immnoreactivity of neurofilament was reduced at 14 days after the treatment, not 7 days. Real-time polymerase chain reaction revealed the reduced gene expression of neurofilament in retina from the eye that was exposed to the AQP4+ sera at 14 days. Retrograde fluorogold-labeling on the retinal flatmount disclosed the significantly reduced number of retinal ganglion cells when the AQP4+ sera were applied. The present model has demonstrated that the sera from patients with seropositive NMOSDs led to the regional astrocytic degeneration and inflammatory cell invasion in the optic nerve, resulting in the ultimate loss of RGCs and their axons at areas beyond the injury site.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is an important factor that renders the continuation of chemotherapy difficult. Prevention and treatment of CIPN are indispensable in improving patients’ quality of life and promoting the continuation of chemotherapy that may improve survival. Numbness and pain are currently evaluated using subjective methods such as the visual analogue scale (VAS). However, the assessment of pain can vary greatly depending on the mood and physical state of the patient at the time of assessment. In this stage, objective evaluation methods have not been used for evaluations of CIPN in clinical trials because they have not been established as quantified evaluation methods for CIPN yet. A method to quantify CIPN objectively and easily is necessary. The PainVision PS-2100 (PV) is an analytical instrument that was designed to quantitatively and objectively assess sense perception and nociception in patients. The advantage of PV is that it can evaluate pain in a relatively short time, as well as assess pain without causing further pain to patients. Methods We examined a total of 73 CIPN patients with metastatic CRC received chemotherapy between April 2014 and December 2015 by using VAS, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (NTX), the Disk-Criminator™ test, the monofilament test and PV. And then, we evaluated the correlation between subjective and objective evaluation methods or correlation between PV and other objective evaluation methods for CIPN. Results The average VAS (hand), VAS (foot) and PV scores of CIPN were 18.4 (range: 0–100), 23.8 (range: 0–100) and 24.7 (range: 0–496), respectively. A strong positive correlation was found between VAS (hand) and VAS (foot) scores (r = 0.798). The VAS (hand), VAS (foot), NTX 2, NTX 4 and NTX 8 significantly correlated with PV. PV showed no correlation with a Disk-Criminator™ or the monofilament test used as an objective evaluation. Conclusions This is the 1st report regarding the correlation between PV and other objective evaluation methods in CIPN patients. The evaluation of CIPN is complicated because numerous factors are involved. And further research and effort are needed to improve objective evaluation of CIPN by PV. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor β (TGF-β) expression and thick stromal fibrosis. However, the association of TGF-β signaling with diffuse-type gastric carcinoma has not been investigated in detail. Methods We used a lentiviral infection system to express a dominant-negative TGF-β type II receptor (dnTβRII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided. Results Expression of dnTβRII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnTβRII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnTβRII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnTβRII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1–knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P < .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues. Conclusions Disruption of TGF-β signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1.

Purpose To assess the diagnostic performance of the macular parameters detected by spectral-domain optical coherence tomography (SD-OCT) in band atrophy (BA) eyes. Methods Forty-nine BA eyes with permanent temporal hemianopia and 89 normal eyes were enrolled. Any patients who had nasal visual field loss were excluded. Each participant was imaged by three-dimensional (3D) OCT-2000, and 10 × 10 grids in the macula were automatically allocated. The thickness of the macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL)+ (GCL+inner plexiform layer [IPL]), and GCL++ (RNFL+GCL+IPL) in both nasal and temporal hemiretina was calculated and compared between the BA and normal eyes. The areas under the receiver operating characteristic curves (AUCs) in these parameters were compared between the nasal hemiretina and the temporal hemiretina. Results All the parameters in the BA eyes were significantly thinner than those in the normal eyes. The AUCs for the mRNFL, GCL+, and GCL++ thickness in the nasal hemiretina were 0.890, 0.988, and 0.981, respectively. The parameters in the nasal hemiretina showed significantly higher AUCs than those parameters in the temporal hemiretina. In the temporal hemiretina, the damaged grids in the mRNFL were located in the arcuate areas in each hemifield. Conclusions The inner macular parameters in the nasal hemiretina exhibited high diagnostic abilities to detect BA. The GCL+ was more affected than mRNFL. The characteristic pattern of mRNFL and GCL+ thinning was implicated in the anatomical architecture regarding the nasotemporal overlap of the crossed and uncrossed fibers around the fovea. (www.umin.ac.jp/ctr number, UMIN000006900.).

