Efficacy of modified thoracoabdominal nerves block through perichondrial approach in open gynecological surgery: a prospective observational pilot study and a cadaveric evaluation.

BACKGROUND: Modified thoracoabdominal nerves block through perichondrial approach (M-TAPA) was first described as a peripheral nerve block by Tulgar in 2019. This technique provides an analgesic effective range from Th7-11 with a single puncture per side. Although the efficacy and effective duration of M-TAPA have been reported, further examination is required. Therefore, this study aimed to evaluate the analgesic range and effective duration of M-TAPA in open gynecologic surgery. METHODS: Following approval, 10 adult female patients scheduled for open radical hysterectomy via a vertical incision or laparotomy using a midline incision from under the xiphoid process to the symphysis pubis were enrolled. The primary outcome was the number of anesthetized dermatomes at 2 and 24 h postoperatively. Secondary outcomes included numerical rating scale scores and the total amount of fentanyl used. Cadaveric evaluation was performed to assess the spread of the dye. RESULTS: The median numbers (interquartile range) of anesthetized dermatomes at 2 and 24 h postoperatively were 6 (5-7) and 6.5 (5-7) in the anterior cutaneous branch area and 5 (4-7) and 7 (5-7) in the lateral cutaneous branch area, respectively. There was an 85% chance of simultaneously acquiring analgesia in areas innervated by Th8-11, including complete block in areas innervated by the anterior cutaneous branches of Th9-10. Cadaveric evaluation showed the spread of the dye in Th8-11. CONCLUSIONS: M-TAPA may have analgesic effects in the areas supplied by the anterior cutaneous branches of Th8-11. TRAIL REGISTRATION: IRB approval (No.2700; registered on July 10, 2020) and registration (UMIN Clinical Trials Registry: UMIN000041137 ; registered on July 17, 2020).

Translation and validation of the Japanese Version of the Quality of Recovery-15 Questionnaire.

PURPOSE: Patient-reported outcomes after surgery and anaesthesia have recently attracted attention. A recent systematic review and a consensus guideline recommend that patients' recovery can be adequately measured using the quality of recovery-15 (QoR-15) during the perioperative period; however, the Japanese version of the QoR-15 (QoR-15J) is not available. We aimed to translate the QoR-15 into Japanese and assess its validity. METHODS: After translating into Japanese, 205 patients who underwent various types of surgery under general anaesthesia were enrolled in the study. QoR-15J was evaluated before surgery and 24 h and 48 h after surgery. Additionally, 30 patients answered the QoR-15J at 25 h after surgery. We assessed the feasibility, reliability, validity, and responsiveness of the QoR-15J. RESULTS: One patient who did not undergo surgery and two patients who were discharged within 24 h were excluded. One hundred and eighty-seven patients answered the QoR-15J at 24 h after surgery (completion rate, 92.6%) and 183 patients with complete data were included in the final analysis. The Cronbach's alpha coefficient for internal reliability and Spearman rank correlation coefficient for test-retest reliability were 0.84 and 0.91, respectively. The Cohen effect size for all items was 1.42. CONCLUSIONS: QoR-15 was translated into Japanese and the Japanese version's validity was assessed in patients undergoing various types of surgery under general anaesthesia. Our results suggest that QoR-15J is feasible, reliable, valid, and responsive.

Association Between Second-hand Smoke Exposure and Depressive Symptoms Among Japanese Adults: A Cross-sectional Study.

BACKGROUND: Second-hand smoke exposure has been associated with poor mental health. However, among Japanese adults, little is known about the association between second-hand smoking and depressive symptoms. We examined this association in a cross-sectional study among a Japanese general adult population sample. METHODS: Japanese adults were recruited from the Japan Multi-Institutional Collaborative Cohort Study in the Okazaki area between 2012 and 2017. Second-hand smoke exposure and smoking status were assessed using a self-administered questionnaire. Based on their frequency of exposure to second-hand smoke, non-smokers and smokers were categorized as "almost never," "sometimes," and "almost every day". Depressive symptoms were defined by a Kessler 6 score ≥5 points. We performed a multivariable Poisson regression analysis to obtain adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) for depressive symptoms. RESULTS: Overall, 5,121 participants (4,547 non-smokers and 574 smokers) were included whose mean age was 63.6 (standard deviation [SD], 10.3) years for non-smokers and 59.33 (SD, 10.2) years for smokers. The association between second-hand smoking and depressive symptoms was significant among non-smokers, but not among smokers. Among non-smokers, PRs compared with "almost never" were 1.25 (95% CI, 1.09-1.42) for "sometimes" and 1.41 (95% CI, 1.09-1.84) for "almost every day" (P for trend <0.001); among smokers, PRs compared with "almost never" were 1.30 (95% CI, 0.82-2.06) for "sometimes" and 1.44 (95% CI, 0.90-2.33) for "almost every day" (P for trend = 0.144). CONCLUSIONS: Second-hand smoking and depressive symptoms were associated among non-smokers. Our findings indicate the importance of tobacco smoke control for mental health.

