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Let $R$ be a positively graded finitely generated $\textbf {k}$-domain with Krull dimension $d+1$. We show that there is a homogeneous valuation ${\mathfrak {v}}: R \setminus \{0\} \to {\mathbb {Z}}^d$ of rank $d$ such that the associated graded $\operatorname {gr}_{\mathfrak {v}}(R)$ is finitely generated. This then implies that any polarized $d$-dimensional projective variety $X$ has a flat deformation over ${\mathbb {A}}^1$, with reduced and irreducible fibers, to a polarized projective complexity-one $T$-variety (i.e., a variety with a faithful action of a $(d-1)$-dimensional torus $T$). As an application we conclude that any $d$-dimensional complex smooth projective variety $X$ equipped with an integral Kähler form has a proper $(d-1)$-dimensional Hamiltonian torus action on an open dense subset that extends continuously to all of $X$.

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Recently, we reported that gonadotropin-releasing hormone (GnRH) stimulates annexin A1 (Anxa1) and A5 (Anxa5) mRNA expression through the GnRH-receptor-mitogen-activated protein kinase cascade in LβT2 cells. As LβT2 cells respond to activin, we examined the effect of activin A on Anxa1 and a5 expression in LβT2 cells. Activin A (0.4 and 4 ng/mL) treatment decreased Anxa5 mRNA levels in a dose-dependent manner, but did not affect Anxa1 mRNA levels at concentrations up to 40 ng/mL. After activin A treatment (4 ng/mL), Anxa5 mRNA levels significantly decreased at 6 h, gradually declined until 24 h, and remained low until 48 h, whereas Anxa1 mRNA levels did not significantly change following treatment. Pretreatment with activin A for 24 h increased GnRH agonist (GnRHa)-induced Anxa1 increase by approximately 7-fold compared with GnRHa stimulation alone, but Anxa5 was not affected. As previously reported, these activin A treatments increased gonadotropin β subunit and GnRH receptor mRNA levels and slightly decreased common α-glycoprotein subunit mRNA levels. Furthermore, we examined the effect of activin A on Nr4a3, which is repressed by ANXA5 and which reduces Fshb expression, and found that activin A augmented Nr4a3 expression and slightly decreased the GnRHa-induced increase in Nr4a3. These results suggest that in gonadotrope cells, the mechanism regulating Anxa1 and a5 expression is differentially coupled with activin A signal transduction. Activin A suppresses Anxa5 expression under increased Nr4a3 expression, whereas activin A and GnRH synergistically stimulate Anxa1 expression. These GnRH-inducible annexins may have different specific functions in gonadotropes.

Background Matrix-producing breast carcinoma (MPBC) is a very rare and usually aggressive triple-negative breast cancer. We successfully established a patient-derived orthotopic xenograft (PDOX) model from a patient with MPBC and used it to study tumor sensitivity to various agents. Case report A 40-year-old woman was diagnosed with MPBC with a triple-negative phenotype. Due to axillary lymph-node metastases found during radical mastectomy, the patient was subsequently treated with epirubicin, cyclophosphamide and paclitaxel. In addition, radiotherapy was directed to the chest wall and subclavicular fossa. A portion of the cancer tissue from the mastectomy was used to establish a PDOX nude-mouse model. The PDOX model was resistant to paclitaxel, bevacizumab, vinorelbine, cisplatinum and olaparib, and sensitive to eribulin. Metastases in mediastinal lymph nodes and the right ovary were observed in the patient 14 months after mastectomy. Thoracoscopic mediastinal lymph-node biopsy and laparoscopic oophorectomy were performed, and both confirmed breast-cancer metastasis. The patient was then treated with paclitaxel and bevacizumab but no response was observed, which correlated with the inability of these drugs to arrest tumor growth in the PDOX models of the patient's tumor. The patient was then given eribulin based on the PDOX-model result, but treatment had to be stopped because of rapid progression of metastasis into the cervical lymph nodes and thyroid gland. The patient was subsequently treated with atezolizumab and nab-paclitaxel. Unfortunately, the patient died of her cancer 8 months after recurrence. Conclusion The present study demonstrates that the PDOX model of a patient's triple-negative MPBC accurately predicted that paclitaxel and bevacizumab would not arrest the patient's tumor growth. Eribulin may have been effective if administered at an earlier stage of the patient's cancer course. Drug-screening results from PDOX models should be used as early as possible in order to improve patient outcome.

