RESUMO
Histiocytic sarcoma (HS) is a rare aggressive hematological malignancy reported to occur secondary to B cell lymphoma. We report a case of HS secondary to splenic marginal zone lymphoma (SMZL) complicated by autoimmune hemolytic anemia (AIHA) in a 64-year-old man. He was referred to our department with anemia and was diagnosed as having AIHA. After starting treatment with prednisolone, atypical lymphocytes appeared in his blood tests, and a bone marrow biopsy revealed invasion by B cell lymphoma. A CT scan showed splenomegaly and a pancreatic mass, which confirmed the diagnosis of SMZL. The patient received bendamustine and rituximab as chemotherapy, which rapidly improved the anemia and splenomegaly and reduced atypical lymphocytes. However, left lumbar back pain appeared along with an increase in the pancreatic mass, and he died suddenly of acute renal failure. An autopsy revealed that the tumor had invaded several organs including the pancreas, and immunohistochemistry was positive for CD163, leading to the diagnosis of HS. Furthermore, the specimens of SMZL and HS were positive for IgH gene reconstitution, and exome analysis showed genetic abnormalities in 226 genes including CARD11, suggesting that the SMZL and HS had the same origin.
Assuntos
Sarcoma Histiocítico , Linfoma de Zona Marginal Tipo Células B , Neoplasias Esplênicas , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/diagnóstico , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Sarcoma Histiocítico/patologia , Sarcoma Histiocítico/genética , Sarcoma Histiocítico/diagnóstico , Sequenciamento do Exoma , Evolução FatalRESUMO
BACKGROUND: Fluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer. METHODS: We analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates. RESULTS: We detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher's exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. CONCLUSIONS: The two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.
Assuntos
Neoplasias Colorretais , Recidiva Local de Neoplasia , Humanos , Estudos Retrospectivos , Recidiva Local de Neoplasia/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Biomarcadores , Quimioterapia Adjuvante , Nucleotídeos/uso terapêutico , Estadiamento de Neoplasias , Fluoruracila/uso terapêutico , Biomarcadores Tumorais/genética , PTEN Fosfo-Hidrolase/genéticaRESUMO
Mouse spermatogenesis, from spermatogonial stem cell proliferation to sperm formation, can be reproduced in vitro by culturing testis tissue masses of neonatal mice. However, it remains to be determined whether this method is also applicable when testis tissues are further divided into tiny fragments, such as segments of the seminiferous tubule (ST), a minimal anatomical unit for spermatogenesis. In this study, we investigated this issue using the testis of an Acrosin-GFP/Histone H3.3-mCherry (Acr/H3) double-transgenic mouse and monitored the expression of GFP and mCherry as indicators of spermatogenic progression. Initially, we noticed that the cut and isolated stretches of ST shrunk rapidly and conglomerated. We therefore maintained the isolation of STs in two ways: segmental isolation without truncation or embedding in soft agarose. In both cases, GFP expression was observed by fluorescence microscopy. By whole-mount immunochemical staining, meiotic spermatocytes and round and elongating spermatids were identified as Sycp3-, crescent-form GFP-, and mCherry-positive cells, respectively. Although the efficiency was significantly lower than that with tissue mass culture, we clearly showed that spermatogenesis can be induced up to the elongating spermatid stage even when the STs were cut into short segments and cultured in isolation. In addition, we demonstrated that lowered oxygen tension was favorable for spermatogenesis both for meiotic progression and for producing elongating spermatids in isolated STs. Culturing isolated STs rather than tissue masses is advantageous for explicitly assessing the various environmental parameters that influence the progression of spermatogenesis.
Assuntos
Sêmen , Espermatogônias , Masculino , Camundongos , Animais , Espermatogônias/metabolismo , Túbulos Seminíferos/metabolismo , Espermatogênese , Testículo/metabolismo , Espermátides/metabolismo , Camundongos TransgênicosRESUMO
Management of the ischial fragment in acetabular fractures is a considerable problem. In this report, we presented how to drill or screw around the posterior column and ischium from the anterior approach using a novel 'sleeve guide technique' and the difficulty of plating. A sleeve, drill, depth gauge and driver from DepuySynthes were prepared. The portal was about 2-3 cm inside the anterior superior iliac spine opposite to the side of the fracture. The sleeve was inserted to the screw point around quadrilateral area through the retroperitoneal space. Drilling, measuring screw length by a depth gauge and the screwing were performed through the sleeve. Case 1 used a one-third plate and case 2 used a reconstruction plate. With this technique, the approach angles to the posterior column and ischium were inclined, and plating and screw insertion could be performed with a low risk of organ injury.
