S haplotype collection in Brassicaceae crops-an updated list of S haplotypes.

Self-incompatibility is the system that inhibits pollen germination and pollen tube growth by self-pollen. This trait is important for the breeding of Brassica and Raphanus species. In these species, self-incompatibility is governed by the S locus, which contains three linked genes (a set called the S haplotype), i.e., S-locus receptor kinase, S-locus cysteine-rich protein/S-locus protein 11, and S-locus glycoprotein. A large number of S haplotypes have been identified in Brassica oleracea, B. rapa, and Raphanus sativus to date, and the nucleotide sequences of their many alleles have also been registered. In this state, it is important to avoid confusion between S haplotypes, i.e., an identical S haplotype with different names and a different S haplotype with an identical S haplotype number. To mitigate this issue, we herein constructed a list of S haplotypes that are easily accessible to the latest nucleotide sequences of S-haplotype genes, together with revisions to and an update of S haplotype information. Furthermore, the histories of the S-haplotype collection in the three species are reviewed, the importance of the collection of S haplotypes as a genetic resource is discussed, and the management of information on S haplotypes is proposed.

Improved anti-solid tumor response by humanized anti-podoplanin chimeric antigen receptor transduced human cytotoxic T cells in an animal model.

Recently, research has been conducted with chimeric antigen receptor (CAR)-T cells to improve efficacy against solid tumors. Humanized CAR improved the long-term survival of CAR-T cells in patients' peripheral blood, resulting in increased therapeutic efficacy. Therefore, the humanization of the CAR-gene sequence is considered an effective method. Podoplanin (PDPN) is a glycosylated transmembrane protein that is highly expressed in solid tumors and is associated with poor prognosis in patients with cancer. Therefore, PDPN is considered a biomarker and good target for cancer treatment with CAR-T cells. Previously, an anti-PDPN CAR was generated from a conventional nonhumanized antibody-NZ-1, the only anti-PDPN antibody for which a CAR was produced. In this study, we investigated other anti-PDPN CARs from the antibody NZ-27, or humanized NZ-1, to enhance the therapeutic potential of CAR-T cells. The CAR signal intensity was enhanced by the efficient expression of CAR proteins on the T-cell surface of NZ-27 CAR-T cells, which show tumor-specific cytotoxicity, proinflammatory cytokine production, and anti-tumor activity against PDPN-expressing tumor xenografts in mice that were significantly better than those in nonhumanized NZ-1 CAR-T cells.

The therapeutic potential of multiclonal tumoricidal T cells derived from tumor infiltrating lymphocyte-1derived iPS cells.

Tumor-infiltrating lymphocytes (TIL), which include tumor-specific T lymphocytes with frequency, are used for adoptive cell transfer therapy (ACT) in clinical practice. The optimization of TIL preparation has been investigated to reduce the senescence and increase the abundance of TIL, as both the quality and quantity of the transferred cells have great influence on the outcome of TIL-based ACT (TIL-ACT). Considering the effects of cell reprogramming on senescence, we expected that the anti-tumor effect could be enhanced by TIL regeneration. To confirm this hypothesis, we established tumor-specific TIL-derived iPS cells (TIL-iPSC) with human colorectal cancer specimens. T cells differentiated from TIL-iPSC (TIL-iPS-T) retained not only intrinsic T cell functions and tumor specificity, but also exhibited improved proliferation capacity and additional killing activity. Moreover, less differentiated profiles and prolonged persistency were seen in TIL-iPS-T compared with primary cells. Our findings imply that iPSC technology has great potential for TIL-ACT.

Eribulin mesylate-induced c-Fos upregulation enhances cell survival in breast cancer cell lines.

Anticancer agents are used for cancer therapy. Studies on the biological response to treatment with an agent facilitate its effective use. Eribulin mesylate (eribulin) is an anticancer agent. In this study, we found that c-Fos is upregulated in response to eribulin treatment in the triple-negative breast cancer cell lines MDA-MB-231 and HCC70, which have low eribulin sensitivity. c-Fos expression was not upregulated in other cell lines investigated, including high eribulin-sensitive cells. We hypothesized that c-Fos upregulation is involved in low eribulin sensitivity and thus used the c-Fos inhibitor, T-5224. In MDA-MB-231 and HCC70 cells, combined treatment with eribulin and T-5224 showed a stronger anticancer effect than treatment with eribulin alone in cell growth assays, cell death assays and a mouse xenograft tumor model, whereas T-5224 alone showed no anticancer effect. These results suggest that T-5224 may enhance the anticancer effect of eribulin. Our findings contribute to the improvement of cancer therapy.

