RESUMO
BACKGROUND: Recently, a method using deep learning has been developed to estimate the risk of developing dementia. This method uses general blood test data from routine health examinations that reveal lifestyle-related diseases, which can lead to vascular cognitive impairment via arteriosclerosis, as well as systemic metabolic disorders that are unrelated to lifestyle, such as nutritional disorders. In this study, we investigated the differences in the accuracy of estimating the risk of dementia based on the presence or the absence of blood test parameters reflecting nutritional disorders while focusing on the association between malnutrition and the risk of dementia in frail, elderly individuals. OBJECTIVES: The objective of this study was to evaluate the impact of including or excluding serum albumin, which reflects nutritional status, on the accuracy of predicting cognitive function in older adults using blood test data. METHODS: We estimated cognitive function, as measured by the Mini-Mental State Examination (MMSE), using the deep learning model (DLM). The estimation was performed based on general blood test data, including complete blood tests and basic metabolic panels, obtained from a selection of 1287 patients admitted to Osaka Medical and Pharmaceutical University Hospital. The data were divided into two groups: individuals aged 65 and above and those aged below 65. The impact of including or excluding serum albumin on the predictive performance of MMSE was examined within each group. RESULTS: In those aged below 65, the mean squared error (MSE) of the DLM was 5.33 without albumin and 4.62 with albumin, showing a -0.71 improvement with albumin. In those aged 65 and above, the MSE of the DLM was 6.38 without albumin and 6.28 with albumin, showing a -0.1 improvement with albumin. DISCUSSION: The present study demonstrated that including serum albumin in the input data resulted in lower estimation errors for MMSE across all applied algorithms in the group aged 65 and above. This is consistent with previously reported studies that have shown the adverse effects of malnutrition on cognitive function in older adults. CONCLUSIONS: This study highlighted the significance of serum albumin, which reflects nutritional status, as an important assessment variable for estimating MMSE from blood test data, particularly in individuals aged 65 and above.
Assuntos
Cognição , Aprendizado Profundo , Humanos , Idoso , Feminino , Masculino , Cognição/fisiologia , Idoso de 80 Anos ou mais , Demência/sangue , Demência/diagnóstico , Estado Nutricional , Albumina Sérica Humana/análise , Pessoa de Meia-Idade , Testes de Estado Mental e Demência , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Testes Hematológicos/métodos , Desnutrição/sangue , Desnutrição/diagnóstico , Albumina Sérica/análiseRESUMO
N-[(4R)-5,7-Difluoro-2'-(5-methylpyridin-2-yl)-4'-oxo-2,2',3,4',5',7'-hexahydrospiro[1-benzopyran-4,6'-pyrazolo[4,3-c]pyridin]-3'-yl]-2-(methanesulfonyl)acetamide (S-309309) is an anti-obesity drug developed by Shionogi & Co., Ltd. that has a monoacylglycerol acyltransferase 2 inhibitory effect. S-309309 has poor wettability, and the amount of the degradation product (4R)-3'-amino-5,7-difluoro-2'-(5-methylpyridin-2-yl)-2,2',3,7'-tetrahydrospiro[[1]benzopyran-4,6'-pyrazolo[4,3-c]pyridin]-4'(5'H)-one (compound 8) increases over time under acidic conditions. In this study, we have tried to improve S-309309 wettability and suppress the amount of degradation product increased under acidic conditions. As a result of the study, we found that by mixing with a water-soluble polymer, the wettability of S-309309 and its dissolved concentration in fluid were increased suggesting that its dissolution behavior should be enhanced. In addition, by encapsulating S-309309, the increase of degradation product amount was suppressed under acidic conditions, suggesting that the suppression of degradation product formation would be expected in the stomach after oral dosing. Overall, these results suggest that the drug property issues of S-309309 can be overcome by mixing S-309309 with a water-soluble polymer and encapsulation.
