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Artificial insemination (AI) and embryo transfer (ET) are important in the reproduction of dairy cows. The conception rate after AI or ET is an essential indicator when selecting appropriate breeding methods. However, information on the environmental factors affecting ET conception rate when compared with AI is limited. We aimed to investigate environmental factors affecting ET conception rate and characterize the differences in environmental factors between AI and ET. Records of the first AI (n = 1,870,143) and ET (n = 29,922) from Holstein nulliparous, primiparous, and multiparous cows in Hokkaido, Japan, were analyzed using separate multivariable logistic regression models. For each breeding method, we grouped primiparous and multiparous cows according to milk yield at peak lactation (PY; < 25, 25-30, 30-35, ≥ 35 kg in primiparous, < 40, 40-45, 45-50, ≥ 50 kg in multiparous) and the interval from calving to first AI or ET (CFI/CFT; < 60, 60-79, 80-99, ≥ 100 d) to evaluate the effects of PY and CFI/CFT on conception rate. AI conception rate decreased with increasing PY in primiparous and multiparous cows, whereas ET conception rate did not decrease significantly. Additionally, the ET conception rate did not decrease even in primiparous and multiparous cows slightly earlier than 60 d in CFI/CFT when compared with those in CFI/CFT after 60 d, which differed from the AI conception rate. Collectively, breeding by ET leads to the avoidance of negative effects of high milk yield and calving on the conception rate, indicating that cows are fertile by ET within 60 d after calving.
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Although pregnant women's fish consumption is beneficial for the brain development of the fetus due to the DHA in fish, seafood also contains methylmercury (MeHg), which adversely affects fetal brain development. Epidemiological studies suggest that high DHA levels in pregnant women's sera may protect the fetal brain from MeHg-induced neurotoxicity, but the underlying mechanism is unknown. Our earlier study revealed that DHA and its metabolite 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) produced by cytochrome P450s (P450s) and soluble epoxide hydrolase (sEH) can suppress MeHg-induced cytotoxicity in mouse primary neuronal cells. In the present study, DHA supplementation to pregnant mice suppressed MeHg-induced impairments of pups' body weight, grip strength, motor function, and short-term memory. DHA supplementation also suppressed MeHg-induced oxidative stress and the decrease in the number of subplate neurons in the cerebral cortex of the pups. DHA supplementation to dams significantly increased the DHA metabolites 19,20-epoxydocosapentaenoic acid (19,20-EDP) and 19,20-DHDP as well as DHA itself in the fetal and infant brains, although the expression levels of P450s and sEH were low in the fetal brain and liver. DHA metabolites were detected in the mouse breast milk and in human umbilical cord blood, indicating the active transfer of DHA metabolites from dams to pups. These results demonstrate that DHA supplementation increased DHA and its metabolites in the mouse pup brain and alleviated the effects of MeHg on fetal brain development. Pregnant women's intake of fish containing high levels of DHA (or DHA supplementation) may help prevent MeHg-induced neurotoxicity in the fetus.
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Compuestos de Metilmercurio , Lactante , Animales , Humanos , Embarazo , Femenino , Ratones , Compuestos de Metilmercurio/toxicidad , Ácidos Docosahexaenoicos/farmacología , Encéfalo , Estrés Oxidativo , FetoRESUMEN
CaMK phosphatase (CaMKP/POPX2/PPM1F) is a Ser/Thr protein phosphatase that belongs to the PPM family. Accumulating evidence suggests that CaMKP is involved in the pathogenesis of various diseases, including cancer. To clarify the relationship between CaMKP activity and human breast cancer cell motility, we examined the phosphatase activity of CaMKP in cell extracts. CaMKP activity assays of the immunoprecipitates prepared from the cell extract revealed that cells exhibiting higher motility had higher CaMKP activity, with no significant differences in the specific activity being observed. Two CaMKP-specific inhibitors, 1-amino-8-naphthol-4-sulfonic acid (ANS) and 1-amino-8-naphthol-2,4-disulfonic acid (ANDS), inhibited the migration of highly invasive MDA-MB-231 breast cancer cells without significant cytotoxicity, while an inactive analog, naphthionic acid, did not. Furthermore, the cells lost their elongated morphology and assumed a rounded shape following treatment with ANS, whereas they retained their elongated morphology following treatment with naphthionic acid. Consistent with these findings, ANS and ANDS significantly enhanced the phosphorylation level of CaMKI, a cellular substrate of CaMKP, while naphthionic acid did not. The present data suggest that CaMKP could be a novel therapeutic target for cancer metastasis.