To establish a rat glaucoma model with chronic intraocular pressure (IOP) elevation induced by microbeads suspended in sodium sulfate–sodium hyaluronate. Chronic elevation of IOP was induced unilaterally by injecting polystyrene microbeads, suspended in 4 % sodium sulfate and 3 % sodium hyaluronate, into the anterior chamber. The microbead suspension was injected through either the clear corneal (CC) or sclerocorneal (SC) tunnel. IOP changes were monitored up to 8 weeks after injection. The loss of retinal ganglion cells (RGCs) was assessed using fluorogold retrograde labeling of RGCs. RGC axons were evaluated by immunohistochemistry and immunoblotting. The resulting IOP elevation was maintained up to 3 weeks after the intracameral injection of microbeads through the CC route and up to 4 weeks after injection through the SC route. The density of RGCs was significantly reduced at 4 weeks after injection, with the SC route leading to more RGC loss than the CC route (p = 0.037). The neurofilament immunoreactivity and protein levels in the optic nerve were also significantly reduced at 4 weeks after injection. Some eyes in the SC route cohort received re-injection of the microbead suspension at 4 weeks after the initial injection, which led to an elevated IOP more than 8 weeks after the initial injection, and eventually a 27.5 % loss of RGC density compared with the control eyes. The intracameral injection of microbeads suspended in hyaluronate effectively produced chronic IOP elevation and subsequent RGC degeneration in rat eyes. The sclerocorneal tunnel approach yielded a longer period of IOP elevation than the clear corneal approach. Our modified microbead injection offers a reliable high-pressure glaucoma model.

The analysis of genes preferentially expressed in the peripheral blood cells of atopic dermatitis patients may provide information on the molecular pathogenesis of the disease. We employed differential display PCR to clone a new gene (AB100163) with 99% homology to coiled-coil domain containing 132, transcript variant 1 (CCDC132) (NM_017667) (aliases, FLJ20097, FLJ23581, KIAA1861 and MGC176659). Full-length CCDC132 of approximately 4 kbp encodes mRNA expressed in almost all tissues, in particular brain tissue and skeletal muscle. A homologous gene has also been identified in mice. Using Western blot analysis, 111 kDa CCDC132 protein was detected in two human T-cell lines, MOLT-4 and Jurkat, and in the human cervical adenocarcinoma cell line HeLa. Quantitative RT-PCR revealed transcription levels of CCDC132 in the T cells of atopic dermatitis patients to be higher than in those of normal individuals. This suggests that changes in CCDC132 expression may be involved in the course of atopic dermatitis.

PAICS (Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase) is an important bifunctional enzyme in de novo purine biosynthesis. It could be an attractive target for anticancer drug design, since rapidly dividing cancer cells rely on the purine through de novo pathway for synthesis of adenine and guanine, whereas normal cells favor the salvage pathway. Previous reports demonstrated that PAICS expression was up-regulated in ALL, lung cancer, and glioblastoma. In the present study, we first performed the comparison of PAICS mRNA expression between cancer tissue and normal colonic mucosa in 83 colorectal cancer (CRC) patients by realtime RT-PCR. We further investigated PAICS expression by immunohistochemical staining in 258 CRC patients and analyzed the association between PAICS expression and clinicopathological factors and prognosis. To understand the biological significance of PAICS expresssion, knockdown experiments of PAICS expression were performed by a siRNA method using the colon cancer cell line, HCT116. We analyzed the relationship between PAICS mRNA expression and genetic status and prognosis using several databases. PAICS mRNA expression in CRC tissue was significantly enhanced when compared to that in normal tissue. In immunohistochemical examination, PAICS expression was observed in cytoplasm of cancer cells. PAICS expression was detected in 55% cases of colorectal cancer patients. There were significant association between PAICS expression and histology (p = 0.049). There was not significant correlation between PAICS expression and overall survival in CRC patients. Regarding CRC patients with stage III, patients with positive expression of PAICS had significantly good prognosis as compared to those with negative expression (p = 0.015). Knockdown of PAICS expression acquired the ability of cellular invasion using colon cancer cell lines, HCT116 and SW480. In all CRC databases we analyzed, stage III patients with high expression of PAICS had good prognosis as compared to those with low expression of PAICS. We concluded that PAICS expression was up-regulated in approximately 55% CRC, and higher level of PAICS expression might serve as a good prognostic marker in advanced CRC patients. Citation Format: Yusuke Kobayashi, Kensuke Kumamoto, Yoshiko Matsumoto, Motonobu Saito, Tatsuo Shimura, Seiichi Takenoshita. PAICS is the prognostic marker in colorectal cancer patients with stage III. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3415. doi:10.1158/1538-7445.AM2015-3415