Assuntos
Inibidores Enzimáticos , Molhabilidade , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Aciltransferases/antagonistas & inibidores , Aciltransferases/metabolismo , Estabilidade de Medicamentos , Desenho de Fármacos , Animais , Composição de Medicamentos , Estrutura Molecular , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/síntese químicaRESUMO
OBJECTIVES: To determine candidates for extended pelvic lymph node dissection using a novel nomogram to assess the risk of lymph node invasion in Japanese prostate cancer patients in the robotic era. METHODS: A total of 538 patients who underwent robot-assisted radical prostatectomy with extended pelvic lymph node dissection in three hospitals were retrospectively analyzed. Medical records were reviewed uniformly and the following data collected: prostate-specific antigen, age, clinical T stage, primary and secondary Gleason score at prostate biopsy, and percentage of positive core numbers. Finally, data from 434 patients were used for developing the nomogram and data from 104 patients were used for external validation. RESULTS: Lymph node invasion was detected in 47 (11%) and 16 (15%) patients in the development and validation set, respectively. Based on multivariate analysis, prostate-specific antigen, clinical T stage ≥3, primary Gleason score, grade group 5, and percentage of positive cores were selected as variables to incorporate into the nomogram. The area under the curve values were 0.781 for the internal and 0.908 for the external validation, respectively. CONCLUSIONS: The present nomogram can help urologists identify candidates for extended pelvic lymph node dissection concomitant with robot-assisted radical prostatectomy among patients with prostate cancer.
Assuntos
Neoplasias da Próstata , Procedimentos Cirúrgicos Robóticos , Robótica , Masculino , Humanos , Nomogramas , Antígeno Prostático Específico , Estudos Retrospectivos , Metástase Linfática/patologia , Excisão de Linfonodo , Linfonodos/cirurgia , Linfonodos/patologia , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/patologia , ProstatectomiaRESUMO
miRNAs play critical roles in various biological processes by targeting specific mRNAs. Current approaches to identifying miRNA targets are insufficient for elucidation of a miRNA regulatory network. Here, we created a cell-based screening system using a luciferase reporter library composed of 4,891 full-length cDNAs, each of which was integrated into the 3' UTR of a luciferase gene. Using this reporter library system, we conducted a screening for targets of miR-34a, a tumor-suppressor miRNA. We identified both previously characterized and previously uncharacterized targets. miR-34a overexpression in MDA-MB-231 breast cancer cells repressed the expression of these previously unrecognized targets. Among these targets, GFRA3 is crucial for MDA-MB-231 cell growth, and its expression correlated with the overall survival of patients with breast cancer. Furthermore, GFRA3 was found to be directly regulated by miR-34a via its coding region. These data show that this system is useful for elucidating miRNA functions and networks.
Assuntos
Neoplasias da Mama/genética , Biblioteca Gênica , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , MicroRNAs/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , MicroRNAs/metabolismo , RNA Helicases/genética , Transativadores/genéticaRESUMO
Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4DCAF15 mediated ubiquitination in human cancer cell lines. Both CRISPR-Cas9-based knockout of DCAF15 and a single amino acid substitution of CAPERα conferred resistance against sulfonamide-induced CAPERα degradation and cell-growth inhibition. Thus, these sulfonamides represent selective chemical probes for disrupting CAPERα function and designate DCAFs as promising drug targets for promoting selective protein degradation in cancer therapy.
