RESUMO
CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.
Assuntos
Antígenos CD7 , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Indução de Remissão , Humanos , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Adolescente , Pessoa de Meia-Idade , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Adulto Jovem , Criança , Recidiva , Transplante Homólogo , Receptores de Antígenos Quiméricos/uso terapêutico , Resultado do Tratamento , Pré-Escolar , Taxa de SobrevidaRESUMO
Endosymbiosis is a widespread and important phenomenon requiring diverse model systems. Ciliates are a widespread group of protists that often form symbioses with diverse microorganisms. Endosymbioses between the ciliate Euplotes and heritable bacterial symbionts are common in nature, and four essential symbionts were described: Polynucleobacter necessarius, "Candidatus Protistobacter heckmanni," "Ca. Devosia symbiotica," and "Ca. Devosia euplotis." Among them, only the genus Polynucleobacter comprises very close free-living and symbiotic representatives, which makes it an excellent model for investigating symbiont replacements and recent symbioses. In this article, we characterized a novel endosymbiont inhabiting the cytoplasm of Euplotes octocarinatus and found that it is a close relative of the free-living bacterium Fluviibacter phosphoraccumulans (Betaproteobacteria and Rhodocyclales). We present the complete genome sequence and annotation of the symbiotic Fluviibacter. Comparative analyses indicate that the genome of symbiotic Fluviibacter is small in size and rich in pseudogenes when compared with free-living strains, which seems to fit the prediction for recently established endosymbionts undergoing genome erosion. Further comparative analysis revealed reduced metabolic capacities in symbiotic Fluviibacter, which implies that the symbiont relies on the host Euplotes for carbon sources, organic nitrogen and sulfur, and some cofactors. We also estimated substitution rates between symbiotic and free-living Fluviibacter pairs for 233 genes; the results showed that symbiotic Fluviibacter displays higher dN/dS mean value than free-living relatives, which suggested that genetic drift is the main driving force behind molecular evolution in endosymbionts. IMPORTANCE: In the long history of symbiosis research, most studies focused mainly on organelles or bacteria within multicellular hosts. The single-celled protists receive little attention despite harboring an immense diversity of symbiotic associations with bacteria and archaea. One subgroup of the ciliate Euplotes species is strictly dependent on essential symbionts for survival and has emerged as a valuable model for understanding symbiont replacements and recent symbioses. However, almost all of our knowledge about the evolution and functions of Euplotes symbioses comes from the Euplotes-Polynucleobacter system. In this article, we report a novel essential symbiont, which also has very close free-living relatives. Genome analysis indicated that it is a recently established endosymbiont undergoing genome erosion and relies on the Euplotes host for many essential molecules. Our results provide support for the notion that essential symbionts of the ciliate Euplotes evolve from free-living progenitors in the natural water environment.
Assuntos
Betaproteobacteria , Euplotes , Filogenia , Simbiose/genética , Euplotes/genética , Euplotes/microbiologia , Betaproteobacteria/genética , Bactérias/genética , Genoma Bacteriano , GenômicaRESUMO
BACKGROUND: The aim of this study was to assess the risk factors for anastomotic stricture in esophageal cancer patients undergoing esophagectomy. Esophageal anastomotic stricture is the most common long-term complication for esophagectomy. The risk factors for esophageal anastomotic stricture still remain controversial. METHODS: MEDLINE, Cochrane Library, and EMBASE were searched to identify observational studies reporting the risk factors for esophageal anastomotic stricture after esophagectomy. A meta-analysis was conducted to investigate the impact of various risk factors on esophageal anastomotic stricture. The GRADE [Grading of Recommendations Assessment, Development and Evaluation] approach was used for quality assessment of evidence on outcome levels. RESULTS: This review included 14 studies evaluating 5987 patients.The meta-analysis found that anastomotic leakage (odds ratio [OR]: 2.75; 95% confidence interval[CI]:2.16-3.49), cardiovascular disease [OR:1.62; 95% CI: 1.22-2.16],diabete [OR: 1.62; 95% CI: 1.20-2.19] may be risk factors for esophageal anastomotic stricture.There were no association between neoadjuvant therapy [OR: 0.78; 95% CI:0.62-0.97], wide gastric conduit [OR:0.98; 95% CI: 0.37-2.56],mechanical anastomosis [OR: 0.84; 95% CI:0.47-1.48],colonic interposition[OR:0.20; 95% CI: 0.12-0.35],and transhiatal approach[OR:1.16; 95% CI:0.81-1.64],with the risk of esophageal anastomotic stricture. CONCLUSIONS: This meta-analysis provides some evidence that anastomotic leakage,cardiovascular disease and diabete may be associated with higher rates of esophageal anastomotic stricture.Knowledge about those risk factors may influence treatment and procedure-related decisions,and possibly reduce the anastomotic stricture rate.