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Neoplasias de la Mama , Naftoles , Humanos , Femenino , Células MDA-MB-231 , Fosfoproteínas Fosfatasas/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina , Movimiento Celular , Línea Celular TumoralRESUMEN
Accelerating age at first calving (AFC) is a strategy for sustainable dairy farming, whereas the impact of a reduction in AFC on long-term performance remains unclear. In this study, longevity and milk productivity until the end of the third lactation period were investigated retrospectively according to AFC. A total of 169 cows were categorized according to AFC as young, moderate, old, and very old (< 22.5, 22.5 -< 24.0, 24.0 -< 25.5, and > 25.5 months). The young AFC group had approximately 70 kg lower body weight before first calving (620 vs. 695 kg, P < 0.05) and experienced their first calving approximately 4.2 months earlier than the very old AFC group (21.9 vs. 26.1 months, P < 0.05). The survival rate at the third calving stage was 61% in the young AFC group, which was higher than those in the moderate (42%), old (35%), and very old (33%) AFC groups. In the young AFC group, no cows were culled because of low productivity and hoof disease, compared to 5.0-8.1% of older AFC cows. The young AFC group had a higher overall lifetime milk yield (cumulative milk yield/days from birth to the end of final lactation) than the old AFC group (14.3 vs. 8.7 kg/d, P = 0.11). The cows that survived the third calving had better reproductive performance than non-surviving cows; however, no statistical difference was detected among the AFC groups. In conclusion, AFC as early as 22.5 months could be associated with better survivability and higher overall lifetime milk yield than older AFC without impairing reproductive performance. Our results suggest that accelerating AFC may lead to higher profitability.
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Longevidad , Leche , Femenino , Bovinos , Animales , Japón , Estudios Retrospectivos , Lactancia , FertilidadRESUMEN
It has been suggested that domestication has turned cattle from seasonal breeders to annual breeders. This study examined the seasonal differences in early postpartum ovulation and subsequent reproductive performance in 542 Holstein cows. Cows displaying corpora lutea in the ovary at 26 days postpartum were defined as early ovulators. Factors affecting the occurrence of early ovulation were analyzed, and subsequent reproductive traits were compared between cows with and without early ovulation. During the summer season, 70.6% of calving cows showed early ovulation, whereas 48.7, 39.2, and 47.2% presented this condition in autumn, winter, and spring, respectively (P < 0.01). Third parity cows showed early ovulation more often than their first parity counterparts (P < 0.05). Cows with a 2.50 to 3.00 or > 3.00 body condition score (BCS) more frequently became early ovulators than those with BCSs < 2.50 (P < 0.01). Calving year was a risk factor, and uterine abnormalities were also often risk factors for early ovulation. The survival analysis showed that seasonal differences in the occurrence of early ovulation did not completely affect the time to first service and pregnancy. Proportional hazard regression analysis revealed that calving year, parity, and early ovulation were risk factors for the time to first service and that calving year was a risk factor for the time to pregnancy. In conclusion, domesticated dairy cows maintain seasonality in postpartum ovarian activity but not in subsequent fertility.