Assuntos
Indóis/farmacologia , Proteínas Nucleares/metabolismo , Splicing de RNA , Proteínas de Ligação a RNA/metabolismo , Sulfonamidas/metabolismo , Antineoplásicos/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteólise/efeitos dos fármacos , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Sulfonamidas/farmacologiaRESUMO
OBJECTIVES: To examine the effectiveness of intravesical irrigation with physiological saline solution or distilled water for the prevention of bladder recurrence in patients undergoing laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma. METHODS: This retrospective study involved 109 upper urinary tract urothelial carcinoma patients who underwent laparoscopic nephroureterectomy, and were evaluated at Chiba University Hospital and Yokohama Rosai Hospital between 2001 and 2018. We investigated the outcomes and analyzed various clinical factors including with or without intravesical irrigation related to bladder carcinoma recurrence after surgery. Physiological saline solution or distilled water was used for irrigation, which was carried out only during surgery. RESULTS: The median follow-up period after surgery was 26.1 months. Bladder recurrence was confirmed within 2 years for 45 of the 109 patients in the present study. Irrigation was carried out for 48 cases (distilled water, 26 patients; physiological saline solution, 22 patients). Tumor grade (G1-2 vs G3; P = 0.05) and intravesical irrigation (yes vs no; P = 0.0058) were related to bladder recurrence on univariate analyses. On multivariate analyses, intravesical irrigation was the independent factor involved in the prevention of bladder recurrence (P = 0.0051). Comparison between the irrigation and non-irrigation groups showed that bladder recurrence rates were significantly lower in the irrigation group (irrigation group vs non-irrigation group: 25.0% vs 52.5%, P = 0.0066). There was no significant difference in the recurrence rate between the two solutions used for irrigation. CONCLUSIONS: Intravesical irrigation during surgery of upper urinary tract urothelial carcinoma might decrease postoperative bladder recurrence rates.
Assuntos
Carcinoma de Células de Transição/cirurgia , Neoplasias Renais/cirurgia , Recidiva Local de Neoplasia/prevenção & controle , Nefroureterectomia/métodos , Solução Salina/administração & dosagem , Neoplasias Ureterais/cirurgia , Administração Intravesical , Idoso , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Inoculação de Neoplasia , Estudos Retrospectivos , Irrigação Terapêutica/métodos , Bexiga Urinária , Água/administração & dosagemRESUMO
Osteoarthritis (OA), the most prevalent aging-related joint disease, is characterized by insufficient extracellular matrix synthesis and articular cartilage degradation, mediated by several proteinases, including Adamts-5. miR-140 is one of a very limited number of noncoding microRNAs (miRNAs) specifically expressed in cartilage; however, its role in development and/or tissue maintenance is largely uncharacterized. To examine miR-140 function in tissue development and homeostasis, we generated a mouse line through a targeted deletion of miR-140. miR-140(-/-) mice manifested a mild skeletal phenotype with a short stature, although the structure of the articular joint cartilage appeared grossly normal in 1-mo-old miR-140(-/-) mice. Interestingly, miR-140(-/-) mice showed age-related OA-like changes characterized by proteoglycan loss and fibrillation of articular cartilage. Conversely, transgenic (TG) mice overexpressing miR-140 in cartilage were resistant to antigen-induced arthritis. OA-like changes in miR-140-deficient mice can be attributed, in part, to elevated Adamts-5 expression, regulated directly by miR-140. We show that miR-140 regulates cartilage development and homeostasis, and its loss contributes to the development of age-related OA-like changes.
Assuntos
Cartilagem/crescimento & desenvolvimento , Homeostase/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas ADAM/metabolismo , Proteína ADAMTS5 , Animais , Desenvolvimento Ósseo/genética , Homeostase/genética , Articulação do Joelho/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Osteoartrite/patologiaRESUMO
BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects in the early stage of atherosclerosis in patients with type 2 diabetes, although similar effects in advanced atherosclerosis were not shown in recent randomized placebo-controlled studies. Therefore, we investigated the efficacy of DPP-4 inhibitor on endothelial function and glycemic metabolism compared with high-dose metformin. METHODS: In this multicenter, open-labeled, prospective, randomized, parallel-group comparison study, patients with type 2 diabetes treated with low-dose metformin (500-750 mg/day) were enrolled and randomly assigned to a vildagliptin, a DPP-4 inhibitor, add-on group (Vilda) or a double dose of metformin group (high Met) for 12 weeks. Flow-mediated dilation (FMD) and serum metabolic markers were assessed before and after treatment. In addition, glycemic control and metabolic parameters were also assessed. RESULTS: Ninety-seven subjects (aged 58.7 ± 11.0 years; body mass index, 25.9 ± 4.4 kg/m2; HbA1c, 7.3 ± 0.5%; FMD, 5.8 ± 2.6%) were enrolled. Eight subjects dropped out by the end of the study. There were no significant differences between the two groups in baseline characteristics. After 12 weeks, HbA1c was significantly improved in the Vilda group compared with the high Met group (- 0.80 ± 0.38% vs. - 0.40 ± 0.47%, respectively; p < 0.01). However, there were no significant differences in FMD (- 0.51 [- 1.08-0.06]% vs. - 0.58 [- 1.20-0.04]%). Although the apolipoprotein B/apolipoprotein A1 ratio was significantly reduced in the Vilda group compared with baseline (0.66-0.62; p < 0.01), the change did not differ significantly between the two groups (- 0.04 vs. 0.00; p = 0.27). Adiponectin levels were significantly increased in the Vilda group compared with the high Met group (0.75 µg/mL vs. 0.01 µg/mL; p < 0.01). CONCLUSIONS: Regardless of glycemic improvement, combination therapy of vildagliptin and metformin did not affect endothelial function but may exert favorable effects on adipokine levels and lipid profile in patients with type 2 diabetes without advanced atherosclerosis.
Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Nitrilas/administração & dosagem , Pirrolidinas/administração & dosagem , Adamantano/administração & dosagem , Adulto , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada , Endotélio Vascular/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , VildagliptinaRESUMO
Spinocerebellar ataxia type 31 (SCA31) is known as a late-onset, relatively pure cerebellar form of ataxia, but a longitudinal prospective study on the natural history of SCA31 has not been done yet. In this prospective cohort study, we enrolled 44 patients (mean ± standard deviation 73.6 ± 8.5 years) with genetically confirmed SCA31 from 10 ataxia referral centers in the Nagano area, Japan. Patients were evaluated every year for 4 years using the Scale for the Assessment and Rating of Ataxia (SARA) and the Barthel Index (BI). Of the 176 follow-up visits (91.5%), 161 were completed in this study. Five patients (11.4%) died during the follow-up period, and two patients (4.5%) were lost to follow-up. The annual progression of the SARA score was 0.8 ± 0.1 points/year and that of the BI was -2.3 ± 0.4 points/year (mean ± standard error). Shorter disease duration at baseline was associated with faster progression of the SARA score. Our study indicated the averaged clinical course of SCA31 as follows: the patients develop ataxic symptoms at 58.5 ± 10.3 years, become wheelchair bound at 79.4 ± 1.7 years, and died at 88.5 ± 0.7 years. Our prospective dataset provides important information for clinical trials of forthcoming disease-modifying therapies for cerebellar ataxia. It also represents a useful resource for SCA31 patients and their family members in genetic counseling sessions.
Assuntos
Ataxias Espinocerebelares/fisiopatologia , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Família , Feminino , Seguimentos , Humanos , Japão , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Análise de Regressão , Índice de Gravidade de Doença , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/reabilitação , Fatores de Tempo , Cadeiras de RodasRESUMO
κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.
Assuntos
Analgésicos/farmacologia , Descoberta de Drogas , Morfinanos/farmacologia , Dor/tratamento farmacológico , Receptores Opioides kappa/agonistas , Compostos de Espiro/farmacologia , Ácido Acético , Analgésicos/síntese química , Analgésicos/química , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Conformação Molecular , Morfinanos/síntese química , Morfinanos/química , Dor/induzido quimicamente , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
(Objectives) Radiation induced cystitis (RC) is one of the toxicities we must often treat after radiation therapy for prostate cancer.Some patients require urinary diversion with or without cystectomy.We evaluated the clinical risks and management of RC. (Patients and methods) The clinical records of 303 patients who underwent radiation therapy for prostate cancer (199 only radiation therapy; 104 adjuvant or salvage radiation therapy after radical prostatectomy) between 2005 and 2015 in our institute, were reviewed.We defined RC based on the presence of macrohematuria, not caused by reccurence of prostate cancer or occurrence of bladder cancer. (Results) The median follow up time was 37 months (range 1-132).Thirty patients (9.9%) developed RC.Compared to radiation therapy alone, adjuvant/salvage radiation therapy was found to be a risk for RC (4.5% vs. 20.1%, p< 0.01).Ten out of 30 RC patients needed hospitalization and 6 patients underwent urinary diversion with or without cystectomy.Two patients who underwent urinary diversion without cystectomy were hospitalized for a longer period compared with 4 patients with cystectomy. (Conclusion) Adjuvant/salvage therapy is a risk factor of RC after radiation therapy for prostate cancer.About 2% of the patients needed urinary diversion and cystectomy improved their prognosis.
