Involvement of D1 dopamine receptor in the nucleus of the solitary tract of rats in stress-induced hypertension and exercise.

OBJECTIVE: Chronic stress can cause hypertension, whereas daily exercise promotes healthy well being through destressing. Although the nucleus of the solitary tract (NTS) is involved in the development of hypertension, the molecular and physiological mechanisms of stress and exercise remain unclear. In this study, we tested whether gene expression in the NTS is altered by stress and daily exercise and whether this is involved in cardiovascular regulation. METHODS: We have performed RT2 Profiler PCR arrays targeting a panel of neurotransmitter receptor genes in the NTS of Wistar rats subjected to chronic restraint stress (1 h a day over 3 weeks) with or without voluntary wheel exercise. We also performed immunohistochemistry to determine whether the identified molecules were expressed at the protein level. Additionally, microinjection studies in anesthetized rats were performed to examine whether validated molecules exhibit physiological roles in cardiovascular regulation of the NTS. RESULTS: We observed that blood pressure was significantly increased by stress and the increase was suppressed by exercise. Using PCR analysis, we determined that the expression levels of four genes in the NTS, including the dopamine receptor D1 gene (Drd1), were significantly affected by stress and suppressed by exercise. We also examined dopamine D1 receptor (D1R) expression in NTS neurons and found significantly greater expression in the stressed than nonstressed animals. Furthermore, the microinjection of a D1R agonist into the NTS in anesthetized rats induced hypotensive effects. CONCLUSION: These results suggest that NTS D1R plays a role in the counteracting processes of stress-induced hypertension.

Impacts of cytoplasmic p53 aggregates on the prognosis and the transcriptome in lung squamous cell carcinoma.

The tumor suppressor TP53 gene, the most frequently mutated gene in human cancers, produces the product tumor protein p53, which plays an essential role in DNA damage. p53 protein mutations may contribute to tumorigenesis by loss of tumor suppressive functions and malignancy of cancer cells via gain-of-oncogenic functions. We previously reported that mutant p53 proteins form aggregates and that cytoplasmic p53 aggregates were associated with poor prognosis in human ovarian cancer. However, the prognostic impact of p53 aggregation in other tumors including lung squamous cell carcinoma (SCC) is poorly understood. Here, we demonstrated that lung SCC cases with cytoplasmic p53 aggregates had a significantly poor clinical prognosis. Analysis via patient-derived tumor organoids (PDOs) established from lung SCC patients and possessing cytoplasmic p53 aggregates showed that eliminating cytoplasmic p53 aggregates suppressed cell proliferation. RNA sequencing and transcriptome analysis of p53 aggregate-harboring PDOs indicated multiple candidate pathways involved in p53 aggregate oncogenic functions. With lung SCC-derived cell lines, we found that cytoplasmic p53 aggregates contributed to cisplatin resistance. This study thus shows that p53 aggregates are a predictor of poor prognosis in lung SCC and suggests that detecting p53 aggregates via p53 conventional immunohistochemical analysis may aid patient selection for platinum-based therapy.

Updated outcomes of surgical treatment for recurrent thymic tumour: a report from the Japanese nationwide database.

OBJECTIVES: This study aimed to analyse the surgical outcomes for recurrent thymic epithelial tumours and identify the factors associated with post-recurrence survival, using an updated Japanese nationwide database. METHODS: The cohort that developed recurrence after the initial resection was extracted from an updated database of patients whose thymic epithelial tumours were treated surgically between 1991 and 2010. Furthermore, we reviewed clinicopathological and prognostic factors of re-resected cases. Post-recurrence survival outcomes and cause-specific deaths in non-re-resected cases were also reviewed. RESULTS: We enrolled 191 patients who underwent re-resection and 259 patients who did not. In the surgery group, more patients with early stage disease, less aggressive World Health Organization (WHO) histological classification, initial complete resection and shorter recurrence-free intervals were included. Non-thymic carcinoma, absence of preoperative treatment, longer recurrent-free interval, single-site recurrence and R0-1 re-resection were all significantly favourable prognostic factors for post-recurrence survival in the surgery group, according to univariable analyses. Non-thymic carcinoma histology, longer recurrence-free interval and R0-1 re-resection were identified as independent prognostic factors according to multivariable analysis. The post-recurrence survival of the entire cohort with R2 re-resection was significantly better than that of the non-surgery group, although it was not demonstrated that patients with thymoma who underwent R2 re-resection had significantly better post-recurrence and lower cause-specific death. CONCLUSIONS: R0-1 re-resection was newly identified as a prognostic factor after re-resection, in addition to non-thymic carcinoma histological classification and longer recurrence-free intervals, as documented in the initial report.

