Generation of chimpanzee induced pluripotent stem cell lines for cross-species comparisons.

As humans' closest living relatives, chimpanzees offer valuable insights into human evolution. However, technical and ethical limitations hinder investigations into the molecular and cellular foundations that distinguish chimpanzee and human traits. Recently, induced pluripotent stem cells (iPSCs) have emerged as a novel model for functional comparative studies and provided a non-invasive alternative for studying embryonic phenomena. In this study, we generated five new chimpanzee iPSC lines from peripheral blood cells and skin fibroblasts with SeV vectors carrying four reprogramming factors (human OCT3/4, SOX2, KLF4, and L-MYC) and characterized their pluripotency and differentiation potential. We also examined the expression of a human-specific non-coding RNA, HSTR1, which is predicted to be involved in human brain development. Our results show that the chimpanzee iPSCs possess pluripotent characteristics and can differentiate into various cell lineages. Moreover, we found that HSTR1 is expressed in human iPSCs and their neural derivatives but not in chimpanzee counterparts, supporting its possible role in human-specific brain development. As iPSCs are inherently variable due to genetic and epigenetic differences in donor cells or reprogramming procedures, it is essential to expand the number of chimpanzee iPSC lines to comprehensively capture the molecular and cellular properties representative of chimpanzees. Hence, our cells provide a valuable resource for investigating the function and regulation of human-specific transcripts such as HSTR1 and for understanding human evolution more generally.

Possible Use of Non-purine Selective Xanthine Oxidoreductase Inhibitors for Prevention of Exercise-induced Acute Kidney Injury Associated with Renal Hypouricemia.

Exercise-induced acute kidney injury (EIAKI) is frequently complicated with renal hypouricemia (RHUC). In patients with RHUC, limiting anaerobic exercise can prevent EIAKI. However, it is challenging to reduce exercise intensity in athletes. We herein report a 16-year-old Japanese football player with familial RHUC with compound heterozygous mutations in urate transporter 1 (URAT1) who presented with recurrent EIAKI. As prophylaxis (hydration during exercise) could not prevent EIAKI, febuxostat was initiated. EIAKI was not observed for 16 months despite exercising intensively. Hence, non-purine-selective xanthine oxidoreductase inhibitors may decrease the incidence of EIAKI in athletes with RHUC.

Different Clinical Courses of Nephronophthisis in Dizygotic Twins.

Siblings with nephronophthisis occasionally show different clinical courses; however, the reasons for this remain unclear. We herein report cases of nephronophthisis in a pair of dizygotic twins with different clinical courses. The brother developed end-stage kidney disease at 17 years old; however, his sister did not show kidney insufficiency. Kidney biopsies revealed severe tubulointerstitial damage at 14 and 22 years old in the brother and sister, respectively. Both had a homozygous NPHP1 deletion with different heterozygous mutations related to hereditary cystic kidney disease. Since the dizygotic twins were exposed to similar environmental factors, genetic factors may have influenced their clinical course more strongly than environmental factors.

Evaluation of a quantitative PCR-based method for chimerism analysis of Japanese donor/recipient pairs.

Chimerism analysis is a surrogate indicator of graft rejection or relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Although short tandem repeat PCR (STR-PCR) is the usual method, limited sensitivity and technical variability are matters of concern. Quantitative PCR-based methods to detect single nucleotide polymorphisms (SNP-qPCR) are more sensitive, but their informativity and quantitative accuracy are highly variable. For accurate and sensitive chimerism analysis, a set of KMR kits (GenDx, Utrecht, Netherlands), based on detection of insertions/deletions (indels) by qPCR, have been developed. Here, we investigated informativity and validated the accuracy of KMR kits in Japanese donor/recipient pairs and virtual samples of DNA mixtures representative of Japanese genetic diversity. We found that at least one recipient-specific marker among 39 KMR-kit markers was informative in all of 65 Japanese donor/recipient pairs. Moreover, the percentage of recipient chimerism estimated by KMRtrack correlated well with ratios of mixed DNA in virtual samples and with the percentage of chimerism in HSCT recipients estimated by STR-PCR/in-house SNP-qPCR. Moreover, KMRtrack showed better sensitivity with high specificity when compared to STR-PCR to detect recipient chimerism. Chimerism analysis with KMR kits can be a standardized, sensitive, and highly informative method to evaluate the graft status of HSCT recipients.

