Regioselective photocyclodimerization of 2-anthracenecarboxylic acid through ATP hydrolysis-driven conformational change using simulation prediction-designed GroEL mutant.

GroEL, a chaperone protein responsible for peptide and denatured protein folding, undergoes substantial conformational changes driven by ATP binding and hydrolysis during folding. Utilizing these conformational changes, we demonstrated the GroEL-mediated regioselective photocyclodimerization of 2-anthracenecarboxylic acid (AC) using ATP hydrolysis as an external stimulus. We designed and prepared an optimal GroEL mutant to employ in a docking simulation that has been actively used in recent years. Based on the large difference in the motif of hydrogen bonds between AC and GroEL mutant compared with the wild-type, we predicted that GroELMEL, in which the 307‒309th amino acid residues were mutated to Ala, could alter the orientation of bound AC in GroEL. The GroELMEL-mediated photocyclodimerization of AC can be used for regioselective inversion upon ATP addition to a moderate extent.

Predictors of the development of febrile neutropenia in chemotherapy for advanced germ cell tumors.

OBJECTIVES: To identify the predictive factors for the development of febrile neutropenia (FN) in the course of chemotherapy for patients with germ cell tumors. METHODS: From January 2005 to December 2018, 80 patients were treated with induction chemotherapy for advanced germ cell tumors at Kanagawa Cancer Center Hospital, Japan. Of these, we retrospectively analyzed 267 cycles of chemotherapy. The incidence of FN was used as the objective variable. As predictive factors, we analyzed age, international germ cell consensus classification (IGCCC), laboratory data at the start of chemotherapy in each cycle, length of the largest metastatic lesion, number of cycles, and prophylactic use of granulocyte colony stimulating factor (G-CSF). RESULTS: We finally analyzed 267 cycles in 78 patients. The median age was 36 years (15-64). There was a total of 267 cycles. FN occurred in 40 cycles (15%) in 31 patients (40%). The first cycle was accompanied by a significantly higher FN than the subsequent cycles (p < 0.001). The univariate analysis identified age ≧36 years (p = 0.001), creatinine clearance (CCr) <70 (p < 0.001), serum albumin <3.3 (p = 0.002), maximum tumor diameter ≧60 mm (p = 0.036), and first cycle as significant risk factors. The multivariate analysis identified age, CCr, and first cycle as independent predictive factors of FN development. CONCLUSION: We identified older age, renal dysfunction, and first cycle of chemotherapy as predictive factors for FN. No statistically significant difference was shown in the usage of prophylactic G-CSF. Special attention should be given to FN in patients with high-risk factors.

Coloration Modeling and Processing of Commodity Plastic Buttons in Supercritical Carbon Dioxide.

We examined the color processing of the commodity plastic buttons made of acrylic, polyester, nylon, and casein with scCO2. The buttons' dyeing color depth (K/S) was measured over a wide range of scCO2 and correlated accurately with the response surface method. Moreover, we measured the solubility of C.I. Disperse Red 22 in scCO2 to formulate a dye-sorption model for the K/S value in the color processing of the plastic buttons. Finally, the dye-sorption model for the K/S value combining the dye solubility in scCO2 with the dye diffusion inside the buttons successfully represented the color processing of the buttons.

A case involving laparoscopic decortication of a large simple renal cyst using conventional monopolar device.

INTRODUCTION AND IMPORTANCE: Simple renal cysts are common in adults, but most of them are asymptomatic. Usually, percutaneous puncture is an initial treatment, but laparoscopic decortication may be effective for recurrent simple renal cyst. Herein, we report a case in which a large symptomatic simple renal cyst was treated with laparoscopic decortication using conventional monopolar device. CASE PRESENTATION: A 34-year-old female visited our hospital with chief complaints of back pain and abdominal fullness. Computed tomography showed a right simple renal cyst (diameter: 140 mm). We performed percutaneous drainage with sclerotherapy, but the cyst recurred a month later. Thus, we carried out laparoscopic decortication. We opened the cyst wall via a retroperitoneal approach and trimmed it using monopolar scissors. The operation time was 124 min. The patient's postoperative course was uneventful, and no complications were observed. Following surgery, the patient was asymptomatic. CLINICAL DISCUSSION: In our case, we performed operation using a conventional monopolar device without sealing devices. It has been reported that the use of sealing devices can make laparoscopic surgery safer and reduce the operation time, but we herein report that laparoscopic decortication with a conventional monopolar device is an effective and safe treatment option for symptomatic simple renal cysts and that more expensive energy sources are not required. CONCLUSION: We successfully performed laparoscopic decortication of a large symptomatic simple renal cyst. This operation is minimally invasive and safe.