Social anhedonia is a psychological state with difficulty in experiencing pleasure from social interactions and is observed in various diseases, such as depressive disorders. Although the relationships between social reward responses and anxiety- and depression-like behaviors have remained unclear, a social reward conditioned place preference (SCPP) test can be used to analyze the rewarding nature of social interactions. To elucidate these relationships, we used 5-week-old male mice of AKR, BALB/c, and C57BL/6J strains and conducted behavioral tests in the following order: elevated plus-maze test (EPM), open field test (OFT), SCPP, saccharin preference test (SPT), and passive avoidance test. The nucleus accumbens of these mice were collected 24 h after these behavioral tests and were used for western blotting to determine the levels of receptors for brain-derived neurotrophic factors and glucocorticoids. BALB/c mice displayed the highest levels of anxiety-like behavior in EPM and OFT as well as physical anhedonia-like behaviors in SPT. They also showed increased responses to social rewards and huddling behaviors in SCPP, with downregulated glucocorticoid receptor (GR). Regression analysis results revealed positive influences of anxiety- and physical anhedonia-like behaviors and expressions of GR on social reward responses. Collectively, temperament associated with anxiety and physical anhedonia may affect social reward responses, which possibly is influenced by the expression of GR that can modify these psychological traits.

Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX). The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks. The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p

The expression of annexin A1 (ANXA1) is augmented by gonadotrophin releasing hormone (GnRH) in LβT2 gonadotroph. We examined the distribution of ANXA1 in the pituitary tissues and the effect of ovariectomy. ANXA1 was mainly stained on folliculostellate cell-like irregular shaped cells with extended process of adult female rats. Large gonadotroph, so called castration cells, appeared two weeks after the ovariectomy. ANXA1 in castration cells exists around cells although another GnRH responsive annexin, ANXA5, was apparent also in the cytoplasm. The pituitary expression of ANXA1 after ovariectomy was significantly higher than intact rats. These difference in tissue distribution of two annexins suggest ANXA1 and ANXA5 bear different physiological function in the gonadotroph under GnRH regulation.

Pituitary gonadotropin secretion is regulated by several pituitary factors as well as GnRH and ovarian hormones. To elucidate the regulatory mechanisms of pituitary gonadotropin secretions, we observed changes in the mRNA levels of pituitary factors, namely annexin A1 (Anxa1) and Anxa5, inhibin/activin subunits, follistatin (Fst), and vitamin D receptor (Vdr), in female rat pituitary glands during the estrous cycle. Additionally, levels of LHβ subunit (Lhb), FSHβ subunit (Fshb), and GnRH receptor (Gnrh-r) mRNA were examined. During proestrus, Anxa1, Anxa5, Vdr, and inhibin α-subunit (Inha) exhibited the lowest levels, while during estrus, activin βB-subunit (Actbb), Lhb, and Gnrh-r were the lowest. Moreover, Fshb exhibited the highest value during metestrus, whereas Fst did not differ significantly. Correlation analyses revealed 16 statistically significant gene combinations. In particular, four combinations, namely Anxa5 and Inha, Anxa5 and Actbb, Inha and Vdr, and Inha and Actbb, were highly significant (P0.0001), while four combinations, Anxa1 and Anxa5, Anxa1 and Vdr, Anxa5 and Vdr, and Lhb and Gnrh-r, were moderately significant (P0.001). The remaining eight combinations that exhibited statistical significance were Anxa1 and Inha, Anxa1 and Actbb, Vdr and Actbb, Anxa1 and Fshb, Inha and Lhb, Actbb and Fshb, Actbb and Lhb, and Fst and Fshb (P0.05). These results highlight strong correlations among Anxa1, Anxa5, Vdr, Inha, and Actbb, thereby suggesting that an interaction among ANXA1, ANXA5, and VDR may lead to further communications with inhibin and/or activin in the pituitary gland.