RESUMO
Influenza A virus is an RNA virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle. Knowledge of these host cell requirements not only informs us of the molecular pathways exploited by the virus but also provides further targets that could be pursued for antiviral drug development. Here we use an integrative systems approach, based on genome-wide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signalling, ubiquitination and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host-pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wild-type influenza virus growth, and further analysis of a subset of genes showed 23 factors necessary for viral entry, including members of the vacuolar ATPase (vATPase) and COPI-protein families, fibroblast growth factor receptor (FGFR) proteins, and glycogen synthase kinase 3 (GSK3)-beta. Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) IIbeta (CAMK2B). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and we show that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.
Assuntos
Fatores Biológicos/genética , Fatores Biológicos/fisiologia , Interações Hospedeiro-Patógeno/fisiologia , Vírus da Influenza A/crescimento & desenvolvimento , Influenza Humana/genética , Influenza Humana/virologia , Replicação Viral/fisiologia , Animais , Linhagem Celular , Chlorocebus aethiops , Biblioteca Gênica , Genoma Humano/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Vírus da Influenza A Subtipo H1N1/classificação , Vírus da Influenza A Subtipo H1N1/crescimento & desenvolvimento , Vírus da Influenza A/classificação , Interferência de RNA , Células Vero , Internalização do VírusRESUMO
(Objectives) To evaluate the safety and oncologic efficacy of laparoscopic radical nephrectomy (LRN) for renal cell carcinoma (RCC) >7 cm, we retrospectively reviewed the clinical outcome and long-term cancer control of patients who underwent LRN in comparison to open radical nephrectomy (ORN). (Patients and methods) The clinical records of 79 patients with RCC >7 cm, who underwent radical nephrectomy (37 LRN; 42 ORN) between 1993 and 2014, were reviewed. (Results) The 2 groups (LRN and ORN) were comparable regarding age, body mass index and mean tumor size (86.5 mm vs. 94.6 mm).The operative time was significantly longer in the LRN group than ORN group (204 min vs. 168 min; p<0.05) and blood loss was significantly lower in the LRN group than in the ORN group (144 ml vs. 930 ml; p<0.05).No statistically significant difference was found in complication rate (10.8% vs. 23.8%) and the 2-year recurrence-free survival rate (85.6% vs. 83.8%). (Conclusion) Despite the longer operative time, LRN for large RCC was associated with lower blood loss. This study provides evidence of the safety and efficacy of LRN for large RCC.
RESUMO
A 68-year-old woman presented with asymptomatic gross hematuria. Computed tomography (CT) scan revealed noninvasive tumor in the right ureteropelvic junction. After diagnosis with right pelvis carcinoma by ureteroscopy, she underwent laparoscopic nephroureterectomy in Aug. 2008. Six months later, hepatic metastasis was detected. Three courses of combination chemotherapy consisting of gemcitabine and cisplatin (GC) were conducted, and then partial response (PR) was achieved. In Aug. 2009, radical metastasectomy for liver metastasis was performed. More than four years and five months after hepatectomy, the patient has achieved a high quality of life.
