RESUMO
Analyses of ancient DNA typically involve sequencing the surviving short oligonucleotides and aligning to genome assemblies from related, modern species. Here, we report that skin from a female woolly mammoth (Mammuthus primigenius) that died 52,000 years ago retained its ancient genome architecture. We use PaleoHi-C to map chromatin contacts and assemble its genome, yielding 28 chromosome-length scaffolds. Chromosome territories, compartments, loops, Barr bodies, and inactive X chromosome (Xi) superdomains persist. The active and inactive genome compartments in mammoth skin more closely resemble Asian elephant skin than other elephant tissues. Our analyses uncover new biology. Differences in compartmentalization reveal genes whose transcription was potentially altered in mammoths vs. elephants. Mammoth Xi has a tetradic architecture, not bipartite like human and mouse. We hypothesize that, shortly after this mammoth's death, the sample spontaneously freeze-dried in the Siberian cold, leading to a glass transition that preserved subfossils of ancient chromosomes at nanometer scale.
Assuntos
Genoma , Mamutes , Pele , Animais , Mamutes/genética , Genoma/genética , Feminino , Elefantes/genética , Cromatina/genética , Fósseis , DNA Antigo/análise , Camundongos , Humanos , Cromossomo X/genéticaRESUMO
BACKGROUND: Despite most metastatic castration-resistant prostate cancer (mCRPC) patients benefit from abiraterone acetate plus prednisone 5 mg bid (AA + P), resistance eventually occurs. Long-term use of prednisone has been suggested as one of the mechanisms driving resistance, which may be reversed by switching to another steroid. METHODS: SWITCH was a single-arm, open-label, single-stage phase II study. The primary objective was to evaluate the antitumour activity of abiraterone acetate plus dexamethasone 0.5 mg daily (AA + D) in mCRPC patients progressing to AA + P. Clinically stable mCRPC patients who had prostate-specific antigen (PSA) and/or limited radiographic progression after at least 12 weeks on AA + P, were eligible. The primary endpoint was measured as the proportion of patients achieving a PSA decline of ≥ 30% (PSA30) from baseline after 6 weeks on AA + D. Secondary endpoints included: PSA50 response rate at 12 weeks, time to biochemical and radiological progression, overall survival, safety profile evaluation, benefit from subsequent treatment lines and the identification of biomarkers of response (AR copy number, TMPRSS2-ERG status and PTEN expression). RESULTS: Twenty-six patients were enrolled. PSA30 and PSA50 were 46.2% and 34.6%, respectively. Median time to biochemical and radiological progression were 5.3 and 11.8 months, respectively. Two radiological responses were observed. Median overall survival was 20.9 months. Patients with AR gain detected in plasma circulating tumour DNA did not respond to switch, whereas patients with AR normal status benefited the most. No significant toxicities were observed and PSA50 response rate to subsequent taxane was 50%. CONCLUSIONS: In selected clinical stable mCRPC patients with limited disease progression on AA + P, a steroid switch from prednisone to dexamethasone can lead to PSA and radiological responses.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Dexametasona/administração & dosagem , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , PTEN Fosfo-Hidrolase/genética , Projetos Piloto , Prednisona/uso terapêutico , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: To describe one case of hematocele secondary to rupture of an abdominoscrotal hydrocele in an adult patient. METHODS AND RESULTS: We report a huge hematocele in a patient with this unusual type of hydrocele that suffered a minimal scrotal trauma. It was a hydrocele that extended through the inguinal canal to the retroperitoneal space. CONCLUSIONS: Abdominoscrotal hydrocele is a rare condition in children and even rarer in adults. The presence of a hematocele requires early surgical treatment.
Assuntos
Hematocele/etiologia , Hematocele/patologia , Hidrocele Testicular/complicações , Hidrocele Testicular/patologia , Edema/patologia , Hematocele/cirurgia , Humanos , Masculino , Ruptura , Escroto/patologia , Escroto/cirurgia , Hidrocele Testicular/cirurgia , Procedimentos Cirúrgicos Urológicos , Adulto JovemRESUMO
BACKGROUND: Several studies have reported the association of germline BRCA2 (gBRCA2) mutations with poor clinical outcomes in prostate cancer (PCa), but the impact of concurrent somatic events on gBRCA2 carriers survival and disease progression is unknown. PATIENTS AND METHODS: To ascertain the role of frequent somatic genomic alterations and histology subtypes in the outcomes of gBRCA2 mutation carriers and non-carriers, we correlated the tumour characteristics and clinical outcomes of 73 gBRCA2 and 127 non-carriers. Fluorescent in-situ hybridisation and next-generation sequencing were used to detect copy number variations in BRCA2, RB1, MYC and PTEN. Presence of intraductal and cribriform subtypes was also assessed. The independent impact of these events on cause-specific survival (CSS), metastasis-free survival and time to castration-resistant disease was assessed using cox-regression models. RESULTS: Somatic BRCA2-RB1 co-deletion (41% versus 12%, p < 0.001) and MYC amplification (53.4% versus 18.8%, p < 0.001) were enriched in gBRCA2 compared to sporadic tumours. Median CSS from diagnosis of PCa was 9.1 versus 17.6 years in gBRCA2 carriers and non-carriers, respectively (HR 2.12; p = 0.002), Median CSS in gBRCA2 carriers increased to 11.3 and 13.4 years in the absence of BRCA2-RB1 deletion or MYC amplification, respectively. Median CSS of non-carriers decreased to 8 and 2.6 years if BRCA2-RB1 deletion or MYC amplification were detected. CONCLUSIONS: gBRCA2-related prostate tumours are enriched for aggressive genomic features, such as BRCA2-RB1 co-deletion and MYC amplification. The presence or absence of these events modify the outcomes of gBRCA2 carriers.
