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1.
Sci Adv ; 10(23): eadk3081, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38848367

RESUMO

Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas inflammation, oxidative stress during islet isolation, and harsh engraftment conditions in the liver's vasculature. We describe a thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to protect islet redox status and function and to enable extrahepatic omentum islet engraftment. PPCN solution transitions from a liquid to a hydrogel at body temperature. Islets entrapped in PPCN and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a plasma-thrombin biologic scaffold. In the nonhuman primate (NHP) omentum, PPCN is well-tolerated and mostly resorbed without fibrosis at 3 months after implantation. In NHPs, autologous omentum islet transplantation using PPCN restores normoglycemia with minimal exogenous insulin requirements for >100 days. This preclinical study supports TP-IAT with PPCN in patients with CP and highlights antioxidant properties as a mechanism for islet function preservation.


Assuntos
Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Omento , Estresse Oxidativo , Transplante das Ilhotas Pancreáticas/métodos , Omento/metabolismo , Animais , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Cítrico/farmacologia , Humanos , Antioxidantes/farmacologia , Pancreatite Crônica/metabolismo , Pancreatite Crônica/cirurgia , Pancreatite Crônica/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Masculino , Transição de Fase
2.
Biomacromolecules ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38857534

RESUMO

Postmodification of alginate-based microspheres with polyelectrolytes (PEs) is commonly used in the cell encapsulation field to control microsphere stability and permeability. However, little is known about how different applied PEs shape the microsphere morphology and properties, particularly in vivo. Here, we addressed this question using model multicomponent alginate-based microcapsules postmodified with PEs of different charge and structure. We found that the postmodification can enhance or impair the mechanical resistance and biocompatibility of microcapsules implanted into a mouse model, with polycations surprisingly providing the best results. Confocal Raman microscopy and confocal laser scanning microscopy (CLSM) analyses revealed stable interpolyelectrolyte complex layers within the parent microcapsule, hindering the access of higher molar weight PEs into the microcapsule core. All microcapsules showed negative surface zeta potential, indicating that the postmodification PEs get hidden within the microcapsule membrane, which agrees with CLSM data. Human whole blood assay revealed complex behavior of microcapsules regarding their inflammatory and coagulation potential. Importantly, most of the postmodification PEs, including polycations, were found to be benign toward the encapsulated model cells.

3.
Clin Transplant ; 38(1): e15208, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38041492

RESUMO

BACKGROUND: End-stage liver disease (ESLD) and end-stage renal disease (ESRD) are prevalent diseases for which the definitive treatment is transplantation. With limited organ supply, strategies to maximize organ availability has led to increasing rates of split liver transplantations for ESLD patients. Therefore, simultaneous split liver and kidney transplantations (SSLK) for patients with ESLD and ESRD could represent a treatment option for comorbid patients. However, current practice and outcomes after SSLK are unknown. METHODS: We aim to report national trends and our experience with patients undergoing SSLK. We performed a retrospective review of the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research file from January 2011-April 2022. Descriptive analysis of preoperative characteristics, postoperative outcomes and actuarial graft and patient survivals are reported. RESULTS: National review of the UNOS transplant registry from 2011-2021 of adult patients undergoing initial transplantation via SSLK demonstrates that this procedure remains uncommon, with only 76 such cases captured in that time. Nevertheless, survival rates at 1, 3, and 5 years remains robust, at 94%, 92%, and 90% for patients overall, 90%, 88%, 88%, for the liver graft, and 93%, 91%, 88% for the kidney graft, respectively. Review of a single center experience with three such patients from 2019-2021 has shown a safe, enduring transplant option with no graft complications seen. CONCLUSIONS: SSLK is both safe and a feasible option to optimize organ supply while allowing recipients to receive quality liver and kidney grafts and should be considered more often by transplant centers going forward.


Assuntos
Doença Hepática Terminal , Falência Renal Crônica , Transplante de Rim , Transplante de Fígado , Adulto , Humanos , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Falência Renal Crônica/cirurgia , Falência Renal Crônica/etiologia , Doença Hepática Terminal/cirurgia , Estudos Retrospectivos , Rim , Sobrevivência de Enxerto , Resultado do Tratamento
4.
Am J Transplant ; 23(12): 1980-1989, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37748554

RESUMO

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.