Physical Activity Earlier in Life Is Inversely Associated With Insulin Resistance Among Adults in Japan.

BACKGROUND: It is known that physical activity affects glucose metabolism. However, there have been no reports on the influence of physical activity earlier in life on subsequent glucose metabolism. Therefore, we analyzed the influence of physical activity in earlier decades of life on insulin resistance in middle aged and older residents in Japan. METHODS: The subjects were 6,883 residents of Okazaki City between the ages of 40 and 79 years who underwent physical examinations at the Okazaki City Medical Association Public Health Center from April 2007 through August 2011. They gave informed consent for participation in the study. Data on individual characteristics were collected via a questionnaire and from the health examination records. Fasting blood glucose and insulin levels were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR). HOMA-IR >1.6 was considered to indicate insulin resistance for the purpose of logistic regression models. RESULTS: The study sample included 3,683 men and 3,200 women for whom complete information was available. For those who exercised regularly throughout their teens to their 30s-40s, the odds ratio for having insulin resistance was 0.75 (95% confidence interval [CI], 0.58-0.96) for men and 0.76 (95% CI, 0.58-0.99) for women after adjusting for other variables, including age, body mass index, and present physical activity. A linear trend was also observed in both men and women. CONCLUSIONS: Subjects who have exercised regularly in the early decades of life are less likely to have insulin resistance later in life.

Handling missing data in an FFQ: multiple imputation and nutrient intake estimates.

OBJECTIVE: We aimed to examine missing data in FFQ and to assess the effects on estimating dietary intake by comparing between multiple imputation and zero imputation. DESIGN: We used data from the Okazaki Japan Multi-Institutional Collaborative Cohort (J-MICC) study. A self-administered questionnaire including an FFQ was implemented at baseline (FFQ1) and 5-year follow-up (FFQ2). Missing values in FFQ2 were replaced by corresponding FFQ1 values, multiple imputation and zero imputation. SETTING: A methodological sub-study of the Okazaki J-MICC study.ParticipantsOf a total of 7585 men and women aged 35-79 years at baseline, we analysed data for 5120 participants who answered all items in FFQ1 and at least 50% of items in FFQ2. RESULTS: Among 5120 participants, the proportion of missing data was 3·7%. The increasing number of missing food items in FFQ2 varied with personal characteristics. Missing food items not eaten often in FFQ2 were likely to represent zero intake in FFQ1. Most food items showed that the observed proportion of zero intake was likely to be similar to the probability that the missing value is zero intake. Compared with FFQ1 values, multiple imputation had smaller differences of total energy and nutrient estimates, except for alcohol, than zero imputation. CONCLUSIONS: Our results indicate that missing values due to zero intake, namely missing not at random, in FFQ can be predicted reasonably well from observed data. Multiple imputation performed better than zero imputation for most nutrients and may be applied to FFQ data when missing is low.

Associated factors with delayed ambulation after abdominal surgery.

PURPOSE: After abdominal surgery, ambulatory status is an important indicator of postoperative recovery. This study investigated the inability to ambulate on postoperative day 1 and identified associated predictive factors in patients undergoing abdominal surgery, focusing on preoperative hematologic markers such as the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index. METHODS: Adult patients undergoing abdominal surgery from May 2018 to October 2018 were investigated consecutively. Only patients with duration of surgery ≥ 3 h were included for observation. Data on patient characteristics were collected from medical charts and laboratory results. Univariate analysis and multivariate logistic regression were used to determine associations with inability to ambulate without human assistance on postoperative day 1 and postoperative length of stay. RESULTS: Of 416 eligible patients, 217 patients were included in the analysis. Sixty-nine patients (31.7%) were not able to ambulate on postoperative day 1. The NLR (odds ratio, 1.11; 95% confidence interval, 1.01-1.23), duration of surgery (odds ratio per 1 h, 1.27; 95% confidence interval, 1.06-1.43), and American Society of Anesthesiologists physical status of 3 (odds ratio, 4.99; 95% confidence interval, 1.15-21.5) were independently associated with the inability to ambulate without assistance on postoperative day 1, which was also associated with longer hospital stays (13 [11, 22] vs 21 [15, 39] days, P < 0.001). CONCLUSIONS: The NLR, surgical duration, and American Society of Anesthesiologists physical status were significantly associated with the inability to ambulate without human assistance on postoperative day 1 and prolonged hospitalization.