Assuntos
Anastomose Cirúrgica , Neoplasias Esofágicas , Estenose Esofágica , Esofagectomia , Humanos , Esofagectomia/efeitos adversos , Fatores de Risco , Estenose Esofágica/etiologia , Estenose Esofágica/epidemiologia , Anastomose Cirúrgica/efeitos adversos , Neoplasias Esofágicas/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Fístula Anastomótica/etiologia , Fístula Anastomótica/epidemiologia , Razão de ChancesRESUMO
Our knowledge of ciliate endosymbiont diversity greatly expanded over the past decades due to the development of characterization methods for uncultivable bacteria. Chlamydia-like bacteria have been described as symbionts of free-living amoebae and other phylogenetically diverse eukaryotic hosts. In the present work, a systematic survey of the bacterial diversity associated with the ciliate Euplotes octocarinatus strain Zam5b-1 was performed, using metagenomic screening as well as classical full-cycle rRNA approach, and a novel chlamydial symbiont was characterized. The metagenomic screening revealed 16S rRNA gene sequences from Polynucleobacter necessarius, three previously reported accessory symbionts, and a novel chlamydia-like bacterium. Following the full-cycle rRNA approach, we obtained the full-length 16S rRNA gene sequence of this chlamydia-like bacterium and developed probes for diagnostic fluorescence in situ hybridizations. The phylogenetic analysis of the 16S rRNA gene sequences unambiguously places the new bacterium in the family Rhabdochlamydiaceae. This is the first report of chlamydia-like bacterium being found in Euplotes. Based on the obtained data, the bacterium is proposed as a new candidate genus and species: "Candidatus Euplotechlamydia quinta."
Assuntos
Chlamydia , Cilióforos , Euplotes , Filogenia , Euplotes/genética , RNA Ribossômico 16S/genética , Bactérias/genética , Chlamydia/genética , Cilióforos/genética , Simbiose , Análise de Sequência de DNARESUMO
There are a limited number of studies comparing outcomes of busulfan (BU)-based myeloablative hematopoietic stem cell transplantation using unmanipulated haploidentical donors (HIDs), HLA-matched unrelated donors (MUDs), and HLA-matched sibling related donors (MSDs) in acute myeloid leukemia (AML) patients with complete remission (CR) status. With this background, we compared outcomes among 377 cases of CR following consecutive HID-HSCT for AML (CR) to 86 MUD and 92 MSD-HSCT cases. All patients received BU-based myeloablative conditioning and an unmanipulated graft within the same period. The median patient age was 23 years (range 1.1 to 65 years), and 230 patients (41.4%) were under age18. Among the 555 patients, 432 (77.8%) were of intermediate cytogenetic risk and 123 (22.2%) were of adverse risk. A total of 113 patients (20.5%) had FLT3-ITD+ AML, 425 patients (76.6%) were in first complete remission (CR1) post-transplant, and 130 (23.4%) patients were in second CR (CR2). GVHD prophylaxis included mycophenolate mofetil (MMF), cyclosporine-A (CSA) with short-term methotrexate (MTX) for HID, and MUD-HSCT. MMF is not used for MSD-HSCT. The median survival follow-up time was 42 months (range 18-91 months). The 3-year leukemia-free survival (LFS) among the HID, MUD, and MSD cohorts was 73.8% ± 4.8%, 66.4% ± 8.5%, 74.5% ± 2.4%, respectively (P = 0.637). Three-year overall survival (OS) was 74.9% ± 2.4%, 81.8% ± 4.3%, and 77.5% ± 4.5% among the HID, MUD, and MSD cohorts, respectively (P = 0.322). There were no difference among the relapse rate among the HID, MUD, and MSD donor cohorts (14.3% ± 4.0% vs 20.3% ± 6.4% vs 14.5% ± 2.2, respectively; P = 0.851) or the non-relapse mortality (NRM) (12.3% ± 3.5% vs 9.5% ± 3.2% vs 14.0% ± 1.8%, respectively; P = 0.441). Multivariate analyses showed that MRD-positive pre-HSCT was the only risk factor associated with a lower OS and LFS and higher risk of relapse among all 555 patients. Compared with the use of a MUD or MSD, an HID for HSCT had similar outcomes among AML patients with CR states who underwent an allo-HSCT with BU-based myeloablative conditioning. MFC-MRD-positive pre-HSCT was an independent negative factor impact on outcomes for AML patients in CR. We conclude that for AML patients who do not have a MSD or if an urgent transplant is required, HSCT from an HID is a valid option.
