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BACKGROUND AND AIMS: Pancreatic adenocarcinoma is a deadly disease characterized by metastatic progression and resistance to conventional therapeutics. Mutation of KRAS is the most frequent early event in pancreatic tumor progression. AKT isoforms are frequently activated in pancreatic cancer, and reports have implicated hyperactivation of AKT1, as well as AKT2, in pancreatic tumor formation. The objective here is to delineate the role of AKT in facilitating in vivo pancreatic tumor progression in the context of KRAS mutation and predisposition to pancreatic cancer. METHODS: Mice with Akt1 and KRas mutant alleles expressed using the pancreas Pdx promoter were mated to characterize the incidence and frequency of histologic and genetic alterations known to occur commonly in human pancreatic ductal adenocarcinoma. RESULTS: Active Akt1 (Akt1Myr, containing a myristoylation sequence) cooperated with active mutant KRasG12D to accelerate pancreatic carcinoma onset and progression and increase phosphorylation of downstream effectors in the Akt pathway. Mucin and smooth muscle actin expression was found in and around pancreatic intraepithelial neoplasms (PanINs), and accelerated time to metastasis was found in Akt1Myr/KRasG12D mice. CONCLUSIONS: In contrast to prior reports of pancreatic KRas mutant mice mated with mice deficient for various tumor suppressor genes, which resulted in aggressive disease within a few months of age, Akt1Myr/KRasG12D mice enabled the study of PanINs and spontaneous pancreatic transformation more characteristic of human pancreatic progression in elderly individuals. The Akt1Myr/KRasG12D model holds promise for delineating the tumor biology and biomarkers critical for understanding their cooperation in cancer oncogenesis and future targeting in therapeutic strategies.

Energy release rates for an edge delamination of a laminated beam subjected to through-thickness temperature gradient are analyzed on the basis of the classical beam theory. The decomposition of the energy release rate into mode 1 and mode II components is made by combining the analyses of the energy release rates by Toya (1992) and the two-dimensional elasticity solutions for a split-beam element by Suo and Hutchinson (1990). The energy release rate is a quadratic function of the temperatures of the top and bottom surfaces of the beam. The transition of the type of crack growth between pure mode II and mixed mode type occurs at the temperature difference corresponding to the minimum energy release rate. Numerical analyses based on finite-element method are also carried out, which show that the theory agrees well with numerical results when temperature jump across the delaminated surfaces is relatively small as compared with the temperature difference between the top and bottom surfaces of the layered beam. [DOI: 10.1115/1.1978917]

A classical beam theory was used to analyze an asymmetric three-point bending of a simple layered beam with an internal interface crack. The delaminated beam was regarded as two lapped beams hinged at both ends to determine the axial forces. Numerical analyses based on the finite element method showed that delamination growth occurs in mixed mode subscribes to the fracturing process.

Objective: The forkhead box O1 (FOXO1) transcription factor is a key regulator of autophagy. In chondrocytes, reduced FOXO1 expression with aging causes osteoarthritis due to dysfunction of autophagy, but the mechanisms underlying regulation of FOXO1 expression and the reduction in expression with aging remain unclear. We investigated the mechanism by which transforming growth factor β1 (TGFβ1) signaling regulates the FOXO1-autophagy axis.Methods: Expression of FOXO1 was measured in chondrocytes after TGFβ1 treatment. Immunohistochemistry was performed to estimate the levels of activin receptor-like kinase 5 (ALK5) and FOXO1 in the knee joints of young, middle-aged and old mice. The effects of the ALK5 inhibitor and SMAD3 or SMAD2 knockdown on FOXO1 expression were evaluated. The role of TGFβ1 in autophagy after hydrogen peroxide (H2O2) treatment was analyzed. The protective effect of TGFβ1 against H2O2 treatment was assessed by cell viability assay and TUNEL assay.Results: TGFβ1 promoted the expression of FOXO1 mRNA and protein. Both ALK5 and FOXO1 expression decreased with aging. ALK5 inhibition and SMAD3 knockdown suppressed induction of FOXO1 expression by TGFβ1, whereas SMAD2 knockdown increased it. TGFβ1 promoted the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3)-I protein via the SMAD3-FOXO1 pathway. Furthermore, under H2O2 treatment, TGFβ1 promoted expression of LC3-II. TGFβ1 pretreatment suppressed cell death of chondrocytes following H2O2 treatment, but this protective effect was abolished by FOXO1 knockdown.Conclusions: TGFβ1 protects chondrocytes against oxidative stress via the FOXO1-autophagy axis, and a reduction in ALK5 expression might cause reduced FOXO1 expression with aging. [ABSTRACT FROM AUTHOR]