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Lactancia , Ovario , Embarazo , Femenino , Humanos , Bovinos , Animales , Leche , Reproducción , Periodo Posparto , OvulaciónRESUMEN
A 66-year-old man presenting with cStage â ¢c rectal cancer underwent laparoscopic low anterior resection(D3 lymph node dissection and R0 resection)following neoadjuvant chemoradiotherapy(capecitabine, 45 Gy/25 Fr)and received adjuvant chemotherapy(CAPOX). A year after surgery, abdominal contrast-enhanced computed tomography revealed recurrence near the rectal anastomosis with prostate invasion. The patient underwent robot-assisted abdominoperineal resection alongside en bloc prostatectomy and vesico-urethral anastomosis after 12 courses of neoadjuvant chemotherapy(FOLFIRI and panitumumab). He exhibited a good postoperative course and was discharged on the 12th postoperative day. After 7 months of surgery, no recurrence was observe; and urinary incontinence seen immediately after surgery gradually improved.
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Proctectomía , Neoplasias del Recto , Robótica , Masculino , Humanos , Anciano , Vejiga Urinaria/cirugía , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , Prostatectomía/métodos , Anastomosis QuirúrgicaRESUMEN
BACKGROUND: Valproic acid (VPA) is a clinically used antiepileptic drug, but it is associated with a significant risk of a low verbal intelligence quotient (IQ) score, attention-deficit hyperactivity disorder and autism spectrum disorder in children when it is administered during pregnancy. Prenatal VPA exposure has been reported to affect neurogenesis and neuronal migration and differentiation. In addition, growing evidence has shown that microglia and brain immune cells are activated by VPA treatment. However, the role of VPA-activated microglia remains unclear. METHODS: Pregnant female mice received sodium valproate on E11.5. A microglial activation inhibitor, minocycline or a CCR5 antagonist, maraviroc was dissolved in drinking water and administered to dams from P1 to P21. Measurement of microglial activity, evaluation of neural circuit function and expression analysis were performed on P10. Behavioral tests were performed in the order of open field test, Y-maze test, social affiliation test and marble burying test from the age of 6 weeks. RESULTS: Prenatal exposure of mice to VPA induced microglial activation and neural circuit dysfunction in the CA1 region of the hippocampus during the early postnatal periods and post-developmental defects in working memory and social interaction and repetitive behaviors. Minocycline, a microglial activation inhibitor, clearly suppressed the above effects, suggesting that microglia elicit neural dysfunction and behavioral disorders. Next-generation sequencing analysis revealed that the expression of a chemokine, C-C motif chemokine ligand 3 (CCL3), was upregulated in the hippocampi of VPA-treated mice. CCL3 expression increased in microglia during the early postnatal periods via an epigenetic mechanism. The CCR5 antagonist maraviroc significantly suppressed neural circuit dysfunction and post-developmental behavioral disorders induced by prenatal VPA exposure. CONCLUSION: These findings suggest that microglial CCL3 might act during development to contribute to VPA-induced post-developmental behavioral abnormalities. CCR5-targeting compounds such as maraviroc might alleviate behavioral disorders when administered early.
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Trastorno del Espectro Autista , Efectos Tardíos de la Exposición Prenatal , Animales , Trastorno del Espectro Autista/inducido químicamente , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Maraviroc/uso terapéutico , Maraviroc/toxicidad , Ratones , Minociclina/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Receptores CCR5/genética , Ácido Valproico/toxicidadRESUMEN
Nanoparticle corona phases, especially those surrounding anisotropic particles, are central to determining their catalytic, molecular recognition, and interfacial properties. It remains a longstanding challenge to chemically synthesize and control such phases at the nanoparticle surface. In this work, the supramolecular chemistry of rosette nanotubes (RNTs), well-defined hierarchically self-assembled nanostructures formed from heteroaromatic bicyclic bases, is used to create molecularly precise and continuous corona phases on single-walled carbon nanotubes (SWCNTs). These RNT-SWCNT (RS) complexes exhibit the lowest solvent-exposed surface area (147.8 ± 60 m-1 ) measured to date due to its regular structure. Through Raman spectroscopy, molecular-scale control of the free volume is also observed between the two annular structures and the effects of confined water. SWCNT photoluminescence (PL) within the RNT is also modulated considerably as a function of their diameter and chirality, especially for the (11, 1) species, where a PL increase compared to other species can be attributed to their chiral angle and the RNT's inward facing electron densities. In summary, RNT chemistry is extended to the problem of chemically defining both the exterior and interior corona interfaces of an encapsulated particle, thereby opening the door to precision control of core-shell nanoparticle interfaces.
