[Effect of Relative Dose Intensity(RDI)-Guided Dose Adjustments of Palbociclib on Duration of Treatment in Patients with Severe Neutropenia].

The study subjects consisted of 54 patients with inoperable or recurrent breast cancer who were administered a combination of palbociclib plus endocrine therapy. We examined the onset of neutropenia during the first course of treatment and evaluated the influence that various risk factors had on treatment continuity. Patients with neutropenia Grade≥3 had significantly lower relative dose intensity(RDI) values during the first course of treatment than did patients with neutropenia Grade ≤2. Patients with neutropenia Grade≥3 showed significantly longer treatment to failure than did patients with neutropenia Grade≤2. These results suggest that the degree of neutropenia during the first course of treatment might contribute to treatment continuity and that it is important to improve the curative effect by maintaining appropriate RDI and by continuously administering palbociclib in patients with neutropenia Grade≥3.

Tendencies of Woman Doctors Registered in Japan during the Taisho Era.

The Taisho-Era (1912 to 1926) was a period during which Japanese women increasingly took part in various social activities and employment. The author surveyed the registered woman-doctors listed in the official gazette and the journal of the Japanese Society of Woman Doctors from the first to the 10th years of the Taisho-Era (1912 to 1921) and investigated their medical life-times, including with regard to their husbands and family surroundings, hobbies, and so on. According to the author, there were 467 woman doctors during the first 10 years of the Taisho-Era, far more than the 239 during the Meiji-Era (1886 to 1912). Immediately after medical registration they had a tendency to choose employment in large cities such as Tokyo because there were many medical facilities suitable' for clinical training there. After several years of this training, some of them moved their activities to the countryside. The 1923 Great Kanto Earthquake caused tremendous damagp,to people, including the woman doctors, who were affected by the collapse of buildings and fires (this subject is developed in a separate paper).

Effect of a dienogest for an experimental three-dimensional endometrial culture model for endometriosis.

The pathogenesis of endometriosis remains poorly understood at least in part because early stages of the disease process are difficult to investigate. Previous studies have proposed a three-dimensional fibrin matrix culture model to study human endometriosis. We examined the ultrastructural features of the endometriosis in this model and assessed the effect of a progestin on endometrial outgrowth and apoptosis in this culture system. Endometrial explants were placed in three-dimensional fibrin matrix culture and treated with and without various concentrations of the progestin dienogest. By the second week, endometrial gland-like formation was established in outgrowths both attached to and at a distance from the explants. These cells formed a combination of clumps and tubular monolayers surrounding a central cavity. Electron microscopy demonstrated that these cells are polarized with microvilli on the apical surface, desmosome-like structures, and basement membrane; features consistent with glandular epithelial cells. Outgrowth of endometrial stromal cells and glandular formation was impaired in response to dienogest in a dose-dependent manner. Our study shows that the human endometrial explants cultured in three-dimensional fibrin matrix establish outgrowths that ultrastructurally resemble ectopic endometrial implants. This model may provide insight into the cellular processes leading to endometriosis formation and enables screening of therapeutic compounds.

Unilateral hypoglossal nerve palsy following orthognathic surgery: A case report and literature review.

INTRODUCTION: Hypoglossal nerve palsy (HNP) can be caused by nerve damage from the central nerve to a peripheral nerve, and individuals with multiple factors could be predisposed to HNP. We report a case of isolated unilateral HNP after orthognathic surgery. CASE PRESENTATION: A 56-year-old Japanese woman complained of jaw distortion and malocclusion. She had undergone a Le Fort I osteotomy and bilateral sagittal split ramus osteotomy (BSSRO) under general anesthesia in August 2021. On postoperative day 3, she experienced tongue motility, and when the tongue protruded forward, the tongue tip shifted to the right, and swelling of the right lateral pharyngeal wall was observed. An additional blood test revealed increased antibody titer levels (40×), cytomegalovirus IgG EIA titer (16.9 U/mL), HSV-IgG EIA titer (40 U/mL), and EBV-viral capsid antigen (VCA) IgG EIA titer (1.4 U/mL). We administered valacyclovir hydrochloride 1000 mg/day for 7 days, prednisolone (PSL) 60 mg/day, mecobalamin 1500 µg/day, and adenosine triphosphate (ATP) disodium hydrate 300 mg/day. A neurological examination revealed no central lesions, and we continued the patient's tongue-function training and oral hygiene guidance. The tongue apex deviation was resolved approx. 3 months postoperatively. DISCUSSION: There are no major reports on the etiology of HNP after orthognathic surgery. The possibility of HNP triggered by endotracheal intubation or through packing gauze under general anesthesia and viral infection cannot be ruled out. CONCLUSION: Clinicians should be aware of the possibility of unilateral HNP following orthognathic surgery.