Differential cellular stiffness across tissues that contribute to Xenopus neural tube closure.

During the formation of the neural tube, the primordium of the vertebrate central nervous system, the actomyosin activity of cells in different regions drives neural plate bending. However, how the stiffness of the neural plate and surrounding tissues is regulated and mechanically influences neural plate bending has not been elucidated. Here, we used atomic force microscopy to reveal the relationship between the stiffness of the neural plate and the mesoderm during Xenopus neural tube formation. Measurements with intact embryos revealed that the stiffness of the neural plate was consistently higher compared with the non-neural ectoderm and that it increased in an actomyosin activity-dependent manner during neural plate bending. Interestingly, measurements of isolated tissue explants also revealed that the relationship between the stiffness of the apical and basal sides of the neural plate was reversed during bending and that the stiffness of the mesoderm was lower than that of the basal side of the neural plate. The experimental elevation of mesoderm stiffness delayed neural plate bending, suggesting that low mesoderm stiffness mechanically supports neural tube closure. This study provides an example of mechanical interactions between tissues during large-scale morphogenetic movements.

Nearly Ideal Random Tiling with Dodecagonal Symmetry from Pentablock Quarterpolymers of the AB1CB2D Type.

Two-dimensional tiling manners as cross-sectional views of cylindrical domain assembly formed by pentablock quarterpolymers of the AB1CB2D type in bulk were investigated. Several binary and ternary blends from three mother polymers having different ϕB1/ϕB2 ratios (ϕB1 and ϕB2 are the volume fractions of the B1 and B2 blocks, respectively) represent nonperiodic but ordered triangle/square tilings, where the N3/N4 ratios (N3 and N4 are the numbers of triangles and squares in the observed area, respectively) are all close enough to the theoretical value of 4/√3 ≑ 2.31 for the dodecagonal quasicrystalline (DDQC) state, irrespective of the total number of polygons. The TEM images, having almost the same N3/N4 ratios, were proved to show 4- and 6-fold symmetries in terms of the angular appearance of equilateral polygon sides via image analyses. Among them, a ternary blend showed a nearly ideal random tiling pattern that is almost equivalent to the theoretically predicted tiling by SCFT. Moreover, the magnitude of phason strain estimated for a TEM image from the ternary blend was proved to be quite small when the observing area is narrow, while it deviates from the ideal quasicrystalline tiling with an increasing number of vertices in the observing area.

Influence of Gd-EOB-DTPA on proton-density fat fraction in the liver using chemical shift-encoded magnetic resonance imaging at 3-T.

Non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), have become increasingly prevalent owing to the rise in metabolic syndromes. Accurate assessment of hepatic fat deposition and inflammation is crucial for diagnosing and managing NAFLD/NASH. We investigated the influence of Gd-EOB-DTPA, (EOB) on proton-density fat fraction (PDFF) measurements using chemical shift-encoded magnetic resonance imaging (CSE-MRI) at 3-T. In total, 431 patients who underwent EOB contrast-enhanced MRI were included. PDFF measurements were obtained from pre- and post-contrast CSE-MRI. Linear regression and Bland-Altman analyses were performed to assess the correlation and agreement between pre- and post-EOB PDFF measurements. Relative enhancement (RE) of the liver was calculated as an EOB uptake index. There was a significant decrease in PDFF following EOB administration compared with the pre-contrast values (P < 0.0001), which was observed across all PDFF ranges (< 10% and ≥ 10%). Linear regression analysis revealed high correlation between pre- and post-EOB PDFF measurements. Bland-Altman analysis indicated a small bias between pre- and post-EOB PDFF values. Subgroup analysis based on RE showed a significant difference in ΔPDFF between patients with high RE (> 120%) and those with lower RE levels. EOB administration resulted in a slight decrease in PDFF measurements obtained using CSE-MRI at 3-T. We were able to generalize and clarify that the PDFF of the liver on 3D CSE-MRI at 3-T was slightly decreased after EOB administration as we used a larger group of patients compared to previous studies.