Assuntos
Transplante de Rim , Humanos , Idoso , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Adulto , Transplante de Rim/efeitos adversos , Doadores Vivos , Sobrevivência de Enxerto , Rejeição de Enxerto/etiologia , Antígenos HLA , Fatores de Risco
5.
Clin Transplant ; 37(11): e15099, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37589889

RESUMO

BACKGROUND: Living donor liver transplantation (LDLT) in the elderly population is currently not well studied. There are single-center studies indicating that patient age should not be a barrier to LDLT, with similar outcomes compared to younger recipients. METHODS: Using UNOS/STAR data from 2010 to 2022 we retrospectively analyzed patients ≥70 years old receiving a living donor graft (LDLT ≥70y group) versus a deceased donor graft (DDLT ≥70y group). In addition, we compared recipients ≥70 years old undergoing LDLT versus patients 18-69 years old also undergoing LDLT. Donor and recipient baseline characteristics, as well as postoperative outcomes including graft and patient survival were analyzed and compared between groups. RESULTS: Recipients in the LDLT ≥70y group showed less disease burden and spent significantly less time on the waitlist when compared to recipients in the DDLT ≥70y group (102 [49-201] days versus 170 [36-336] days) respectively; p = .004. With the exception of a longer length of stay (LOS) in the LDLT ≥70y group (p ≤ .001), postoperative outcomes were comparable with recipients in the DDLT ≥70y group, including similar graft and patient survival rates at 1-, 3-, and 5-years. When compared to younger recipients of a graft from a living donor, patients in the LDLT ≥70y group had similar post-transplant functional status, re-transplant rates and similar causes contributing to graft failure. However, significantly lower graft and patient survival rates were observed. CONCLUSION: LDLT for recipients aged 70 or greater represents a faster access to transplantation in a safe and feasible manner when compared to similar- aged recipients undergoing DDLT.


Assuntos
Transplante de Fígado , Humanos , Idoso , Estados Unidos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores Vivos , Tempo de Internação , Sobrevivência de Enxerto , Resultado do Tratamento
6.
Int J Med Robot ; 19(5): e2527, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37190677

RESUMO

BACKGROUND: Robotic transplant surgery has garnered worldwide attention since 2002. Discussions on this issue have led to more publications over the past decade. This study assessed global robotic organ transplantation studies using bibliometric analysis. METHOD: The study sample was robotic technique use in organ transplantation publications from 2002 to 2021 in the Web of Science database. We analysed top-cited authors, countries, institutions, journals, and keywords. Citations were used to visualise and analyse target literature in VOSviewer. RESULTS: 160 articles were included in the bibliometric study. Among the nations that are presently involved in the use of robotics in organ transplantation research, the United States of America leads robotic organ transplantation studies. The American Journal of Transplantation published the most articles overall. CONCLUSION: Based on publication and citation numbers, robotic organ transplantation techniques are becoming more global attention. This robotic abdominal organ transplant surgery bibliometric analysis review covers research output and hotspots.


Assuntos
Transplante de Órgãos , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Estados Unidos , Bibliometria , Bases de Dados Factuais
7.
Nat Biomed Eng ; 7(7): 867-886, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37106151

RESUMO

Screening implantable biomaterials for antifibrotic properties is constrained by the need for in vivo testing. Here we show that the throughput of in vivo screening can be increased by cellularly barcoding a chemically modified combinatorial library of hydrogel formulations. The method involves the implantation of a mixture of alginate formulations, each barcoded with human umbilical vein endothelial cells from different donors, and the association of the identity and performance of each formulation by genotyping single nucleotide polymorphisms of the cells via next-generation sequencing. We used the method to screen 20 alginate formulations in a single mouse and 100 alginate formulations in a single non-human primate, and identified three lead hydrogel formulations with antifibrotic properties. Encapsulating human islets with one of the formulations led to long-term glycaemic control in a mouse model of diabetes, and coating medical-grade catheters with the other two formulations prevented fibrotic overgrowth. High-throughput screening of barcoded biomaterials in vivo may help identify formulations that enhance the long-term performance of medical devices and of biomaterial-encapsulated therapeutic cells.


Assuntos
Alginatos , Hidrogéis , Camundongos , Animais , Alginatos/química , Hidrogéis/química , Células Endoteliais , Primatas , Materiais Biocompatíveis/química
8.
PLoS One ; 18(3): e0282771, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36862649

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0161834.].