Assuntos
Bussulfano/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Irmãos , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Doadores não Relacionados , Adulto JovemRESUMO
Prior studies have suggested that for leukemia patients with high-risk features, haplo-identical-hematopoietic stem cell transplantation (HID-HSCT) has a stronger anti-leukemia effect compared with HSCT using an identical sibling donor (ISD-HSCT). However, it is unclear whether an HID-HSC transplant also augments the graft-versus-leukemia (GVL) effect among refractory/relapsed (R/R) acute myeloid leukemia (AML) patients who are not in remission (NR). We conducted a retrospective analysis of 124 R/R AML patients with NR status who underwent HID-HSCT between April 2012 and December 2016 and compared these to 27 R/R AML patients who underwent an ISD-HSCT within the same timeframe. Among all of the patients, 68 (45.0%) had primary induction failure (PIF) and 83 (54.9%) were relapsed and had failed to respond to at least one cycle of salvage combination chemotherapy. Myeloablative conditioning regimens were administered to all patients. Here, we present a retrospective multivariate analysis of pre-transplantation risk factors and characteristics of all 151 patients and developed a predictive scoring system to predict patient survival. The median period of follow-up was 46 months for all patients. The HID cohort had a higher 5-year overall survival (OS) compared with the ISD cohort (48.6% ± 4.6% vs 25.9% ± 8.4, respectively; P = 0.017) and higher LFS (leukemia-free survival) (41.6% ± 7.5% vs 25.9% ± 8.4%, respectively; P = 0.019). There was no difference in the 5-year cumulative incidence of non-relapse mortality (NRM) (18.0% ± 3.8% and 34.9% ± 12.6%, respectively; P = 0.212) between the two group. However, the 5-year cumulative incidence of relapse (CIRs) was lower in the HID group compared with the ISD group (55.4% ± 8.9% vs 67.3% ± 9.9%, respectively; P = 0.021). Multivariate analysis showed three risk factors associated with OS and LFS: (1) ISD-HSCT, (2) use of a standardized conditioning regimen, and (3) less than 50% proportional reduction of blast cells in the bone marrow (BM). Based on these three risk factors, we developed a predictive scoring system for R/R AML patients undergoing HSCT. Patients who had a predictive score of 0 and 1 had a 66.6% ± 4.5% and 44.1% ± 3.6% OS rate at 5 years, respectively. Patients with a score ≥ 2 had only a 4.4 ± 0.2% OS rate at 5 years. An HID-HSCT had a better anti-leukemia effect among R/R AML patients with an NR status compared with an ISD-HSCT. We also identified pre-transplantation risk factors to delineate subgroups that could derive maximal benefit from HSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Doadores Vivos , Irmãos , Transplante Haploidêntico/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/tendências , Teste de Histocompatibilidade/métodos , Teste de Histocompatibilidade/tendências , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/tendências , Transplante Haploidêntico/tendências , Resultado do Tratamento , Adulto JovemRESUMO
Reproductive health is a key aim of the population health strategy, and male reproductive health constitutes an important part of reproductive health. This article systematically analyzes the applications to and grants from the National Natural Science Foundation of China (NSFC) and some related scientific problems in the field of male reproductive health in the past 30 years. It also discusses the development of the basic researches on male reproductive health in China and the facilitating role of NSFC in this field.