Assuntos
Neoplasias Renais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pélvicas/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Hepatectomia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Laparoscopia , Neoplasias Hepáticas/cirurgia , Metastasectomia , Nefrectomia , Neoplasias Pélvicas/tratamento farmacológico , Neoplasias Pélvicas/cirurgia , Recidiva , GencitabinaRESUMO
A 77-year-old man was diagnosed with cold agglutinin disease in 2004. He had been treated with prednisolone with stabilization of hemoglobin in the 6- to 8-g/dl range. However, his hemolytic anemia worsened, and computed tomography showed systemic lymphadenopathy in May 2012. A pathological diagnosis of small lymphocytic lymphoma was made based on an inguinal lymph node biopsy. Treatment was started with rituximab. However, there was no response to 6 doses of rituximab monotherapy. He next received 6 courses of bendamustine in combination with rituximab. This resulted in stabilization of hemoglobin and independence from transfusion support. To the best of our knowledge, this is only the second case report describing bendamustine plus rituximab treatment for non-Hodgkin lymphoma complicated by cold agglutinin disease. Our results in this case suggest bendamustine to potentially be a useful therapeutic option in patients with cold agglutinin disease.
Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Compostos de Mostarda Nitrogenada/uso terapêutico , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Cloridrato de Bendamustina , Humanos , Masculino , Compostos de Mostarda Nitrogenada/administração & dosagem , Rituximab , Resultado do TratamentoRESUMO
Cancer is a leading cause of death and still awaits effective therapies. Rapid industrialization has contributed to increase in incidence of cancer. One of the reasons why most of the cancers fail therapy is due to their metastatic property. Hence identification of factors leading to metastasis is highly important to design effective and novel anti-cancer therapeutics. In our earlier study (Inoue, A., Sawata, S. Y., Taira, K., and Wadhwa, R. (2007) Loss-of-function screening by randomized intracellular antibodies: identification of hnRNP-K as a potential target for metastasis. Proc. Natl. Acad. Sci. U.S.A. 104, 8983-8988), we had reported that the involvement of heterogeneous nuclear ribonucleoprotein K (hnRNP-K) in metastasis. Here, we established hnRNP-K-overexpressing and -underexpressing derivative cell lines and examined their proliferation and metastatic properties in vitro and in vivo. Whereas hnRNP-K compromised cells showed delayed tumor growth, its overexpression resulted in enhanced malignancy and metastasis. Molecular basis of the hnRNP-K induced malignant and metastatic phenotypes was dissected by cDNA microarray and pathway analyses. We found that the hnRNP-K regulates extracellular matrix, cell motility, and angiogenesis pathways. Involvement of the selected genes (Cck, Mmp-3, Ptgs2, and Ctgf) and pathways was validated by gene-specific expression analysis. Our results demonstrated that the hnRNP-K is a potential target for metastasis therapy.
Assuntos
Movimento Celular , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/biossíntese , Proteínas de Neoplasias/biossíntese , Neoplasias Experimentais/metabolismo , Neovascularização Patológica/metabolismo , Animais , Linhagem Celular Tumoral , Matriz Extracelular/genética , Matriz Extracelular/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologiaRESUMO
The first enantioselective total synthesis of penostatin E has been accomplished. Two highly efficient and diastereoselective reactions, a Hosomi-Sakurai allylation and an intramolecular Pauson-Khand reaction, were utilized for the construction of the basic carbon framework of the target molecule as the key steps. A late-stage introduction of the side chain and a successful base-promoted elimination reaction afforded an efficient synthetic route to (+)-penostatin E.
Assuntos
Alcenos/química , Indenos/química , Indenos/síntese química , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
Cerebral toxoplasmosis is a rare, potentially fatal, complication of hematopoietic cell transplantation. Early definitive diagnosis is very difficult and it may be associated with a poor prognosis. Herein, we describe a 60-year-old woman who developed cerebral toxoplasmosis after cord blood transplantation for myelodysplastic syndrome. During treatment with tacrolimus and methylprednisolone for relapsed grade 2 acute gut GVHD, fever and disturbance of consciousness occurred on day 210. Brain MRI showed multiple ring-enhancing nodular lesions in the thalamus, basal ganglia, brainstem, and subcortical white matter. Cerebrospinal fluid (CSF) assessment revealed elevations of both anti-to-xoplasma IgM and IgG, which were also elevated in serum, but no evidence of other infections or malignancies. Notably, the IgM level was higher in the CSF than in serum. Thus, cerebral toxoplasmosis was diagnosed. Soon after administration of oral sulfamethoxazole/trimethoprim and intravenous clindamycin in combination with short-term dexamethasone for the cerebral edema, her symptoms and signs began to improve. On day 229, both IgM and IgG titers in CSF had clearly decreased but remained essentially constant in serum. She was discharged without clinically significant neurological disorders. This case suggests that CSF specific anti-toxoplasma IgM titers might be useful for early diagnosis of cerebral toxoplasmosis after transplantation.