Pediatric bilateral ureteral stone successfully removed using single-use flexible ureteroscopy with a holmium: YAG laser.

A 12-year-old boy received steroid for his minimal change nephrotic syndrome for 10 years, and bilateral renal and ureteral stones and hydronephrosis were observed. Single-use flexible ureteroscopy is usable for pediatric lithotripsy with Ho: YAG laser.

C-reactive protein at 1 month after treatment of nivolumab as a predictive marker of efficacy in advanced renal cell carcinoma.

PURPOSE: Nivolumab is part of the standard therapy for mRCC. Although deep and long-lasting responses are seen in some patients, the benefit of treatment is limited to some patients and the majority of patients will experience disease progression. PD-L1 is still under evaluation as a predictive biomarker and there is an urgent need to establish biomarkers for the treatment of nivolumab. Here, we investigate C-reactive protein (CRP) at 1 month after treatment of nivolumab as a target to predict the response of patients with metastatic renal cell carcinoma (mRCC) to nivolumab. METHODS: After approval of the study by our institutional review board, 64 patients with mRCC who underwent nivolumab treatment at Kanagawa Cancer Center and Yokohama City University Hospital were enrolled. The patient characteristics, blood examination data at start of nivolumab treatment and 1 month after treatment, response to treatment and progression-free survival (PFS) were evaluated. Tumour responses were assessed according to both the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the immune RECIST (iRECIST) criteria. Moreover, in 12 patients who agreed to an additional blood examination, several serum inflammatory factors were investigated and their correlation with CRP level was examined. RESULTS: The median follow-up was 8.3 months (range 0.2-29.8 months). The median PFS period was 4.5 months and the median immune-PFS (iPFS) period was 5.3 months. RECIST 1.1 criteria underestimated the benefits of nivolumab in four (6.4%) cases. Multivariate analyses showed that an Eastern Cooperative Oncology Group performance status (≥ 2) at start of treatment and CRP level at 1 month after treatment (≥ 1.5 mg/dL) were independent risk factors for a poor iPFS of nivolumab. The CRP level at baseline was not an independent prognostic factor for iPFS. When compared with the responder group (iCR + iPR + iSD), the non-responder group (iPD) had a significantly higher CRP levels at 1 month after treatment (p < 0.001). In the responder group, there was significant decrease in the CRP level after nivolumab treatment when compared with the baseline (p = 0.002), whereas there was a significant increase in the non-responder group (p = 0.019). Even patients with high baseline CRP (≥ 1.5 mg/dL) obtained good iPFS if CRP was decreased (< 1.5 mg/dL) 1 month after treatment. In addition, the classification of Glasgow prognostic score (GPS), which is a cumulative prognostic score based on CRP and albumin, was a significant predictor for iPFS. A strong correlation (|r| > 0.7) with CRP level at 1 month after treatment was seen for sCD163, IL-34, MMP-1, MMP-2, osteopontin, sTNF-R1 and sTNF-R2. Of these, MMP-1 and MMP-2 were not correlated at baseline. CONCLUSION: Our results indicated that the CRP level at 1 month after treatment with nivolumab appears to be a promising predictive biomarker for response to nivolumab treatment in patients with mRCC. It is clinically useful to be able to predict the effect within a short period. Further prospective trials are needed to prove these preliminary findings.

A lower psoas muscle volume was associated with a higher rate of recurrence in male clear cell renal cell carcinoma.

