RESUMO
The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on hematopoietic stem cells (HSCs), along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells. In addition, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease and cytokine release syndrome. Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.
Assuntos
Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Células T Matadoras Naturais , Receptores de Antígenos Quiméricos , Humanos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Animais , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Camundongos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Edição de Genes , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias/terapia , Neoplasias/imunologia , Linhagem Celular Tumoral , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
Pain-related aversive memory is common in chronic pain patients. Electroacupuncture has been demonstrated to block pain-related aversive memory. The insular cortex is a key region closely related to aversive behaviors. In our study, a potential mechanism underlying the effect of electroacupuncture treatment on pain-related aversive memory behaviors relative to the insular cortex was investigated. Our study used the chemogenetic method, pharmacological method, electroacupuncture intervention, and behavioral detection. Our study showed that both inhibition of gamma-aminobutyric acidergic neurons and activation of the kappa opioid receptor in the insular cortex blocked the pain-related aversive memory behaviors induced by 2 crossover injections of carrageenan in mice; conversely, both the activation of gamma-aminobutyric acidergic neurons and inhibition of kappa opioid receptor in the insular cortex play similar roles in inducing pain-related aversive memory behaviors following 2 crossover injections of carrageenan. In addition, activation of gamma-aminobutyric acidergic neurons in the insular cortex reversed the effect of kappa opioid receptor activation in the insular cortex. Moreover, electroacupuncture effectively blocked pain-related aversive memory behaviors in model mice, which was reversed by both activation of gamma-aminobutyric acidergic neurons and inhibition of kappa opioid receptor in the insular cortex. The effect of electroacupuncture on blocking pain-related aversive memory behaviors may be related to the activation of the kappa opioid receptor and inhibition of gamma-aminobutyric acidergic neurons in the insular cortex.
Assuntos
Dor Crônica , Eletroacupuntura , Camundongos , Humanos , Animais , Receptores Opioides kappa/metabolismo , Córtex Insular , Carragenina/toxicidade , Neurônios GABAérgicos/fisiologia , Ácido gama-Aminobutírico/farmacologia , Doença Crônica , RecidivaRESUMO
Human mucosal-associated invariant T (MAIT) cells are characterized by their expression of an invariant TCR α chain Vα7.2-Jα33/Jα20/Jα12 paired with a restricted TCR ß chain. MAIT cells recognize microbial peptides presented by the highly conserved MHC class I-like molecule MR1 and bridge the innate and acquired immune systems to mediate augmented immune responses. Upon activation, MAIT cells rapidly proliferate, produce a variety of cytokines and cytotoxic molecules, and trigger efficient antitumor immunity. Administration of a representative MAIT cell ligand 5-OP-RU effectively activates MAIT cells and enhances their antitumor capacity. In this review, we introduce MAIT cell biology and their importance in antitumor immunity, summarize the current development of peripheral blood mononuclear cell-derived and stem cell-derived MAIT cell products for cancer treatment, and discuss the potential of genetic engineering of MAIT cells for off-the-shelf cancer immunotherapy.
Assuntos
Células T Invariantes Associadas à Mucosa , Neoplasias , Humanos , Células T Invariantes Associadas à Mucosa/metabolismo , Leucócitos Mononucleares/metabolismo , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Imunoterapia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/metabolismoRESUMO
BACKGROUND: We aimed to introduce our modified hand-assisted retroperitoneoscopic living donor nephrectomy (HARPLDN) technique and define the learning curve. METHODS: One hundred thirty-eight kidney donors who underwent modified HARPLDN by the same surgeon between May 2015 and March 2022 were included. A cumulative sum (CUSUM) learning curve analysis was performed with the total operation time as the study outcome. RESULTS: In total, the mean operative time was 138.2 ± 32.1 min. The median warm ischemic time (WIT) and estimated blood loss were 90 s and 50 ml, respectively. The learning curve for the total operative time was best modeled as a second-order polynomial with the following equation: CUSUMOT (min) = (-0.09 case number2) + (12.88 case number) - 67.77 (R2 = 0.7875; p<0.05). The CUSUM learning curve included the following three unique phases: phase 1 (the initial 41 cases), representing the initial learning curve; phase 2 (the middle 43 cases), representing expert competence; and phase 3 (the final 54 cases), representing mastery. The overall 6-month graft survival rate was 99.3%, with 94.9% immediate onset of graft function without delayed graft function and 0.7% ureteral complications. CONCLUSIONS: Our modified method is safe and effective for living donor nephrectomy and has the advantages of a shorter operating time and optimized WIT. The surgeon can become familiar with the modified HARPLDN after 41 cases and effectively perform the next 97 cases.