Current perspectives of viral hepatitis.

Viral hepatitis represents a major danger to public health, and is a globally leading cause of death. The five liver-specific viruses: Hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus, each have their own unique epidemiology, structural biology, transmission, endemic patterns, risk of liver complications, and response to antiviral therapies. There remain few options for treatment, in spite of the increasing prevalence of viral-hepatitis-caused liver disease. Furthermore, chronic viral hepatitis is a leading worldwide cause of both liver-related morbidity and mortality, even though effective treatments are available that could reduce or prevent most patients' complications. In 2016, the World Health Organization released its plan to eliminate viral hepatitis as a public health threat by the year 2030, along with a discussion of current gaps and prospects for both regional and global eradication of viral hepatitis. Today, treatment is sufficiently able to prevent the disease from reaching advanced phases. However, future therapies must be extremely safe, and should ideally limit the period of treatment necessary. A better understanding of pathogenesis will prove beneficial in the development of potential treatment strategies targeting infections by viral hepatitis. This review aims to summarize the current state of knowledge on each type of viral hepatitis, together with major innovations.

The relationship between diffusion tensor imaging and the clinical classification of cubital tunnel syndrome.

The purpose of the study was to investigate the relationship between diffusion tensor imaging (DTI) and the clinical classification of cubital tunnel syndrome (CuTS). Ten patients with CuTS (7 men and 3 women; mean age: 52.7 years) and 5 patients without ulnar neuropathy (2 men and 3 women; mean age: 38.0 years) were enrolled in this retrospective study. Fifteen patients were clinically classified into three groups: "Normal", "1 and 2A", and "2B and 3" by an orthopedic surgeon using the modified McGowan stages. DTI was acquired using a 3.0-T MRI. Fractional anisotropy (FA) of the ulnar nerve was measured in slices covering 20 mm proximal to 20 mm distal to ulnar sulcus. Median FA values in each group were compared by Kruskal-Wallis and Steel-Dwass test (P < 0.05). Five patients with CuTS were classified as "1 and 2A" and five patients as "2B and 3". The FA values, proximal 12 mm to the ulnar sulcus were 0.486 ± 0.117, 0.425 ± 0.166 and 0.298 ± 0.0386 in the "Normal", "1 and 2A" and "2B and 3" groups, respectively. The FA values of patients classified as "Normal" were significantly higher than those classified as "2B and 3" (P = 0.0326 in Steel-Dwass test). FA proximal to the ulnar sulcus might be associated to the modified McGowan stages for the clinical classification of CuTS.

Circulating microRNA profile of long-lived Okinawans identifies novel potential targets for optimizing lifespan and health span.

Nonagenarians and centenarians serve as successful examples of aging and extended longevity, showcasing robust regulation of biological mechanisms and homeostasis. Given that human longevity is a complex field of study that navigates molecular and biological mechanisms influencing aging, we hypothesized that microRNAs, a class of small noncoding RNAs implicated in regulating gene expression at the post-transcriptional level, are differentially regulated in the circulatory system of young, middle-aged, and nonagenarian individuals. We sequenced circulating microRNAs in Okinawan males and females <40, 50-80, and >90 years of age accounting for FOXO3 genetic variations of single nucleotide polymorphism (SNP) rs2802292 (TT - common vs. GT - longevity) and validated the findings through RT-qPCR. We report five microRNAs exclusively upregulated in both male and female nonagenarians with the longevity genotype, play predictive functional roles in TGF-ß, FoxO, AMPK, Pi3K-Akt, and MAPK signaling pathways. Our findings suggest that these microRNAs upregulated in nonagenarians may provide novel insight into enhanced lifespan and health span. This discovery warrants further exploration into their roles in human aging and longevity.