Prediction of oral intake recovery for inpatients with aspiration pneumonia by videoendoscopic evaluation using the Hyodo-Komagane score in Japan.

OBJECTIVE: To verify the validity of the prediction of oral intake recovery for inpatients with aspiration pneumonia using the Hyodo-Komagane score. BACKGROUND: Patients admitted for treatment of aspiration pneumonia sometimes have difficulty in resuming oral intake due to decreased swallowing function. Predicting whether the swallowing function will recover enough to achieve oral ingestion at discharge is an important factor in developing a treatment strategy. No studies have investigated the prediction of oral intake recovery using videoendoscopic examination. METHODS: Subjects were 65 patients who were admitted to an acute care hospital for the treatment of aspiration pneumonia. The patients were divided into two groups, the oral feeding group and the tube feeding group, according to their oral intake status at discharge or transfer. Logistic regression analysis was performed using the condition that tube feeding was not required as an objective variable and the items with significant differences between the two groups as explanatory variables. Additionally, the receiver operating characteristic curve was used to identify patients who could take food orally at discharge. RESULTS: The odds ratios for the Hyodo-Komagane score and the pharyngeal clearance score were 1.485 and 3.379, respectively. When the cut-off values of the Hyodo-Komagane score and the pharyngeal clearance score were 6 and 1, the sensitivity was 0.88 and 0.91, and the specificity was 0.64 and 0.70, respectively. CONCLUSION: The Hyodo-Komagane score and especially the pharyngeal clearance score are useful indices to predict oral intake recovery for inpatients with aspiration pneumonia.

Relationship between oral intake level and oral health assessment tool scores in the convalescent ward.

PURPOSE: To examine the relationship between oral intake function and oral health status in convalescent inpatients. METHODS: Subjects were 222 patients admitted to a convalescent hospital between 1 January and 30 June 2018. Investigation items were age, sex, causative disease, body mass index, functional oral intake scale (FOIS), functional independence measure, occlusal contact, assistance with oral cleaning, and oral health assessment tool (OHAT) scores. Multiple regression analysis was performed with FOIS as the dependent variable, and investigation items were related to FOIS as independent variables. RESULTS: Results of multiple regression analysis for all patients suggested that saliva and denture scores were significantly associated with FOIS. However, analysis excluding non-oral feeding patients did not show a significant association between FOIS and OHAT scores. CONCLUSION: The results of this study suggest that oral health status is associated with oral intake function. In addition, the oral health status of inpatients may be strongly related to whether or not they are eating orally. Therefore, it is necessary to take good care of oral health in non-oral feeding patients in the convalescent ward.

Time Course and Recovery of the Movements of Hyoid Bone and Thyroid Cartilage During Swallowing in a Patient With Sarcopenic Dysphagia.

Sarcopenia is known to adversely affect swallowing function. In this report, we describe the treatment progress of an older patient with dysphagia caused by sarcopenia and the analysis results from videofluorographic examination images. An 89-yr-old man who had been hospitalized for lumbar fracture experienced lower back pain and thus had his oral intake reduced. After transfer to a rehabilitation hospital, he developed aspiration pneumonia and then sarcopenia with low nutrition and low activity. At the beginning of intervention, he aspirated food paste, but he recovered sufficiently to be able to ingest a normal meal via a nutritional approach combined with rehabilitation at the time of discharge. During this process, the maximum amounts of displacements and maximum moving velocities of his hyoid bone and thyroid cartilage during swallowing of moderately thick water were improved. Adequate nutrition intake and training for hyoid muscles are considered effective for the patient with sarcopenic dysphagia. It was concluded that measuring the maximum displacements and moving velocities of the hyoid bone and thyroid cartilage during swallowing in patients with sarcopenic dysphagia was an effective way to monitor their improvement.