Prophylactic recombinant thrombomodulin treatment prevents hepatic sinusoidal obstruction syndrome in high-risk pediatric patients that undergo hematopoietic stem cell transplants.

Hepatic SOS is a potentially life-threatening complication of conditioning for allogeneic HSCT. rTM is a new drug for treating DIC. We report our experience of the use of rTM as a prophylaxis against SOS in high-risk pediatric patients that underwent HSCT. We evaluated the cases of 19 pediatric hematology and oncology patients who underwent HSCT at our institution between 2007 and 2016. The patients who received HSCT after 2012 (n = 8) were treated with rTM as a prophylaxis against SOS together with UDCA and LMWH, whereas the others (n = 11) were only treated with UDCA and LMWH. Although SOS occurred by post-HSCT day 35 in 3 (27%) patients in the control group, SOS was not seen in the rTM group. Two of the former three patients suffered severe SOS, and one died of the condition. The mean peak level of PAI-1 (a marker of endothelial damage) was significantly lower in the rTM group. rTM appears to be a safe prophylaxis for SOS. The present findings suggest that prophylactic rTM after HSCT might help to prevent SOS.

[Initial presentation of lymphoblastic crisis in a pediatric chronic myelogenous leukemia patient].

A 9-year-old girl was referred to our hospital because of facial palsy. Both physical and blood examination revealed hepatosplenomegaly and leukocytosis, respectively. A bone marrow examination demonstrated marked hypercellularity involving myeloblasts and lymphoblasts. Based on these results, we suspected mixed phenotype acute leukemia. However, her leukemic blasts expressed B-cell antigens, and a chromosomal analysis of her bone marrow cells revealed the following karyotype: 46, XX, t (9;22) (q34;q11.2). All her neutrophils were positive for the breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion protein. Based on these findings, she was diagnosed with a lymphoblastic crisis of chronic myelogenous leukemia (CML). Combined chemotherapy, involving imatinib, resulted in complete molecular remission. She received cord blood transplant (CBT) during the first complete remission; she is alive and has not suffered a relapse since two years after the CBT. The sudden onset of a blastic crisis in pediatric CML is rare, and it may be difficult to distinguish such cases from de novo Ph-positive leukemia. For diagnostic purposes, it is essential to consider a patient's clinical course and blood test results.

Comparison of weighed food record procedures for the reference methods in two validation studies of food frequency questionnaires.

BACKGROUND: Although open-ended dietary assessment methods, such as weighed food records (WFRs), are generally considered to be comparable, differences between procedures may influence outcome when WFRs are conducted independently. In this paper, we assess the procedures of WFRs in two studies to describe their dietary assessment procedures and compare the subsequent outcomes. METHODS: WFRs of 12 days (3 days for four seasons) were conducted as reference methods for intake data, in accordance with the study protocol, among a subsample of participants of two large cohort studies. We compared the WFR procedures descriptively. We also compared some dietary intake variables, such as the frequency of foods and dishes and contributing foods, to determine whether there were differences in the portion size distribution and intra- and inter-individual variation in nutrient intakes caused by the difference in procedures. RESULTS: General procedures of the dietary records were conducted in accordance with the National Health and Nutrition Survey and were the same for both studies. Differences were seen in 1) selection of multiple days (non-consecutive days versus consecutive days); and 2) survey sheet recording method (individual versus family participation). However, the foods contributing to intake of energy and selected nutrients, the portion size distribution, and intra- and inter-individual variation in nutrient intakes were similar between the two studies. CONCLUSION: Our comparison of WFR procedures in two independent studies revealed several differences. Notwithstanding these procedural differences, however, the subsequent outcomes were similar.

Chylomicron remnant model emulsions induce intracellular cholesterol accumulation and cell death due to lysosomal destabilization.