Changes in spinal motoneuron excitability during the improvement of fingertip dexterity by actual execution combined with motor imagery practice.

Since there is an upper limit to skill improvement through the repetition of actual execution, we examined whether motor imagery could be used in combination with actual execution to maximize motor skill improvement. Fingertip dexterity was evaluated in 25 healthy participants performing a force adjustment task using a pinch movement with the left thumb and index finger. In the intervention condition, six sets of repetitions of combined actual execution and motor imagery were performed, while in the control condition, the same flow was performed, but with motor imagery replaced by rest. Changes in the excitability of spinal motoneurons during motor imagery compared to rest were compared in terms of the F/M amplitude ratio. Motor skill changes were compared before and after repeated practice and between the conditions, respectively, using the absolute amount of adjustment error between the target pinch force value and the delivered pinch force value (absolute error) as an index. The results showed that the repetition of exercise practice and motor imagery decreased the absolute error, which was greater than that of exercise practice alone in terms of motor skill improvement. The F/M amplitude ratio for motor imagery compared to rest did not increase. This suggests that motor imagery is involved in the degree of the increase of spinal motoneuron excitability based on the real-time prediction of motor execution and that there may be no need for an increase in excitability during motor skill control.

Gas Gangrene of the Spleen Caused by Clostridium perfringens After Mild Blunt Trauma.

Splenic gas gangrene caused by Clostridium perfringens is rare. A 73-year-old woman was referred to our hospital because of fatigue, dyspnea, and left hypochondrial pain. She had a history of blunt trauma to the left abdomen eight days ago. She presented with hypoxemia and a high inflammatory response on blood tests. A CT showed left pleural effusion and gas in the spleen. She was treated with antimicrobials and underwent splenectomy. C. perfringens was identified from blood and intraoperative ascites cultures. She recovered and was discharged on day 34 of hospitalization. As C. perfringens is part of the normal gut microbiota and can translocate to other parts of the body, this bacterium should be considered a splenic abscess pathogen when an intracorporeal anaerobic environment is suspected.

Gitelman syndrome and in vitro fertilization-embryo transfer: advancing preconception care in nephrology.

We report a case of a pregnant patient with Gitelman syndrome (GS) who conceived by in vitro fertilization-embryo transfer (IVF-ET). A 39-year-old woman was referred for hypokalemia, with a serum potassium level of 2.2 mEq/L. She had difficulty conceiving spontaneously. Because of her age, her hypokalemia could be exacerbated by pregnancy. We provided preconception care and managed her pregnancy by frozen-thawed embryo transfer with careful monitoring of the K levels. However, her serum K level dropped to 2.5 mEq/L at 8 weeks of gestation. It was expected that her K demand would increase with pregnancy; hence, she required hospitalization and a 1.5-fold increase in replacement dose to maintain her K levels. At 11 weeks of gestation, her serum K level rose to 3.0 mEq/L. The baby was born adequately sized after 38 weeks of gestation via vaginal delivery. The patient's K levels were stable during the postpartum period. Genetic testing revealed three heterozygous missense variants in SLC12A3 that were consistent with GS. In conclusion, preconception care and cooperation between internal medicine and obstetrics led to an excellent and successful delivery of an IVF fetus in an older patient with GS. There are no guidelines for electrolyte disorders in pregnancy, and only a few studies have reported on GS during pregnancy, including detailed postpartum assessments.

Tension Pneumomediastinum in Anti-MDA5 Antibody-positive Dermatomyositis-associated Interstitial Lung Disease: A Case Report and Literature Review.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM)-associated interstitial lung disease (ILD) can sometimes be complicated by pneumomediastinum, although tension pneumomediastinum is extremely rare. We herein report a case of anti-MDA5 antibody-positive DM-ILD that worsened subcutaneous and mediastinal emphysema during treatment. Hypotension and worsening respiratory failure were observed on day 20 of treatment. Mediastinal drainage under video-assisted thoracoscopic surgery promptly improved the patient's circulatory and respiratory status. Tension pneumomediastinum is a rare complication; however, it is a serious condition that may lead to hypotension or cardiac arrest and requires a prompt diagnosis and treatment.