RESUMO
The safety of osimertinib is limited in patients with severe or moderate renal impairment, or low body weight. This study aimed to investigate the safety, pharmacokinetics (PK) and recommended dose (RD) of osimertinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with impaired renal function and low body weight. Thirty-one eligible patients were enrolled and allocated into four cohorts: A, normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 mL/min/1.73 m2 ) and normal body weight (≥45 kg); B, moderate renal impairment (eGFR = 30-50 mL/min/1.73 m2 ); C, low body weight (<45 kg); and D, severe renal impairment (eGFR <30 mL/min/1.73 m2 or undergoing dialysis). PK parameters and safety were evaluated with a starting dose of 80 mg osimertinib administered orally once daily in cohorts A, B, and C and 40 mg once daily in cohort D. The PK parameters in cohorts A, B, and C were found to be similar. No dose-limiting toxicity was observed, and the RD was determined to be 80 mg once daily in patients with moderate renal function and low body weight. Four serious adverse events, acneiform rash, diarrhea, QTc prolongation, and interstitial lung disease, were noted. Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in patients with impaired renal function and low body weight. Clinicians should prescribe osimertinib with caution in NSCLC patients with impaired renal function and low body weight.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Insuficiência Renal , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Anilina/efeitos adversos , Rim/fisiologia , Peso Corporal , Mutação , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
OBJECTIVES: The dosing pattern of pembrolizumab is based on population pharmacokinetic (Pop-PK) analysis of clinical trials. Data for Japanese patients or patient populations with poor conditions such as cachexia are scarce. In this study, we performed a Pop-PK analysis of Japanese non-small cell lung cancer patients and analyzed the relationship between exposure, treatment effect, and survival. MATERIALS AND METHODS: A total of 270 blood samples from 76 patients who received 200 mg pembrolizumab every 3 weeks between March 2017 and December 2018 were included. Blood concentrations of pembrolizumab were measured using mass spectrometry, and Pop-PK analysis was conducted using the Phoenix NLME software with a one-compartment model. RESULTS: The estimated median of clearance (CL) in this analysis population was 0.104 L/day, about half of the historical data for Western data. Overall, pembrolizumab CL decreased over time, with some populations showing increased CL early in the treatment and others showing decreased CL over time. When the time-varying CL was stratified by quartile, the group with decreasing CL showed significantly better treatment response and survival than the group with increasing CL, even though the group included more patients with cachexia. Detailed analysis suggested that the patient population that responded to pembrolizumab treatment had an improved general condition and reduced protein catabolism, further decreasing CL. CONCLUSION: In populations that benefit from pembrolizumab treatment, CL may be reduced early in their treatment, which may be a predictive and prognostic factor. However, further prospective validation of our findings is needed.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Caquexia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
DNA methylation, repressive histone modifications, and PIWI-interacting RNAs are essential for controlling retroelement silencing in mammalian germ lines. Dysregulation of retroelement silencing is associated with male sterility. Although retroelement silencing mechanisms have been extensively studied in mouse germ cells, little progress has been made in humans. Here, we show that the Krüppel-associated box domain zinc finger proteins are associated with DNA methylation of retroelements in human primordial germ cells. Further, we show that the hominoid-specific retroelement SINE-VNTR-Alus (SVA) is subjected to transcription-directed de novo DNA methylation during human spermatogenesis. The degree of de novo DNA methylation in SVAs varies among human individuals, which confers significant inter-individual epigenetic variation in sperm. Collectively, our results highlight potential molecular mechanisms for the regulation of retroelements in human male germ cells.
Assuntos
Metilação de DNA , Retroelementos , Animais , Epigenômica , Células Germinativas/metabolismo , Humanos , Masculino , Mamíferos/genética , Camundongos , Retroelementos/genética , Espermatogênese/genéticaRESUMO
PURPOSE: Aprepitant is used with dexamethasone and 5-HT3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant. METHODS: Urinary 11ß-hydroxytestosterone (11ß-OHT)/testosterone concentration ratio and plasma 4ß-hydroxycholesterol (4ß-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers. RESULTS: The urinary 11ß-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4ß-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4ß-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy. CONCLUSION: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.
