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1.
Anticancer Res ; 39(10): 5803-5809, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570485

RESUMO

BACKGROUND/AIM: Cabazitaxel (CBZ) is approved for docetaxel-resistant castration-resistant prostate cancer (CRPC). This retrospective study aimed at assessing the efficacy and prognostic markers of cabazitaxel treatment in Japanese CRPC patients. PATIENTS AND METHODS: The medical records of 44 consecutive Japanese patients with CRPC who started cabazitaxel at our Institution between January 2011 and February 2019 were reviewed and statistically analysed. RESULTS: The median follow-up period after cabazitaxel initiation was 13.2 [interquartile range (IQR)=6.9-21.5] months. The objective response rate, median progression-free survival period, and median overall survival period (OS) were 45.5%, 4.3 months, and 20.7 months, respectively. On multivariate analysis, higher prostate-specific antigen (PSA; >100 ng/ml), lower haemoglobin (<10 g/dl), and lower number of prior docetaxel therapy cycles (<10) were predictors for shorter OS. CONCLUSION: Patients with anemia, high PSA, and lower number of docetaxel therapy cycles might have shorter survival period from introduction of cabazitaxel therapy. In addition, PSA decline might still be a useful indicator as a predictor of prognosis of the metastatic CRPC patients treated with cabazitaxel.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Docetaxel/uso terapêutico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/mortalidade , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
2.
J Vis Exp ; (150)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31475990

RESUMO

Through whole-exome/genome sequencing, human geneticists identify rare variants that segregate with disease phenotypes. To assess if a specific variant is pathogenic, one must query many databases to determine whether the gene of interest is linked to a genetic disease, whether the specific variant has been reported before, and what functional data is available in model organism databases that may provide clues about the gene's function in human. MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) is a one-stop data collection tool for human genes and variants and their orthologous genes in seven model organisms including in mouse, rat, zebrafish, fruit fly, nematode worm, fission yeast, and budding yeast. In this Protocol, we provide an overview of what MARRVEL can be used for and discuss how different datasets can be used to assess whether a variant of unknown significance (VUS) in a known disease-causing gene or a variant in a gene of uncertain significance (GUS) may be pathogenic. This protocol will guide a user through searching multiple human databases simultaneously starting with a human gene with or without a variant of interest. We also discuss how to utilize data from OMIM, ExAC/gnomAD, ClinVar, Geno2MP, DGV and DECHIPHER. Moreover, we illustrate how to interpret a list of ortholog candidate genes, expression patterns, and GO terms in model organisms associated with each human gene. Furthermore, we discuss the value protein structural domain annotations provided and explain how to use the multiple species protein alignment feature to assess whether a variant of interest affects an evolutionarily conserved domain or amino acid. Finally, we will discuss three different use-cases of this website. MARRVEL is an easily accessible open access website designed for both clinical and basic researchers and serves as a starting point to design experiments for functional studies.

3.
Intern Med ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31554755
4.
J Vis Exp ; (150)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31498321

RESUMO

Advances in sequencing technology have made whole-genome and whole-exome datasets more accessible for both clinical diagnosis and cutting-edge human genetics research. Although a number of in silico algorithms have been developed to predict the pathogenicity of variants identified in these datasets, functional studies are critical to determining how specific genomic variants affect protein function, especially for missense variants. In the Undiagnosed Diseases Network (UDN) and other rare disease research consortia, model organisms (MO) including Drosophila, C. elegans, zebrafish, and mice are actively used to assess the function of putative human disease-causing variants. This protocol describes a method for the functional assessment of rare human variants used in the Model Organisms Screening Center Drosophila Core of the UDN. The workflow begins with gathering human and MO information from multiple public databases, using the MARRVEL web resource to assess whether the variant is likely to contribute to a patient's condition as well as design effective experiments based on available knowledge and resources. Next, genetic tools (e.g., T2A-GAL4 and UAS-human cDNA lines) are generated to assess the functions of variants of interest in Drosophila. Upon development of these reagents, two-pronged functional assays based on rescue and overexpression experiments can be performed to assess variant function. In the rescue branch, the endogenous fly genes are "humanized" by replacing the orthologous Drosophila gene with reference or variant human transgenes. In the overexpression branch, the reference and variant human proteins are exogenously driven in a variety of tissues. In both cases, any scorable phenotype (e.g., lethality, eye morphology, electrophysiology) can be used as a read-out, irrespective of the disease of interest. Differences observed between reference and variant alleles suggest a variant-specific effect, and thus likely pathogenicity. This protocol allows rapid, in vivo assessments of putative human disease-causing variants of genes with known and unknown functions.