Assuntos
Curva de Aprendizado , Doadores Vivos , Nefrectomia , Humanos , Nefrectomia/métodos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Laparoscopia Assistida com a Mão/métodos , Espaço Retroperitoneal/cirurgia , Estudos Retrospectivos , Transplante de Rim/educação , Transplante de Rim/métodos , Duração da Cirurgia , Coleta de Tecidos e Órgãos/métodos , Coleta de Tecidos e Órgãos/educaçãoRESUMO
BACKGROUND: Few studies have systematically explored the factors influencing the difficulty of hand-assisted laparoscopic living donor nephrectomy. To investigate the relationship between the difficulty of hand-assisted laparoscopic living donor nephrectomy and postoperative complications of the donor as well as the recipient, and then build a model for predicting the difficulty of surgery. METHODS: In this study, 60 patients who underwent hand-assisted laparoscopic living donor nephrectomy by the same surgeon from September 2022 to March 2024 were included as the modeling group. 20 patients operated on by another surgeon served as the external validation group. The subjective score (1-3 points) of surgical difficulty was used as the quantitative index of surgical difficulty. Pearson and Spearman correlation tests were used to explore the correlation between preoperative data and surgical difficulty scores of kidney donors, and finally built a prediction model through multiple linear regression analysis. RESULTS: With the increase in the difficulty of operation, both donors and recipients' complications were increased. Linear regression analysis showed that only the number of renal arteries, visceral fat thickness and MAP score were independent risk factors for the difficulty of hand-assisted laparoscopic living donor nephrectomy. The prediction equation is as follows: Difficulty score = 0.584*Number of renal arteries + 0.731*MAP score + 0.110*visceral fat thickness. CONCLUSIONS: Donors with higher surgical difficulty are more likely to have serious complications after surgery as well as the recipient. We also established a reliable prediction model for the difficulty of hand-assisted laparoscopic donor nephrectomy.
Assuntos
Laparoscopia Assistida com a Mão , Doadores Vivos , Nefrectomia , Complicações Pós-Operatórias , Humanos , Nefrectomia/métodos , Nefrectomia/efeitos adversos , Laparoscopia Assistida com a Mão/métodos , Laparoscopia Assistida com a Mão/efeitos adversos , Feminino , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Adulto , Pessoa de Meia-Idade , Transplante de Rim/métodos , Coleta de Tecidos e Órgãos/efeitos adversos , Coleta de Tecidos e Órgãos/métodos , Estudos RetrospectivosRESUMO
Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between CSCs and the tumor microenvironment (TME) is observed, with the TME providing a supportive niche for CSC survival and self-renewal, while CSCs, in turn, influence the polarization and persistence of the TME, promoting an immunosuppressive state. Consequently, these interactions hinder the efficacy of current cancer therapies, necessitating the exploration of novel therapeutic approaches to modulate the TME and target CSCs. In this review, we highlight the intricate strategies employed by CSCs to evade immune surveillance and develop resistance to therapies. Furthermore, we examine the dynamic interplay between CSCs and the TME, shedding light on how this interaction impacts cancer progression. Moreover, we provide an overview of advanced therapeutic strategies that specifically target CSCs and the TME, which hold promise for future clinical and translational studies in cancer treatment.