BACKGROUND: Sarcopenia is defined as a low skeletal muscle volume. Recent studies have reported that sarcopenia is associated with a poor prognosis in various cancers. The purpose of this study is to evaluate the correlation between the psoas muscle volume and recurrence-free survival in patients with localized clear cell renal cell carcinoma (ccRCC). METHODS: A total of 316 male patients with localized ccRCC who underwent radical nephrectomy at Yokohama City University Hospital (Yokohama, JAPAN) and Kanagawa Cancer Center (Yokohama, JAPAN) between 2002 and 2018 were enrolled in this study. The psoas muscle index (PMI) was calculated by normalizing the psoas muscle area on the contralateral side of the tumor on axial CT, which was calculated at the level of L4 (mm2) divided by the square of the body height (m2). We divided patients into two groups based on the median PMI (409.64mm2/m2). RESULTS: The lower PMI group showed poorer recurrence-free survival (RFS) than the higher PMI group (p = 0.030). Regarding 5-year RFS, a lower PMI was a significant predictor of recurrence (p = 0.022, hazard ratio (HR): 2.306) and a multivariate analysis revealed that a lower PMI (4 cm (p = 0.044, HR: 2.341), and pathological stage >2 (p<0.001, HR: 3.660) were independent risk factors for poor RFS. CONCLUSIONS: The presence of sarcopenia (lower PMI) was found to be associated with poor RFS in male ccRCC patients. The PMI might serve as a measure of patient frailty and might be useful for prognostic risk stratification in ccRCC.

[A CASE OF EXTRASKELETAL EWING'S SARCOMA IN THE RETROPERITONEUM].

A 23-year-old man was admitted to our hospital with a huge pelvic tumor. MRI showed a tumor mixed with a solid component and polycystic cyst with maximum diameter of about 20 cm. Percutaneous tumor needle biopsy was performed and diagnosis was Ewing sarcoma. At that time, operation is extremely difficult, so the neoadjuvant chemotherapy with ifosfamide, etoposide, Adriamycin, and vincristine were administered. After 6 courses, MRI showed tumor reduction to maximum diameter of 10 cm. We planned tumor resection with total cystectomy for radical resection, but we also tried to preserve bladder considering the young age and quality of life. Although the bladder was partially resected, tumor resection was succeeded without removing surrounding organs. Histopathological examination revealed viable cells remained, but more than 95% was disappeared and the surgical margins were negative. Here we report a case of extra skeletal Ewing sarcoma in the retroperitoneum that was treated with chemotherapy and surgery without scarifying surrounding organs.

Squamous Cell Carcinoma Developing from a Testicular Epidermal Cyst: A Case Report and Literature Review.

A 50-year-old Japanese man with a two-year history of a painless right scrotal mass visited our hospital. Considering laboratory findings and computed tomography, the patient was diagnosed with an uncharacteristic testicular tumor. No metastases were present on radiographic study at the first visit. Emergent high radical orchiectomy was performed, and the tumor was identified as a squamous cell carcinoma (SCC) of a testicular epidermal cyst. He is alive without recurrence or metastasis six months after surgery. Testicular SCC is an extremely rare tumor. This is the third case of testicular SCC associated with an epidermal cyst in English literature.

Control Mechanism for Carbon-Chain Length in Polyunsaturated Fatty-Acid Synthases.

Polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are essential fatty acids. PUFA synthases are composed of three to four subunits and each create a specific PUFA without undesirable byproducts. However, detailed biosynthetic mechanisms for controlling final product profiles have been obscure. Here, the bacterial DHA and EPA synthases were carefully dissected by in vivo and in vitro experiments. In vitro analysis with two KS domains (KSA and KSC ) and acyl-acyl carrier protein (ACP) substrates showed that KSA accepted short- to medium-chain substrates while KSC accepted medium- to long-chain substrates. Unexpectedly, condensation from C18 to C20 , the last elongation step in EPA biosynthesis, was catalyzed by KSA domains in both EPA and DHA synthases. Conversely, condensation from C20 to C22 , the last elongation step for DHA biosynthesis, was catalyzed by the KSC domain in DHA synthase. KSC domains therefore determine the chain lengths.

[PREDICTIVE AND PROGNOSTIC SIGNIFICANCE OF PRE-TREATMENT LYMPHOCYTE COUNT IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA TREATED WITH PLATINUM-BASED FIRST-LINE CHEMOTHERAPY].