Efficacy and safety of mycophenolate mofetil in treating immune-related hepatitis induced by immune checkpoint inhibitor use: A retrospective study.

Background and Aim: To investigate the outcomes in eight Japanese patients with cancer treated with mycophenolate mofetil (MMF) and corticosteroids for immune checkpoint inhibitor treatment-induced severe immune-related hepatitis (ir-hepatitis) and the efficacy and safety of MMF. Methods: We retrospectively examined patient background, treatment course, as well as examination and imaging data using electronic medical records. Results: The ratio of male to female patients was 7:1, and the median age was 60 years (27-72 years). There were five and two cases of kidney cancer and malignant melanoma, respectively, and one case of lung cancer. The median number of days until MMF administration in addition to systemic corticosteroid therapy after the onset of ir-hepatitis was 14.5 (2-42). The patients were categorized as four "good responders" who showed an improvement in the liver function tests following MMF treatment and four "poor responders" who did not. Furthermore, the time from the onset of ir-hepatitis to initial MMF administration was significantly shorter in good responders (median 3 days, range 2-15 days) than in poor responders (median 25.5 days, range 14-42 days) (P = 0.042). No significant intergroup difference was observed in other clinical factors. No serious adverse events caused by MMF were observed in any case. Conclusions: According to these findings, early recognition of corticosteroid refractoriness and the use of MMF may be beneficial in patients with ir-hepatitis.

Identification of a new gibberellin receptor agonist, diphegaractin, by a cell-free chemical screening system.

Gibberellin (GA) is a phytohormone that regulates various developmental processes during the plant life cycle. In this study, we identify a new GA agonist, diphegaractin, using a wheat cell-free based drug screening system with grape GA receptor. A GA-dependent interaction assay system using GA receptors and DELLA proteins from Vitis vinifera was constructed using AlphaScreen technology and cell-free produced proteins. From the chemical compound library, diphegaractin was found to enhance the interactions between GA receptors and DELLA proteins from grape in vitro. In grapes, we found that diphegaractin induces elongation of the bunch and increases the sugar concentration of grape berries. Furthermore, diphegaractin shows GA-like activity, including promotion of root elongation in lettuce and Arabidopsis, as well as reducing peel pigmentation and suppressing peel puffing in citrus fruit. To the best of our knowledge, this study is the first to successfully identify a GA receptor agonist showing GA-like activity in agricultural plants using an in vitro molecular-targeted drug screening system.

HSG1, a grape Bcl-2-associated athanogene, promotes floral transition by activating CONSTANS expression in transgenic Arabidopsis plant.

HSG1 (Heat shock-induced gene 1) is one of the high-temperature-induced proteins in grapevine. Sequence analysis has demonstrated that HSG1 is a grape Bcl-2-associated athanogene (BAG) that contains IQ and BAG domains in its sequence. HSG1 expression was not detected in leaves without heat treatment, while tendrils, stems, flowers, and berries expressed HSG1 even without heat treatment. By heat treatment at 45°C for 60 min, HSG1 expression was upregulated in both leaves and berries. HSG1-overexpressing Arabidopsis plant remained viable even after exposure to extremely high temperatures. Although no morphological changes were observed, the HSG1-overexpressing Arabidopsis plant exhibited faster floral transition than the control plant. Analysis of the transcription profile of HSG1-overexpressing seedling by cDNA microarray and quantitative RT-PCR demonstrated that the gene expression of the flowering promoter, CONSTANS (CO), in the photoperiod pathway was up-regulated in the seedling. Importantly, the overexpression of HSG1 increased CO expression by ~400% compared with the control seedling. Meanwhile, heat treatment upregulated grape CO expression in grape leaves. Our study provides the possibility that plant BAG protein may be related to the regulation of floral transition by activating CO expression in the photoperiod pathway.