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Nanopartículas , Nanoestructuras , Nanotubos de Carbono , Nanotubos de Carbono/química , Solventes , Agua/químicaRESUMEN
CaMK phosphatase (CaMKP/PPM1F/POPX2) is a Mn2+-dependent, calyculin A/okadaic acid-insensitive Ser/Thr protein phosphatase that belongs to the PPM family. CaMKP is thought to be involved in regulation of not only various protein kinases, such as CaM kinases and p21-activated protein kinase, but also of cellular proteins regulated by phosphorylation. A large-scale screening of a chemical library identified gallic acid and some of its alkyl esters as novel CaMKP inhibitors highly specific to CaMKP. Surprisingly, they caused specific carbonylation of CaMKP, leading to its inactivation. Under the same conditions, no carbonylation nor inactivation was observed when PPM1A, which is affiliated with the same family as CaMKP, and λ-phosphatase were used. The carbonylation reaction was inhibited by SH compounds such as cysteamine in a dose-dependent manner with a concomitant decrease in CaMKP inhibition by ethyl gallate. The pyrogallol structure of gallate was necessary for the gallate-mediated carbonylation of CaMKP. Point mutations of CaMKP leading to impairment of phosphatase activity did not significantly affect the gallate-mediated carbonylation. Ethyl gallate resulted in almost complete inhibition of CaMKP under the conditions where the carbonylation level was nearly identical to that of CaMKP carbonylation via metal-catalyzed oxidation with ascorbic acid/FeSO4, which resulted in only a partial inhibition of CaMKP. The gallate-mediated carbonylation of CaMKP absolutely required divalent cations such as Mn2+, Cu2+, Co2+ and Fe2+, and was markedly enhanced by a phosphopeptide substrate. When MDA-MB-231 cells transiently expressing CaM kinase I, a CaMKP substrate, were treated by ethyl gallate, significant enhancement of phosphorylation of CaM kinase I was observed, suggesting that ethyl gallate can penetrate into cells to inactivate cellular CaMKP. All the presented data strongly support the hypothesis that CaMKP undergoes carbonylation of its specific amino acid residues by incubation with alkyl gallates and the divalent metal cations, leading to inactivation specific to CaMKP.
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Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina , Fosfoproteínas Fosfatasas , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/química , Oxidación-Reducción , Fosfoproteínas Fosfatasas/química , Fosforilación , Carbonilación Proteica , Proteína Fosfatasa 1/genética , Proteína Fosfatasa 1/metabolismo , Proteína Fosfatasa 2/metabolismoRESUMEN
Prenatal and postnatal biphasic increases in plasma testosterone levels derived from perinatal testes are considered critical for defeminizing/masculinizing the brain mechanism that regulates sexual behavior in male rats. Hypothalamic kisspeptin neurons are indispensable for stimulating GnRH and downstream gonadotropin, as well as the consequent testicular testosterone production/release in adult male rats. However, it is unclear whether kisspeptin is responsible for the increase in plasma testosterone levels in perinatal male rats. The present study aimed to investigate the role of Kiss1/kisspeptin in generating perinatal plasma LH and the consequent testosterone increase in male rats by comparing the plasma testosterone and LH profiles of wild-type (Kiss1+/+) and Kiss1 knockout (Kiss1-/-) male rats. A biphasic pattern of plasma testosterone levels, with peaks in the prenatal and postnatal periods, was found in both Kiss1+/+ and Kiss1-/- male rats. Postnatal plasma testosterone and LH levels were significantly lower in Kiss1-/- male rats than in Kiss1+/+ male rats, whereas the levels in the prenatal embryonic period were comparable between the genotypes. Exogenous kisspeptin challenge significantly increased plasma testosterone and LH levels and the number of c-Fos-immunoreactive GnRH neurons in neonatal Kiss1-/- and Kiss1+/+ male rats. Kiss1 and Gpr54 (kisspeptin receptor gene) were found in the testes of neonatal rats, but kisspeptin treatment failed to stimulate testosterone release in the cultured testes of both genotypes. These findings suggest that postnatal, but not prenatal, testosterone increase in male rats is mainly induced by central kisspeptin-dependent stimulation of GnRH and consequent LH release.