Chylomicron remnants, which carry dietary fats and cholesterol, play a role in promoting atherosclerosis. Chylomicron remnants are characterized by high cholesterol content at the surface, different from low-density lipoproteins (LDLs) containing high amounts of esterified cholesterol (CE) in the core. We prepared cholesterol-rich emulsions (TO-PC/cholesterol emulsions) as models for chylomicron remnants and compared their effects on J774 macrophages with acetylated-LDL (ac-LDL). Internalization of TO-PC/cholesterol emulsions into macrophages reduced cell viability, whereas ac-LDL did not. Surprisingly, there was no difference in intracellular free cholesterol content between cells incubated with TO-PC/cholesterol emulsions and with ac-LDL. Furthermore, cholesterol in TO-PC/cholesterol emulsions and ac-LDL both were internalized into J774 macrophages; however, incubation with TO-PC/cholesterol emulsions induced leakage of lysosomal protease, cathepsin-L, to cytosol, which was not observed for incubation with ac-LDL. Inhibition of the activity of cathepsin-L recovered the viability of macrophages that ingested TO-PC/cholesterol emulsions. We suggest an alternative fate of cholesterol-rich emulsions taken up by macrophages, which is different from other atherogenic lipoproteins rich in CE; internalization of TO-PC/cholesterol emulsions into macrophages induces rapid free cholesterol accumulation in lysosomes and cell death due to lysosomal destabilization.

An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA.

Constitutive expression of telomerase in human cells prevents the onset of senescence and crisis by maintaining telomere homeostasis. However, accumulating evidence suggests that the human telomerase reverse transcriptase catalytic subunit (TERT) contributes to cell physiology independently of its ability to elongate telomeres. Here we show that TERT interacts with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), a gene that is mutated in the inherited pleiotropic syndrome cartilage-hair hypoplasia. Human TERT and RMRP form a distinct ribonucleoprotein complex that has RNA-dependent RNA polymerase (RdRP) activity and produces double-stranded RNAs that can be processed into small interfering RNA in a Dicer (also known as DICER1)-dependent manner. These observations identify a mammalian RdRP composed of TERT in complex with RMRP.

Regio- and stereoselective oxygenation of proline derivatives by using microbial 2-oxoglutarate-dependent dioxygenases.

We evaluated the substrate specificities of four proline cis-selective hydroxylases toward the efficient synthesis of proline derivatives. In an initial evaluation, 15 proline-related compounds were investigated as substrates. In addition to l-proline and l-pipecolinic acid, we found that 3,4-dehydro-l-proline, l-azetidine-2-carboxylic acid, cis-3-hydroxy-l-proline, and l-thioproline were also oxygenated. Subsequently, the product structures were determined, revealing cis-3,4-epoxy-l-proline, cis-3-hydroxy-l-azetidine-2-carboxylic acid, and 2,3-cis-3,4-cis-3,4-dihydroxy-l-proline.

Maintenance of tumor initiating cells of defined genetic composition by nucleostemin.

Recent work has identified a subset of cells resident in tumors that exhibit properties similar to those found in normal stem cells. Such cells are highly tumorigenic and may be involved in resistance to treatment. However, the genes that regulate the tumor initiating cell (TIC) state are unknown. Here, we show that overexpression of either of the nucleolar GTP-binding proteins nucleostemin (NS) or GNL3L drives the fraction of genetically defined tumor cells that exhibit markers and tumorigenic properties of TICs. Specifically, cells that constitutively express elevated levels of NS or GNL3L exhibit increased TWIST expression, phosphorylation of STAT3, expression of genes that induce pluripotent stem cells, and enhanced radioresistance; in addition, they form tumors even when small numbers of cells are implanted and exhibit an increased propensity to metastasize. GNL3L/NS forms a complex with the telomerase catalytic subunit [human telomerase reverse transcriptase (hTERT)] and the SWItch-Sucrose NonFermentable (SWI-SNF) complex protein brahma-related gene 1 (BRG1), and the expression of each of these components is necessary to facilitate the cancer stem cell state. Together, these observations define a complex composed of TERT, BRG1, and NS/GNL3L that maintains the function of TICs.

Prognostic value of circulating regulatory T cells for worsening heart failure in heart failure patients with reduced ejection fraction.