Background: Analysis of genes that are differentially expressed in patients with atopic dermatitis (AD) and normal individuals will provide important information on the underlying molecular pathogenetic mechanisms of AD. Methods: Transcript of freshly isolated peripheral blood T cells from 59 individuals were analyzed with a fluorescent differential display (FDD) method. Ninety-two differentially expressed genes were identified in this manner. Additionally, real-time quantitative RT-PCR was employed to investigate the expression of the FDD-selected genes and also genes related to T cell function. Results: A number of genes, including CC chemokine receptor 4, T cell-specific tyrosine kinase (Emt/Itk), integrin β1, integrin α6, IQGAP1 and MAR/SAR DNA-binding protein (SATB1), were shown to be more highly expressed in patients with moderate and/or severe AD than in controls or patients with mild AD. Because the products of these upregulated genes influence chemotaxis, adhesion, migration and Th2 polarization, it is suggested that in more severe AD, circulating T cells may function differently in this regard. Several other genes, the role of which in T cell function is currently unknown, were also found to be differentially expressed in AD. These included the heat shock protein 40 and vasopressin-activated calcium-mobilizing receptor 1. Conclusion: The upregulated genes identified in this work may serve as useful markers for moderate to severe AD as opposed to normal or mild AD and also as markers indicating progression to more severe AD. Further functional characterization will provide a better understanding of the pathophysiology of circulating T cells in AD.

e14006 Background: A suppression of cell mediated immunity and malnutrition are commonly seen in patients with advanced cancer and it has been reported that chronic inflammation plays a key role in induction of these conditions. We have reported that MDSC: myeloid-derived suppressor cells, found as a new type of immune suppressor cells that is closely related to chronic inflammation, is increased in patients with various types of cancer including gastrointestinal, hepatopancreatic, breast, thyroid and ovarian cancers, and the levels of MDSC were closely related to systemic inflammation, immunosuppression and nutritional impairment. Especially in breast cancer, the levels of MDSC have been reported to decrease after the removal of the tumor and to increase with recurrence. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 106 preoperative patients with breast cancer including 19 patients with stage I, 48 with stage II, 12 with stage III and 27 with stage IV diseases, and these cells we...

Background Cyclosporine A (CYA) is an immunosuppressive agent which is being used in the treatment of an increasingly wide range of dermatologic diseases, but its use has been avoided in carriers of hepatitis C virus (HCV). Methods We administered small doses of CYA (maximum, 3 mg/kg/day) for a long time to treat dermatologic diseases in one HCV-antibody-positive patient with no HCV-RNA in the blood, one patient with a small amount of HCV-RNA in the blood, and two patients with large amounts of HCV-RNA in the blood. Results Skin lesions improved in all patients, but recurred upon complete or partial withdrawal of CYA. In the absence of HCV-RNA in the blood, or when only a small quantity of HCV-RNA was present in the blood, HCV-RNA load showed no apparent change. In one patient with a large blood HCV-RNA load, CYA dosage reduction was followed by increases in alanine aminotransferase (ALT) levels and decreases in blood HCV-RNA. Aggravation of hepatitis due to immunologic reactivation was suspected in this patient. Conclusions The reduction of CYA dosage is a key element in the use of this agent for cutaneous diseases.

Cerebrovascular diseases, especially cerebral hemorrhage, have been thought the most frequent cause of death in Japan. The Ministry of Health and Welfare has reported that cerebrovascular diseases have been the top of the cause of death in Japan since 1951. Pathologists, however, do not have experienced so many autopsy cases who died of cerebrovascular diseases. Then, we investigated the cause of death in two leprosaria and compared it with informations from the Ministry of Health and Welfare.One hundred and twenty seven patients died in Komyo-en Leprosarium between 1962, January, and 1971, June. Autopsy was done on 110 cases. The average age was 62.5 years old. Malignant neoplasms (33 cases) were more frequent than cerebrovascular diseases (hemorrhage: 9 cases, softening: 3, microscopic hemorrhage: 11). The major direct cause of death was bronchopneumonia. Investigation of the death certificates in Seisho-en Leprosarium for the years 1967-1976 also revealed that cerebrovascular diseases were not the major cause of death. These results are different from informations of the cause of death in Japan published by the Ministry of Health and Welfare. This discrepancy probably comes from inaccurate description of the death certificates and low autopsy rate in this country.

295 lepromatous and 74 tuberculoid leprosy patients were typed for HLA-A, -B and -C and compared to 110 healthy controls. It was found that frequency of HLA-B7 was significantly high and that of Bw54 was significantly low in lepromatous leprosy. HLA-DR and MT types were investigated in 84 lepromatous and 28 tuberculoid patients and compared to 55 controls. Both lepromatous and tuberculoid patients showed a marked increase in DR2 frequency. The relative risk is 8.7 and 5.9. Lepromatous leprosy showed an increase in frequency of MT1 and decreases in those of DRw9 and MT3 too.