Crystal structure of magnesium dichloride decahydrate determined by X-ray and neutron diffraction under high pressure.

Magnesium dichloride decahydrate (MgCl2·10H2O) and its deuterated counterpart (MgCl2·10D2O) are identified for the first time by in-situ powder synchrotron X-ray and spallation neutron diffraction. These substances are crystallized from a previously unidentified nanocrystalline compound, which originates from an amorphous state at low temperature. A combination of a recently developed autoindexing procedure and the charge-flipping method reveals that the crystal structure of MgCl2·10H2O consists of an ABCABC··· sequence of Mg(H2O)6 octahedra. The Cl(-) anions and remaining water molecules unconnected to the Mg(2+) cations bind the octahedra, similar to other water-rich magnesium dichloride hydrates. The D positions in MgCl2·10D2O, determined by the difference Fourier methods using the neutron powder diffraction patterns at 2.5 GPa, show the features such as bifurcated hydrogen bonds and tetrahedrally coordinated O atoms, which were not found in other forms of magnesium chloride hydrates.

Role of tumor-infiltrating CD11b+ antigen-presenting cells in the progression of gastric cancer.

BACKGROUND: Tumor-infiltrating antigen-presenting cells (APCs), involving tumor-associated macrophages and tumor-infiltrating dendritic cells, play an important role in tumor immunity and immune escape. The aim of this study was to determine whether tumor infiltrating CD11b(+) APCs may affect tumor progression and clinical outcome. METHODS: The immunohistochemical analysis was used to evaluate the expression of CD11b, FOXP3, and CD8 in 214 gastric cancer tissues. Concentrations of immunosuppressive cytokines in medium conditioned by gastric cancer cells were measured by enzyme-linked immunosorbent assay. Effects of addition of tumor-conditioned media on CD11c(+) cells were examined by flow cytometry. RESULTS: Almost all tumor-infiltrating CD11b(+) cell expressed CD11c and was considered to be APCs. High CD11b(+) cell infiltration was significantly correlated with huge tumor, positive venous invasion, lymph node metastasis, and tumor, node, metastasis stage. Patients with high CD11b(+) cell infiltration had a poorer surgical outcome than those with low CD11b infiltration. Multivariate analysis revealed that CD11b(+) cell infiltration was one of the independent prognostic factors. Tumor-conditioned medium obtained from several gastric cancer cell lines contained immunosuppressive cytokines, transforming growth factor-beta, interleukin-10, and vascular endothelial growth factor. The addition of tumor-conditioned medium decreased the expression of major histocompatibility complex-II and increased the expression of CD11b and programmed death ligand 2 on CD11c(+) APCs. Infiltration of CD11b(+) cells significantly correlate with the degree of FOXP3(+) cell infiltration but not with CD8(+) cell infiltration. CONCLUSIONS: Tumor-infiltrating CD11b(+) APCs affected local tumor cell-immune cell interactions and correlated to the poor prognosis of the patients with gastric cancer.

Intranodal lymphangiogenesis precedes development of lymph node metastasis and accelerates progression of gastric cancer.

INTRODUCTION: Peritumoral lymphangiogenesis is significantly correlated with lymph node metastasis and poor prognosis in various cancers. However, there are few reports concerning the role of intranodal lymphangiogenesis in lymphatic metastasis. The aim of this study was to examine the association of lymphangiogenesis in regional lymph nodes with the progression of gastric cancer. MATERIALS AND METHODS: Lymphatic vessel density (LVD) was immunohistochemically estimated in 1,596 lymph nodes from 52 patients who underwent gastrectomy. RESULTS: Intranodal LVD was significantly correlated with the size of metastasis and the progression of cancer. Patients in the high LVD group had significantly poorer prognosis relative to patients in the low LVD group. Furthermore, expression of VEGF-C mRNA was significantly up-regulated in lymph nodes of pathological node positive patients compared to node negative patients. DISCUSSION: Thus, intranodal lymphangiogenesis was correlated with nodal metastasis and poor prognosis of patients with gastric cancer. Lymphangiogenesis in regional lymph nodes plays an early role in spreading of tumor cells through the lymphatic system to distant organs in gastric cancer.