Regulatory T cells (Tregs) play a crucial role in the negative regulation of immune responses. Recent studies suggest that Tregs are involved in the pathogenesis of atherosclerosis and myocarditis. Here, we investigated the involvement of Tregs on worsening heart failure (HF) in patients with reduced ejection fraction (HF-REF). The study population consisted of 32 HF-REF patients who were hospitalized for worsening HF, and 18 control subjects. Cardiac function was evaluated by echocardiography. A single venous blood sample was collected before discharge. Circulating T cells were evaluated by flow cytometry. Tregs were defined as CD4(+)CD25(+)Foxp3(+)T cells, and the correlations between the frequency of Tregs and CRP, IL-6 and several echoparameters were analysed. Furthermore, all HF-REF patients were followed up to 12 months from discharge to examine the predictors of recurrent hospitalization.In HF-REF patients, Tregs were significantly decreased (5.9 ± 1.4 versus 8.0 ± 2.2%, P < 0.01), while CD4(+)HLADR(+)T cells were increased (10.1 ± 5.4 versus 7.3 ± 3.1%, P < 0.05), compared with controls. Tregs were negatively correlated with left ventricular end-diastolic dimension, and levels of CRP and IL-6. Eleven of 32 HF-REF patients were rehospitalized for worsening HF within 12 months. Multivariate Cox regression analysis showed that CD4/CD8 and frequency of Tregs were independent predictors for recurrent hospitalization. Furthermore, HF-REF patients expressing under 6% Treg/CD4(+)T cells showed a significantly higher incidence of recurrent hospitalization for worsening HF within 12 months.Our data suggest that Tregs might be involved in the pathogenesis of decompensated HF, and may be a novel predictor of poor prognosis in HF-REF patients.

"Crawling-type" adenocarcinoma of the stomach: a distinct entity preceding poorly differentiated adenocarcinoma.

BACKGROUND: Gastric "crawling-type" adenocarcinoma (CTAC) is a neoplasm histologically comprising irregularly fused glands with low-grade cellular atypia that tends to spread laterally in the mucosa. It is necessary to elucidate the clinicopathological characteristics of CTAC. METHODS: We evaluated 25 CTACs-16 intramucosal (M-) and 9 submucosal invasive (SM-) cancers-clinicopathologically and immunohistochemically. RESULTS: CTAC was most frequently located in the lesser curvature of the middle-third of the stomach. Macroscopically, 21 lesions were superficial-depressed and 4 were superficial-flat type. Histologically, all CTACs had cystic dilated glands and 16 lesions had focal signet-ring cells. All invasive areas of the SM-CTACs were occupied by poorly differentiated adenocarcinoma with an infiltrative growth pattern and abundant stroma. Fifteen CTACs were surrounded by mucosa with partial or no intestinal metaplasia. In the intramucosal area, 24 lesions were mixed phenotype with mucin and brush border immunoexpression. SM-CTAC was frequent in lesions with an intramucosal poorly differentiated component (PDC) greater than 10 mm in size (P = 0.041), and lymph node metastasis (LNM) was frequent in lesions with a PDC greater than 20 mm (P = 0.039). The frequency of an expanded pattern (Ki-67-positive cells occupying > 50 % of the mucosa) was higher in SM-CTAC than in M-CTAC (P = 0.027). p53 overexpression was not detected in the intramucosal areas of any of the lesions. CONCLUSION: CTAC is a distinct subgroup of gastric adenocarcinoma in the early phase. A larger PDC and a Ki-67 expanded pattern were predictive of submucosal invasion or LNM.

Association between intraoperative hypotension and postoperative nausea and vomiting: a retrospective analysis of 247 thyroidectomy cases.

BACKGROUND: Postoperative nausea and vomiting (PONV) are major complications after general anesthesia. Although various pathways are involved in triggering PONV, hypotension plays an important role. We hypothesized that intraoperative hypotension during general anesthesia might be responsible for the incidence of PONV. METHODS: We retrospectively investigated patients who underwent thyroidectomy. The initial blood pressure measured before induction of anesthesia was used as the baseline value. The systolic blood pressure measured during the operation from the start to the end of anesthesia was extracted from anesthetic records. The time integral value when the measured systolic blood pressure fell below the baseline value was calculated as area under the curve (AUC) of s100%. RESULTS: There were 247 eligible cases. Eighty-eight patients (35.6%) had PONV. There was no difference in patient background between the patients with or without PONV. Univariate analysis showed that the total intravenous anesthesia (TIVA) (p=0.02), smoking history (p=0.02), and AUC-s100% (p=0.006) were significantly associated with PONV. Multiple logistic regression analysis revealed that TIVA (OR: 0.54, 95% CI: 0.29...0.99), smoking history (OR: 0.60, 95% CI: 0.37...0.96), and AUC-s100% (OR: 1.006, 95% CI: 1.0...1.01) were significantly associated with PONV. CONCLUSION: Intraoperative hypotension evaluated by AUC-s100% was related to PONV in thyroidectomy.