5.
Curr Protoc Bioinformatics ; 67(1): e85, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31524990

RESUMO

One of the greatest challenges in the bioinformatic analysis of human sequencing data is identifying which variants are pathogenic. Numerous databases and tools have been generated to address this difficulty. However, these many useful data and tools are broadly dispersed, requiring users to search for their variants of interest through human genetic databases, variant function prediction tools, and model organism databases. To solve this problem, we collected data and observed workflows of human geneticists, clinicians, and model organism researchers to carefully select and display valuable information that facilitates the evaluation of whether a variant is likely to be pathogenic. This program, Model organism Aggregated Resources for Rare Variant ExpLoration (MARRVEL) v1.2, allows users to collect relevant data from 27 public sources for further efficient bioinformatic analysis of the pathogenicity of human variants. © 2019 by John Wiley & Sons, Inc.

6.
Int J Clin Oncol ; 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31522314

RESUMO

BACKGROUND: Nivolumab, which has a promising anti-tumor efficacy and a manageable safety profile, has being rapidly introduced in metastatic renal cell cancer therapy in Japan. We evaluated the efficacy and adverse events of nivolumab in real world clinical practice in Japan. METHODS: The medical records of 45 consecutive patients who started treatment with nivolumab, up to September 2018, were reviewed and statistically analyzed. RESULTS: The median follow-up period was 22.3 months. The best responses were a complete response in three patients (8%), a partial response in 14 patients (36%), stable disease in 14 patients (36%), and progressive disease in eight patients (20%). The median progression-free survival period and 1 year progression-free survival rate were 14.9 months and 54.5%, respectively. The estimated overall survival period and 1-year and 2-year overall survival rates from initiation of nivolumab were not reached, and 91.1%, and 86.2%, respectively. Twenty-seven patients (60%) experienced adverse events including four (10%) severe adverse events (Grade 3 or 4). The most common adverse event was rash (n = 9, 20%). Five patients discontinued nivolumab therapy, because of an adverse event (Grade 3 diarrhea, one patient; Grade 2 fatigue, one patient; Grade 3 uveitis, two patients; and Grade 3 adrenal insufficiency, one patient). CONCLUSIONS: Nivolumab has a relatively favorable efficacy and safety profile for Japanese metastatic renal cell cancer patients in clinical practice.

8.
Urol Int ; : 1-6, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31461724

RESUMO

OBJECTIVES: To analyze the incidence and predictors of deep vein thrombosis (DVT) in patients with elevated D-dimer prior to surgery for urologic malignancy. METHODS: Between January 2015 and September 2017, 987 consecutive patients underwent surgery for urologic malignancy under general anesthesia in our institution. Of these, 191 patients underwent preoperative venous ultrasonography of the lower extremities for DVT due to elevated D-dimer. We analyzed the incidence and predictors of DVT in these patients. RESULTS: The median age was 69 years. DVT was detected in 18% of patients (35/191). Multivariate analysis showed that the primary site of urologic malignancy (p < 0.01) and older age (p < 0.01) were independent predictors of DVT. Patients with bladder cancer had the highest incidence of DVT. When bladder cancer and age of 70 or older were defined as predictors for DVT, the incidence of DVT in zero, 1, and 2 predictors was 3.4% (3/89), 29% (22/77), and 44% (11/25), respectively. CONCLUSIONS: DVT was found in 18% of patients with elevated D-dimer prior to surgery for urologic malignancy. Bladder cancer patients and older patients in whom D-dimer has been elevated should undergo careful early examination for DVT.

9.
Anticancer Res ; 39(7): 3887-3892, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262917

RESUMO

BACKGROUND/AIM: Pembrolizumab was approved as second-line treatment for patients with metastatic urothelial cancer (UC) in Japan. We performed a retrospective pilot study to assess the potency of pembrolizumab treatment in Japan. PATIENTS AND METHODS: The medical records of 40 consecutive Japanese patients with metastatic UC who started pembrolizumab between January and October 2018 were reviewed and statistically analyzed to clarify the efficacy and safety of the drug. RESULTS: The objective response rate, median progression-free survival period, and median overall survival period were 20.6%, 4.1 months and 10.0 months, respectively. Multivariate analysis indicated the presence of liver metastasis, worse performance status (≥2), and higher C-reactive protein as factors predictive of shorter OS. CONCLUSION: We demonstrated for the first time, a comparable efficacy and safety profile of pembrolizumab for Japanese patients with metastatic UC, as in the KEYNOTE-045 study. The results indicate the features of pembrolizumab therapy in the current Japanese clinical practice.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Urológicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Análise de Sobrevida , Resultado do Tratamento , Neoplasias Urológicas/patologia
10.
Behav Processes ; 166: 103906, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301426