Assuntos
Neoplasias , Humanos , Neoplasias/patologia , Imunoterapia , Transformação Celular Neoplásica , Células-Tronco Neoplásicas/patologia , Microambiente TumoralRESUMO
BACKGROUND: The high incidence of Gleason score upgrading (GSU) made urologists underestimate the disease, leading to the inaccurate therapeutic decision. The study aimed to explore relevant laboratory examination evidence associated with GSU. METHODS: Patients diagnosed with prostate carcinoma undergoing radical prostatectomy in our center between January 2015 and December 2019 were included in this retrospective study. Patients were divided into GSU and NGSU groups according to the occurrence of GSU. Medical records were reviewed and analyzed between groups. RESULTS: A total of 130 patients were enrolled, including 52 patients diagnosed with GS = 6 (20 NGSU and 32 GSU) and 78 patients with GS = 7 (36 NGSU and 42 GSU). No significant differences in demographic characteristics were found between groups. An increased neutrophil count (OR = 1.326, 95% CI = 1.005-1.748) and a decreased percentage of lymphocytes (OR = 0.951, 95% CI = 0.904-1) were associated with GSU in the GS = 6 group, whereas a high HDL level (OR = 7.735, 95% CI = 0.998-59.957) was associated with GSU in GS = 7 group. Preoperative high neutrophile count and low lymphocyte percentage were correlated with GSU in patients with low-grade prostate cancer. In contrast, high HDL level was associated with GSU in patients with high-grade prostate cancer. CONCLUSIONS: These laboratory examination data could provide urologists with information before making a therapeutic protocol.
Assuntos
Carcinoma , Neoplasias da Próstata , Humanos , Masculino , Carcinoma/patologia , Lipoproteínas HDL , Gradação de Tumores , Próstata/patologia , Antígeno Prostático Específico , Prostatectomia , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: De novo urothelial carcinoma (UC) is a leading cause of death after kidney transplant (KT). The efficacy of various treatments, apart from surgery, and the prognosis for patients with urothelial carcinoma after kidney transplantation remain unclear. METHODS: We retrospectively reviewed the efficacy of chemotherapy with gemcitabine + cisplatin (GC) or gemcitabine + carboplatin (GCa), bladder infusion chemotherapy, and immunosuppression therapy for de novo UC in kidney transplantation recipients at different sites and T stages. We evaluated the prognosis and compared the difference using Kaplan-Meier analysis and the log-rank test. RESULTS: Of the 97 kidney transplantation recipients with de novo UC, 51 (52.6%) were diagnosed with upper urinary tract carcinoma (UTUC), 17 (17.5%) with bladder carcinoma (BC), and 29 (29.9%) with both UTUC and BC. The five-year survival rates for BC, UTUC, and BC + UTUC with ≤ T1 stage were 100%, 88.2%, and 57.7%, respectively, while the survival rates for UTUC, BC + UTUC with ≥ T2 stage were 90.2% and 48.2%. Cyclosporine A significantly improved progression-free survival (PFS) in UTUC with ≤ T1 stage (p = 0.017). Rapamycin significantly improved PFS in UTUC with ≥ T2 stage (p = 0.026). Bladder infusion chemotherapy and GC/GCa chemotherapy had no significant effect on each T stage and site. Patients with UTUC + BC had the poorest overall survival (OS) compared with those with BC and UTUC. CONCLUSION: The prognosis of UC in different sites varies. GC/GCa chemotherapy and bladder infusion chemotherapy appear to have no effect on prognosis. Rapamycin can delay the progression of advanced UTUC.