Auxin-nonresponsive grape Aux/IAA19 is a positive regulator of plant growth.

We report the characterization of VvIAA19, an auxin/indole-3-acetic acid (Aux/IAA) protein, in grapevine (Vitis vinifera L.). VvIAA19 was expressed abundantly in berries. VvIAA19 transcription was rapidly increased at pre-anthesis and then decreased during fruit set. Before véraison, however, VvIAA19 gene expression was upregulated again and maximum expression was maintained until the end of ripening. Exogenous IAA did not induce VvIAA19 expression in grape leaves, suggesting that VvIAA19 might be auxin-nonresponsive. The overexpression of VvIAA19 in Arabidopsis thaliana had a notable effect on plant growth. Although no morphological changes were observed, transgenic Arabidopsis plants overexpressing VvIAA19 exhibited faster growth, including root elongation and floral transition, than the control plant, suggesting that the constitutive expression of VvIAA19 protein resulted in increased growth rates without any detectable harm. Taken together, we conclude that grape Aux/IAA19 protein is likely to play a crucial role as a plant growth regulator.

Auxin-responsive grape Aux/IAA9 regulates transgenic Arabidopsis plant growth.

We report the characterization of VvIAA9, an auxin/indole-3-acetic acid (Aux/IAA) protein, in grapevine (Vitis vinifera L.). VvIAA9 was expressed abundantly in leaves and berries. VvIAA9 transcription was drastically upregulated from anthesis to onset of ripening (termed véraison), in which berry diameter rapidly increased. Treatment with exogenous IAA induced VvIAA9 expression in grape leaves, suggesting that VvIAA9 is an auxin-responsive Aux/IAA protein. The overexpression of VvIAA9 in Arabidopsis thaliana promoted plant growth, including rapid floral transition. However, no morphological differences were observed between the control plant and the VvIAA9-overexpressing plant. The overexpression of VvIAA9 in Arabidopsis plants rendered the plants hyposensitive to exogenous IAA. The exogenous IAA treatment did not induce VvIAA9-overexpressing Arabidopsis plant growth and expression of IAA-responsive HAT2. Taken together, we conclude that grape Aux/IAA9 protein is likely to play a crucial role as a plant growth regulator.

Characterization of grape C-repeat-binding factor 2 and B-box-type zinc finger protein in transgenic Arabidopsis plants under stress conditions.

Simultaneous induction of multiple stress tolerance by single-gene transfer is a powerful strategy to engineer crop plants to improve tolerance to environmental stress under field condition. The possibility of enhancement of multiple stress tolerance by four grape transcription factors that enhance low-temperature tolerance (VvCBF2, VvCBF4, VvCBFL, and VvZFPL) were analyzed using the Arabidopsis plants overexpressing these factors. Consequently, two of the four proteins, VvCBF2 and VvZFPL, were found to confer tolerance to cold, drought, and salinity stresses in Arabidopsis plants, but not to heat stress. Photosynthesis-related genes were down-regulated in both CBF2- and ZFPL-overexpressing plants, resulting in plant growth retardation. On the other hand, the overexpression of VvCBF2 activated the transcription of CBL-interacting protein kinase 7, a serine/threonine kinase involved in cold response, in Arabidopsis plants. Our study provides that one of grape CBF family, VvCBF2, and one of B-box ZFP family, VvZFPL, confer multiple stress tolerance to plants.

Association between impaired healing after orthognathic surgery and irritable bowel syndrome: A case report and literature review.

