Effective and Steady Differentiation of a Clonal Derivative of P19CL6 Embryonal Carcinoma Cell Line into Beating Cardiomyocytes

The P19CL6 cell line is a useful model to study cardiac differentiation in vitro. However, large variations were noticed in the differentiation rates among previous reports as well as our individual experiments. To overcome the unstable differentiation, we established P19CL6-A1, a new clonal derivative of P19CL6 that could differentiate into cardiomyocytes more efficiently and stably than the parent using the double stimulation with 5-Aza and DMSO based on the previous report. We also introduced a new software, Visorhythm, that can analyze the temporal variations in the beating rhythms and can chart correlograms displaying the oscillated rhythms. Using P19CL6-A1-derived cardiomyocytes and the software, we demonstrated that the correlograms could clearly display the enhancement of beating rates by cardiotonic reagents. These indicate that a combination of P19CL6-A1 and Visorhythm is a useful tool that can provide invaluable assistance in inotropic drug discovery, drug screening, and toxicity testing

Association of Regular Cervical Cancer Screening with Socioeconomic, COVID-19 Infection and Vaccine Status Among Japanese Population: Cohort Observational Study

Purpose: Among the Organisation for Economic Co-operation and Development countries, Japan has one of the lowest cervical cancer screening coverages. Cancer screening coverage has worsened due to the coronavirus disease of 2019 (COVID-19) pandemic. This study investigated the relationship between socioeconomic background, COVID-19 infection history and vaccine status, and regular cervical cancer screening (CCS) during the two years of the COVID-19 era in Japan. Patients and Methods: We used data from the Japan COVID-19 and Society Internet Survey, a nationwide, Internet-based, selfreport cohort observational study conducted in 2022. The outcome variable was identified by asking whether the participants had undergone CCS within the last two years. Cervical cytology was performed in Japan by brushing the external cervical os. This study used multivariate log-binomial regression models to evaluate inequalities during regular checkups for CCS. Adjusted prevalence ratios (APRs) with 95% confidence intervals (CIs) were estimated to incorporate the socioeconomic background variables. Results: Of the 12,066 participants, 5597 (46.4%) had undergone regular CCS for over two years. The prevalence ratio (PR) of patients who underwent CCS was 0.70 for those in their 20s and 0.78 for those in their 60s, compared to those in their 40s. Socioeconomic inequities were found in the following groups: unemployed/student, unmarried, high school graduate or lower, and household income below 4 million Yen. Our final multivariate analysis revealed that participants who were in their 20s or 60s, had a household income below 4 million Yen, were unmarried, had no annual health check-ups, and were unvaccinated with COVID-19 were at a higher risk of not undergoing CCS. Conclusion: The relationship between socioeconomic inequality and CCS hesitancy is prevalent among younger participants. The CCS coverage in Japan during the COVID-19 pandemic year (2020-2022) was not low compared with the pre-pandemic era

N-cadherin expression in head and neck cancer

The loss of E-cadherin and the gain of N-cadherin expression are known as “cadherin switching”. Cadherin switching is a major hallmark of epithelial-mesenchymal transition (EMT). EMT is a crucial process in cancer progression, providing cancer cells with the ability to escape from the primary focus, to invade stromal tissues and to migrate to distant regions. Although down-regulation of E-cadherin is well known in various cancers, there are a few studies on N-cadherin expression in cancer. Here, therefore, we investigated whether N-cadherin expression was associated with the progression of head and neck squamous cell carcinoma (HNSCC). First, we examined the expression of N-cadherin by immunohistochemistry and its correlation with clinico-pathological findings. High expression of N-cadherin was observed in 52 of 80 HNSCC cases and was significantly correlated with malignant behaviors. Next, we examined the correlation between N-cadherin and E-cadherin. Cadherin switching (high expression of N-cadherin and low expression of E-cadherin) was found in 30 of 80 HNSCC cases and was well correlated with histological differentiation, pattern of invasion and lymph node metastasis in HNSCC cases. Moreover, we examined the expression of N-cadherin and E-cadherin by RT-PCR in 16 HNSCC cell lines to confirm the immunohistochemical findings. N-cadherin expression was observed in 7 of 16 HNSCC cells, and cadherin switching was observed in 2 HNSCC cells. Interestingly, HNSCC cells with cadherin switching have EMT features. In conclusion, we suggest that i) N-cadherin may play an important role in malignant behaviors of HNSCC, and ii) cadherin switching might be considered as a discrete critical event in EMT and metastatic potential of HNSCC

N-cadherin expression in SpCC

Spindle cell carcinoma (SpCC) is a biphasic tumor composed of conventional squamous cell carcinoma and a malignant spindle cell component. SpCC expresses both epithelial and mesenchymal markers by immunohistochemical analysis. There is mounting evidence for sarcomatoid transformation from the epithelial component, supporting the theory that SpCC is a monoclonal neoplasm originating from a stem cell giving rise to both components. The loss of E-cadherin and the gain of N-cadherin expression are known as the “cadherin switching”. Cadherin switching is a major hallmark of epithelial-mesenchymal transition (EMT). EMT is a crucial process in cancer progression providing cancer cells with the ability to escape from the primary focus, to invade stromal tissues and to migrate to distant regions. Although E-cadherin down-regulation is well known in various cancers, there are a few studies on N-cadherin expression in cancer. Here, therefore, we investigated N-cadherin expression in the progression of head and neck SpCC. First we examined cadherin swithching in our established SpCC cell lines, SpCC-1 and SpCC-2. SpCC-1 and SpCC-2 cells were spindle in shape and showed cadherin switching. Moreover, we examined N-cadherin expression in 15 SpCC cases by immunohistochemistry. Although N-cadherin expression was not observed in non-neoplastic squamous epithelium, high expression of N-cadherin was observed in 10 of 15 SpCC cases. Interestingly, 6 of 7 SpCC cases with metastasis showed high expression of N-cadherin. In conclusion, our findings suggest that N-cadherin may play an important role in metastasis of SpCC in addition to the pathogenesis of SpCC of the head and neck