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Kisspeptinas , Testosterona , Animales , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Kisspeptinas/farmacología , Hormona Luteinizante , Masculino , Embarazo , RatasRESUMEN
Dairy cattle must allocate energy to milk production and reproduction. Therefore, understanding the environmental factors that affect conception rates in nulliparous and primiparous cows is helpful in appropriate feeding management strategies before and after calving. Accordingly, the aim of this study was to investigate the influence of environmental factors before and after the first calving on the conception rate, representing the starting point of milk production. The records of the first artificial insemination (AI) from Holstein nulliparous cows (n = 533,672) and primiparous cows (n = 516,710) in Hokkaido, Japan, were analyzed using separate multivariable logistic regression models. The mean conception rates for nulliparous and primiparous cows from 2012 to 2018 were 55.2 and 39.2%, respectively. In both nulliparous and primiparous cows, the conception rate of crossbreeding using Japanese Black (JB) semen was significantly higher than that for purebred Holstein breeding. The conception rate using sexed semen decreased in the warmer months only in nulliparous cows. Moreover, we grouped primiparous cows according to milk yield during peak lactation (PY; < 25, 25-30, 30-35, ≥35 kg) and the interval from calving to first insemination (CFI; < 60, 60-79, 80-99, ≥100 d), and evaluated their combined effect on the conception rate. Both PY and CFI strongly affected the conception rate in primiparous cows, which decreased with an increase in PY, even for the group with CFI ≥100 d; however, the conception rate increased for a CFI ≥60 d regardless of PY. Taken together, this study demonstrates the long-term effect of PY and an independent effect of CFI on the conception rate of cows. These results provide guidance for management to execute appropriate AI implementation strategies before and after lactation.
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Lactancia , Fitomejoramiento , Animales , Bovinos , Femenino , Inseminación Artificial/métodos , Inseminación Artificial/veterinaria , Leche , Paridad , Embarazo , ReproducciónRESUMEN
The method of increments and frozen natural orbital (MI-FNO) framework is introduced to help expedite the application of noisy, intermediate-scale quantum (NISQ) devices for quantum chemistry simulations. The MI-FNO framework provides a systematic reduction of the occupied and virtual orbital spaces for quantum chemistry simulations. The correlation energies of the resulting increments from the MI-FNO reduction can then be solved by various algorithms, including quantum algorithms such as the phase estimation algorithm and the variational quantum eigensolver (VQE). The unitary coupled-cluster singles and doubles VQE framework is used to obtain correlation energies for the case of small molecules (i.e., BeH2, CH4, NH3, H2O, and HF) using the cc-pVDZ basis set. The quantum resource requirements are estimated for a constrained geometry complex catalyst that is utilized in industrial settings for the polymerization of α-olefins. We show that the MI-FNO approach provides a significant reduction in the quantum bit (qubit) requirements relative to the full system simulations. We propose that the MI-FNO framework can create scalable examples of quantum chemistry problems that are appropriate for assessing the progress of NISQ devices.