INTRODUCTION: In the disease irritable bowel syndrome (IBS), gastrointestinal function is worsened even though no organic abnormalities are observed in the gastrointestinal mucosa. We report the case of an orthognathic surgery patient with suspected irritable bowel syndrome. CASE: In September 2017, a 15-year-old Japanese female was referred to us with dental crowding, malocclusion, and mandibular protrusion. In June 2019, a disagreement with classmates led to abdominal pain, diarrhea, and hemorrhage; in August 2019, a preoperative blood test showed sudden anemia, and her surgery was thus postponed. Subsequent upper and lower gastrointestinal endoscopy revealed no organic abnormality, and no definitive diagnosis was made. In March 2020, after an improvement in anemia was observed, a segmental Le Fort I osteotomy and bilateral sagittal split ramus osteotomy (BSSRO) were performed under general anesthesia. On the third post-operative day, due to the mucosal dehiscence adjacent to the suture part, the titanium plate was exposed, and irrigation of the wound with normal saline solution and oral hygiene instruction was continued daily for 2 weeks. Two years and eight months have passed since the surgery, and the healing of the oral mucosa and bone has been uneventful. DISCUSSION: The relationship between IBS and post-operative impaired healing associated with the fragility of the oral mucosa is unknown. However, psychological stress has been reported as a cause of IBS and to be related to oral microorganisms. CONCLUSION: Reducing risk factors for IBS and maintaining proper perioperative oral hygiene is essential in managing similar cases.

ER stress-induced protein, VIGG, disturbs plant cation homeostasis, which is correlated with growth retardation and robustness to ER stress.

VIGG is a putative endoplasmic reticulum (ER) resident protein induced by virus infection and ER stress, and is correlated with fruit quality in grapevine. The present study was undertaken to determine the biological function of VIGG in grapevine. Experiments using fluorescent protein-VIGG fusion protein demonstrated that VIGG is localized in ER and the ER targeting sequence is in the N-terminus. The overexpression of VIGG in Arabidopsis plant led to growth retardation. The rosette leaves of VIGG-overexpressing plants were smaller than those of the control plants and rolled at 42days after seeding. VIGG-overexpressing plants revealed robustness to ER stress as well as the low expression of ER stress marker proteins, such as the luminal binding proteins. These characteristics of VIGG-overexpressing plants were supported by a microarray experiment that demonstrated the disruption of genes related to ER stress response and flowering, as well as cation mobility, in the plants. Finally, cation homeostasis in the plants was disturbed by the overexpression of VIGG. Taken together, these results suggest that VIGG may disturb cation homeostasis in plant, which is correlated with the robustness to ER stress and growth retardation.

Environmental stress enhances biosynthesis of flavor precursors, S-3-(hexan-1-ol)-glutathione and S-3-(hexan-1-ol)-L-cysteine, in grapevine through glutathione S-transferase activation.

The biosynthesis of S-(3-hexan-1-ol)-glutathione (3MH-S-glut) and S-(3-hexan-l-ol)-L-cysteine (3MH-S-cys), which act as flavour precursors in wines, in Vitis vinifera grapes exposed to various environmental stress conditions is reported here. Ultraviolet (UV-C) irradiation, water deficit, and biological stimulation up-regulated 3MH-S-glut and 3MH-S-cys biosynthesis in grape leaves. 3MH-S-glut and 3MH-S-cys contents in grape berries were increased by cold shock, heat shock, UV-C irradiation, and biological stimulation. The results suggest that environmental stress enhances the biosynthesis of both flavour precursors in grapevine. The transcription of VvGST1, VvGST3, VvGST4, and GGT in grapevine exposed to the stress conditions was increased markedly compared with that in control grapevine. Also, UV irradiation increased GST (glutathione S-transferase) and GGT (γ-glutamyl transferase) enzyme activities in grape berries. Recombinant VvGST3 and VvGST4, but not VvGST1, mediated the synthesis of 3MH-S-glut from reduced glutathione and trans-2-hexenal in vitro. The enzymatic mediation of flavour precursor production is a novel function of plant GSTs and may result in the detoxification of damaged grape cells under stress conditions.