Assuntos
Pesquisa Biomédica/tendências , Saúde Reprodutiva , China , Fundações , Humanos , MasculinoRESUMO
Liver diseases affect millions of people worldwide. In most developed countries, the incidence of viral hepatitis is waning as a result of modern advances in disease prevention, diagnosis, and therapies. Expanded programmes for systematic immunisation against hepatitis B virus have also significantly brought down the number of new cases in many countries, including China. In contrast, with the improvement in living standards, the prevalence of metabolic liver diseases including non-alcoholic fatty liver disease and alcohol-related liver disease is set to rise, ultimately leading to more cases of end-stage liver diseases (liver failure, cirrhosis, and liver cancer). Over the past 30â¯years, visionary governments of major nations have provided strong incentives for basic/clinical research, vaccination programmes, and drug discovery and development in the field of hepatology. To get rid of her unflattering title as the "leader in liver diseases", China has also made a serious effort to initiate nationwide preventive measures for liver diseases, global partnerships, and mentoring programmes for young hepatologists. Instrumental to such progress is the continuous support of the National Natural Science Foundation of China (NSFC), which has helped hepatology to thrive in virtually all research directions within the country. In this article, we seek to provide stimulating glimpses into the evolving liver disease epidemiology, institutional research profiles, funding landscape, and drug development trends in China, with an attempt to compare her status and achievements with those of the United States, European countries, and Japan.
Assuntos
Pesquisa Biomédica/tendências , Gastroenterologia/métodos , Hepatopatias , China , Carga Global da Doença , Humanos , Hepatopatias/classificação , Hepatopatias/epidemiologiaRESUMO
Graphene and Au nanorods (AuNRs) coated with SiO2@TiO2 double shells (AuNR@SiO2@TiO2) were incorporated to form novel composite photoanodes in dye sensitized solar cells (DSSCs). The performances of the photoanodes and DSSCs are studied systematically. The short circuit current density (J sc) and power conversion efficiency (PCE) of these composited DSSCs were greatly enhanced and the influences of the graphene, AuNRs and the SiO2@TiO2 double shells were revealed. The optimal properties with the maximal J sc of 16.26 mA cm-2 and PCE of 8.08% are obtained in the DSSC co-doped with graphene and AuNR@SiO2@TiO2, significantly higher than those of the conventional DSSC with pure TiO2 photoanode by 37.7% and 32.9%, respectively. These significant enhancements in J sc and PCE are attributed to the synergistic effect of graphene, the local surface plasma resonance of AuNRs, as well as the outer SiO2@TiO2 double shells, which result in the increased specific surface area and dye adsorption, the increased light absorption, the decreased charge transfer resistance R 2 and electron recombination and thus the increased J sc and PCE of the DSSCs.
RESUMO
Salvage haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is considered in patients with severe aplastic anemia (SAA) if a matched unrelated donor (MUD) is unavailable. However, studies on haplo- and MUD transplantation in SAA are lacking. The present study retrospectively analyzed the outcomes of 89 young SAA patients who underwent unmanipulated alternative HSCT between September 2012 and September 2016 at our single center. Forty-one patients received haploidentical donors and forty-eight patients MUDs for HSCT. Most were heavily transfused and refractory to previous immunotherapy. The median durations for myeloid engraftment in the haplo- and MUD cohorts were 14 (range, 10 to 21) and 13 (range, 10 to 18) days, respectively. Compared with the MUD cohort, haplo-HSCT cohorts had an increased cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV (43.9% ± 7.8% versus 12.5% ± 4.8%, P = .001) and grades III to IV (21.1% ± 6.7% versus 6.6% ± 3.7%, P = .045) and similar limited chronic GVHD (47.7% ± 8.5% versus 38.5% ± 7.3%, P = .129) and extensive chronic GVHD (12.1% ± 6.8% versus 9.1% ± 4.3%, P = .198). The median follow-up time of the surviving patients was 26 months (range, 6 to 45). No significant differences were observed between haplo-HSCT and MUD HSCT cohorts in 3-year overall survival (80.3% ± 5.1% versus 89.6% ± 7.0%, P = .210), disease-free survival (76.4% ± 5.1% versus 89.4% ± 7.7%, P = .127), and GVHD-free failure-free survival (79.0% ± 8.6% versus 71.6% ± 9.3%, P = .976). Thus, haplo-HSCT, as salvage therapy, achieved similar outcomes as MUD HSCT in young SAA patients, thereby rendering it as an effective and safe option for SAA.