Design of Compression Ignition (CI) engines with improved thermal efficiencies needs better understanding of the heat transfer mechanism from spray flame to the combustion chamber wall. In this regard, heat transfer occurring during the interaction between impinging spray flame and wall, under CI engine-like conditions, is investigated in this study using 3-Dimensional numerical simulations based on an Eulerian–Lagrangian framework. Simulations are performed for different fuel spray injection velocities (which are representative of different fuel injection pressures in CI engines), to examine their influence on the heat transfer between impinging spray flame and wall. To couple the convective and radiative heat transfer at the wall surface with the conduction heat transfer occurring within the finite thickness wall, Conjugate Heat Transfer (CHT) is incorporated in the simulations. A Non-Adiabatic Flamelet/Progress Variable (NA-FPV) approach is employed as the combustion model of n -dodecane, which is considered to be the fuel for liquid spray. Dynamics of the liquid film formed on the wall surface by impinging fuel droplets are captured using a particle-based approach. Contribution of radiative heat flux is taken into consideration using the Discrete Ordinates (DO) method. Results indicate that the total heat flux (sum of convective and radiative heat fluxes) at the wall surface increases with the fuel injection velocity. It is observed that the total wall heat flux is largest in the stagnation zone where the spray flame impinges directly on the wall surface, while the radiative heat flux at the wall surface becomes larger as the distance from this stagnation zone increases. Additionally, it is found that the influence of fuel injection velocity on the radiative heat flow rate at the wall surface is rather small. This radiative heat flow rate when expressed as a percentage of the total wall heat flow rate, ranges from ≈ 18% to 30% (depending on the 3 cases investigated), indicating that its contribution cannot be neglected for the CI engine-like conditions under which the present simulations are performed. Furthermore, to characterize the heat transfer occurring during spray flame-wall interaction process, correlations between the Nusselt number N u (corresponding to the wall heat loss) and Reynolds number R e (of the flow field) of the form N u ∝ R e n , are analysed and compared with that of a previous experimental study to assess their applicability. It is found that, depending on how the Nusselt number N u is defined (either using the total wall heat flux or the convective heat flux), the value of the correlation index n changes. When N u is calculated based on the total wall heat flux (which includes the contribution from the radiative heat flux), the value of n is found to be 0.49 which is close to the correlation index value of n = 0.4 reported in the recent experiments performed at Toyota Central R & D Labs., Inc.

Background/aim Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. Materials and methods The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. Results The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). Conclusion Eribulin has clinical potential for triple-negative MPBC patients.

As gonadotropin-releasing hormone (GnRH) is expressed in the thymus, its direct action on thymic cells, including thymic involution, has been suggested. Annexin A5 (ANXA5), a biomarker of GnRH, was used to determine whether GnRH affects the thymus of male rats. Immunohistochemistry showed positive reactions for ANXA5 in large medullary epithelial cells at 30 days of age, and the expression continued until 180 days of age. Organ culture of thymus pieces was performed to examine the direct action of a GnRH agonist (GnRHa) on the expression of Anxa5 and Gnrh mRNA. Thymus tissues obtained from male rats (40-60 days old) were cut into small pieces (2-3 mm

Background/aim Triple-negative matrix-producing breast carcinoma (MPBC) is rare, recalcitrant, and highly aggressive. The present study aimed to determine the efficacy of tumor-targeting leucine-arginine auxotroph Salmonella typhimurium (S. typhimurium) A1-R on a triple-negative MPBC in a patient-derived orthotopic xenograft (PDOX) model. Materials and methods The PDOX MPBC model was established in the left second mammary gland of nude mice by surgical orthotopic implantation (SOI). PDOX models were randomized into two groups when the tumor volume reached over 70 mm3: a control group (n=6); and a tumor-targeting S. typhimurium A1-R group (n=7), [intravenous (i.v.) injection of S. typhimurium A1-R via the tail vein, weekly, for two weeks]. All mice were sacrificed on day 14. Tumor volume and body weight were measured once per week. Results S. typhimurium A1-R exquisitely targeted and arrested the growth of the MPBC PDOX compared to the control group (p=0.017). Conclusion S. typhimurium A1-R has future clinical potential for triple-negative MPBC patients.