Major Depressive Disorder Complicated with Spinocerebellar Ataxia: Report of 2 Cases

Background: It is known that patients with spinocerebellar ataxia (SCA) tend to exhibit depressive symptoms. But the pathology of depressive symptoms complicated with SCA, including the reaction to the stress resulting from decreased motor function and central dysfunction due to neurodegeneration, is controversial and remains to be elucidated. To our knowledge, there have been hardly any reports on treatment methods of major depressive disorder (MDD) complicated with SCA. Case Reports: We report 2 cases in which selective serotonin reuptake inhibitors (SSRIs) were effective against MDD complicated with SCA. Interestingly, one of the patients developed the symptoms of spinocerebellar degeneration (SCD) during the course of the MDD, and the other patient developed the symptoms of MDD during the course of SCA, but complete remission of the MDD occurred in both cases. In our cases, the depressive symptoms may have been caused mainly by an abnormality of reversible neural transmission including serotonin transmission due to central dysfunction, and there is the unlikely possibility that the depressive symptoms are reactive to the stress due to decreased motor function, because the depressive symptoms decreased with SSRIs. Conclusion: Although cerebellar degeneration is irreversible in SCA patients, our cases suggest that MDD complicated with SCA may be reversible and treatable using antidepressants such as SSRIs with few adverse events. Therefore, it is important for neurologists to detect MDD complicated with SCA early and consult a psychiatrist in order to improve quality of life of SCA patients

Non-Invasive Prenatal Genetic Testing (NIPT) Leading to Prenatal Diagnosis of Trisomy 21 Mosaicism and 18q Deletion Syndrome: Two Cases

NIPT is non-definitive testing to estimate the possibility that fetuses have trisomy 21, trisomy 18, or trisomy 13. However, in NIPT-positive and indeterminate cases, rare chromosomal disease may become apparent, requiring advanced genetic considerations and counseling skills. We experienced two such cases, a trisomy 21 mosaicism case triggered by NIPT-positive status and 18q deletion syndrome triggered by NIPT-indeterminate status. These cases have two clinical implications for NIPT. First, it was revealed that trisomy mosaicism might be found in NIPT-positive cases that have lower Z-Scores than those inferred from the fraction of fetal cfDNA in the case of standard trisomy. Second, it is possible that microdeletion syndrome could be the reason for an indeterminate NIPT result. Today’s genetic counseling requires more expertise in ethics and communication as well as genetic science because NIPT can lead to totally unexpected results

Angiotensin II Type 1 Receptor Blockers Reduce Urinary Angiotensinogen Excretion and the Levels of Urinary Markers of Oxidative Stress and Inflammation in Patients with Type 2 Diabetic Nephropathy

Objective To demonstrate that the administration of an angiotensin (Ang) II type 1 receptor (AT1R) blocker (ARB) inhibits the vicious cycle of high glucose (HG)-reactive oxygen species (ROS)-angiotensinogen (AGT)-Ang II-AT1R-ROS by suppressing ROSs and inflammation, thus ameliorating diabetic nephropathy (DN). Research Design and Methods Thirteen hypertensive DN patients were administered ARBs, and the following parameters were evaluated before and 16 weeks after the treatment: urinary AGT (UAGT), albumin (albumin-creatinine ratio: ACR), 8-hydroxydeoxyguanosine (8-OHdG), 8-epi-prostaglandin F2α (8-epi-PGF2α), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, and IL-10. Results ARB treatment reduced the blood pressure and urinary levels of AGT, ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 but increased the urinary levels of IL-10. The reduction rate of UAGT correlated with the reduction rate of blood pressure; the reduction rates of the urinary ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 levels; and the increase rate of the urinary IL-10 levels. Moreover, subjects who had high UAGT values at baseline exhibited higher reduction rates of urinary albumin excretion. Conclusions ARB-induced blockade of the abovementioned vicious cycle contributes to the renoprotective effects of ARBs in DN. The urinary levels of AGT could represent a predictive factor for reduced ACR in patients receiving ARB treatment

A novel method to create a vortex in a Bose-Einstein condensate

It has been shown that a vortex in a BEC with spin degrees of freedom can be created by manipulating with external magnetic fields. In the previous work, an optical plug along the vortex axis has been introduced to avoid Majorana flips, which take place when the external magnetic field vanishes along the vortex axis while it is created. In the present work, in contrast, we study the same scenario without introducing the optical plug. The magnetic field vanishes only in the center of the vortex at a certain moment of the evolution and hence we expect that the system will lose only a fraction of the atoms by Majorana flips even in the absence of an optical plug. Our conjecture is justified by numerically solving the Gross-Pitaevskii equation, where the full spinor degrees of freedom of the order parameter are properly taken into account. A significant simplification of the experimental realization of the scenario is attained by the omission of the optical plug.Comment: 8 pages, 11 figure

Role of premature leptin surge in obesity resulting from intrauterine undernutrition

SummaryIntrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to “developmental origins of health and disease.