Assuntos
Carcinoma de Células de Transição , Transplante de Rim , Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Humanos , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/patologia , Estudos Retrospectivos , Neoplasias Urológicas/tratamento farmacológico , Resultado do Tratamento , Cisplatino , DesoxicitidinaRESUMO
BACKGROUND: Long-term prognosis and risk factors of de novo upper tract urothelial carcinoma after renal transplantation were rarely studied. Thus, the aim of this study was to investigate the clinical features, risk factors, and long-term prognosis of de novo upper tract urothelial carcinoma after renal transplantation, especially the impact of aristolochic acid on tumor, using a large sample. METHODS: 106 patients were enrolled in retrospective study. The endpoints included overall survival, cancer-specific survival, bladder or contralateral upper tract recurrence-free survival. Patients were grouped according to aristolochic acid exposure. Survival analysis was performed using Kaplan-Meier curve. Log-rank test was used to compare the difference. Multivariable cox regression was conducted to evaluate the prognostic significance. RESULTS: Median time from transplantation to development of upper tract urothelial carcinoma was 91.5 months. Cancer-specific survival rate at 1, 5, 10 years was 89.2%, 73.2%, 61.6%. Tumor staging (≥ T2), lymph node status (N +) were independent risk factors for cancer-specific death. Contralateral upper tract recurrence-free survival rate at 1, 3, 5 years was 80.4%, 68.5%, 50.9%. Aristolochic acid exposure was independent risk factor for contralateral upper tract recurrence. The patients exposed to aristolochic acid had more multifocal tumors and higher incidence of contralateral upper tract recurrence. CONCLUSION: Both higher tumor staging and positive lymph node status were associated with a worse cancer-specific survival in patients with post-transplant de novo upper tract urothelial carcinoma, which highlighted the importance of early diagnosis. Aristolochic acid was associated with multifocality of tumors and higher incidence of contralateral upper tract recurrence. Thus, prophylactic contralateral resection was suggested for post-transplant upper tract urothelial carcinoma, especially for patients with aristolochic acid exposure.
Assuntos
Carcinoma de Células de Transição , Transplante de Rim , Neoplasias Ureterais , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/epidemiologia , Carcinoma de Células de Transição/etiologia , Carcinoma de Células de Transição/cirurgia , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Prognóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Ureterais/epidemiologiaRESUMO
Allogeneic cell therapies, defined by genetically mismatched transplantation, have the potential to become a cost-effective solution for cell-based cancer immunotherapy. However, this type of therapy is often accompanied by the development of graft-versus-host disease (GvHD), induced by the mismatched major histocompatibility complex (MHC) between healthy donors and recipients, leading to severe complications and death. To address this issue and increase the potential for allogeneic cell therapies in clinical practice, minimizing GvHD is a crucial challenge. Innate T cells, encompassing subsets of T lymphocytes including mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, and gamma delta T (γδ T) cells, offer a promising solution. These cells express MHC-independent T-cell receptors (TCRs), allowing them to avoid MHC recognition and thus GvHD. This review examines the biology of these three innate T-cell populations, evaluates research on their roles in GvHD modulation and allogeneic stem cell transplantation (allo HSCT), and explores the potential futures for these therapies.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células T Invariantes Associadas à Mucosa , Células T Matadoras Naturais , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Imunoterapia/efeitos adversosRESUMO
Invariant natural killer T (iNKT) cells have the capacity to mount potent anti-tumor reactivity and have therefore become a focus in the development of cell-based immunotherapy. iNKT cells attack tumor cells using multiple mechanisms with a high efficacy; however, their clinical application has been limited because of their low numbers in cancer patients and difficulties in infiltrating solid tumors. In this study, we aimed to overcome these critical limitations by using α-GalCer, a synthetic glycolipid ligand specifically activating iNKT cells, to recruit iNKT to solid tumors. By adoptively transferring human iNKT cells into tumor-bearing humanized NSG mice and administering a single dose of tumor-localized α-GalCer, we demonstrated the rapid recruitment of human iNKT cells into solid tumors in as little as one day and a significantly enhanced tumor killing ability. Using firefly luciferase-labeled iNKT cells, we monitored the tissue biodistribution and pharmacokinetics/pharmacodynamics (PK/PD) of human iNKT cells in tumor-bearing NSG mice. Collectively, these preclinical studies demonstrate the promise of an αGC-driven iNKT cell-based immunotherapy to target solid tumors with higher efficacy and precision.