Assuntos
Antieméticos , Aprepitanto , Carcinoma Pulmonar de Células não Pequenas , Cisplatino , Citocromo P-450 CYP3A , Dexametasona , Neoplasias Pulmonares , Antieméticos/uso terapêutico , Aprepitanto/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Dexametasona/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Vômito/induzido quimicamente , Vômito/prevenção & controleRESUMO
Epigenome research has employed various methods to identify the genomic location of proteins of interest, such as transcription factors and histone modifications. A recently established method called CUT&Tag uses a Protein-A Tn5 transposase fusion protein, which cuts the genome and inserts adapter sequences nearby the target protein. Throughout most of the CUT&Tag procedure, cells are held on concanavalin A (con A)-conjugated magnetic beads. Proper holding of cells would be decisive for the accessibility of Tn5 to the chromatin, and efficacy of the procedure of washing cells. However, BioMag®Plus ConA magnetic beads, used in the original CUT&Tag protocol, often exhibit poor suspendability and severe aggregation. Here, we compared the BioMag beads and Dynabeads® magnetic particles of which conjugation of con A was done by our hands, and examined the performance of these magnetic beads in CUT&Tag. Among tested, one of the Dynabeads, MyOne-T1, kept excessive suspendability in a buffer even after overnight incubation. Furthermore, the MyOne-T1 beads notably improved the sensitivity in CUT&Tag assay for H3K4me3. In conclusion, the arrangement and the selection of MyOne-T1 refine the suspendability of beads, which improves the association of chromatin with Tn5, which enhances the sensitivity in CUT&Tag assay.
Assuntos
Concanavalina A/administração & dosagem , Histonas/metabolismo , Proteína Estafilocócica A/genética , Transposases/genética , Animais , Linhagem Celular , Concanavalina A/química , Concanavalina A/farmacologia , Epigenômica , Células HEK293 , Código das Histonas , Humanos , Separação Imunomagnética , Campos Magnéticos , Metilação , Camundongos , Tamanho da Partícula , Proteínas Recombinantes de Fusão/metabolismo , Proteína Estafilocócica A/metabolismo , Transposases/metabolismoRESUMO
OBJECTIVE: To report a case of second-degree atrioventricular block associated with concomitant use of aprepitant and amlodipine. CASE: A 73-year-old man with lung cancer was treated with aprepitant for prophylactic use for the prevention of nausea and vomiting, concomitantly with cisplatin, gemcitabine, and an investigational drug (anti-epidermal growth factor receptor monoclonal antibody). He was diagnosed with first-degree atrioventricular block and was taking amlodipine for hypertension. During the first cycle of chemotherapy, 5 days after the start of aprepitant, he experienced Wenckebach second-degree atrioventricular block (Mobitz type I), and amlodipine was discontinued. After day 6, the atrioventricular block was not shown. According to the Naranjo adverse drug reaction scale, a score of 7 was obtained (causality: probable). In addition, using the Drug Interaction Probability Scale, a score of 6 was obtained (causality: probable). CONCLUSION: The drug-drug interaction between aprepitant and amlodipine was considered to have deteriorated his atrioventricular block, conceivably due to the inhibition of cytochrome P450 (CYP) 3A-mediated metabolism of amlodipine by aprepitant.
Assuntos
Antieméticos , Bloqueio Atrioventricular , Neoplasias Pulmonares , Idoso , Anlodipino/efeitos adversos , Aprepitanto/uso terapêutico , Bloqueio Atrioventricular/induzido quimicamente , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Morfolinas/efeitos adversos , VômitoRESUMO
Post-transplantation cyclophosphamide (PTCy) is a new method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation. Although the use of dexamethasone is recommended as prophylaxis against chemotherapy-induced nausea and vomiting (CINV) for patients who receive high-dose cyclophosphamide, corticosteroids cannot be used during PTCy administration to exploit depletion of alloreactive T cells. Thus, CINV may not be adequately controlled in this situation. We retrospectively examined antiemetic efficacy of the combination of a 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA) and a NK1 receptor antagonist (NK1 RA) in 36 patients who received PTCy, and compared this efficacy with that of the same combination together with dexamethasone in 27 patients conditioned with cyclophosphamide and total body irradiation (CY/TBI). The proportion of patients who had no vomiting during the acute phase of PTCy administration was 81%, and was lower than 100% in the CY/TBI group (p = 0.02). Our results suggest that prevention of CINV using 5-HT3 RA and NK1 RA during PTCy administration is suboptimal and that addition of antiemetic is necessary in patients who receive PTCy.