(Purpose) Pre-treatment low lymphocyte count may result from cytokine secretion by the tumor microenvironment, in association with aggressive tumor biology. We sought to establish the prognostic impact of the absolute lymphocyte count (ALC) in advanced urothelial carcinoma. (Patients and method) We retrospectively reviewed 63 patients with unresectable or metastatic urothelial carcinoma who were treated with platinum-based first-line systemic chemotherapy between January 2011 and April 2018. We evaluated the importance of the ALC in patients who underwent systematic chemotherapy. (Results) Thirty-eight patients (60%) died from urothelial carcinoma, with a median follow-up interval of 12.2 months. The median overall survival (OS) duration was 15.3 months. The mean ALC in the stable and progressive disease group was lower than that in the complete and partial response group (1,312 /µL and 1,666 /µL, respectively, p=0.004). The ALC of 1,460 /µL was determined as the cut-off on Receiver operating characteristic curve analysis. The log-rank test revealed that the lymphocytopenia group (ALC <1,460 /µL) showed significantly poorer prognoses than the non-lymphocytopenia group (p=0.001). Multivariate analyses showed that lymphocytopenia was an independent poor prognostic factor (hazard ratios of 3.46, p=0.002). (Conclusions) Pre-treatment low lymphocyte count is an independent poor prognostic factor in patients with urothelial carcinoma who underwent platinum-based first-line systemic chemotherapy.

Case of acute respiratory distress syndrome in a patient with an extragonadal germ cell tumor without lung metastasis in which choriocarcinoma syndrome was suspected.

INTRODUCTION: Choriocarcinoma syndrome is caused by bleeding from metastatic germ cell tumors with choriocarcinoma components. Here, we report a case of acute respiratory distress syndrome, which arose after first-line chemotherapy for an extragonadal germ cell tumor without lung metastasis. CASE PRESENTATION: A 41-year-old male visited our institution with chief complaints of back pain and weight loss. Computed tomography showed multiple lymph node metastases in the retroperitoneal cavity. There were no lung metastases. A lymph node biopsy resulted in a diagnosis of choriocarcinoma. Bleomycin etoposide cisplatin therapy was started as induction chemotherapy. On the first day, he was diagnosed with acute respiratory distress syndrome due to choriocarcinoma syndrome. We administered high-dose hydrocortisone therapy for 3 days. The patient's respiratory status improved. CONCLUSION: In patients who are at high risk of developing choriocarcinoma syndrome, induction chemotherapy might lead to the development of acute respiratory distress syndrome due to the release of cytokines despite the absence of lung metastasis.

Incidence and Outcomes of Central Venous Catheter-related Blood Stream Infection in Patients with Inflammatory Bowel Disease in Routine Clinical Practice Setting.

BACKGROUND: Patients with inflammatory bowel disease (IBD) occasionally require central venous catheter (CVC) placement to support a therapeutic plan. Given that CVC can predispose patients to infection, this investigation was undertaken to assess the incidence, risk factors, and outcomes of CVC-related blood stream infection (CRBSI) in patients with IBD during routine clinical practice. METHODS: Data were compiled using retrospective chart reviews of 1367 patients treated at our IBD center between 2007 and 2012 during routine clinical practice. Among the 1367 patients, 314 who had received CVC placements were included. Patients with positive blood culture were considered as "definite" CRBSI, whereas "possible" CRBSI was defined as patients in whom fever alleviated within 48 hours post-CVC without any other infection. Patients' demographic variables including age, body mass index, serum albumin, duration of CVC placement, use of antibiotics, medications for IBD, and perioperative status between CRBSI and non-CRBSI subgroups were compared by applying a multivariate Poisson logistic regression model. RESULTS: Among the 314 patients with CVC placement, there were 83 CRBSI cases (26.4%). The average time to the onset of CRBSI was 22.5 days (range 4-105 days). The jugular vein access was found to be the most serious risk of CRBSI (risk ratio 2.041 versus subclavian vein). All patients with CRBSI fully recovered. CONCLUSIONS: In this investigation, regardless of the patients' demographic features including immunosuppressive therapy, up to 30% of febrile IBD patients with CVC showed CRBSI. It is believed that CVC placement per se is a risk of CRBSI in patients with IBD.

GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow.

GATA2 plays a crucial role for the mast cell fate decision. We herein demonstrate that GATA2 is also required for the maintenance of the cellular identity in committed mast cells derived from mouse bone marrow (BMMCs). The deletion of the GATA2 DNA binding domain (GATA2ΔCF) in BMMCs resulted in a loss of the mast cell phenotype and an increase in the number of CD11b- and/or Ly6G/C-positive cells. These cells showed the ability to differentiate into macrophage- and neutrophil-like cells but not into eosinophils. Although the mRNA levels of basophil-specific genes were elevated, CD49b, a representative basophil marker, never appeared on these cells. GATA2 ablation led to a significant upregulation of C/EBPα, and forced expression of C/EBPα in wild-type BMMCs phenocopied the GATA2ΔCF cells. Interestingly, simultaneous deletion of the Gata2 and Cebpa genes in BMMCs restored the aberrant increases of CD11b and Ly6G/C while retaining the reduced c-Kit expression. Chromatin immunoprecipitation assays indicated that GATA2 directly binds to the +37-kb region of the Cebpa gene and thereby inhibits the RUNX1 and PU.1 binding to the neighboring region. Upregulation of C/EBPα following the loss of GATA2 was not observed in cultured mast cells derived from peritoneal fluid, whereas the repression of c-Kit and other mast cell-specific genes were observed in these cells. Collectively, these results indicate that GATA2 maintains cellular identity by preventing Cebpa gene activation in a subpopulation of mast cells, whereas it plays a fundamental role as a positive regulator of mast cell-specific genes throughout development of this cell lineage.

A prospective study of factors associated with risk of turnover among care workers in group homes for elderly individuals with dementia.

OBJECTIVES: A prospective study was conducted to assess factors associated with risk of turnover among care workers in group homes (GHs) for elderly individuals with dementia. METHODS: In January, 2010, 51 out of 238 GHs in Sapporo City responded to our request for participation in a survey. During February and March of 2010, 438 out of 700 care workers (62.6%) in the GHs returned a completed questionnaire to us. They were followed up with until March of 2012, and 395 subjects (90.1%) responded to our survey, which was conducted twice. Over the course of 2 years, 91 subjects left their jobs. Cox's proportional hazards model was used for analysis, adjusting for gender and age. RESULTS: Less provision of social support by supervisors, colleagues, family or friends was significantly associated with increased risk of turnover. Financial aids for off-the-job training was marginally significantly associated with reduced risk of turnover. Longer duration of working for frail elderly care was significantly associated with decreased risk of turnover. Habitual smoking was significantly associated with increased risk of turnover. CONCLUSIONS: Social support in the workplace may be important to reduce the risk of turnover in care workers at GHs. Further prospective studies are required in other areas in Japan.

A cross-sectional study on association of work environment, coping style, and other risk factors with depression among caregivers in group homes in Japan.

A cross-sectional study was conducted to explore the potential association between work environment and/or stress coping ability, and depressive status among caregivers working for "group homes (GHs)" in Japan. In January 2010, 438 out of 700 caregivers working at GHs in Sapporo City returned completed questionnaires to us. The questionnaires consisted of the Center of Epidemiological Scales-Depression, items about worker's attributions, Ozeki's coping scale, and so on. An analysis using a logistic regression model was used to find the associations adjusting for gender and age. Subjects who were 45 yr or older, had a spouse, had job training, a standard workload and scored high in emotion-oriented coping were significantly associated with a decreased risk of depression. Subjects who were less proud of their job, less willing to continue care for the frail elderly and had fewer acceptances by their supervisors or colleagues for consultation were significantly associated with an increased risk of depression. This study supports our hypothesis that there can be possible variables among individual factors, work environment and/or coping style for stress which may modulate a risk on the depressive status of caregivers.

Relationship between hepatocellular carcinoma and impaired glucose tolerance among Japanese.