Assuntos
Anemia Aplástica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Transplante Haploidêntico/métodos , Adolescente , Adulto , Anemia Aplástica/patologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Resultado do Tratamento , Doadores não Relacionados , Adulto JovemRESUMO
Controlled-release systems based on mesoporous silica nanomaterials (MSNs) have drawn great attention owing to their potential biomedical applications. Various switches have been designed to control the release of cargoes through the construction of physical blocking units on the surface of MSNs. However, such physical blockages are limited by poor sealing ability and low biocompatibility, and most of them lack closure ability. Herein, a voltage-responsive controlled-release system was constructed by functionalizing the nanopore of MSNs with ferrocene. The system realized free-blockage controlled release and achieved pulsatile release. The nanopores of the ferrocene-functionalized MSNs were hydrophobic enough to prevent invasion of the solution. Once a suitable voltage was applied, the nanopores became hydrophilic, which was followed by invasion of the solution and the release of the cargos. Moreover, pulsatile release was realized, which avoided unexpected release after the stimulus disappeared. Thus, we believe that our studies provide new insight into highly effective blockage for MSNs. Furthermore, the voltage-responsive release system is expected to find use in electrical stimulation combination therapy and bioelectricity-responsive release.
Assuntos
Preparações de Ação Retardada/química , Compostos Ferrosos/química , Metalocenos/química , Nanopartículas/química , Dióxido de Silício/química , Eletricidade , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , PorosidadeRESUMO
OBJECTIVE: To study the funding and achievements in the field of organ transplantation support by the National Natural Science Foundation of China (NSFC). METHODS: A search of NSFC database was made by using the key word "transplantation" and excluding "bone marrow transplantation" for the projects funded between 1988 and 2013. SCI indexed publications that marked with NSFC project number were collected by searching each grant number in the database of the Web of Science. RESULTS: Six hundreds fifty-five projects were identified and received about 220 million yuan in grant funding. These funded research projects were distributed among 25 provinces and autonomous regions, however, which were mainly in the developed coastal areas; of them, 43 (6.56%) projects were granted in xenotransplantation and 17 projects (2.60%) were funded in the field of traditional Chinese medicine-related organ transplantation; Transplantation on blood vessels, heart, kidney, liver, lung, small intestine, pancreatic, cornea, trachea, skin, etc. were primarily performed in research. Nine hundreds and sixty-one SCI-indexed publications were achieved. CONCLUSIONS: Magnitude and intensity of NSFC funding, output of SCI publications have been increasing, suggesting that NSFC positively promotes the development of organ transplantation. Although a great progress of transplantation has been made, basic and translational studies should be vigorously strengthened.
Assuntos
Pesquisa Biomédica/economia , Fundações , Transplante , China , Apoio Financeiro , HumanosRESUMO
T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients with t(8;14)(q24;q11)/TCRA/D::MYC translocation represent a rare subgroup, with an aggressive course. In our retrospective analysis of 14 patients, all were identified during refractory or relapsed stages (5 primary tumor, 9 relapse). Notably, extramedullary invasion was detected in most patients. Four exhibited STIL::TAL1 translocation, and six demonstrated CDKN2A/B gene loss. The therapeutic outcomes were notably poor for all seven patients who received only chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT); all eventually succumbed to the disease with a median OS of 3 months. In the application of CD7 CAR-T therapy in six patients, five achieved CR. Of the four patients who underwent HSCT following CAR-T therapy, all have remained disease-free. The prognosis for T-ALL/LBL patients with t(8;14) translocation remains bleak, but interventions involving CD7 CAR-T may offer a potential pathway to CR. HSCT following CAR-T could be a viable strategy for long-term survival.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores de Antígenos Quiméricos , Humanos , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptores de Antígenos Quiméricos/genética , Estudos Retrospectivos , Translocação GenéticaRESUMO
Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. Methods: A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. Results: The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). Conclusions: Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.