Incidence of phrenic nerve injury during pulmonary vein isolation using different cryoballoons: data from a large prospective ablation registry.

AIMS: Phrenic nerve injury (PNI) is the most common complication during cryoballoon ablation. Currently, two cryoballoon systems are available, yet the difference is unclear. We sought to compare the acute procedural efficacy and safety of the two cryoballoons. METHODS: This prospective observational study consisted of 2,555 consecutive atrial fibrillation (AF) patients undergoing pulmonary vein isolation (PVI) using either conventional (Arctic Front Advance) (AFA-CB) or novel cryoballoons (POLARx) (POLARx-CB) at 19 centers between January 2022 and October 2023. RESULTS: Among 2,555 patients (68.8 ± 10.9 years, 1,740 men, paroxysmal AF[PAF] 1,670 patients), PVIs were performed by the AFA-CB and POLARx-CB in 1,358 and 1,197 patients, respectively. Touch-up ablation was required in 299(11.7%) patients. The touch-up rate was significantly lower for POLARx-CB than AFA-CB (9.5% vs. 13.6%, p = 0.002), especially for right inferior PVs (RIPVs). The touch-up rate was significantly lower for PAF than non-PAF (8.8% vs. 17.2%, P < 0.001) and was similar between the two cryoballoons in non-PAF patients. Right PNI occurred in 64(2.5%) patients and 22(0.9%) were symptomatic. It occurred during the right superior PV (RSPV) ablation in 39(1.5%) patients. The incidence was significantly higher for POLARx-CB than AFA-CB (3.8% vs. 1.3%, P < 0.001) as was the incidence of symptomatic PNI (1.7% vs. 0.1%, P < 0.001). The difference was significant during RSPV (2.5% vs. 0.7%, P < 0.001) but not RIPV ablation. The PNI recovered more quickly for the AFA-CB than POLARx-CB. CONCLUSIONS: Our study demonstrated a significantly higher incidence of right PNI and lower touch-up rate for the POLARx-CB than AFA-CB in the real-world clinical practice.

A Case of Aggressive Lung Squamous Cell Carcinoma With Aberrant Cytoplasmic p53 Aggregation.

Background: Immunohistochemistry for p53 was a well-established method for cancer diagnosis in pathology. Aberrant cytoplasmic p53 positivity reflects the accumulation of p53 aggregates, which has been shown to be associated with chemoresistance and to be a predictive marker of a worse clinical course in ovarian cancer. Case Report: A 65-year-old Japanese man was diagnosed with lung cancer, and surgical resection was performed. Multiple metastasis were found 21 months post-surgery. The lesions were resistant to chemotherapy, and he succumbed to the disease 29 months post-surgery. The resected primary lesion was pathologically diagnosed as squamous cell carcinoma, with notable cytoplasmic p53 positivity indicated by immunohistochemistry. Conclusion: Notable aberrant cytoplasmic accumulation of p53 aggregate was observed in the cancer cells of this case. Chemotherapy was ineffective for the recurrent lesions, suggesting a role of p53 aggregates in chemoresistance. Pathological analysis of p53 via immunohistochemistry may be useful in predicting chemoresistance of lung squamous cell carcinoma.

NUF2 Expression in Cancer Tissues and Lymph Nodes Suggests Post-Surgery Recurrence of Non-Small Cell Lung Cancer.

In non-small cell lung cancer (NSCLC) cases, detecting potential lymph node metastases is essential to determine the indications for sublobar resection or adjuvant therapy. NUF2 is a tumor-specific antigen that is highly expressed in lung cancer tissues. However, the significance of analyzing NUF2 expression in dissected lymph nodes has not yet been studied. Thus, we investigated the association between NUF2 expression in lung cancer tissues and dissected lymph nodes and early recurrence of NSCLC to determine its usefulness as a marker of lymph node micrometastasis. This retrospective study quantified NUF2 expression in the cancer tissues of 88 patients with NSCLC who underwent complete resection using real-time polymerase chain reaction and investigated its relationship with clinicopathological features and prognosis. We also quantified NUF2 RNA expression in mediastinal lymph nodes from 255 patients with pN0 NSCLC who underwent complete resection with lymph node dissection and analyzed its association with prognosis. NUF2 expression in primary tumors was correlated with lymph node metastasis and unfavorable outcomes in terms of poor recurrence-free and cancer-specific survival. In N0 NSCLC cases, high NUF2 expression in mediastinal lymph nodes indicated poor prognosis, especially in lymph node recurrence. NUF2 emerges as a promising marker for predicting lymph node metastatic recurrence, offering potential utility in guiding post-surgical adjuvant therapy for lung cancer or assisting in intraoperative decisions for sublobar resection.