Previous research has shown that ethics is very important when conducting business domestically and internationally. There has been extensive ethics research done as it relates to managers in large firms and the ethical issues they encounter. What appears to be a limited area are the ethical issues encountered by entrepreneurs and small business owners. In this article, we will discuss some of the issues encountered by the entrepreneurs and small business owners. We will also discuss some of the ethical issues encountered by entrepreneurs and small business owners specifically in the Middle East and North Africa (MENA) region. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to examine the efficacy of an ovarian tissue transportation network for fertility preservation (FP) for cancer patients in Japan. Methods: PubMed was searched for papers on transportation of human ovarian tissue for FP. We analyzed population, area, number of cancer patients for ovarian tissue cryopreservation (OTC), quality control/assessment and safety, cost of a cryopreservation center for the building for 30 years, and medical fees of cancer patients (operation, cryopreservation, and storage of ovarian tissue). Results: More than twenty babies have been born in Denmark and Germany through a transportation system. Up to 400 new patients a year need OTC. The fees for removal, cryopreservation, and storage for 5 years, and transplantation of ovarian tissue are around €5,000, €4,000, and €5,000, respectively. It costs more than €5 million to establish and maintain one cryopreservation center for 30 years. If we have a few cryopreservation centers in Japan, we can cryopreserve 400 patients' ovarian tissue per year by safer slow freezing and maintain quality control/assessment. We need to lighten the patients' burden for easy to use FP by a government subsidy and medical insurance coverage. Conclusions: This model has been termed the Danish model ('the woman stays - the tissue moves'). This is truly patient-centered medicine. We can have maximum effects with the minimum burden. A transportation network like those of Denmark and Germany is the best strategy for FP in Japan. It may be the best system for cancer patients, medical staff, and the Ministry of Health, Labor, and Welfare. [ABSTRACT FROM AUTHOR]

Protein kinase B/AKT has three isoforms (AKT1-3) and is renowned for its central role in the regulation of cell growth and proliferation, due to its constitutive activation in various cancers. AKT2, which is highly expressed in insulin-responsive tissues, has been identified as a primary regulator of glucose metabolism as Akt2 knockout mice (Akt2-/-) are glucoseintolerant and insulin-resistant. However, the role of AKT1 in glucose metabolism is not as clearly defined. We previously showed that mice with myristoylated Akt1 (AKT1Myr) expressed through a bicistronic Pdx1-TetA and TetO-MyrAkt1 system were susceptible to islet cell carcinomas, and in this study we characterized an early onset, prediabetic phenotype. Beginning at weaning (3 weeks of age), the glucose-intolerant AKT1Myr mice exhibited non-fasted hyperglycemia, which progressed to fasted hyperglycemia by 5 months of age. The glucose intolerance was attributed to a fasted hyperglucagonemia, and hepatic insulin resistance detectable by reduced phosphorylation of the insulin receptor following insulin injection into the inferior vena cava. In contrast, treatment with doxycycline diet to turn off the transgene caused attenuation of the non-fasted and fasted hyperglycemia, thus affirming AKT1 hyperactivation as the trigger. Collectively, this model highlights a novel glucagon-mediated mechanism by which AKT1 hyperactivation affects glucose homeostasis and provides an avenue to better delineate the molecular mechanisms responsible for diabetes mellitus and the potential association with pancreatic cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: Pancreatic adenocarcinoma is a deadly disease characterized by metastatic progression and resistance to conventional therapeutics. Mutation of KRAS is the most frequent early event in pancreatic tumor progression. AKT isoforms are frequently activated in pancreatic cancer, and reports have implicated hyperactivation of AKT1, as well as AKT2, in pancreatic tumor formation. The objective here is to delineate the role of AKT in facilitating in vivo pancreatic tumor progression in the context of KRAS mutation and predisposition to pancreatic cancer. METHODS: Mice with Akt1 and KRas mutant alleles expressed using the pancreas Pdx promoter were mated to characterize the incidence and frequency of histologic and genetic alterations known to occur commonly inhuman pancreatic ductal adenocarcinoma. RESULTS: Active Akt1 (Akt1Myr, containing a myristoylation sequence) cooperated with active mutant KRasG12D to accelerate pancreatic carcinoma onset and progression and increase phosphorylation of downstream effectors in the Akt pathway. Mucin and smooth muscle actin expression was found in and around pancreatic intraepithelial neoplasms (PanINs), and accelerated time to metastasis was found in Akt1Myr/KRasG12D mice. CONCLUSIONS: In contrast to prior reports of pancreatic KRas mutant mice mated with mice deficient for various tumor suppressor genes, which resulted in aggressive disease within a few months of age, Akt1Myr/KRasG12D mice enabled the study of PanINs and spontaneous pancreatic transformation more characteristic of human pancreatic progression in elderly individuals. The Akt1Myr/KRasG12D model holds promise for delineating the tumor biology and biomarkers critical for understanding their cooperation in cancer oncogenesis and future targeting in therapeutic strategies. [ABSTRACT FROM AUTHOR]