Assuntos
Variações do Número de Cópias de DNA , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Proteína BRCA2/genética , Heterozigoto , Mutação , Células Germinativas/patologia , Mutação em Linhagem GerminativaRESUMO
BACKGROUND: Radium-223 is an active therapy option for bone metastatic castration-resistant prostate cancer (mCRPC). The lack of adequate biomarkers for patient selection and response assessment are major drawbacks for its use. OBJECTIVE: To assess the prognostic value of bone metabolism biomarkers (BMBs) in ra-223-treated mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of mCRPC patients treated with Ra-223 (PRORADIUM study: NCT02925702) was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main objective of the study was to evaluate the association between high (≥median) baseline values in at least three bone formation (bone alkaline phosphatase [BAP] and C-terminal type-I collagen propeptide) and bone resorption (N-terminal telopeptide and pyridinoline) biomarkers, and survival. The independent prognostic value of each BMB was also assessed. The association with time to radiographic, clinical, and prostate-specific antigen (PSA) progression; time to skeletal-related events; and PSA response were secondary objectives. Multivariable (MV) Cox-regression models were evaluated. RESULTS AND LIMITATIONS: A total of 169 patients were included. Of the patients, 70.4% received Ra-223 in second/third line; 144 (85.2%) were Eastern Cooperative Oncology Group 0-1, 126 (74.6%) were in pain, and 80 (47.5%) had more than ten bone metastases. Sixty-seven (39.6%) patients had elevation in at least three BMBs. The median overall survival was 12.1 mo (95% confidence interval [CI]: 10-14.7). No association was observed with other treatment-related secondary outcome parameters. Patients with high values in three or more BMBs had significantly worse survival (9.9 vs 15.2 mo; hazard ratio [HR]: 1.8 [95% CI: 1.3-2.5]; p < 0.001) in the univariate analysis, but not independent in the MV analysis (HR: 1.33; 95% CI: 0.89-2; p = 0.181). High baseline BAP was the only biomarker associated with survival in the MV model (HR: 1.89; 95% CI: 1.28-2.79; p = 0.001). Addition of BAP to the MV clinical model increased the area under the receiver operating characteristic curve 2-yr value from 0.667 to 0.755 (p = 0.003). CONCLUSIONS: Biomarkers of bone formation, especially BAP, have prognostic value in mCRPC patients treated with radium-223. Its predictive value remains to be assessed, ideally in prospective, adequately powered, randomised clinical trials. PATIENT SUMMARY: In this study, we evaluate the role of bone metabolism biomarkers to help improve the use of radium-223 as therapy for advanced prostate cancer. We found that bone alkaline phosphatase may be a suitable tool.
RESUMO
The injection of Botulinum toxin type A (BoNT/A) into the prostate is a minimally invasive alternative treatment for lower urinary tract symptoms. To summarize the action mechanisms of BoNT/A on experimental animals and to analyze its effectiveness according to published clinical studies, we located 24 papers on the treatment of HBP with BoNT/A. The doses applied ranged from 100 (OnabotA) to 600 U (OnabotA and AbobotA). The IPSS score presented a mean post-treatment reduction, for all series, of 10.8 + 2.66 points. Other significant results included the overall mean reduction in QoL score of 2.1 ± 0.62 points, and the pre and post-treatment differences in prostate volume (22.43 ± 20.2 cm(3)), post-voiding residue (76.77 + 51.72 cm(3)) and PSA (1.15 + 0.93 ng/ml). However, only two clinical trials were on sufficient quality to be selected for meta-analysis, and it was observed that the difference of the means, pre- and post-treatment of maximum flow, prostate volume, IPSS and PSA were not statistically significant (P = 0.18). Neither was there any statistically significant difference between pre- and post-treatment post-voiding residue (P = 0.65). In conclusion, BoNT/A alleviates lower urinary tract symptoms due to HBP, but different studies present considerable variations regarding the dose administered, inclusion criteria and follow-up time, as well as poorly defined retreatment, losses to follow up and, above all, a high degree of variability in the communication of results (with large standard deviations). In consequence, further clinical trials are needed.
Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Hiperplasia Prostática/tratamento farmacológico , Animais , Toxinas Botulínicas Tipo A/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Injeções , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Modelos Animais , Hiperplasia Prostática/complicações , Resultado do TratamentoRESUMO
OBJECTIVES: Dorsal urethroplasty as described by Barbagli has gained wide acceptance in the treatment of urethral stricture, given the simplification afforded by obtaining a free graft versus a flap. We present a series of 50 patients treated in our department of urethral stricture by dorsal onlay free graft urethroplasty (Barbagli's technique), in combination or not to other techniques in more complex strictures. METHODS: The average age of patients was 48.8 years (23-77), the mean follow up 42.9 months (12-96) and the most frequently observed etiology has been the inflammatory urethral stricture (50%). RESULTS: Overall success rate was 82% (41 cases) and failure 18% (9 cases). In the longer follow-up group, there was a slight drop in success rate of 80% (24 cases) without any significant differences between groups (p= 0.9). Analyzing the variables length of free graft (p= 0.50, p> 36= 0.53), age (p= 0.12, p>36= 0.59), etiology of stricture (p= 0.77, p>36 = 0.77) and type of graft used (p=0.24, p>36= 0.38) did not show any influence on the final outcome of surgery, both in the total sample and the subgroup with follow-up > 36 months. The location of the stricture in bulbar urethra has shown better functional outcome than those operated on for strictures affecting also other urethral locations (p= 0.001) maintaining that result in the group of longer follow up (p>36= 0,001). The lack of treatment prior to urethral surgery has influenced the success of it, since 90.6% of patients without prior treatment before urethroplasty have seen a good functional outcome, compared to treatment prior to surgery that obtained a 66.7% (p= 0.03). This significance is also demonstrated in the group of follow-up > 36 months (p>36= 0.01). CONCLUSION: The dorsal onlay free graft urethroplasty is a versatile and reproducible technique with acceptable results which allows combination with other techniques when the stenosis extends to the penile urethra. In exceptional cases of panurethral strictures secondary to lichen sclerosus when there is no significant spongiofibrosis and an acceptable urethral plate, can be applied to the whole urethra.
Assuntos
Estreitamento Uretral/cirurgia , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos Masculinos/métodos , Adulto JovemAssuntos
Litíase/etiologia , Bexiga Urinária/cirurgia , Coletores de Urina , Procedimentos Cirúrgicos Urológicos/métodos , Idoso , Constrição Patológica , Cistectomia , Humanos , Litíase/diagnóstico por imagem , Masculino , Complicações Pós-Operatórias/diagnóstico por imagem , Radiografia , Ureter/cirurgiaAssuntos
Corpos Estranhos/diagnóstico por imagem , Corpos Estranhos/cirurgia , Uretra/diagnóstico por imagem , Doenças Uretrais/diagnóstico por imagem , Doenças Uretrais/cirurgia , Cateteres Urinários/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Cateterismo Urinário/efeitos adversos , Retenção Urinária/diagnóstico por imagem , Retenção Urinária/etiologia , Procedimentos Cirúrgicos Urológicos MasculinosRESUMO
OBJECTIVE: To study the response to posterior tibial nerve stimulation in patients with overactive bladder refractory to medical treatment. METHODS: A cohort of 53 patients were treated by posterior tibial nerve stimulation and followed up for a maximum of 24 months. All patients completed the International Consultation on Incontinence Modular Questionnaire-Short Form quality of life questionnaire and kept a urination diary to record the daytime urination frequency and night-time urination frequency. Urodynamic studies were also conducted. RESULTS: At 6 months of follow-up, a cure/improvement rate of 92.4% (49 of 53 cases) had been achieved. Ten patients were given additional treatment and were excluded from subsequent follow-up analysis. At 12 months of follow-up, a cure/improvement rate of 91.69% had been achieved (39 of 43). At 24 months of follow-up, of the 16 patients initially included during the first year, a cure/improvement rate of 62.5% had been achieved (10 of 16). The first sensation of bladder filling had increased by the end of treatment, with differences observed before and after posterior tibial nerve stimulation (P ≤ .001). The average post-treatment bladder capacity had increased by 72.7 mL compared with the initial value (P ≤ .001). At 24 months of follow-up, the group of 16 patients evaluated recorded a significant worsening of night-time urination frequency (P ≤ .05) and quality of life (P ≤ .01). CONCLUSION: Posterior tibial nerve stimulation is a good option for the treatment of overactive bladder. In our series, the optimal point to start retreatment would be at 24 months after therapy completion.