Assuntos
Linfoma de Burkitt , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Doença Aguda , Neoplasia ResidualRESUMO
Glyphosate (GPS) is a wildly-used pesticide throughout the world. It affects metal behaviors in soil-water system as its functional groups such as amine, carboxylate and phosphonate can react with metal ions to form metal complexes. The reaction will result in the decreasing of heavy metal bioavailability. A laboratory experiment was conducted to investigate the interactions between GPS and copper (Cu) on the acute toxicity of soil invertebrate earthworm (Eisenia fetida), which was exposed to aqueous solutions for 48 h with different mixing concentrations of Cu and GPS (technical-grade Gly acid). The mortality rates, Cu uptake by earthworm, and some biomarkers such as superoxide dismutase (SOD) activity, glutathione (GSH) content, and acetylcholinesterase (AchE) activity were measured. The mortality rates and whole-worm metal burdens increased significantly with the increasing Cu concentration in solution. However, toxicity of GPS to earthworms was not observed in this study. Furthermore, the presence of GPS could significantly reduce the acute toxicity of Cu to earthworms. The mortality rates decreased sharply and the uptake of Cu was nearly halted in the presence of GPS. In addition, the SOD activity, GSH content, and AchE activity almost declined to the levels of the control. These results demonstrate that GPS could control the toxicity as well as the bioavailability of heavy metals in soil solutions where both GPS and heavy metals often coexist.
Assuntos
Cobre/toxicidade , Glicina/análogos & derivados , Oligoquetos/efeitos dos fármacos , Poluentes do Solo/toxicidade , Animais , Disponibilidade Biológica , Cobre/farmacocinética , Glicina/farmacocinética , Glicina/toxicidade , Oligoquetos/metabolismo , Poluentes do Solo/farmacocinética , Espectrofotometria , Espectrofotometria Atômica , GlifosatoRESUMO
Rare and undiagnosed diseases tend to be diverse, misdiagnosed, and difficult to diagnose. In some cases, the disease is progressive and life-threatening. Yet, to date, an estimated 95% of rare diseases have no approved therapy. Therefore, rare and undiagnosed diseases are considered the ultimate challenges for understanding human diseases. Here, we review the research progress, research frontiers, and important scientific issues related to rare and undiagnosed diseases. We mainly focus on five topics: (1) the identification and functional analysis of disease-causing genes; (2) the construction of cells, organoids, and animal models for mechanism validation; (3) subtyping and diagnosis; (4) treatment and drug screening based on causative genes and mutations; and (5) new technologies and methods for studying rare and undiagnosed diseases. In this review, we briefly update and discuss the pathogenic mechanisms and precision medicine for rare and undiagnosed diseases.
RESUMO
We analyzed the outcomes of 32 patients with paroxysmal nocturnal hemoglobinuria (PNH) who underwent either a haploidentical donor (HID) or a matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). Seventeen patients received an HSCT from an HID and 15 patients received an HSCT from an MUD. The median follow-up time of the surviving patients was 36 months (range: 12-96 months). No significant differences were observed in the 3-year overall survival (OS) between the HID and MUD cohorts (74.1%±11.4% vs. 93.3%±6.4%, respectively, p=.222) or in the 3-year failure-free survival (68.8%±11.8% vs. 86.7%±8.8%, respectively, p=.307). Treatment-related mortality occurred in five patients. A univariate analysis of risk factors revealed platelet engraftment failure negatively impacted OS and FFS. We conclude that HID and MUD-HSCT are feasible and can be effective options for those PNH patients with concomitant bone marrow failure, recurrent life-threatening thrombosis, and uncontrollable hemolysis.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística , Pancitopenia , Transtornos da Insuficiência da Medula Óssea , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/terapia , Humanos , Pancitopenia/etiologia , Estudos Retrospectivos , Condicionamento Pré-Transplante , Doadores não RelacionadosRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic malignancy characterized by poor prognosis even following an allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed 15 patients diagnosed with BPDCN who underwent an allo-HSCT with myeloablative conditioning (MAC) at our center. The male to female ratio was 11:4. The median age of 36 (range: 6-70) years, all patients initially presented with extramedullary lesions (13 with cutaneous lesions, 1 in the breast and 1 in the lymph nodes) and involved the bone marrow, two cases were diagnosed as central nervous system leukemia (CNSL). Nine patients were in CR1 and six patients were in CR2 status prior to HSCT. All patients received the MAC regimen and an unmanipulated graft. All patients successfully engraftment and achieved full donor chimerism. One patient developed poor graft function, three patients developed aGVHD (Grade I, II, and IV), and seven patients developed cGVHD (mild in 6; moderate in 1). The median follow-up time for survival was 34 (range: 6-64) months. The primary endpoint, overall leukemia-free survival (LFS) rate and overall survival rate was 73.3 ± 10.5%. Allo-HSCT with MAC is a valid option for BPDCN patients in complete remission.