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We previously showed that the antiepileptic drug levetiracetam (LEV) inhibits microglial activation, but the mechanism remains unclear. The purpose of this study was to identify the target of LEV in microglial activity suppression. The mouse microglial BV-2 cell line, cultured in a ramified form, was pretreated with LEV and then treated with lipopolysaccharide (LPS). A comprehensive analysis of LEV targets was performed by cap analysis gene expression sequencing using BV-2 cells, indicating the transcription factors BATF, Nrf-2, FosL1 (Fra1), MAFF, and Spic as candidates. LPS increased AP-1 and Spic transcriptional activity, and LEV only suppressed AP-1 activity. FosL1, MAFF, and Spic mRNA levels were increased by LPS, and LEV only attenuated FosL1 mRNA expression, suggesting FosL1 as an LEV target. FosL1 protein levels were increased by LPS treatment and decreased by LEV pretreatment, similar to FosL1 mRNA levels. The FosL1 siRNA clearly suppressed the expression of TNFα and IL-1ß. Pilocarpine-induced status epilepticus increased hippocampus FosL1 expression, along with inflammation. LEV treatment significantly suppressed FosL1 expression. Together, LEV reduces FosL1 expression and AP-1 activity in activated microglia, thereby suppressing neuroinflammation. LEV might be a candidate for the treatment of several neurological diseases involving microglial activation.
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Regulación hacia Abajo/efectos de los fármacos , Levetiracetam/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Levetiracetam/uso terapéutico , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos ICR , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteínas Proto-Oncogénicas c-fos/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fos/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Transcripción Genética/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The consumption of fish now involves a risk of methylmercury (MeHg) exposure but also provides the benefit of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) such as docosahexaenoic acid (DHA). Some epidemiological studies have suggested that the intake of DHA can alleviate the neurotoxicity of MeHg, but the underlying mechanism is not known. Herein, we observed that pretreatment with 0.1-1 µM DHA suppressed MeHg-induced cytotoxicity in human neuroblastoma (SH-SY5Y) cells and mouse primary neuronal cells. These effects of DHA were canceled in the presence of the retinoid X receptor (RXR) antagonist UVI3003. An RXR agonist, bexarotene, suppressed the cytotoxicity of MeHg. DHA also suppressed the MeHg-induced production of reactive oxygen species (ROS) via an induction of antioxidant genes (catalase and SOD1). Pretreatment with DHA did not change the incorporation of MeHg. We showed previously that in the brain, the intake of DHA increased the level of 19,20-DHDP, which is the metabolite produced by cytochrome P450 and soluble epoxide hydrolase from DHA. In the present study, we observed that 19,20-DHDP also suppressed neurotoxicity from MeHg. These results indicate that DHA and its metabolites have a protective role in MeHg-induced neurotoxicity.
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Ácidos Docosahexaenoicos/farmacología , Compuestos de Metilmercurio/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Antioxidantes/farmacología , Línea Celular Tumoral , Células Cultivadas , Ácidos Docosahexaenoicos/análogos & derivados , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Receptores X Retinoide/agonistasRESUMEN
Miyazaki Urological Cancer Database (MUCD) is a web-based database containing background, treatment, and prognosis of patients with prostate, renal, and urothelial cancers diagnosed in Miyazaki. We entered information on patients diagnosed with urothelial carcinoma from 2014 to 2018 at 4 of the 17 facilities that diagnose urothelial carcinoma in Miyazaki Prefecture. We analyzed the overall survival for bladder cancer and upper urinary tract cancer, and examined its correlation with the presence of symptoms, urine cytology, and clinical TNM classification. There were 487 patients with urothelial carcinoma, comprising 372 (76%) with bladder cancer and 115 (24%) with upper tract urinary cancer. In the bladder cancer group, 301 (81%) patients had symptomatic disease and 119 (32%) had positive urine cytology. The stage according to the TNM classification was Ta-1N0, T2-4N0, N1-2M0 and M1 in 248 (67%), 94 (26%), 19 (5%) and 11 (3%) patients, respectively. In the upper urinary tract cancers group, 89 (76%) had symptomatic disease and 41 (36%) had positive urine cytology. The stage according to the TNM classification was Ta-1N0, T2-4N0, N1-2M0 and M1 in 45 (39%), 37 (32%), 11 (10%) and 22 (19%) patients, respectively. The 3-year survival rates for bladder and upper urinary tract cancer were 83.4% and 67.8%, respectively. TNM classification (≤T1 vs ≥T2≥) was significantly associated with overall survival (bladder cancer : HRï¼7.07, 95% CIï¼3.13-16.0, pï¼0.0001 ; upper tract urinary cancer : HRï¼6.33, 95% CIï¼2.13-18.8, pï¼0.0009). The prognosis of patients with urothelial carcinoma diagnosed in multiple institutions could be evaluated using MUCD. The clinical T stage was significantly associated with overall survival in patients with bladder cancer and patients with upper urinary tract cancer.