9.
Microsyst Nanoeng ; 9: 14, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36760229

RESUMO

One distinct advantage of microfluidic-based cell assays is their scalability for multiple concentrations or gradients. Microfluidic scaling can be extremely powerful when combining multiple parameters and modalities. Moreover, in situ stimulation and detection eliminates variability between individual bioassays. However, conventional microfluidics must combat diffusion, which limits the spatial distance and time for molecules traveling through microchannels. Here, we leveraged a multilayered microfluidic approach to integrate a novel oxygen gradient (0-20%) with an enhanced hydrogel sensor to study pancreatic beta cells. This enabled our microfluidics to achieve spatiotemporal detection that is difficult to achieve with traditional microfluidics. Using this device, we demonstrated the in situ detection of calcium, insulin, and ATP (adenosine triphosphate) in response to glucose and oxygen stimulation. Specifically, insulin was quantified at levels as low as 25 pg/mL using our imaging technique. Furthermore, by analyzing the spatial detection data dynamically over time, we uncovered a new relationship between oxygen and beta cell oscillations. We observed an optimum oxygen level between 10 and 12%, which is neither hypoxic nor normoxic in the conventional cell culture sense. These results provide evidence to support the current islet oscillator model. In future applications, this spatial microfluidic technique can be adapted for discrete protein detection in a robust platform to study numerous oxygen-dependent tissue dysfunctions.

10.
Transplant Direct ; 9(2): e1419, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36700062

RESUMO

Compared with calcineurin inhibitor-based immunosuppression, belatacept (BELA)-based treatment has been associated with better renal function but higher acute rejection rates. This phase 2 study (NCT02137239) compared the antirejection efficacy of BELA plus everolimus (EVL) with tacrolimus (TAC) plus mycophenolate mofetil (MMF), each following lymphocyte-depleting induction and rapid corticosteroid withdrawal. Methods: Patients who were de novo renal transplant recipients seropositive for Epstein-Barr virus were randomized to receive BELA+EVL or TAC+MMF maintenance therapy after rabbit antithymocyte globulin induction and up to 7 d of corticosteroids. The primary endpoint was the rate of biopsy-proven acute rejection at month 6. Results: Because of an unanticipated BELA supply constraint, enrollment was prematurely terminated at 68 patients, of whom 58 were randomized and transplanted (intention-to-treat [ITT] population: n = 26, BELA+EVL; n = 32, TAC+MMF). However, 25 patients received BELA+EVL' and 33 received TAC+MMF (modified ITT population). In the ITT population, the 6-mo biopsy-proven acute rejection rates were 7.7% versus 9.4% in the BELA+EVL versus TAC+MMF group. The corresponding 24-mo biopsy-proven acute rejection rates were 19.2% versus 12.5% in the ITT population and 16.0% versus 15.2% in the mITT population; all events were Banff severity grade ≤IIA and similar between groups. One patient in each group experienced graft loss unrelated to acute rejection. The 24-mo mean unadjusted estimated glomerular filtration rates were 71.8 versus 68.7 mL/min/1.73 m2 in the BELA+EVL versus TAC+MMF groups. Posttransplant lymphoproliferative disorder was reported for 1 patient in each group. No deaths or unexpected adverse events were observed. Conclusions: A steroid-free maintenance regimen of BELA+EVL may be associated with biopsy-proven acute rejection rates comparable to TAC+MMF.

11.
Front Endocrinol (Lausanne) ; 13: 1039912, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36440196

RESUMO

Smartphone technology has been recently applied for biomedical image acquisition and data analysis due to its high-quality imaging capability, and flexibility to customize multi-purpose apps. In this work, we developed and characterized a smartphone-microfluidic fluorescence imaging system for studying the physiology of pancreatic islets. We further evaluated the system capability by performing real-time fluorescence imaging on mouse islets labeled with either chemical fluorescence dyes or genetically encoded fluorescent protein indicators (GEFPIs). Our results showed that the system was capable of analyzing key beta-cell insulin stimulator-release coupling factors in response to various stimuli with high-resolution dynamics. Furthermore, the integration of a microfluidics allowed high-resolution detection of insulin secretion at single islet level. When compared to conventional fluorescence microscopes and macro islet perifusion apparatus, the system has the advantages of low cost, portable, and easy to operate. With all of these features, we envision that this smartphone-microfluidic fluorescence imaging system can be applied to study islet physiology and clinical applications.