Assuntos
Ciclofosfamida/efeitos adversos , Náusea/induzido quimicamente , Náusea/prevenção & controle , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Cuidados Pós-Operatórios/efeitos adversos , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Vômito/induzido quimicamente , Vômito/prevenção & controle , Adulto , Antieméticos/administração & dosagem , Dexametasona/uso terapêutico , Quimioterapia Combinada , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: Fluoropyrimidine plus platinum, followed by paclitaxel (PTX) plus ramucirumab is a recommended treatment strategy for advanced gastric cancer (AGC). We investigated how peripheral neuropathy (PN), induced by platinum in first-line chemotherapy, affected the tolerability of second-line chemotherapy with PTX (2nd-PTX). METHODS: The subjects were AGC patients who received second-line chemotherapy with PTX (2nd-PTX) after the failure of platinum-based chemotherapy between March 2015 and June 2018. We retrospectively reviewed PN severity, and dose reduction and/or discontinuation due to PN during 2nd-PTX, and compared the cumulative incidence of grade 2 PN between the two groups according to first-line chemotherapy containing oxaliplatin (L-OHP) or cisplatin (CDDP). RESULTS: The L-OHP and CDDP groups consisted of 50 patients each. PN severity before 2nd-PTX was grade 1/2 in 46/12% of patients in the L-OHP group, and 100/0% in the CDDP group. The worst grades of chemotherapy-induced PN during 2nd-PTX were grades 1/2/3 in 40/34/14% of patients in the L-OHP group, and 36/18/0% in the CDDP group. Median time to grade 2 PN after starting second-PTX was 2.5 months in the L-OHP group and 8.6 months in the CDDP group (hazard ratio 3.34, p = 0.002). The frequencies of a PN-related dose reduction and/or discontinuation of PTX were 18% in the L-OHP group and 8% in the CDDP group (p = 0.234). CONCLUSIONS: The severity of PN and tolerability of 2nd-PTX may be affected by first-line chemotherapy with L-OHP or CDDP for AGC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Paclitaxel/administração & dosagem , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , RamucirumabRESUMO
This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m2 amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72 , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m2 for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.
Assuntos
Antraciclinas/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neutropenia/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/farmacocinética , Antineoplásicos/farmacocinética , Área Sob a Curva , Povo Asiático , Superfície Corporal , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Esquema de Medicação , Feminino , Humanos , Japão , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
Gonocyte-to-spermatogonia transition is a critical fate determination process to initiate sperm production throughout the lifecycle. However, the molecular dynamics of this process has not been fully elucidated mainly due to the asynchronized differentiation stages of neonatal germ cells. In this study, we employed single cell RNA sequencing analyses of P1.5-5.5 germ cells to clarify the temporal dynamics of gene expression during gonocyte-to-spermatogonia transition. The analyses identified transcriptional modules, one of which regulates spermatogonial gene network in neonatal germ cells. Among them, we identified Dec2, a bHLH-type transcription factor, as a transcriptional repressor for a spermatogonial differentiation factor Sohlh1. Deficiency of Dec2 in mice induces significant reduction of undifferentiated spermatogonia, and transplantation assay using Dec2-depleted cells also demonstrated the impaired efficiency of engraftment, suggesting its role in maintaining spermatogonial stem cells (SSCs). Collectively, this study revealed the intrinsic role of a new SSC factor Dec2, which protects germ cells from inadequate differentiation during neonatal testis development.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação da Expressão Gênica no Desenvolvimento , Espermatogênese/genética , Espermatogônias/fisiologia , Fatores de Transcrição/metabolismo , Animais , Animais Recém-Nascidos , Diferenciação Celular/genética , Masculino , Camundongos , Camundongos Transgênicos , Análise de Célula Única , Células-Tronco/fisiologia , Testículo/citologia , Testículo/crescimento & desenvolvimento , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Single-dose i.v. fosaprepitant has been approved as an alternative to 3 day oral aprepitant, a neurokinin-1 receptor antagonist, and improves prevention of chemotherapy-induced nausea and vomiting (CINV). Because fosaprepitant has shown similar efficacy to aprepitant in adult patients only, this study compared the efficacy and safety of aprepitant and fosaprepitant in pediatric patients. METHODS: Children younger than 18 years who received aprepitant or fosaprepitant to manage CINV between January 2015 and March 2018 at the National Cancer Center Hospital (Tokyo) were recruited to this study. The primary endpoint was complete response (CR; no vomiting/rescue medication) between 0 and 120 h after the start of chemotherapy. Secondary endpoints were safety based on the frequency of severe adverse events, and evaluation of patient characteristics as risk factors (effect of age and sex). RESULTS: A total of 125 chemotherapy cycles were evaluated. In the aprepitant group, CR was observed in 36 of 80 treatment cycles (45.0%), whereas in the fosaprepitant group, it was observed in 19 of 45 cycles (42.2%; P = 0.852). No treatment-related severe adverse events were observed in either group. The number of non-CR was greater than that of CR in patients aged 6-14 years. The difference in CR rate between male and female patients was not statistically significant (47.1% vs 40.0%, respectively; P = 0.471). CONCLUSIONS: Aprepitant and fosaprepitant were safely used and may be equally useful for pediatric patients receiving highly emetogenic chemotherapy. CR rate may be associated with patient age.