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Humanos , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante , Doença Aguda , Transtornos Mieloproliferativos/patologia , Células Dendríticas/patologiaRESUMO
Introduction: We aimed to evaluate prognostic factors of a second allogeneic stem cell transplantation (allo-HSCT2) among hematological malignancy patients who have relapsed after the first allo-HSCT(allo-HSCT1). Methods: We retrospectively analyzed 199 hematological malignancy patients who received allo-HSCT2 as a salvage treatment post allo-HSCT1 relapse between November 2012 and October 2021. Results: The median age at allo-HSCT2 was 23 (range: 3-60) years. The median time to relapse after HSCT1 was 9 (range: 1-72) months. Prior to allo-HSCT2, patients had the following hematopoietic cell transplantation-comorbidity indexes (HCT-CI): 127 with a score of 0, 52 with a score of 1, and 20 with a score of 2 or greater. Fifty percent of patients received chimeric antigen receptor (CAR) T-cell therapy following HSCT1 relapse. Disease status was minimal residual disease (MRD)-negative complete remission (CR) among 119 patients, MRD-positive CR among 37 patients and non-remission (NR) for 43 patients prior to allo-HSCT2. Allo-HSCT2 was performed from a new donor in 194 patients (97.4%) and 134 patients (67.3%) received a graft with a new mismatched haplotype. The median follow-up time was 24 months (range: 6-98 months), and the 2-year OS and LFS were 43.8% ± 4.0% and 42.1% ± 4.1%, respectively. The 2-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) was 30.0%±4.8% and 38.5%±3.8%, respectively. Cox regression multivariate analysis showed that disease statusof MRD-negative CR, HCT-CI score of 0 prior to allo-HSCT2, and new mismatched haplotype donor were predictive factors of improved OS and LFS compared to patients without these characteristics. Based on these three favorable factors, we developed a predictive scoring system for patients who received allo-HSCT2. Patients with a prognostic score of 3 who had the three factors showed a superior 2-year OS of 63.3% ± 6.7% and LFS of 63.3% ± 6.7% and a lower CIR of 5.5% ± 3.1% than patients with a prognostic score of 0. Allo-HSCT2 is feasible and patients with good prognostic features prior to allo-HSCT2 -disease status of CR/MRD- and HCT-CI score of 0 as well as a second donor with a new mismatched haplotype could have the maximal benefit from the second allo-HSCT. Conclusions: Allo-HSCT2 is feasible and patients with good prognostic features prior to allo-HSCT2 -disease status of CR/MRD- and HCT-CI score of 0 as well as a second donor with a new mismatched haplotype could have the maximal benefit from the second allo-HSCT.
Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transplante Homólogo , Recidiva Local de Neoplasia/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias Hematológicas/terapia , Doença CrônicaRESUMO
We retrospectively analyzed the outcomes of 240 pediatric SAA patients who underwent unmanipulated alternative HSCT between September 2012 and November 2020 at our center. The incidence of GF (PGF + SGF) was higher in the UCBD cohort compared to the MUD and HID cohorts [(13.5% ± 6.5%) vs (0%), and (1.6% ± 5.3%), respectively, p = .0001]. The incidence of platelet engraftment within 180 days post-HSCT was lower in the UCBD cohort (82.4% ± 2.3%) compared to the HID group (96.2% ± 1.3%) and the MUD group (97.4% ± 0.5%) (p = .020). the median duration time for platelet engraftment in the UCBD cohort was 29 days, longer than in HID cohort 14 days and the MUD cohort 13 days (p = .005). UCBD cohort had a lower 3-year failure-free survival (FFS) (70.5% ± 8.4%) compared to the HID cohort (81.1% ± 4.3%) and the MUD cohort (92.5% ± 3.1%) (p = .030) and lower 3-year GVHD/relapse free survival (GRFS) (63.3% ± 9.5.4%) compared to the HID cohort (75.5% ± 6.8%) and MUD cohort (87.9% ± 4.5%) (p = .002). UCBD-HSCT had inferior FFS and GRFS compared to an HSCT with an HID or MUD in pediatric patients with acquired SAA. A UCBD-HSCT had a higher GF and lower incidence of platelet engraftment and longer platelet engraftment time.