BACKGROUND/AIMS: Both the incidence of diabetes mellitus (DM) and mortality from Hepatocellular carcinoma (HCC) are increasing in Japan. As the association of overall cancer and HCC with impaired glucose tolerance (IGT) has been studied rarely in the world including Japan, this study assessed their associations using cohort data of Hokkaido, Japan. METHODOLOGY: After getting ethical consent, this study included 908 men and 1,081 women aged 30-77 years during 1977-78 and collected detailed information using the baseline survey. The subjects were followed until 2002 and deaths were recorded using ICD-9. Classifying them into three groups of diabetes status namely DM, IGT, and normal, the relative risk (RR) of mortality was estimated by diabetes status using multivariate Cox model. RESULTS: This study revealed no association between overall cancer and diabetes status. However, the RR of mortality from HCC was about 11 times (HR= 10.8, 95%CI: 1.3-92.5) higher in IGT compared with normal group. DM group also showed higher risk of mortality than normal group. CONCLUSIONS: HCC mortality was significantly high among IGT group. However, as the results of the study were based on small data, further studies with large cohort are needed to address the association of IGT with overall cancer and HCC mortality in Japan.

Levels of blood and urine chemicals associated with longer duration of having arsenicosis in Bangladesh.

Arsenicosis is presently one of the significant public health problems in Bangladesh. Employing household screening of over 3.6 million people living in 6 arsenic-affected Upzilas of Bangladesh, 1,503 arsenicosis patients were identified at first and then blood and urine were collected from some of them and analyzed through laboratory techniques. As the relation between blood and urine chemicals with duration of having arsenicosis (DHA) is not clear, this study presented all findings by shorter versus longer DHA. Complications namely chronic bronchitis, conjunctivitis/congestions, weakness, and wasting were common, with relatively higher rates in longer group. Logistic regression analysis adjusted for age, sex, education, smoking, duration of drinking tube-well water, and whether any arsenicosis patients were in the family-indicated higher odds ratio (OR) of longer DHA (LDHA) in 3rd tertile with respect to GOT (OR = 2.12; 95%CI: 1.09-4.13), and blood glucose (OR = 2.00; 95%CI: 1.07-3.72) than 1st tertile. The OR of LDHA was significantly lower (OR = 0.48; 95%CI: 0.25-0.93) in 3rd tertile for triglycerides compared with 1st tertile. Albumin/globulin (A/G) ratio of 2nd tertile showed significantly lower OR of LDHA (OR=0.51; 95%CI: 0.28-0.95) than 1st tertile. Further epidemiological investigations based on a large sample, through cohort or case control studies, may be useful for validating and generalizing the results in Bangladesh.

Manifestation of arsenicosis patients and factors determining the duration of arsenic symptoms in Bangladesh.

This study analyzed a total of 1482 arsenicosis patients living in 6 of 496 upzilas (sub-districts) of Bangladesh, who were identified through household screening and then confirmed by a trained medical team headed by medical officer. Melanosis was common (97%) among them but about two-thirds (68.7%) of the patients were suffering from keratosis. Average age was 36 years and average duration of arsenic symptoms was 3 (median) years. About 50% of the patients had been drinking tubewell water more than 24 years. Melanosis was significantly associated with younger patients (P=0.031), shallower tubewell (P=0.005), and complication of conjunctivitis (P<0.001). Keratosis was also significantly associated with older age (P=0.022), shallower tubewell (P<0.001), complication of conjunctivitis (P<0.001), bronchitis (P<0.001), loss of appetite (P<0.001), and wasting (P<0.001). Duration of arsenic symptoms was significantly associated with older age (P<0.001), male (P=0.002), married (P<0.001), smoking (P=0.002), longer duration of consuming tubewell water (P<0.001), complication of conjunctivitis (P=0.002), loss of appetite (P<0.001), wasting (P=0.006), and social problem faced having arsenicosis (P=0.040). Multivariate odds ratio (OR) and 95% confidence interval (CI) indicated that keratosis (OR=2.00; 95% CI: 1.56-2.56) was significantly associated with longer duration of arsenic symptoms; loss of appetite (OR=1.40; 95% CI: 1.12-1.74) was a significant complication for longer duration. Similarly smoking (OR=1.33; 95% CI: 1.06-1.68) was positively associated with longer duration of arsenic symptom. These findings will help the policy makers of Bangladesh to understand about the factors that may affect the severity condition of the patients through prolongation of arsenic symptoms.