[Our experience of eribulin treatment in advanced breast cancer].

The clinical outcomes, including adverse events, in 40 advanced breast cancer patients treated with eribulin were analyzed to confirm the effectiveness and safety of this treatment. The objective response rate (ORR) in patients was 35.0%. The median overall survival and time to treatment failure (TTF) in these patients was 479 and 63 days, respectively. Cases wherein eribulin was used as early-line treatment experienced significantly longer TTF compared to the cases wherein eribulin was used as late-line treatment; however, there was no difference in this value according to the breast cancer subtype. Moreover, subtype analysis revealed no significant difference in adverse events. We observed no difference in the benefit or tolerability of eribulin treatment among different breast cancer subtypes. However, our results suggest that a significant therapeutic effect can be expected when using eribulin as early-line treatment.

[Effectiveness of eribulin chemotherapy for squamous cell carcinoma of the breast].

The patient was a 40-year-old woman who was aware of a tumor in her left breast that was gradually increasing in size. Ultrasonography revealed a hypoechoic mass with a skin cyst, approximately 3 cm in size, in the C area of the left breast. Core needle biopsy indicated estrogen receptor (ER) -negative, progesterone receptor (PR) -negative, and human epidermal growth factor receptor 2 (HER2) -negative squamous cell carcinoma. Overall examination did not indicate distant metastasis. A diagnosis of T4bN2aM0, stage IIIB triple-negative left breast cancer was made. Eribulin was administered at a dose of 1.4 mg/m2. The effect of eribulin was considered to be long-term stable disease( long-term SD). The patient did not experience severe adverse events during treatment. After 24 weeks of eribulin treatment, mastectomy of the left breast with axillary lymph node dissection was performed. At present, 1 year after surgery, the patient is alive with no recurrence. We conclude that eribulin chemotherapy is useful for the treatment of patients with squamous cell carcinoma of the breast.

[Case of a patient with inflammatory breast cancer who responded to preoperative chemotherapy with paclitaxel plus bevacizumab and could subsequently undergo surgery].

A 58-year-old woman observed swelling in her left breast a few weeks prior to presentation. Rigidity in the D area, breast warmth, swelling, and a peau d'orange appearance in the whole left breast was observed. She was diagnosed with inflammatory breast cancer (luminal A type) T4dN2M0, Stage IIIB. The patient underwent primary systemic therapy with 7 courses of FEC. Following FEC treatment, the disease was stable. We subsequently administered 4 courses of bevacizumab plus paclitaxel combination therapy. The patient exhibited a partial response to FEC chemotherapy. Thereafter, a left mastectomy with level II axillary lymph node dissection was performed. At present, 1 year after surgery, the patient is alive with no recurrence. We conclude that the combination therapy of bevacizumab plus paclitaxel is a useful treatment for inflammatory breast cancer.

[Usefulness of bevacizumab combination chemotherapy for advanced breast cancer].

Bevacizumab combination chemotherapy prolongs progression-free survival but not overall survival in patients with advanced breast cancer. Here, we report our experience with bevacizumab plus paclitaxel treatment in our department. We believe that this regimen confers some benefit to a patient's quality of life. Nineteen patients with inoperable, metastatic, or recurrent breast cancer were treated with bevacizumab plus paclitaxel. The median age was 55 years; all patients were females. Of the 19 patients, 14, 1, and 4 had luminal A, luminal B, and triple-negative type tumors, respectively. The response rate was 63%: partial response (PR) was obtained in 12 patients, stable disease (SD) in 5 patients, and progressive disease( PD) in 2 patients. Adverse events of Grade 3 or more were high blood pressure( 4 patients), peripheral neuropathy (1 patient), and neutropenia (9 patients). All side effects could be tolerated. There was a high rate of response to bevacizumab plus paclitaxel chemotherapy. We believe that this chemotherapy is useful in patients with more advanced breast cancer in whom a high response rate is required.