Molecular Imaging of PD-1 Unveils Unknown Characteristics of PD-1 Itself by Visualizing "PD-1 Microclusters".

Programmed cell death-1 (PD-1) is one of the most famous coinhibitory receptors that are expressed on effector T cells to regulate their function. The PD-1 ligands, PD-L1 and PD-L2, are expressed by various cells throughout the body at steady state and their expression was further regulated within different pathological conditions such as tumor-bearing and chronic inflammatory diseases. In recent years, immune checkpoint inhibitor (ICI) therapies with anti-PD-1 or anti-PD-L1 has become a standard treatment for various malignancies and has shown remarkable antitumor effects. Since the discovery of PD-1 in 1992, a huge number of studies have been conducted to elucidate the function of PD-1. Herein, this paper provides an overview of PD-1 biological findings and sheds some light on the current technology for molecular imaging of PD-1.

Duodenal Papillary Metastasis of Lung Cancer with Bleeding Controlled by Endoscopic Treatment and Systemic Osimertinib Therapy: Case Report.

Introduction: Solid organ malignancies rarely metastasize to the duodenal papilla. We describe a case of primary lung cancer with duodenal papillary metastasis in a patient who presented with melena. To the best of our knowledge, this is only the second report of duodenal papillary metastasis from lung cancer. Case Presentation: A 65-year-old woman presented with complaints of anorexia, weight loss, and black stool. Imaging studies led to a clinical diagnosis of stage IVB lung cancer, and anticoagulants were initiated to treat pulmonary artery thrombosis. However, endoscopic hemostasis was challenging because of bleeding from a duodenal papillary tumor. Fortunately, the patient was positive for the plasma epidermal growth factor receptor (EGFR) gene mutation, and osimertinib, an EGFR tyrosine kinase inhibitor, was administered, successfully achieving hemostasis. Subsequently, endoscopic ultrasonography-guided transbronchial needle aspiration of an enlarged mediastinal lymph node and duodenal papillary tumor biopsy confirmed duodenal papillary metastasis of the primary lung adenocarcinoma. Conclusion: Although duodenal papillary metastasis is extremely rare, a good clinical outcome was achieved in this case by considering duodenal papillary metastasis from lung cancer as the differential diagnosis and administering systemic osimertinib therapy.

Novel protective effect of the FOXO3 longevity genotype on mechanisms of cellular aging in Okinawans.

The genetic association of FOXO3 genotypes with human longevity is well established, although the mechanism is not fully understood. We now report on the relationship of the FOXO3 longevity variant rs2802292 with telomere length, telomerase activity, FOXO3 expression, and inflammatory cytokine levels in men and women. In agreement with earlier work, the FOXO3 longevity variant conferred protection against telomere shortening of peripheral blood mononuclear cells from adults aged 55 years and older. This was accompanied by higher levels of telomerase activity in mononuclear cells for carriers of the longevity-associated FOXO3 G-allele of SNP rs2802292 (P = 0.015). FOXO3 mRNA expression increased slightly with age in both young (P = 0.02) and old (P = 0.08) G-allele carriers. Older female G-allele carriers displayed a modest decline in levels of pro-inflammatory cytokine IL-6 with age (P = 0.07). In contrast, older male G-allele carriers displayed an age-dependent increase in levels of anti-inflammatory cytokine IL-10 with age (P = 0.04). Thus, FOXO3 may act through several different pro-longevity mechanisms, which may differ by age and sex.