Assuntos
Células T Matadoras Naturais , Neoplasias , Animais , Antígenos CD1d , Galactosilceramidas/farmacologia , Humanos , Camundongos , Neoplasias/terapia , Distribuição TecidualRESUMO
Careful selection of the host embryo is critical to the efficient production of knockout (KO) mice when injecting mouse embryonic stem (mES) cells into blastocysts. B6(Cg)-Tyrc-2j/J (B6 albino) and C57BL/6NTac (B6NTac) strains of mice are widely used to produce host blastocysts for such procedures. Here, we tested these two strains to identify an appropriate match for modified agouti C57BL/6N (JM8A3.N1) mES cells. When comparing blastocyst yield, super-ovulated B6NTac mice produced more injectable blastocysts per female than B6 albino mice (8.2 vs. 5.4). There was no significant difference in birth rate when injected embryos were transferred to the same pseudopregnant recipient strain. However, the live birth rate was significantly higher for B6NTac blastocysts than B6 albino blastocysts (62.7% vs. 50.2%). In addition, the proportion of pups exhibiting high-level and complete chimerism, as identified by coat color, was also significantly higher in the B6NTac strain. There was no obvious difference in the efficiency of germline transmission (GLT) when compared between B6NTac and B6 albino host embryos (61.5% vs. 63.3% for mES clones; 64.5% vs. 67.9% for genes, respectively), thus suggesting that an equivalent GLT rate could be obtained with only a few blastocyst injections for B6NTac embryos. In conclusion, our data indicate that B6NTac blastocysts are a better choice for the microinjection of JM8A3.N1 mES cells than B6 albino blastocysts.
Assuntos
Blastocisto/metabolismo , Transferência Embrionária , Camundongos Knockout/genética , Células-Tronco Embrionárias Murinas/transplante , Animais , Embrião de Mamíferos , Células Germinativas/crescimento & desenvolvimento , Camundongos , Camundongos Knockout/crescimento & desenvolvimento , Microinjeções , Células-Tronco Embrionárias Murinas/citologiaRESUMO
BACKGROUND: Long-term outcome of DAAs therapy in kidney transplant recipients was unknown. Thus, we aimed to evaluate it in a Chinese cohort of HCV-infected kidney transplant recipients. METHODS: Single-center and retrospective study of HCV-infected kidney transplant recipients initiating an DAAs regimen between January 2015 and December 2017 was conducted. Totally 26 KTX recipients were divided into three groups, including KTX-HD Group, DAA-KTX Group and KTX-DAA Group. On-treatment response was defined as target not detected within 12 weeks. SVR 48, 96 were defined as HCV-RNA negativity 48, 96 weeks after treatment cessation, respectively. RESULTS: HCV genotype was predominantly 1b (80.8%), followed by 2a. All (100%) patients achieved on-treatment response. Time to first TnD was 1.9 ± 0.6 weeks, with no significant difference among the three groups. All patients achieved SVR, with an SVR rate of 100.0% (26/26) among the patients who were followed up over 48 weeks after treatment cessation, and the same SVR rate (24/24) among the patients who were followed up over 96 weeks. Trough levels of Tac remained stable under DAAs therapy, without any dose adjustment. Two patients with abnormal GFR before treatment experienced serum creatinine elevation. Other adverse events included nausea, diarrhea, acid regurgitation, bilirubin elevation and edema of lower limbs. All patients recovered after treatment cessation without reductions in dose, or withdrawal of DAAs or immunosuppressive agents. CONCLUSIONS: HCV genotype 1b and 2a are the only genotypes and 1b is predominant in our center. Antiviral treatment with DAAs in HCV-infected kidney transplant recipients is persistently effective and well tolerated during long-term follow-up. A regular monitoring of renal function in patients who receive DAAs regimens with preexisting impaired renal function is strongly recommended. Furthermore, the trough CNIs levels were recommended to be frequently monitored.
Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Transplante de Rim/efeitos adversos , Adulto , Antivirais/efeitos adversos , China , Feminino , Seguimentos , Genótipo , Hepacivirus/genética , Hepatite C/virologia , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplantados , Resultado do TratamentoRESUMO
BACKGROUND: Chronic kidney disease (CKD) and end stage renal disease (ESRD) are not well characterized in prostate cancer patients. This study aimed to examine the clinical characteristics and postsurgical outcomes of patients with or without CKD and ESRD undergoing radical prostatectomy for prostate cancer. METHODS: This population-based, retrospective study used patient data from the Nationwide Inpatient Sample, the largest all-payer US inpatient care database. From 2005 to 2014, 136,790 male patients aged > 20 years diagnosed with prostate cancer and who received radical prostatectomy were included. Postoperative complications, postoperative acute kidney injury (AKI) and urinary complications, and length of hospital stay were compared between patients with or without underlying CKD and ESRD. RESULTS: After adjusting for relevant factors, the CKD group had a significantly higher risk of postoperative complications than the non-CKD group. In addition, the CKD group had a 5-times greater risk of postoperative AKI and urinary complications than the non-CKD group. Both CKD and ESRD groups had significantly longer hospital stays than the non-CKD group. Patients receiving RARP had a lower risk of postoperative complications than those who received open radical prostatectomy, regardless of having CKD or not. Both non-CKD and CKD patients receiving RARP had shorter hospital stays than those who received open surgery. CONCLUSIONS: Prostate cancer patients with underlying CKD had significantly greater risk of postoperative complications, postoperative AKI and urinary complications, and longer hospital stays than those without CKD. The use of RARP significantly shortened hospital stays and reduced complications for these patients.
Assuntos
Prostatectomia , Neoplasias da Próstata/complicações , Neoplasias da Próstata/cirurgia , Insuficiência Renal Crônica/complicações , Adulto , Bases de Dados Factuais , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Prostatectomia/métodos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Due to the increasing number of DCD transplantations since 2015, the transmission of rabies through solid organ transplantation has become a notable problem in China and has attracted the attention of the public. CASE PRESENTATION: From 2015 to 2017, four solid organ recipients in our centre were successively diagnosed with rabies that was considered to have been transmitted from two donors who died due to viral encephalitis of unknown cause and acute disseminated encephalomyelitis. The incubation periods were 44, 48, 158 and 303 days. The four patients had neurological symptoms associated with rabies and died. The survival times were 44, 34, 8 and 6 days. Another kidney transplant recipient received timely post-exposure prophylaxis and has remained asymptomatic. CONCLUSIONS: Organs should be discarded whenever rabies is confirmed or suspected, especially in cases diagnosed as encephalitis of unknown cause. It is important to establish a supervisory system to manage donor-derived infectious diseases. When rabies-infected donor organs are inadvertently transplanted, the recipients must receive post-exposure prophylaxis in a timely manner, which may be the only possible effective method to prevent the transmission of rabies.