Gonadotropin-releasing hormone (GnRH) stimulation of annexin A1 (ANXA1) and A5 (ANXA5) mRNA expression was analyzed in LβT2 gonadotrope cells. Quantitative polymerase chain reaction results showed that a GnRH analog (GnRHa) stimulated the expression of both ANXA1 and A5 mRNA with a peak at 12 h of incubation; however, ANXA1 mRNA was extremely stimulated (60 folds). Immunocytochemical analysis confirmed these findings. A GnRH antagonist inhibited the effect of GnRHa. ANXA1 and A5 mRNA levels were significantly increased by protein kinase C (PKC) activator (12-O-Tetradecanoylphorbol-13-acetate; TPA), but not by dibutyryl cAMP. GnRHa-stimulated induction of ANXA1 and A5 mRNA was inhibited by PKC (GF109203) and MEK inhibitors (PD98059). TPA increased ANXA1 and A5 mRNA expression in a dose-dependent manner (1 nM to 10 μM), while the extent of the increase was much greater in ANXA1. After stimulation with 10 nM or 1 μM TPA, ANXA1 and A5 mRNA levels were increased at 6 h. ANXA1 mRNA levels were higher in the 1 μM TPA than in the 10 nM TPA treatment, whereas 1 μM TPA did not show further stimulation of ANXA5 mRNA compared to 10 nM TPA. These results clearly show that ANXA1 mRNA expression is stimulated by GnRH through PKC like ANXA5, and the response of ANXA1 is much larger than that of ANXA5. A close relationship between these annexins and a significant role for ANXA1 in GnRH action at gonadotropes is suggested.

The present study created an artificial intelligence (AI)-automated diagnostics system for uterine cervical lesions and assessed the performance of these images for AI diagnostic imaging of pathological cervical lesions. A total of 463 colposcopic images were analyzed. The traditional colposcopy diagnoses were compared to those obtained by AI image diagnosis. Next, 100 images were presented to a panel of 32 gynecologists who independently examined each image in a blinded fashion and diagnosed them for four categories of tumors. Then, the 32 gynecologists revisited their diagnosis for each image after being informed of the AI diagnosis. The present study assessed any changes in physician diagnosis and the accuracy of AI-image-assisted diagnosis (AISD). The accuracy of AI was 57.8% for normal, 35.4% for cervical intraepithelial neoplasia (CIN)1, 40.5% for CIN2-3 and 44.2% for invasive cancer. The accuracy of gynecologist diagnoses from cervical pathological images, before knowing the AI image diagnosis, was 54.4% for CIN2-3 and 38.9% for invasive cancer. After learning of the AISD, their accuracy improved to 58.0% for CIN2-3 and 48.5% for invasive cancer. AI-assisted image diagnosis was able to improve gynecologist diagnosis accuracy significantly (P

Background/aim The discovery of the nude mouse model enabled the experimental growth of human-patient tumors. However, the low establishment rate of tumors in nude and other immunodeficient strains of mice has limited wide-spread clinical use. Materials and methods In order to increase the establishment rate of surgical specimens of patient tumors, we transplanted tumors to nude mice subcutaneously along with large amounts of surrounding tissue of the tumor. Results The new transplantation method increased the establishment rate in nude mice to 66% compared to the old method of implanting the surgical tumor specimen with surrounding tissue removed (14%). High stage and presence of metastasis in the patient donor are positively correlated to tumor engraftment in nude mice. Conclusion The new method can potentially allow most cancer patients who undergo surgery or biopsy to have their own mouse model for drug-sensitivity testing.