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Aprepitanto/uso terapêutico , Morfolinas/uso terapêutico , Vômito/tratamento farmacológico , Adolescente , Antieméticos/efeitos adversos , Aprepitanto/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Morfolinas/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Tóquio , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
Organ culture experiments can be hampered by central degeneration or necrosis due to the inadequate permeation of oxygen and nutrients, which deteriorates the function and growth of cultured tissues. In the current study, we aimed to overcome this limitation of organ culture through spreading the tissue two dimensionally on an agarose gel stand and molding into a disc shape by placing a ceiling of polydimethylsiloxane (PDMS) chip, which is highly oxygen permeable. By this, every part of the tissue can receive a sufficient supply of oxygen through PDMS as well as nutrients through the agarose gel below. This method not only prevented central necrosis of tissues, but also supported the tissue growth over time. In addition, such growth, as volume enlargement, could be easily measured. Under these conditions, we examined the effect of several factors on the growth of neonatal mouse testis, and found that follicle stimulating hormone (FSH) and insulin significantly promoted the growth. These results are in good agreement with previous in vivo reports. Notably, the growth achieved over 7 days in our in vitro system is almost comparable to, about 80% of, that observed in vivo. Thus, we successfully monitored the promotion of tissue growth beyond the limits of the conventional organ culture method. This extremely simple method could offer a unique platform to evaluate the growth as well as functional properties of organs, not only the testis but also others as well.
Assuntos
Técnicas de Cultura de Órgãos/instrumentação , Técnicas de Cultura de Órgãos/métodos , Testículo/citologia , Testículo/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Células Cultivadas , Dimetilpolisiloxanos/química , Dispositivos Lab-On-A-Chip , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Nylons/química , Células de Sertoli/citologiaRESUMO
The question of whether retained histones in the sperm genome localize to gene-coding regions or gene deserts has been debated for years. Previous contradictory observations are likely caused by the non-uniform sensitivity of sperm chromatin to micrococcal nuclease (MNase) digestion. Sperm chromatin has a highly condensed but heterogeneous structure and is composed of 90%â¼99% protamines and 1%â¼10% histones. In this study, we utilized nucleoplasmin (NPM) to improve the solubility of sperm chromatin by removing protamines in vitro. NPM treatment efficiently solubilized histones while maintaining quality and quantity. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses using NPM-treated sperm demonstrated the predominant localization of H4 to distal intergenic regions, whereas modified histones exhibited a modification-dependent preferential enrichment in specific genomic elements, such as H3K4me3 at CpG-rich promoters and H3K9me3 in satellite repeats, respectively, implying the existence of machinery protecting modified histones from eviction.
Assuntos
Histonas/metabolismo , Espermatozoides/metabolismo , Animais , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Ilhas de CpG , Histonas/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Repetições de Microssatélites/genética , Nucleoplasminas/metabolismo , Nucleossomos/metabolismo , Regiões Promotoras Genéticas , Protaminas/metabolismoRESUMO
PURPOSE: Hand-foot syndrome (HFS) is a major side effect of pegylated liposomal doxorubicin (PLD). Regional cooling during PLD infusion was shown to improve severe HFS. We investigated the utility of frozen gloves and socks (FGS) as a simpler cooling method. METHODS: To evaluate the utility and safety of regional cooling with FGS for PLD-induced HFS, we retrospectively analyzed patients with advanced ovarian cancer who used FGS during PLD-containing regimens. RESULTS: Ninety-six patients were analyzed. The incidence of HFS was 51% (≥ grade 2, 32%) in the PLD group and 38% (≥ grade 2, 6%) in the PLD + CBDCA group. The respective percentages of patients who underwent PLD dose modification/discontinuation were 41%/75% in the PLD group and 9%/30% in the PLD + CBDCA group. The reasons for discontinuation of PLD and PLD + CBDCA therapy were progressive disease, HFS, allergy, oral mucositis, and others. HFS was the only reason for PLD dose modification in both the PLD and PLD + CBDCA groups. The completion rate of FGS was 96%, with discontinuation in three cases due to pain from cooling. CONCLUSIONS: Our study indicates that FGS is a safe, simple method with good tolerability. A prospective study is needed for further assessment.