Cute has become the favored language of (the predominantly female) popular consumer culture. This paper examines the roots of “cute” and its evolution with reference to its relevance to marketers. We follow the cultural appropriation of Japan’s “Kawaii” by the Western “cute”, and introduce a social, marketing-oriented description and analysis of the concept. We present its socio-cultural, experiential, symbolic, and ideological relevance to consumption in general, and to consumer culture theory in particular. This examination steers clear of scientific generalizations prevalent in consumer behavior research and aims, instead, to illuminate the cultural dimensions of the consumption cycle, and allow a better understanding of what it is like to form social attachment and loyalty in the context of cute consumption and consumer culture theory. Especially interesting questions arise regarding the trans-social acculturating elements of cute, as well as the apparent mainstreaming (cultural appropriation) of the cute Asian subculture into the dominant Western consumer and material cultures. [ABSTRACT FROM PUBLISHER]

Purpose: The aim of this study was to evaluate prospectively the difference in contrast enhancement of liver parenchyma between male and female subjects when the total amount of contrast material is determined by the total body weight (TBW).Materials and Methods: Computed tomography of the abdomen was performed with a total amount of iodine of 597 ± 3.9 mg I/kg (mean ± SD) over a mean ± SD total injection time of 30 ± 0.26 s. Postcontrast attenuation during the portal venous phase was measured in the liver parenchyma, portal vein, and aorta. These values were summed for each and compared to those obtained before contrast injection. A total of 565 consecutive patients without a history of underlying liver/heart disease, including 297 male and 268 female subjects (age 16-92 years, mean 67 years) were scanned and analyzed using a two-tailed t-test.Results: The difference between precontrast and the portal venous phase in the male subjects was 315.4 ± 40.5 HU (mean ± SD), and that in female subjects was 358.6 ± 44.8 HU. This difference was statistically significant (P < 0.0001).Conclusion: The contrast enhancement in females was 13.7% higher than that in males when the amount of iodine administered was based on the TBW. The difference can presumably be attributed to the difference in fat and muscle components. This result suggests that the amount of contrast material used in females should be reduced according to this difference. [ABSTRACT FROM AUTHOR]