Ankle-foot orthosis (AFO) can improve gait in stroke patients. Addition of plantar flexion resistance (PFR) can improve the first foot rocker function. However, the effect of changing the PFR on the ankle muscle force during gait training is unclear. This study aimed to determine the effect of changing the PFR of an AFO on spatiotemporal parameters (speed, bilateral step length, and cadence), peak angle of ankle plantar flexion and knee flexion, and muscle force (tibialis anterior [TA], medial head of the gastrocnemius [MGAS], and soleus) during early stance using a musculoskeletal model. Ten healthy adult men walked under five conditions: a no-AFO condition and PFR conditions 1-4. Spatiotemporal parameters and peak joint angles during the early stance phase were measured from experimental data, with muscle force estimated from simulations of a musculoskeletal model. Increasing the PFR of the AFO decreased TA muscle force and increased MGAS muscle force but had no influence on spatiotemporal parameters and joint angles. Adjustment of the PFR modifies the muscle force around the ankle, which can maximize the effect of AFO during gait training.

Cervical cancer is a recalcitrant disease. To help overcome this problem, we previously established a patient-derived orthotopic xenograft (PDOX) model of cervical cancer. In the previous study, we found the tumor to be resistant to nab-paclitaxal (nab-PTX). We also previously developed the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R). The aim of the present study was to investigate the efficacy of S. typhimurium A1-R to overcome nab-PTX resistance in the cervical cancer PDOX model. Cervical-cancer tumor fragments were implanted orthotopically into the neck of the uterus of nude mice. The cervical-cancer PDOX models were randomized into the following four groups after the tumor volume reached 60 mm3: G1: untreated group; G2: nab-PTX (i.v., 10 mg/kg, biweekly, 3 weeks); G3: Salmonella typhimurium A1-R (i.v., 5 × 107 CFU/body, weekly, 3 weeks); G4: nab-PTX combined with Salmonella typhimurium A1-R (nab-PTX, 10 mg/kg, i.v., biweekly, 3 weeks; S. typhimurium A1-R, 5 × 107 CFU/body, i.v., weekly, 3 weeks). Each group comprised eight mice. All mice were sacrificed on day 22. Tumor volume was measured on day 0 and day 22. Body weight was measured twice a week. Nab-PTX and Salmonella typhimurium A1-R did not show significant efficacy as monotherapy compared to the control group (P = 0.564 and P = 0.120, respectively). In contrast, nab-PTX combined with Salmonella typhimurium A1-R significantly suppressed tumor growth compared to the untreated control group and nab-PTX group (P

Background/AimMatrix-producing breast carcinoma (MPBC), is a rare, recalcitrant and highly aggressive. The present study aimed to determine the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R on a triple-negative MPBC in a patient-derived orthotopic xenograft (PDOX) model.MethodsThe PDOX model was established in the left second mammary gland of a nude mouse by surgical orthotopic implantation (SOI) of the patient triple-negative MPBC PDOX models were randomized into two groups: G1, control group (n=6); G2, tumor-targeting S. typhimurium A1-R group (n=7, intravenous (i.v.) injection via tail vein, weekly, for two weeks). All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week.ResultsS. typhimurium A1-R arrested tumor growth compared to the control group (P = 0.016).ConclusionThe results of the present study suggest that S. typhimurium A1-R has future clinical potential in triple-negative MPBC patients.

Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX).The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks.The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93).PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.

Rab proteins, a family of small guanosine triphosphatases, play key roles in intracellular membrane trafficking and the regulation of various cellular processes. As a Rab isoform, Rab35 is crucial for recycling endosome trafficking, cytokinesis and neurite outgrowth. In this report, we analyzed dynamic structural changes and physicochemical features of Rab35 in response to different external conditions, including temperature, pH, salt concentration and guanosine triphosphate (GTP), by circular dichroism (CD) spectroscopy. CD spectra revealed that the α-helix content of Rab35 varies under different conditions considerably. The addition of GTP increases the α-helix content of Rab35 when the temperature, pH and salt concentration match physiological conditions. The results suggest that the external environment affects the secondary structure of Rab35. In particular, the presence of GTP stabilized the α-helices of Rab35 under physiological conditions. These structural changes may translate to changes in Rab35 function and relate to its role in membrane trafficking., Highlights • The α-helix content of Rab35 is affected by a change in temperature or pH. • GTP increases the α-helix content of Rab35 under physiological conditions. • GTP stabilizes the secondary structure of Rab35 only under physiological conditions.