Isolation and identification of cancer stem cells from a side population of a human hepatoblastoma cell line, HuH-6 clone-5.

PURPOSE: It has been thought that the persistence of even a small number of tumor cells in the body may increase each tumor cell in a similar manner and may allow the disease to proceed. However, only a few percent of such tumor cells exist in cancerous tissue. They are called "cancer stem cells (CSCs)". If an alternative method of annihilating CSCs is found, it will greatly deter relapse and metastasis. We attempted to identify and separate CSCs in hepatoblastoma aiming to develop a new therapy for hepatoblastoma. METHODS: The side population (SP) method was used as an indicator when extracting the CSC candidate group from the hepatoblastoma cells. The SP cells and non-SP cells were studied for tumourigenesis. RESULTS: Although tumors were formed when SP fraction cells were inoculated into mice, tumor formation was not observed in non-SP cells. SP cells had higher tumor formation ability compared to non-SP cells. CONCLUSION: Cancer stem-like cells were separated by the SP fraction method from hepatoblastoma cells. The in vivo experiment proved that SP fraction cells inoculated into mice were self-replicated, and the existence of cancer stem-like cells was identified.

Association of lymphocyte crossmatch and the outcome of intestinal transplantation in swine.

BACKGROUND: The effect of preformed antidonor antibodies have been demonstrated in various types of solid organ transplantation. However, the significance of anti-donor antibodies in intestinal transplantation remains unclear. The aim of this study is to evaluate the impact that the extent of T cell crossmatch has on the outcome of swine intestinal transplantation. MATERIALS AND METHODS: All studies were performed on outbred domestic male pigs weighing from 15 to 20 kg. Intestinal transplantation was performed orthotopically with an exchange of grafts between white and black pigs. FK506 was administered intravenously (0.1 mg/kg per day, POD 0-7) for immunosuppression. A lymphocyte crossmatch test was performed using the direct CDC crossmatch. The results were considered positive when more than 10% of the donor lymphocytes were killed by the recipient's serum. In addition, 0-10, 11-20, 21-30, 31-80 and 81-100% of the killed lymphocytes were classified as grade 1, 2, 4, 6 and 8, respectively. RESULT: A total of 34 intestinal transplantations were performed. All but one case had positive donor specific T cell crossmatches. The number of grade 2, 4, 6 and 8 cases was 11, 14, 6 and 2, respectively. Although there was a tendency towards a decreased survival according to the grade, the survival rate was not statistically different among each different grade. Moreover, the rates of acute cellular rejection and vascular complications were not significantly different among the four grades. CONCLUSION: These results suggest that the extent of positive T cell crossmatch is not associated with the outcome of swine intestinal transplantation.

Efficacy and safety of Infliximab for steroid-resistant immune-related adverse events: A retrospective study.

The present study investigated outcomes of infliximab (IFX) treatment among 8 Japanese patients with various types of cancer (4 with malignant melanoma, 3 with lung cancer and 1 with renal cancer) who developed severe steroid-resistant immune-related adverse events (irAEs) in association with immune checkpoint inhibitors (ICIs) to determine its efficacy and safety. Information, including patient background, treatment progress, examination data and imaging data, was collected retrospectively from electronic medical records. Adverse reactions were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Specific ICIs used were anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibody preparations in 7, 2 and 5 patients, respectively. Specific irAEs included grade 3 diarrhea/colitis in 7 patients and disseminated intravascular coagulation and myocarditis attributed to autoimmune activation in 1 patient. The median duration between systemic steroid and IFX treatments was 9 (range, 2-39) days. A total of 3 patients responded to IFX, 1 of whom responded after one dose and 2 responded after two doses. Respective diseases improved to grade 0 after a median of 18 (range, 9-32) days. No AEs were attributable to IFX. Additionally, anti-cytomegalovirus (CMV) and antibacterial agents were administered in parallel given the presence of CMV and Clostridium difficile (CD) infections in all patients, except in 1 exhibiting a marked IFX response after one dose. The combination of highly immunosuppressive IFX and high-dose systemic steroid administration over a long period presumably predisposed the patients to opportunistic enteric infections. Accordingly, early initiation of IFX treatment in conjunction with systemic steroid therapy should be considered for severe diarrhea/colitis and other irAEs. However, the possibility for CMV and CD infections should be recognized, and for these the treatment strategy may need to be modified at an early stage.