RESUMO

Inferring what others witnessed provides important benefits in social contexts, but evidence remains scarce in nonhuman animals. We investigated this ability in domestic horses by testing whether they could discriminate between two experimenters who differed in what they previously witnessed and decide whom to solicit when confronted with an unreachable food source based on that information. First, horses saw food being hidden in a closed bucket (impossible for them to open) in the presence of two experimenters who behaved identically but differed in their attention to the baiting process (the "witness" experimenter faced the bucket, the "non-witness" faced away). Horses were then let free with both experimenters, and their interest towards each (gaze and touch) was measured. They gazed at and touched the witness significantly more than the non-witness (n = 15, gaze: p = 0.004; touch: p = 0.003). These results might suggest that horses inferred the attentional state of the experimenters during the baiting process and used this information to adapt their later behavior. Although further study would be necessary to conclude, our study provides new insight into attentional state attribution in horses and might hint to the existence of precursors of a Theory of Mind in horses.

11.
Am J Hum Genet ; 105(2): 413-424, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327508

RESUMO

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

12.
Hum Mol Genet ; 2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31227826

RESUMO

Drosophila melanogaster is a unique, powerful genetic model organism for studying a broad range of biological questions. Human studies that probe the genetic causes of rare and undiagnosed diseases using massive-parallel sequencing often require complementary gene function studies to determine if and how rare variants affect gene function. These studies also provide inroads to disease mechanisms and therapeutic targets. In this review we discuss strategies for functional studies of rare human variants in Drosophila. We focus on our experience in establishing a Drosophila Core for the Model Organisms Screening Center (MOSC) for the Undiagnosed Diseases Network (UDN) and concurrent fly studies with other large genomic rare disease research efforts such as the Centers for Mendelian Genomics (CMG). We outline four major strategies that use the latest technology in fly genetics to understand the impact of human variants on gene function. We also mention general concepts in probing disease mechanisms, therapeutics and using rare disease to understand common diseases. Drosophila is and will continue to be a fundamental genetic model to identify new disease-causing variants, pathogenic mechanisms and drugs that will impact medicine.

13.
Nat Commun ; 10(1): 1457, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926811

RESUMO

Deracemization is a powerful method by which a racemic mixture can be transformed into an excess of one enantiomer with the aid of chiral auxiliaries, but has been applied only to small chiral molecular systems. Here we report a deracemization of a racemic double-stranded spiroborate helicate containing a bisporphyrin unit upon encapsulation of chiral aromatic guests between the bisporphyrin. The chiral guest-included helicate is kinetically stable, existing as a mixture of right- and left-handed double helices, which eventually undergo an inversion of the helicity triggered by water resulting from the water-mediated reversible diastereoselective B-O bond cleavage/reformation of the spiroborate groups, thus producing an optically-active helicate with a high enantioselectivity. Quantum chemical calculations suggest that the stereospecific CH-π interactions between the porphyrin hydrogen atoms of the helicate and an aromatic pendant group of the chiral guest play a key role in the enhancement of the helical handedness of the helicate.

14.
Int J Gynaecol Obstet ; 145(1): 122-123, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30648745

RESUMO

A patient had septic pelvic thrombophlebitis complicated by multiple septic emboli after intrauterine device insertion. Fusobacterium necrophorum, a well­known cause of Lemierre's syndrome, was identified.


Assuntos
Dispositivos Intrauterinos/efeitos adversos , Síndrome de Lemierre/microbiologia , Tromboflebite/etiologia , Feminino , Fusobacterium necrophorum/isolamento & purificação , Humanos , Síndrome de Lemierre/complicações , Tromboflebite/diagnóstico por imagem , Tomografia Computadorizada por Raios X
15.
Kidney Int ; 95(3): 526-539, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30661714

RESUMO

Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARγ was expressed in proximal tubules both with and without injury, and αB-crystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation in vitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury.