d-amino acid-containing proteins have been found in several human tissues, and the spontaneous accumulation of d-amino acids in proteins is thought to be involved in age-dependent diseases including dementia. Tau, a microtubule-associated protein, is a major component of neurofibrillary tangles in Alzheimer's disease. Site-specific amino acid D-isomerization in Tau has been observed in the brains of patients with Alzheimer's disease. Here, we conducted amino acid D-isomerization at specific sites in microtubule-binding repeat peptides of Tau (Tau R2 and R3) and examined the effects on Tau structure and fibril formation. Our results demonstrate that amino acid D-isomerization in Tau R2 peptides decreased the rates of β-sheet transition and fibril formation compared with those of the wild-type peptide composed of all l-amino acids. In contrast, Tau R3 peptides that had undergone amino acid D-isomerization at either Asp314, Ser316, or Ser324 showed increased rates of β-sheet transition and fibril formation compared with those of the wild-type Tau R3 peptide.

Background/aim Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In this study, we determined drug sensitivity for a triple-negative MPBC, without BRCA mutations, in a patient-derived orthotopic xenograft (PDOX) model. Materials and methods The MPBC PDOX model was established in the left 2nd mammary gland of nude mouse by implantation of the patient tumor using surgical orthotopic implantation (SOI). We randomized MPBC PDOX mice into 5 groups (n=5 mice/per treatment group) when the tumor volume reached 80 mm3: G1, control-no treatment; G2, bevacizumab [intra-peritoneal (i.p.), weekly, for 2 weeks]; G3, vinorelbine (i.p., weekly, for 2 weeks); G4, olaparib (oral., daily, for 2 weeks); G5, eribulin [intravenous (i.v.), weekly, for 2 weeks]. The mice in each treatment group were sacrificed on day 15. Tumor volume and body weight were measured once/week. Results The MPBC PDOX model was resistant to olaparib (p=0.22). The MPBC PDOX model treated with bevacizumab and vinorelbine showed significantly suppressed tumor growth compared to the untreated group (p=0.005 and 0.002, respectively). However, only eribulin regressed the tumor (p=0.0001). Eribulin was more effective than olaparib (p=0.0001), bevacizumab (p=0.0025) and vinorelbine (p=0.0061). Conclusion Eribulin has clinical potential as treatment for triple-negative MPBC patients that are resistant to a PARP inhibitor such as olaparib.

The effects of immediate dentin sealing (IDS) applications on the bonding of computer-aided design/computer-aided manufacturing (CAD/CAM) ceramic onlay restorations after cyclic loading were examined. Standardized mesial-distal-occlusal-palatal cavities in 32 extracted human molars were prepared. The cavities were divided into four groups: those receiving thin-layered (T), slope-shaped (S), and base-shaped (B) sealing, and the non-sealing group (N) as a control. The intra-cavity dentin walls of the T, S, and B groups were sealed with an all-in-one adhesive and a flowable composite. All cavities were scanned; hence, CAD/CAM onlays were fabricated using ceramic blocks and bonded with a resin cement system. Cyclic loading was applied and the microtensile bond strength (μ-TBS) was measured. It was found that IDS application improved not only the μ-TBS, but also the bonding reliability and durability of the CAD/CAM restoration. In particular, the S restoration exhibited the highest-performance as regards both robust bond strength and stable bonding.

[Purpose] The purpose of this study was to investigate the effect of changing the plantar flexion resistance of an ankle-foot orthosis on knee joint reaction and knee muscle forces. Furthermore, the influence of an ankle-foot orthosis with an over-plantar flexion resistance function on knee joint reaction force was verified. [Participants and Methods] Ten healthy adult males walked under the following three conditions: (1) no ankle-foot orthosis, and with ankle-foot orthoses with (2) a strong and (3) a weak plantar flexion resistance (ankle-foot orthosis conditions). The knee flexion angle, quadricep muscle force, hamstring muscle force, and knee joint reaction force during the stance phase were measured using a motion analysis system, musculoskeletal model, and ankle-foot orthosis model. [Results] The peak knee joint reaction force, knee flexion angle, and quadricep muscle force in the early stance phase significantly increased in the strong plantar flexion resistance condition in comparison with the “no ankle-foot orthosis” condition. [Conclusion] Increased knee joint reaction force with over-plantar flexion resistance suggests that over-plantar flexion resistance causes various knee problems such as knee pain and knee osteoarthritis.