The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas.

BACKGROUND: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. METHODS: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method. RESULTS: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. CONCLUSIONS: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

Nucleostemin and TWIST as predictive markers for recurrence after neoadjuvant chemotherapy for esophageal carcinoma.

We recently demonstrated that overexpression of the nucleolar GTP-binding protein nucleostemin drives the fraction of genetically-defined tumor cells that exhibit markers and tumorigenic properties of tumor initiating cells. More specifically, cells that constitutively express elevated levels of nucleostemin exhibit increased TWIST expression; expression of genes that induced pluripotent stem cells; enhanced radioresistance; tumor formation, even when small numbers of cells are implanted; and an increased propensity to metastasize. An immunohistochemical analysis of cancer stem cell markers, such as nucleostemin and TWIST has not been conducted in surgically-resected esophageal squamous cell carcinomas after neoadjuvant chemotherapy. In the present study, we examined the expression of CD133, CD44, nucleostemin, guanine nucleotide-binding protein-like 3-like, and TWIST by immunohistochemistry in a series of 54 surgically-resected specimens of esophageal squamous cell carcinomas after neoadjuvant chemotherapy. We identified that high nucleostemin proportion, TWIST intensity, and advanced pathological N stage were significantly correlated with poor relapse-free survival. Together, these observations imply nucleostemin and TWIST as the predictive markers for postoperative recurrence.

Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple-negative breast cancer cells.

Patients with triple-negative breast cancers (TNBCs) typically have a poor prognosis because such cancers have no effective therapeutic targets, such as estrogen receptors for endocrine therapy or human epidermal growth factor receptor 2 (HER2) receptors for anti-HER2 therapy. As the phosphatidylinositol 3' kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascade is activated in TNBCs, mTOR is a potential molecular target for anticancer therapy. In this study, we investigated the antitumor activities of everolimus, an oral mTOR inhibitor, in nine TNBC cell lines. Everolimus effectively inhibited cell growth at concentrations under 100 nM (IC(50)) in five cell lines and even in the 1-nM range in three of the five cell lines. To identify specific characteristics that could be used as predictive markers of efficacy, we evaluated the expressions of proteins in the mTOR cascade, basal markers, and cancer stem cell markers using western blotting, fluorescent in situ hybridization (FISH), or immunohistochemistry. All five of the sensitive cell lines were categorized as a basal-like subtype positive for either epidermal growth factor receptor (EGFR) or CK5/6, although resistant cell lines were not of this subtype and tended to exhibit the characteristics of cancer stem cells, with decreased E-cadherin and the increased expression of Snail or Twist. In vivo assays demonstrated antitumor activity in a mouse xenograft model of basal-like breast cancer, rather than non-basal breast cancer. These results suggest that everolimus has favorable activity against basal-like subtypes of TNBCs. Epidermal growth factor receptor and CK5/6 are positive predictive markers of the TNBC response to everolimus, while cancer stem cell markers are negative predictive markers.

Effectiveness of diet versus exercise intervention on weight reduction in local Japanese residents.

OBJECTIVE: To evaluate the effect of diet versus exercise intervention on weight reduction. METHODS: Participants were randomly divided by gender, age, and living area into four groups: group DE (diet and exercise, n = 16), group D (diet only, n = 15), group E (exercise only, n = 15), and group C (control, n = 16). This study ultimately aimed to help participants reduce their body mass index (BMI) by 7% of baseline value. Subjects were 62 residents (men and women ranging in age from 40 to 69 years) of two residential areas in Nara Prefecture, Japan, who participated in annual health checkups in 2006. BMI of the participants was ≥24 and <28 kg/m² at baseline examination. All participants agreed to undergo a 6-month intervention between January 2007 and September 2007. RESULTS: In our intention-to-treat analysis, mean change in BMI from baseline to final examination was as follows: group DE mean BMI decreased 6.6%, group D mean BMI decreased 5.3%, group E mean BMI decreased 2.3%, and group C mean BMI decreased 2.2%. The reduction in BMI from baseline to final examination was significant in all groups (DE, p < 0.001; D, p < 0.001; E, p = 0.009; C, p = 0.019). Further, mean abdominal circumference was significantly reduced in all groups. Blood glucose levels were significantly reduced only in group DE (p = 0.047). CONCLUSION: Combined intervention with diet and exercise proved to be effective in weight reduction, whereas exercise intervention alone was not found to be effective.