Hypertestosteroneemia can be caused by a variety of diseases and drugs, some of which can cause male infertility. We report a case of spinal and bulbar muscular atrophy (SMBA) diagnosed by hypertestosteronemia during infertility treatment. The patient was a 28-year-old man. His wife had no cause of infertility, did not become pregnant after 10 cycles of timed-intercourse. His semen test pointed out insufficient semen volume and asthenozoospermia. Although varicocele surgery was performed at the neighboring general hospital, semen findings did not improve. Even though two cycles of intrauterine insemination (IUI) were performed, she did not become pregnant. The couple were introduced to our clinic in November 2019. Semen findings at the first visit were same as first time. Serum hormone levels were LH 12.0 mIU / mL, FSH 3.9 mIU / mL and total testosterone 19.47 ng / mL. The testicular volume was 13 ml on both sides. SHIM: 22 points, EHS: Grade 3; the erectile function was a slight decreased. Drug-induced hypertestosteroneemia was negative. Microscopic pituitary adenoma revealed at the general hospital, but no pituitary dysfunction. The examination was conducted at the local national hospital, and a high value of CK 621 IU / L was pointed out. SMBA was suspected and the patient visited the neurology department. Finally, he had an allele of 49 CAG repeats and SMBA was diagnosed with mild bulbar palsy, weakness of the extremities Even with 3 courses of IUI, she did not become pregnant and was scheduled for in vitro fertilization (IVF). At the same time as the start of IVF, the patient had a definitive diagnosis of SMBA and was scheduled for LHRH agonist treatment. Because LHRH agonists were predicted to exacerbate semen findings, we performed sperm freezing for the purpose of fertility preservation. In the initial treatment cycle of ovum pick-up, 11 oocytes were collected, and 7 mature oocytes were obtained. Five oocytes were fertilized by ICSI using frozen sperm, and four blastocysts were vitrified. After that, the second vitrified-warmed blastocyst transplantation led to pregnancy, and the pregnancy is currently ongoing. SMBA, also known as Kennedy's Disease, affects adult men aged 30-60 years. It is a slowly progressive neuromuscular disease that causes muscle weakness, muscle atrophy, and fasciculation due to degeneration of lower motor neurons. This is a genetic disorder of X-linked recessive inheritance. It is caused by a trinucleotide repeat expansion; >40 CAG repeats, in the androgen receptor gene located on the X chromosome. Patients are mildly desensitized to androgens, causing gynecomastia, testicular atrophy, and diminished fertility. It is also accompanied by mild hypertestosteroneemia. These findings must have been the same for this patient. This report is the world's first report of fertility-preserving sperm freezing in SMBA patients using ejaculated sperm, and is also the first report of ICSI-induced pregnancy in frozen sperm in SMBA patients. The effectiveness of ART was suggested for SMBA patients. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

Introduction: There have been 12 birth reports following autotransplantation of frozen--thawed ovaries so far. However, the function of frozen--thawed ovaries does not last long due to follicle loss during the freezing-thawing and reimplantation process without anastomosis. Our objective was to establish a technique to cryopreserve the entire ovary, improve the recovery rate of ovarian cells, and maintain long-term ovarian function after transplantation. We report the successful transplantation of ovaries in cynomolgus monkeys and rabbits after cryopreservation by pulsed magnetic field effects. Material and Methods: Experiment 1: Entire ovaries were removed from cynomolgus monkeys and rabbits, and they were frozen by pulsed magnetic field effects. The ovaries were then thawed, fixed, and examined histologically. Experiment 2: Ovaries of monkeys were removed on the first day of menstruation. The ovaries were frozen by pulsed magnetic field effects and preserved for about 1 month in liquid nitrogen. They were then transplanted into the skeletal muscles or kidney capsules of the same females after menstruation. The monkeys' menstruation and hormone levels, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P), were examined. Results: Histological examination of frozen thawed ovaries from monkeys and rabbits showed that the cells had the same structure as seen in non-frozen ovaries, and viable oocytes could be seen immediately after thawing. Although the duration until the return of menstrual cycles varied, menstruation was confirmed in all the subjects. More than 3 years after transplantation, four of five monkeys had regular menstrual cycles. LH, FSH, E2, and P showed ovulatory pattern. Conclusions: This shows that it is possible to maintain long-term ovarian function by cryopreserving and transplanting entire ovaries without cryoprotectants. However, further study is needed to improve the technique of freezing and thawing ovaries, and to develop a technique for suturing blood vessels to the transection site to encourage revascularization. The advantages of cryopreservation by pulsed magnetic field effects are that the entire ovaries can be preserved and cryoprotectants are not used, which makes the thawing process easier . The monkeys in our study experienced restoration of ovarian function much earlier than did the humans reported in other studies, along with long-term maintenance of function. We believe that this technology for freezing the entire ovary could be applied clinically in the near future. Furthermore, the cryopreservation of intact internal organs is an encouraging step toward establishing a frozen-organ bank, which would allow the transplantation of organs between donors and recipients anywhere in the world. [ABSTRACT FROM AUTHOR]