Fibril formation and aggregation of α-synuclein are important for the pathogenesis of neurodegenerative disorders including Parkinson's disease. In familial Parkinson's disease, the G51D mutation of α-synuclein causes severe symptoms and rapid progression. α-Synuclein, an intrinsically disordered protein, was shown to adopt an α-helical tetrameric state that resists fibrillation and aggregation. Here, we isolated the stable dimeric state of recombinant wild-type (WT) α-synuclein and G51D α-synuclein protein. Using circular dichroism spectroscopy, we determined that the α-synuclein dimer and monomer structures were unfolded. The WT α-synuclein dimer was more resistant to fibril formation than the monomer. However, the fibril formation rate of the G51D α-synuclein dimer was similar to that of the G51D α-synuclein monomer. The fibril morphology and properties of the G51D α-synuclein monomer were different from those of the WT α-synuclein monomer and dimer and G51D α-synuclein dimer. Additionally, G51D α-synuclein monomer fibrils were more cytotoxic than other fibrils. Our findings indicate that the structural differences between G51D α-synuclein monomer fibrils and other fibrils are critically responsible for its severe neurotoxicity in familial Parkinson's disease.

A 3D printed solution flow type micro droplet cell (Sf-MDC) was attached to an optical microscope, making it possible to switch between the lens and Sf-MDC at the same observation/measurement area. Using this setup, precipitates in an Al-Si alloy were investigated. Open circuit potential measurements and potentiodynamic measurements were conducted at various surface areas of the Al-Si alloy. The precipitate area ratio affected open circuit potentials and anodic currents. This 3D printed Sf-MDC can be applied for the electrochemical investigation of precipitates in Al-Si alloy.

Camurati-Engelmann disease (CED) is a rare sclerosing bone disorder in humans with autosomal dominant inheritance. Mutations in the gene (TGFB1) that encodes transforming growth factor-β1 (TGF-β1) are causative for CED. TGF-β1 signaling is enhanced by the CED-causing mutations. In this study, we performed Tgfb1 mutation screening in an ENU-mutagenized mouse genomic DNA library. We identified a missense mutation in which cysteine was substituted by serine at position 225 (p.C225S), that corresponded to the CED-causing mutation (p.C225R). TGF-β1 mutant protein carrying p.C225S was secreted normally into the extracellular space. Reporter gene assays showed that the p.C225S mutants enhanced TGF-β signaling at the same level as p.C225R mutants. We generated p.C225S homozygous mice and confirmed that the mature TGF-β1 levels in the culture supernatants of the calvarial cells from the homozygotes were significantly higher than those from wild-type mice. Although the skull and femur are sclerotic in CED, these phenotypes were not observed in p.C225S homozygous mice. These results suggest that human and mouse bone tissue react differently to TGF-β1. These findings are useful to pharmacological studies using mouse models in developing drugs that will target TGF-β signaling.

The tumor microenvironment is critical for metastasis to occur. Subcutaneous xenografts of tumors in immunodeficient mice are usually encapsulated and rarely metastasize as opposed to orthotopic tumors which metastasize if the original tumor was metastatic. In the present report, we were able to reconstitute a metastatic tumor microenvironment by subcutaneously co-transplanting a human cervical cancer cell line and human cervical cancer-associated fibroblasts (CAFs), in athymic mice, which resulted in lymph node metastasis in 40% of the animals. In contrast, no metastasis occurred from the cervical cancer without CAFs. These results suggest that CAFs can overcome an anti-metastatic tumor environment and are a potential target to prevent metastasis.