Estrogen Induces Mammary Ductal Dysplasia via the Upregulation of Myc Expression in a DNA-Repair-Deficient Condition.

Mammary ductal dysplasia is a phenotype observed in precancerous lesions and early-stage breast cancer. However, the mechanism of dysplasia formation remains elusive. Here we show, by establishing a novel dysplasia model system, that estrogen, a female hormone, has the potential to cause mammary ductal dysplasia. We injected estradiol (E2), the most active form of estrogen, daily into scid mice with a defect in non-homologous end joining repair and observed dysplasia formation with cell proliferation at day 30. The protooncogene Myc is a downstream target of estrogen signaling, and we found that its expression is augmented in mammary epithelial cells in this dysplasia model. Treatment with a Myc inhibitor reduced E2-induced dysplasia formation. Moreover, we found that isoflavones inhibited E2-induced dysplasia formation. Our dysplasia model system provides insights into the mechanistic understanding of breast tumorigenesis and the development of breast cancer prevention.

In silico analysis-based identification of the target residue of integrin α6 for metastasis inhibition of basal-like breast cancer.

Metastasis causes death in breast cancer patients. To inhibit breast cancer metastasis, we focused on integrin α6, a membrane protein that contributes to cell migration and metastasis. According to in silico analysis, we identified Asp-358 as an integrin α6-specific vertebrate-conserved residue and consequently as a potential therapeutic target. Because Asp-358 is located on the surface of the ß propeller domain that interacts with other molecules for integrin α6 function, we hypothesized that a peptide with the sequence around Asp-358 competitively inhibits integrin α6 complex formation. We treated basal-like breast cancer cells with the peptide and observed reductions in cell migration and metastasis. The result of the immunoprecipitation assay showed that the peptide inhibited integrin α6 complex formation. Our immunofluorescence for phosphorylated paxillin, a marker of integrin-regulated focal adhesion, showed that the peptide reduced the number of focal adhesions. These results indicate that the peptide inhibits integrin α6 function. This study identified the functional residue of integrin α6 and designed the inhibitory peptide. For breast cancer patients, metastasis inhibition therapy may be developed in the future based on this study.

Visualising peripheral arterioles and venules through high-resolution and large-area photoacoustic imaging.

Photoacoustic (PA) imaging (PAI) has been shown to be a promising tool for non-invasive blood vessel imaging. A PAI system comprising a hemispherical detector array (HDA) has been reported previously as a method providing high morphological reproducibility. However, further improvements in diagnostic capability will require improving the image quality of PAI and fusing functional and morphological imaging. Our newly developed PAI system prototype not only enhances the PA image resolution but also acquires ultrasonic (US) B-mode images at continuous positions in the same coordinate axes. In addition, the pulse-to-pulse alternating laser irradiation shortens the measurement time difference between two wavelengths. We scanned extremities and breasts in an imaging region 140 mm in diameter and obtained 3D-PA images of fine blood vessels, including arterioles and venules. We could estimate whether a vessel was an artery or a vein by using the S-factor obtained from the PA images at two wavelengths, which corresponds approximately to the haemoglobin oxygen saturation. Furthermore, we observed tumour-related blood vessels around breast tumours with unprecedented resolution. In the future, clinical studies with our new PAI system will help to elucidate various mechanisms of vascular-associated diseases and events.

Effects of Steroids on Quality of Recovery and Adverse Events after General Anesthesia: Meta-Analysis and Trial Sequential Analysis of Randomized Clinical Trials.