Two middle-aged cases of deep overbite without molar support treated by orthognathic surgery.

INTRODUCTION: Patients with severe overbite in middle age often undergo prosthetic treatment without a diagnosis of dentofacial deformity, but soft tissue trauma can occur in such patients due to the lack of inter-occlusal space. Comprehensive surgical orthodontic treatment and prosthetic treatment are indicated to correct the overbite and soft tissue injury for such patients. PRESENTATION OF CASE: We report the cases of two middle-aged patients with dentofacial deformity and severe overbite without molar support. In both cases, prosthetic treatment had been performed for many years without any improvement of the occlusion. Case 1: A 47-year-old Japanese man had a maxillary incisor protrusion and reduced lower anterior facial height profile with the left mandibular molars lost due to periodontal disease. After preoperative orthodontic treatment and occlusal elevation in the molar teeth using an implant prosthesis, a sagittal split ramus osteotomy (SSRO) was performed. Case 2: A 57-year-old Japanese woman had mandibular retrognathia with maxilla and mandibular-arch length discrepancy. The left mandibular molars needed to be extracted due to periodontal disease. After preoperative orthodontic treatment and reconstruction of the molar occlusion using an implant prosthesis, three-segment Le Fort I osteotomy and SSRO were performed. DISCUSSION: Malocclusion with dentofacial deformity is a risk factor for severe deep overbite or other occlusion collapse. CONCLUSION: In middle-aged patients with deep overbite with missing molar teeth, we should consider both prosthodontic treatment and comprehensive dental therapy, including orthognathic surgery.

Leaf angle in Chenopodium album is determined by two processes: induction and cessation of petiole curvature.

Petiole curvature is important in regulating light interception by the leaf. To dissect the determination processes of leaf angle, we irradiated the lamina or petiole of Chenopodium album L. with either one or two spots of actinic light, after dark adaptation. When the abaxial side of the petiole was irradiated with blue light, the petiole curvature increased, and under continuous irradiation, the curvature continued for up to 6 h. The rate of curvature increased with increasing blue light intensity. The curvature induced by irradiation of the abaxial side with blue light ceased when the adaxial side of the petiole was simultaneously irradiated with either blue or red light. When an inhibitor for photosynthesis, 3-(3,4-dichlorophenyl)-1,1-dimethylurea, was applied to the adaxial side of the petiole, the cessation of curvature caused by blue light was only weakly inhibited, while the cessation caused by red light was markedly inhibited. When the adaxial side of the petiole was irradiated alternately with red and far-red light, the far-red light antagonized the cessation of curvature caused by the red light. These results clearly show that the petiole curvature is controlled by two processes, the induction and the cessation of curvature. At least three photoreceptor systems, blue-light receptor, photosynthesis and phytochrome, are involved in the reactions.

Antidiabetic effects of novel cell culture established from grapevine, Vitis vinifera cv. Koshu.

Vitis vinifera cv. Koshu is an indigenous cultivar in Japan and has several characteristics that distinguish it from European V. vinifera. In Japan, Koshu is the most popular cultivar for wine making. We report herein a cell culture established from Koshu for use as a system for the production of resveratrol and its derivatives. Grape cell culture YU-1 was developed from the apex tissues of Koshu. YU-1 growth was favorably compared with BY-2 growth, a standard cell line in plant cell biology. Stilbene production and stilbene synthesis gene expression in YU-1 were upregulated by UV-C irradiation. YU-1 irradiated with UV-C decreased hemolymph sugar levels in model animals. Taken together, this study suggests that YU-1 may be used as a source of valuable medicinal components in plant cell bioreactor systems.