Assuntos
Encefalite Viral/diagnóstico , Transplante de Órgãos , Raiva/diagnóstico , Adulto , Criança , Encefalite Viral/etiologia , Encefalite Viral/mortalidade , Feminino , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Profilaxia Pós-Exposição , RNA Viral/urina , Raiva/mortalidade , Raiva/transmissão , Vírus da Raiva/genética , Vírus da Raiva/isolamento & purificação , Saliva/virologia , Escarro/virologia , Doadores de TecidosRESUMO
BACKGROUND: Genomic DNA methylation plays an important role in both the occurrence and development of bladder cancer. Kaempferol (Kae), a natural flavonoid that is present in many fruits and vegetables, exhibits potent anti-cancer effects in bladder cancer. Similar to other flavonoids, Kae possesses a flavan nucleus in its structure. This structure was reported to inhibit DNA methylation by suppressing DNA methyltransferases (DNMTs). However, whether Kae can inhibit DNA methylation remains unclear. METHODS: Nude mice bearing bladder cancer were treated with Kae for 31 days. The genomic DNA was extracted from xenografts and the methylation changes was determined using an Illumina Infinium HumanMethylation 450 BeadChip Array. The ubiquitination was detected using immuno-precipitation assay. RESULTS: Our data indicated that Kae modulated DNA methylation in bladder cancer, inducing 103 differential DNA methylation positions (dDMPs) associated with genes (50 hyper-methylated and 53 hypo-methylated). DNA methylation is mostly relied on the levels of DNMTs. We observed that Kae specifically inhibited the protein levels of DNMT3B without altering the expression of DNMT1 or DNMT3A. However, Kae did not downregulate the transcription of DNMT3B. Interestingly, we observed that Kae induced a premature degradation of DNMT3B by inhibiting protein synthesis with cycloheximide (CHX). By blocking proteasome with MG132, we observed that Kae induced an increased ubiquitination of DNMT3B. These results suggested that Kae could induce the degradation of DNMT3B through ubiquitin-proteasome pathway. CONCLUSION: Our data indicated that Kae is a novel DNMT3B inhibitor, which may promote the degradation of DNMT3B in bladder cancer.
Assuntos
DNA (Citosina-5-)-Metiltransferases/biossíntese , Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quempferóis/farmacologia , Proteínas de Neoplasias/biossíntese , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , DNA Metiltransferase 3BRESUMO
BACKGROUND: We aimed to confirm the advantages of a modified hand-assisted retroperitoneoscopic living donor nephrectomy (HARPLDN) compared to the performance of standard retroperitoneoscopic living donor nephrectomy (RPLDN). METHODS: One hundred twenty-eight consecutive surgical cases were categorized into 2 groups, one receiving standard RPLDN (group 1) and one receiving modified HARPLDN (group 2). Perioperative factors of both groups were evaluated retrospectively, including donors' demographics, overall operating time, warm ischemia time (WIT), graft vessel length, blood loss, complications, pain visual analogue scale (VAS) scores, hospital stay, and matched recipients' perioperative outcomes. One-year follow-up data were also examined. RESULTS: The standard RPLDN group (n = 44) and modified HARPLDN group (n = 84) had comparable age, gender, and body mass index. The RPLDN group donors had longer operative time, shorter vein length and longer WIT than the modified HARPLDN (all p < 0.001). RPLDN had higher VAS scores (p < 0.001), longer carminative time (p = 0.002) and higher morphine requirement (p = 0.039) than the modified HARPLDN. No complications occurred in either group. All recipients and grafts had survived at 1-year follow-up. CONCLUSION: The modified HARPLDN technique is safe and effective for living donor nephrectomy and has shorter operating time, shorter WIT and better pain control. Further study is required to evaluate donors' long-term quality of life and recipients' long-term outcomes.
Assuntos
Laparoscopia Assistida com a Mão/métodos , Transplante de Rim , Nefrectomia/métodos , Coleta de Tecidos e Órgãos/métodos , Adulto , Feminino , Humanos , Doadores Vivos , Masculino , Músculo Esquelético/cirurgia , Espaço Retroperitoneal , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Hearing loss is a prevalent issue resulting from loud noise exposure, aging, diseases, and genetic differences. As individuals age, the likelihood of experiencing hearing loss and depression escalates; yet, the link between hearing loss and the risk of depression remains ambiguous. This study explores the relationship between hearing and depression risk, taking into account sociodemographic and health-related factors. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 2015-2018, a cross-sectional analysis was conducted, focusing on adult participants. It evaluated their hearing status and depression levels using the Patient Health Questionnaire-9 (PHQ-9). The study examined a range of variables, such as age, gender, socioeconomic status, lifestyle choices, and comorbidities, to understand their influence on the link between hearing loss and depression. RESULTS: Analysis indicated a significant association between moderate to severe hearing loss and an increased risk of depression, notably in older adults. This relationship remained significant even after adjusting for a variety of sociodemographic and health factors. LIMITATIONS: This is a study using the NHANES database using self-reported surveys. CONCLUSION: The findings of this study emphasize the need to integrate hearing health in the holistic assessment and treatment of depression, particularly advocating for combined care strategies for the elderly.