[Day surgery of early breast cancer treated with breast-conserving operation following sentinel lymph node navigation biopsy under local anesthesia].

In the early stages of breast cancer when axillary lymph node dissection is avoidable, we performed same day surgery with a breast-conserving operation following sentinel lymph node navigation biopsy under local anesthesia. Initial sentinel lymph node biopsy under local anesthesia is performed to avoid false-negative sentinel lymph node metastasis. Resected sentinel lymph nodes were examined in fixed sections by hematoxylin-eosin staining and immunohistochemistry. The enrolled subjects were 20 patients with breast cancer whose diagnoses were confirmed before treatment. Two (10.0%) patients had metastasis.

[Four cases of meningeal metastasis originating from breast cancer].

Carcinomatous meningitis due to breast cancer is comparatively rare in Japan. Here, we report 4 cases of carcinomatous meningitis due to breast cancer. Meningeal metastasis was present in only 1 of the 4 cases, and the other 3 cases were associated with brain metastasis. Meningeal metastasis frequently causes symptoms associated with intracranial hypertension. Gadolinium-enhanced magnetic resonance imaging and cerebrospinal fluid cytology were useful for the diagnosis of meningeal metastasis. Multidisciplinary therapy, such as radiation and chemotherapy, was performed. Two of the 4 patients were treated with combined intrathecal administration of methotrexate and whole brain radiation. The quality of life was improved by multidisciplinary therapy.

[Needle biopsy using a Monopty Biopsy Instrument for the accurate diagnosis of thyroid cancer].

Aspiration biopsy cytology (ABC) is commonly performed for the diagnosis of thyroid tumor. Because ABC may not provide sufficient tissue for pathological diagnosis, we performed needle biopsy using a Monopty Biopsy Instrument for the accurate diagnosis of thyroid cancer. Furthermore, it is difficult to safely perform a core needle biopsy (CNB) for the diagnosis of breast cancer in the thyroid gland region. In this study, we evaluated the feasibility of using a Monopty Biopsy Instrument as an alternative to conventional ABC or CNB for the biopsy-based diagnosis of thyroid cancer. Twenty patients with clinically suspected thyroid cancer were enrolled, and all patients were thoroughly examined. Seven cases of thyroid cancer were diagnosed, of which 5 cases were papillary carcinoma and 2 were undifferentiated carcinoma.

Serum aminotransferase activity as a predictor of clearance of drugs metabolized by CYP isoforms in rats with acute hepatic failure induced by carbon tetrachloride.

The values of serum aminotransferase activity (AST) in untreated rats and rats with acute hepatic failure at 24h after an oral administration of CCl(4) (0.5 ml/kg) were 85+/-9 IU/l and 4260+/-620 IU/l (mean+/-S.D., n=6), respectively. The values of total clearance (CL(tot)) after intravenous administration of caffeine, tolbutamide, chlorzoxazone or lidocaine (as probe drugs for various CYP isoforms) to CCl(4)-treated rats were decreased to about 1/8, 1/3, 1/3 or 1/2 compared with those in untreated rats. Good correlations were observed between mRNA expression and enzyme activity of CYP2C11, CYP2E1, CYP3A2 and CYP1A2 in livers of rats given various doses of CCl(4). There was also a good negative correlation between serum AST activity and hepatic enzyme activity of each CYP. The serum AST activities corresponding to a 50% decrease of CYP2C 11, CYP2E1, CYP3A2 and CYP1A2 activities were about 710, 780, 1030 and 1300 IU/l, respectively. In conclusion, when the serum AST value in CCl(4)-treated rats reached about 4000 IU/l, the hepatic CYP activities were one-tenth or less of the control, although the degree of decrease of the CL(tot) values varied markedly. Nevertheless, the AST value appears to be a promising candidate for an indicator to predict appropriate dose modification of drugs for patients with acute hepatic failure.