17.
Trop Med Health ; 46: 37, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30410417

RESUMO

Background: Neurological complications from malaria cause significant morbidity and mortality. Severe cerebral malaria occurs as a result of intense sequestration of infected erythrocytes in the cerebral capillaries. However, the pathology of the reversible neurological symptoms remains unclear. We report the case of a patient with malaria who also had mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) causing transient neurological symptoms. Case presentation: A 55-year-old Japanese man was admitted to our hospital with acute fever upon returning from Nigeria. Blood smears and PCR analysis revealed ring forms in the erythrocytes, indicative of Plasmodium falciparum infection. He presented with dysarthria, expressive aphasia, and truncal ataxia, all of which were suggestive of cerebellar ataxia. He had no other signs or symptoms of severe malaria. Artemether/lumefantrine was started on the first day of illness. Although the parasites were undetectable on day 3 of illness, his neurological symptoms persisted. Brain magnetic resonance imaging (MRI) demonstrated a high-signal lesion in the splenium of the corpus callosum on diffusion-weighted images along with a decreased apparent diffusion coefficient. The neurological symptoms gradually improved by day 12. Brain MRI on day 16 showed complete regression of the splenic lesion. Therefore, the patient was diagnosed with MERS due to malaria. Conclusions: MERS often causes transient headaches, seizures, and/or impaired consciousness. The symptoms are compatible with the reversible symptoms of cerebral malaria.

18.
Front Psychol ; 9: 1887, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349497

RESUMO

People often become more altruistic when they think or feel that someone is watching them. Known as the "watching-eyes effect," this is argued to be caused by the motivation to gain and maintain a positive social reputation as an altruistic individual (the "reputation seeking" mechanism). However, an alternative mechanism underlying the watching-eyes effect could be that people suppress their impulsive tendency to pursue benefit rather than increase their altruism, and this may lead to apparent increases in altruistic tendencies. This "suppressing impulsivity" mechanism is considered intrapersonal rather than socially mediated which is associated with "reputation seeking." We examined whether the suppressing impulsivity mechanism would be associated with the watching-eyes effect by measuring participants' impulsivity in the presence of watching-eyes stimuli. In a controlled experiment, we presented life-size pictures of human faces with a direct gaze on a monitor in front of participants taking part in a time-discounting task. Two types of faces, "in-group" (faces of participants' classmates) and "out-group" (unfamiliar faces) were presented to examine the effect of social attribution. We used a flower picture as a control stimulus. In the time-discounting task, participants chose one of two options: a small amount of money that they could get immediately or a larger amount of money that they could get after a given time interval. The results showed no significant difference in participants' time-discount rate regardless of the types of stimuli presented during the time-discount task. A post-task questionnaire confirmed that the participants were aware of the presented stimuli and revealed that they paid more attention to the in-group stimuli than to the out-group and flower stimuli, though this difference in attentive states had no effect on their impulsivity during the task. These results suggest that suppressing impulsivity is not a plausible mechanism for the watching-eyes effect. The null effect for the difference between the in-group and out-group stimuli also supports this conclusion. Thus, it is plausible that the watching-eyes effect is caused by the human tendency to boost social reputation and can be mediated by the social relationship with others.

19.
N Engl J Med ; 379(22): 2131-2139, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30304647

RESUMO

BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

20.
Urology ; 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30171918

RESUMO

OBJECTIVE: To describe a novel and simple technique of preliminary kidney parenchymal ligation using Endoloop ligatures during laparoscopic partial nephrectomy (PN) without hilar clamping for polar complex tumor cases. METHODS: The subjects were 17 patients who had a renal mass with a R.E.N.A.L. nephrometry score ≥7 (7/8/9/10 in 3/6/6/2 patients, respectively) located in the pole of the kidney. Patient-specific 3D reconstructed kidney images were created for preoperative planning in all cases. The renal hilar vessels were meticulously dissected and definitive tumor feeders were sacrificed when the branches directly perfused the peri-tumor area. Following the vascular microdissection, a circumferential cortex-depth incision on the kidney was made all around the tumor. Consequently, several Endoloop ligatures were placed in the incised tumor base to ligate the parenchyma preliminarily. Step-by-step Endoloop tightening facilitated effective parenchymal dissection without the urinary tract. After confirming that the tumor base parenchyma was ligated sufficiently, tumor resection was completed. Neither inner- nor outer-layer renorrhaphy sutures were placed. RESULTS: Perioperative outcomes were satisfactory and all patients had negative surgical margins with no damage in the tumor capsule. Urological complications and renal function lower than predicted at 3 months after surgery involved 1 and 3 cases, respectively. The rate of PN trifecta achievement was 82% (14/17) despite the complexity of the 17 tumors. CONCLUSION: The current technique helped surgeons achieve the trifecta in patients with polar complex masses treated with laparoscopic PN. Use of this technique can provide surgeons with a bloodless operative field even during PN without hilar clamping.

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