Assuntos
Depressão , Perda Auditiva , Inquéritos Nutricionais , Humanos , Masculino , Feminino , Estudos Transversais , Adulto , Pessoa de Meia-Idade , Perda Auditiva/epidemiologia , Idoso , Depressão/epidemiologia , Adulto Jovem , Estados Unidos/epidemiologia , Adolescente , Idoso de 80 Anos ou mais , ComorbidadeRESUMO
PURPOSE: To compare the efficiency and safety between retroperitoneal laparoscopic nephrectomy and traditional open nephrectomy to treat autosomal-dominant polycystic kidney disease before kidney transplantation. MATERIALS AND METHODS: A total of 57 patients diagnosed with huge autosomal-dominant polycystic kidney disease between 2000 and 2020 at our center were included in this study. Patients were divided into a retroperitoneal laparoscopic (RL; n=23) group and traditional open (TO; n = 34) group. We retrospectively analyzed and compared preoperative and perioperative variables between the two groups. RESULTS: Patients in the RL group showed a longer operation time (201.09±83.76min) compared to patients in the TO group (113.38 ± 51.84min, p < 0.001). The RL group also showed significantly less intraoperative blood loss (p = 0.025) and less intraoperative blood transfusion volume (p = 0.016) compared to the TO group. Meanwhile, time of gastrointestinal function recovery, bed leave, catheter indwelling and postoperative hospitalization in the RL group were 2.13 ± 0.63, 1.30 ± 1.0, 5.22 ± 2.09, 7.35±2.48 days, respectively, which were significantly shorter than the TO group (p < 0.05). Pain degree of patients during the first 48 hours after operation was similar between the RL and TO groups, but the opioid use percentage in the RL group was 8.70% (2/23) and was lower than the 26.47% (9/34) in the TO group (p = 0.022). Meanwhile, 5 and 23 patients exhibited postoperative complications in the RL and TO groups, respectively (p < 0.001). CONCLUSION: Both retroperitoneal laparoscopic nephrectomy and traditional open surgery are feasible to treat huge polycystic nephrectomy. However, patients who undergo retroperitoneal laparoscopic nephrectomy experience higher levels of safety and recover more rapidly.
Assuntos
Transplante de Rim , Laparoscopia , Doenças Renais Policísticas , Humanos , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Doenças Renais Policísticas/complicações , Doenças Renais Policísticas/cirurgia , Nefrectomia/efeitos adversos , Laparoscopia/efeitos adversos , Resultado do TratamentoRESUMO
AIMS: To explore whether music intervention improves the quality of life (QOL) of patients undergoing hematopoietic stem cell transplantation (HSCT) and to evaluate its impact on patients' symptoms of depression/anxiety and fatigue. METHODS: This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items of Systematic reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Cochrane CENTRAL, and EMBASE were searched from inception to September 30, 2022. The search strategy used a combination of the keywords "music" and "hematopoietic stem cell transplantation" or "HSCT." The outcomes assessed were QOL, depression and anxiety, and fatigue. Pooled standardized mean differences with 95% confidence intervals were calculated to compare the outcomes between the music intervention and control groups. Heterogeneity across the studies was assessed using a chi-square-based test, and the I2 and Q statistics. RESULTS: Meta-analysis of the included study population showed that music intervention for patients undergoing HSCT was associated with patients' improved QOL, and resulted in reduced depression/anxiety and fatigue compared to patients without music intervention. CONCLUSION: Music intervention benefits HSCT outcomes, including better QOL, less depression/anxiety, and less fatigue postoperatively. Future trials with larger samples are still warranted to strengthen the evidence supporting the benefits of music intervention in this patient population.