This study investigates the effect of the plantar flexion resistance (PFR) of an ankle–foot orthosis (AFO) on the plantar flexor tendon length during gait. We measured and estimated the knee flexion angle, plantar flexion angle, and plantar flexor tendon length in healthy male adults. The results showed that the knee flexion and plantar flexion angle were significantly different in the strong PFR (s-PFR) compared with the no-AFO condition. In addition, the change in the gastrocnemius tendon length significantly decreased in the s-PFR condition compared to the no-AFO condition. These results suggest that over PFR prevents the gait improvement because the extension of the gastrocnemius tendon in the late stance is very important for the forward propulsion during gait.

Ligand-bound nuclear receptors (NR) activate transcription of the target genes. This activation is coupled with histone modifications and chromatin remodeling through the function of various coregulators. However, the nature of the dependence of a NR coregulator action on the presence of the chromatin environment at the target genes is unclear. To address this issue, we have developed a modified position effect variegation experimental model system that includes an androgen-dependent reporter transgene inserted into either a pericentric heterochromatin region or a euchromatic region of Drosophila chromosome. Human androgen receptor (AR) and its constitutively active truncation mutant (AR AF-1) were transcriptionally functional in both chromosomal regions. Predictably, the level of AR-induced transactivation was lower in the pericentric heterochromatin. In genetic screening for AR AF-1 coregulators, Drosophila CREB binding protein (dCBP) was found to corepress AR transactivation at the pericentric region whereas it led to coactivation in the euchromatic area. Mutations of Sir2 acetylation sites or deletion of the CBP acetyltransferase domain abrogated dCBP corepressive action for AR at heterochromatic areas in vivo. Such a CBP corepressor function for AR was observed in the transcriptionally silent promoter of an AR target gene in cultured mammalian cells. Thus, our findings suggest that the action of NR coregulators may depend on the state of chromatin at the target loci.

This paper proposes to use the analysis of human mechanical impedance to predict spatial behavior of tremor. Traditional studies have revealed that the variability in force is proportional to the mean level of force generated, which is described as signal dependent noise. The variability in force sometimes generates unintentional and uncontrollable rhythmic muscle movements, called tremor. Tremor appears most commonly on arms and hands due to not only a symptom of a neurological disorder, but also when we tighten our muscles. This study hypothesizes that the posture-dependent tremor at the hand is affected by the mechanical impedance of the arm, which is represented as the endpoint compliance ellipsoid. To verify this hypothesis, we measured the trajectory of the endpoint of the arm by human experiments, and compared the results with the endpoint compliance ellipsoid computationally obtained. The human experiment where the oscillations at the hand are measured revealed that the simulation results well correspond with the human experiments. This suggests that the posture-dependent motion noise is affected by the mechanical impedance of human body.

myo-Inositol is an essential biomolecule that is synthesized by myo-inositol monophosphatase (IMPase) from inositol monophosphate species. The enzymatic activity of IMPase is inhibited by lithium, a drug used for the treatment of mood swings seen in bipolar disorder. Therefore, myo-inositol is thought to have an important role in the mechanism of bipolar disorder, although the details remain elusive. We screened an ethyl nitrosourea mutant mouse library for IMPase gene (Impa) mutations and identified an Impa1 T95K missense mutation. The mutant protein possessed undetectable enzymatic activity. Homozygotes died perinatally, and E18.5 embryos exhibited striking developmental defects, including hypoplasia of the mandible and asymmetric fusion of ribs to the sternum. Perinatal lethality and morphological defects in homozygotes were rescued by dietary myo-inositol. Rescued homozygotes raised on normal drinking water after weaning exhibited a hyper-locomotive trait and prolonged circadian periods, as reported in rodents treated with lithium. Our mice should be advantageous, compared with those generated by the conventional gene knock-out strategy, because they carry minimal genomic damage, e.g. a point mutation. In conclusion, our results reveal critical roles for intracellular myo-inositol synthesis in craniofacial development and the maintenance of proper brain function. Furthermore, this mouse model for cellular inositol depletion could be beneficial for understanding the molecular mechanisms underlying the clinical effect of lithium and myo-inositol-mediated skeletal development.