The beta(2)-adrenergic receptor (B2AR) is expressed in pancreatic beta-cells and modulates insulin secretion. The purpose of the present study was to evaluate the influence of the Arg16Gly variant allele of B2AR on insulin secretion in patients with type 2 diabetes. We used minimal model analysis of the frequently sampled insulin-modified intravenous glucose tolerance test (FSIGT) and polymerase chain reaction (PCR)-restriction fragment length polymorphism to examine differences of insulin secretion and insulin resistance among three genotypes. There were no significant differences in baseline clinical characteristics, HbA1c, uric acid, CRP or lipid profiles among the three groups. The Gly/Gly group had significantly higher levels of fasting insulin (38.2+/-4.7 pmol/l versus 23.6+/-3.5 pmol/l) and homeostasis model assessment of insulin resistance (HOMA-R) (1.90+/-0.19 versus 1.32+/-0.24), compared with the Arg/Arg group, but there were no significant differences in acute insulin response to glucose (AIRg) bolus, insulin sensitivity (Si), or glucose effectiveness (Sg) among the three genotypes. Several reports have speculated that the Gly16 allele of B2AR exhibits agonist-promoted downregulation, but our findings, elevated fasting insulin concentrations, and previous clinical studies of blood pressure and lypolysis are controversial. The direct mechanism by which the Gly16 allele of B2AR may influence insulin secretion of pancreatic beta-cells is unknown. Further studies of the expression of the allelic receptor in islet cells may help to resolve the role of B2AR in insulin secretion. However, increased sensitivity to catecholamine-induced lipolysis of the Gly allele promotes higher free fatty acids concentrations in the portal system, which could enhance the higher levels of fasting insulin. [ABSTRACT FROM AUTHOR]

Introduction: We have experienced births after calcium ionophore (A23187) and strontium chloride (SrCl2) oocyte activation using sperm with repeatedly failed fertilization following intracytoplasmic sperm injection (ICSI). Material and Methods: 51 couples were selected from patients with unsuccessful ICSI treatments between April 2004 and November 2009 at our clinic. The subjects were divided into two groups, and the clinical results with and without oocyte activation. 26 couples received A23187. 30 minutes after ICSI, the oocytes were placed in 10mM of A32187 for 5 minutes, rinsed, and then cultured. 25 couples received SrCl2. 30 minutes after ICSI, the oocytes were placed in 10mM of SrCl2 for 10 minutes, rinsed, and then cultured. We compared the development of 11 babies from 8 couples after oocyte activation. At the time of the study, the babies were between 5 months old and 4 years and 9 months old. The questionnaires were filled out to assess the child's physical and mental development from birth to 3 years according to the Maternal and Children's Health Handbook issued by the Ministry of Health and Welfare in Japan. Results: The A23187 results were as follows (with vs. without A23187): two pronucleus (2PN) zygote rates, 53.3% (73/132) vs. 23.7% (32/135): P < 0.01; top embryo rates, 36.4% (20/55) vs. 27.0% (10/37): not significant (NS); blastocyst rates, 31.3% (10/32) vs. 29.1% (7/24): NS; expanded blastocyst rates, 15.6% (5/32) vs. 16.6% (4/24): NS; pregnancy rates, 20.0% (6/30) vs. 0% (0/8): NS; and miscarriage rates, 6.6% (1/6) vs. 0% (0/0): NS. The SrCl2 results were as follows (with vs. without SrCl2): 2PN zygote rates, 53.3% (73/132) vs. 27.2% (37/136): P < 0.01; top embryo rates, 26.1% (30/115) vs. 12.2% (5/41): NS; blastocyst rates, 43.5% (43/95) vs. 4.3% (1/23): P < 0.01; expanded blastocyst rates, 18.9% (18/95) vs. 0% (0/23): P < 0.05; pregnancy rates, 25.6% (10/39) vs. 0% (0/11) vs.: NS; and miscarriage rates, 30.0% (3/10) vs. 0% (0/0): NS. Comparing the results with A23187 and with SrCl2, there were no significant differences overall. 3 singletons were born after A23187, and 8 babies were born after SrCl2. Comparing the results of babies born after, the results were as follows (A23187/SrCl2): length of gestation period, 38.7±2.3/38.5±1.3; birth weight, 3.0±0.3/2.7±0.5, birth height, 48.1±2.2/47.8±2.5; girth of chest, 30.7±2.5/30.4±2.0; and girth of head, 33.7±0.8/32.4±2.5. Conclusions: Artificial oocyte activation using A23187 or SrCl2 is beneficial in patients with low or no fertility. This study showed that the method of oocyte activation does not adversely affect the growth or health of babies. Further studies are needed to confirm the safety of oocyte activation. [ABSTRACT FROM AUTHOR]