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Carcinoma de Células Transicionales , Neoplasias Ureterales , Neoplasias de la Vejiga Urinaria , Neoplasias Urológicas , Carcinoma de Células Transicionales/epidemiología , Estudios de Cohortes , Humanos , Masculino , Pronóstico , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias Urológicas/epidemiologíaRESUMEN
A new method for calculating nuclear magnetic shielding in solutions is developed based on the reference interaction site model self-consistent field (RISM-SCF) with spatial electron density distribution (SEDD). In RISM-SCF-SEDD, the electrostatic interaction between the solute and the solvent is described by considering the spread of electron to obtain more realistic electronic structure in solutions. It is thus expected to allow us to predict more quantitative chemical shifts of a wide variety of chemical species in solutions. In this study, the method is applied to a water molecule in water and is validated by examining the dependence of the solvent temperature and density on chemical shifts. The dependence of solvent species is also investigated, and more accurate results are obtained for polar solvents compared to the previous RISM-SCF study. Another application example of this method is the 15N chemical shifts of two azines in water, which is difficult to predict with the polarizable continuum model (PCM). Our results are in good agreement with the previous quantum mechanical/molecular mechanics study and experimental results. It is also shown that our method gives more realistic results for methanol and acetone than the PCM.
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BACKGROUND: Rituximab (RTX) is effective in maintaining remission in patients with nephrotic syndrome (NS), but a standard protocol of RTX administration has not been established. METHODS: This study was a 2-year multicenter observational study, in which consistent treatments and evaluations were performed. We enrolled pediatric patients with refractory NS between January 2015 and December 2015. RTX infusion was performed four times at 6-month intervals, followed by mizoribine pulse therapy with early discontinuation of calcineurin inhibitor (CNI). Primary endpoints were the relapse-free survival rate and the number of relapses after RTX administration. Secondary endpoints were changes in side effects associated with long-term steroid administration. RESULTS: Twenty-two patients were analyzed. The relapse-free survival rate at 1 year and 2 years was 50 and 46%, respectively. Twenty-one patients accomplished our protocol and the frequency of relapse was reduced under the discontinuation of CNI. Although two patients were diagnosed with frequent relapse and/or steroid dependency during the observation period, the frequency of relapse decreased with each rituximab dose. Statistically significant improvements in all steroid complications were observed in the final examination, but no significant improvements were observed from 1 to 2 years after RTX administration. One patient had agranulocytosis, and three patients showed electrocardiographic abnormalities. CONCLUSIONS: Our protocol was useful and safe for refractory NS. However, RTX administration four times might have been excessive in patients who had no relapse by 1 year after the initial RTX administration. Further investigation of the most appropriate method of RTX administration is required.