Assuntos
Anticorpos Antiprotozoários/líquido cefalorraquidiano , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Imunoglobulina M/líquido cefalorraquidiano , Toxoplasma/imunologia , Toxoplasmose Cerebral/diagnóstico , Toxoplasmose Cerebral/etiologia , Biomarcadores/líquido cefalorraquidiano , Clindamicina/uso terapêutico , Diagnóstico Precoce , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Tacrolimo/efeitos adversos , Toxoplasmose Cerebral/tratamento farmacológico , Resultado do Tratamento , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
Introduction: In this study, we investigated the correlation between serum albumin levels and cognitive function, and examined the impact of including serum albumin values in the input layer on the prediction accuracy when forecasting cognitive function using deep learning and other machine learning models. Methods: We analyzed the electronic health record data from Osaka Medical and Pharmaceutical University Hospital between 2014 and 2021. The study included patients who underwent cognitive function tests during this period; however, patients from whom blood test data was not obtained up to 30 days before the cognitive function tests and those with values due to measurement error in blood test results were excluded. The Mini-Mental State Examination (MMSE) was used as the cognitive function test, and albumin levels were examined as the explanatory variable. Furthermore, we estimated MMSE scores from blood test data using deep learning models (DLM), linear regression models, support vector machines (SVM), decision trees, random forests, extreme gradient boosting (XGBoost), and light gradient boosting machines (LightGBM). Results: Out of 5,017 patients who underwent cognitive function tests, 3,663 patients from whom blood test data had not been obtained recently and two patients with values due to measurement error were excluded. The final study population included 1,352 patients, with 114 patients (8.4%) aged below 65 and 1,238 patients (91.6%) aged 65 and above. In patients aged 65 and above, the age and male sex showed significant associations with MMSE scores of less than 24, while albumin and potassium levels showed negative associations with MMSE scores of less than 24. Comparing MMSE estimation performance, in those aged below 65, the mean squared error (MSE) of DLM was improved with the inclusion of albumin. Similarly, the MSE improved when using SVM, random forest and XGBoost. In those aged 65 and above, the MSE improved in all models. Discussion: Our study results indicated a positive correlation between serum albumin levels and cognitive function, suggesting a positive correlation between nutritional status and cognitive function in the elderly. Serum albumin levels were shown to be an important explanatory variable in the estimation of cognitive function for individuals aged 65 and above.
RESUMO
Although novel techniques for avoiding incontinence during robot-assisted radical prostatectomy have been developed, long-term oncological outcomes are unknown. The objective of this study was to determine the long-term oncological outcomes and functional outcomes of novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation for a single surgeon. Data from 100 patients who underwent structure-preserving prostatectomies performed by a single surgeon were retrospectively analyzed. The median console time was 123 min. Bilateral nerve-sparing was performed in 43% of patients underwent, and 57% underwent unilateral nerve-sparing surgery. Most patients (96%) reached complete pad-zero urinary continence by one year after surgery. Satisfactory erectile function was achieved in 97% of patients who underwent bilateral nerve-sparing surgery, and 80% of patients who underwent unilateral nerve-sparing surgery. The surgical margin was positive for 25% of patients, and the biochemical recurrence-free rate at 5 years was 77%. The cancer-specific survival rate was 100% during the median follow-up period of 4.5 years. Clavien-Dindo grade III complications occurred in 1% of cases. The outcomes for novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation were similar to previously reported oncological outcomes, with satisfactory functional outcomes. This operative method may be useful for patients who are eligible for nerve-sparing surgery.