BACKGROUND: Quality of recovery (QoR) after surgery is a relevant outcome. The early postoperative quality of recovery of a patient can be determined using the QoR-40 questionnaire. The aim of this meta-analysis and Trial Sequential Analysis was to determine if perioperative administration of glucocorticosteroids improved patients' quality of recovery after general anesthesia and if adverse events occurred. METHODS: We searched six databases, including trial registration sites. Randomized clinical trials reporting the efficacy of glucocorticosteroids on quality of recovery evaluated using the QoR-40 after general anesthesia were eligible. The QoR-40 data were combined as the mean difference with confidence intervals using a random-effects model. The I2 statistic was used to assess heterogeneity. The quality of the trials was evaluated using the Cochrane methodology. Moreover, Trial Sequential Analysis was carried out to prevent the inflation of type 1 errors caused by multiple testing and sparse data. We also assessed adverse events. RESULTS: Three randomized clinical trials (totaling 301 patients) were analyzed. The results from one published and four unpublished randomized clinical trials were unavailable. Dexamethasone was investigated in all three trials, and the results suggested that it significantly improved QoR-40 at postoperative day one scores compared with placebo (mean difference [95% confidence interval]: 14.2 points [10.4 to 18.1]; P < 0.001; I2 = 0%). We could not conduct sensitivity analysis because of the absence of trials with low risk of bias. The Trial Sequential Analysis-adjusted confidence interval was -1.6 to 30.0, indicating that further trials are required. The reporting of adverse events was insufficient. CONCLUSIONS: These findings indicate that perioperative dexamethasone administration may improve short-term (i.e., one day) quality of recovery after general anesthesia and surgery. We need more randomized clinical trials with low risk of bias assessing the effects of glucocorticosteroids on quality of life, other outcomes, and adverse events. Updated systematic reviews should then be conducted. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000015678.

Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy.

Acute kidney injury (AKI) is a serious problem in critically ill patients of intensive care units. It has been reported previously that AKI can induce acute lung injury (ALI), as well as cause injuries to other remote organs, including the lungs. Patients with AKI complicated by ALI show remarkably high mortality. ALI is characterized by neutrophil infiltration into the lung. Neutrophil elastase (NE) is a key enzyme for tissue injury caused by activated neutrophils, such as occurs in ALI. Therefore, this study investigated the role of NE in AKI-induced ALI using a specific NE inhibitor, sivelestat sodium hydrate (ONO-5046), in a mouse bilateral nephrectomy model. Bilateral nephrectomy showed not only a remarkable increase in blood urea nitrogen levels, but also demonstrated neutrophil infiltration into the lung, increased pulmonary inflammatory cytokine expression [interleukin-6, neutrophil chemokine keratinocyte-derived chemokine, and tumor necrosis factor-α], and protein leakage with early increases in both systemic and pulmonary NE activity. ONO-5046 treatment reduced NE activity and improved these pulmonary inflammatory responses. Additionally, ONO-5046-treated animals had longer survival times. These data demonstrate that increasing NE activity induces pulmonary inflammatory damage in a bilateral nephrectomy model. Blockade of NE activity will be a useful therapeutic strategy for ALI complications in AKI patients.

A rare case of combined syndrome of inappropriate antidiuretic hormone secretion and Fanconi syndrome in an elderly woman.

An 83-year-old Japanese woman was admitted to our hospital with severe hyponatremia (sodium, 108 mEq/L [108 mmol/L]), hypokalemia, hypochloridemia, hypocalcemia, hypophosphatemia, and hypouricemia. Despite low plasma osmolarity (232 mOsm/kg [232 mmol/kg]), urine osmolarity (320 mOsm/kg) was greater than that of plasma, and she had increased urinary sodium excretion (88 mEq/L [88 mmol/L]) and an unsuppressed high plasma level of antidiuretic hormone (ADH; 5.5 pg/mL [5.1 pmol/L]). These findings indicated that she had syndrome of inappropriate ADH secretion (SIADH). In addition, she had a generalized reabsorption defect of the proximal tubules, including decreased tubular reabsorption of phosphate, increased fractional excretion of uric acid, glycosuria despite a normal blood glucose level, and panaminoaciduria. Thus, combined SIADH and Fanconi syndrome was diagnosed. The cause was thought to be the antidepressant paroxetine, which is a selective serotonin reuptake inhibitor (SSRI). Several of the abnormal values resolved within 1 week after discontinuation of this drug. Although the precise mechanism responsible was not elucidated, we report an extremely rare case of combined SIADH and Fanconi syndrome, probably caused by short-term SSRI therapy.