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Inhibidores de la Calcineurina/administración & dosificación , Síndrome Nefrótico/tratamiento farmacológico , Rituximab/administración & dosificación , Adolescente , Niño , Resistencia a Medicamentos , Quimioterapia Combinada/métodos , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/administración & dosificación , Infusiones Intravenosas , Masculino , Síndrome Nefrótico/inmunología , Quimioterapia por Pulso , Recurrencia , Inducción de Remisión/métodos , Ribonucleósidos/administración & dosificación , Resultado del TratamientoRESUMEN
Brain edema is a severe complication that accompanies ischemic stroke. Increasing evidence shows that inflammatory cytokines impair tight junctions of the blood-brain barrier, suggesting the involvement of microglia in brain edema. In this study, we examined the role of microglia in the progression of ischemic brain edema using mice with permanent middle cerebral artery occlusion. The intensity of T2-weighted imaging (T2WI) in the cerebral cortex and the striatum was elevated 3â¯h after occlusion and spread to peripheral regions of the ischemic hemisphere. Merged images of 2,3,5-triphenyl tetrazolium chloride staining and T2WI revealed the exact vasogenic edema region, which spread from the ischemic core to outside the ischemic region. Microglia were strongly activated in the ischemic region 3â¯h after occlusion and, notably, activated microglia were observed in the non-ischemic region 24â¯h after occlusion. Pretreatment with minocycline, an inhibitor of microglial activation clearly suppressed not only vasogenic edema but also infarct formation. We demonstrated in this study that vasogenic edema spreads from the ischemic core to the peripheral region, which can be elicited, at least in part, by microglial activation induced by ischemia.
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Edema Encefálico/etiología , Encéfalo/patología , Infarto de la Arteria Cerebral Media/complicaciones , Microglía/patología , Animales , Edema Encefálico/patología , Progresión de la Enfermedad , Infarto de la Arteria Cerebral Media/patología , Masculino , Ratones Endogámicos ICR , Agua/análisisRESUMEN
The majority of computational methods for predicting toxicity of chemicals are typically based on "nonmechanistic" cheminformatics solutions, relying on an arsenal of QSAR descriptors, often vaguely associated with chemical structures, and typically employing "black-box" mathematical algorithms. Nonetheless, such machine learning models, while having lower generalization capacity and interpretability, typically achieve a very high accuracy in predicting various toxicity endpoints, as unambiguously reflected by the results of the recent Tox21 competition. In the current study, we capitalize on the power of modern AI to predict Tox21 benchmark data using merely simple 2D drawings of chemicals, without employing any chemical descriptors. In particular, we have processed rather trivial 2D sketches of molecules with a supervised 2D convolutional neural network (2DConvNet) and demonstrated that the modern image recognition technology results in prediction accuracies comparable to the state-of-the-art cheminformatics tools. Furthermore, the performance of the image-based 2DConvNet model was comparatively evaluated on an external set of compounds from the Prestwick chemical library and resulted in experimental identification of significant and previously unreported antiandrogen potentials for several well-established generic drugs.
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Aprendizaje Profundo , Descubrimiento de Drogas , Modelos Biológicos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/toxicidad , Algoritmos , Gráficos por Computador , Bases de Datos Farmacéuticas , Descubrimiento de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Humanos , Modelos Químicos , Preparaciones Farmacéuticas/químicaRESUMEN
Estrogen receptor-α positive (ERαâº) breast cancers represent 75% of all invasive breast cancer cases, while de novo or acquired resistance to ER-directed therapy is also on the rise. Numerous factors contribute to this phenomenon including the recently-reported ESR1 gene mutations such as Y537S, which amplifies co-activator interactions with ERα and promotes constitutive activation of ERα function. Herein, we propose that direct targeting of the activation function-2 (AF2) site on ERα represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer. A systematic computer-guided drug discovery approach was employed to develop a potent ERα inhibitor that was extensively evaluated by a series of experiments to confirm its AF2-specific activity. We demonstrate that the developed small-molecule inhibitor effectively prevents ERα-coactivator interactions and exhibits a strong anti-proliferative effect against tamoxifen-resistant cells, as well as downregulates ERα-dependent genes and effectively diminishes the receptor binding to chromatin. Notably, the identified lead compound successfully inhibits known constitutively-active, resistance-associated mutant forms of ERα observed in clinical settings. Overall, this study reports the development of a novel class of ERα AF2 inhibitors, which have the potential to effectively inhibit ERα activity by a unique mechanism and to circumvent the issue of mutation-driven resistance in breast cancer.