Assuntos
Ilhotas Pancreáticas , Microfluídica , Camundongos , Animais , Smartphone , Ilhotas Pancreáticas/metabolismo , Imagem Óptica , Insulina/metabolismo
12.
Pharmacotherapy ; 42(8): 599-633, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36032031

RESUMO

Advances in maintenance immunosuppression over the past three decades have improved solid organ transplantation outcomes dramatically. Uninterrupted access to immunosuppression is paramount to minimize rejection and maintain allograft and patient survival. There is no standardized approach to maintenance immunosuppression management. Agents used vary based on transplanted organ, center-specific protocol, provider expertise, insurance formularies, ability to cover co-pays, recipient characteristics and tolerability. Published data reflects this heterogeneity. Despite this limitation, maintenance immunosuppression usage cross pollinates between organ groups with standard of care agents often being used off-label, making medication access a challenge for many transplant recipients. A multidisciplinary panel of American transplant clinicians was formed to review published literature on maintenance immunosuppression with the goal to formulate consensus recommendations for their use in specific organ groups. These consensus recommendations are intended to provide transplant clinicians with a summary of literature on maintenance immunosuppression in the modern era and to support transplant team members working to secure medication access for patients.


Assuntos
Transplante de Pulmão , Transplante de Órgãos , Farmácia , Consenso , Rejeição de Enxerto , Humanos , Terapia de Imunossupressão , Imunossupressores
13.
Clin Transplant ; 36(12): e14801, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35997030

RESUMO

INTRODUCTION: Split liver transplantation (SLT) emerged due to its potential to contribute to the organ pool and reduce organ shortage. However, SLT is technically challenging and has been associated with higher rates of postoperative complications leading to concerns about graft and patient survival. Moreover, there are few studies on matched-pair adult recipients of SLT and whole-liver transplant (WLT), with conflicting results. METHODS: This retrospective study analyze outcomes among adults who underwent SLT at our institution from 2010 to 2019. A 1:1 propensity score matching analysis was performed based on important donor and recipient variables. Baseline characteristics and postoperative outcomes were analyzed and compared between groups. Actuarial graft and patient survival were analyzed by KM curves. RESULTS: Out of 592 adults receiving a LT in our institution, 21 SLT adult recipients were identified and matched with 21 adults undergoing WLT. As expected donor age was significantly lower in SLT recipients (16 (15-22) vs. 32 (17-47), P = .012). Additional donor characteristics, including anthropometrics, and ischemic times were similar between groups. Baseline recipient characteristics and postoperative outcomes, including length of stay, vascular complications, biliary complications, and re-transplantation were comparable between SLT and WLT recipients. Graft (95/95/95 vs. 100/94/94, P = .98) and patient (100/100/100 vs. 100/94/94, P = .30) survival at 1-, 3-, 5-years, were similar between the SLT- and WLT group, respectively. CONCLUSION: Split liver transplantation has the potential to increase the availability of organs for adult recipients without compromising individual outcomes.


Assuntos
Transplante de Fígado , Adulto , Humanos , Estudos Retrospectivos , Pontuação de Propensão , Resultado do Tratamento , Doadores de Tecidos , Sobrevivência de Enxerto
14.
Commun Biol ; 5(1): 779, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918471

RESUMO

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). To understand mechanisms of ß-cell dysfunction, we generated stem cell-derived pancreatic endocrine cells with hypomorphic mutations in HNF1A. HNF1A-deficient ß-cells display impaired basal and glucose stimulated-insulin secretion, reduced intracellular calcium levels in association with a reduction in CACNA1A expression, and accumulation of abnormal insulin granules in association with SYT13 down-regulation. Knockout of CACNA1A and SYT13 reproduce the relevant phenotypes. In HNF1A deficient ß-cells, glibenclamide, a sulfonylurea drug used in the treatment of HNF1A-MODY patients, increases intracellular calcium, and restores insulin secretion. While insulin secretion defects are constitutive in ß-cells null for HNF1A, ß-cells heterozygous for hypomorphic HNF1A (R200Q) mutations lose the ability to secrete insulin gradually; this phenotype is prevented by correction of the mutation. Our studies illuminate the molecular basis for the efficacy of treatment of HNF1A-MODY with sulfonylureas, and suggest promise for the use of cell therapies.


Assuntos
Diabetes Mellitus Tipo 2 , Insulina , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Insulina/metabolismo , Insulina Regular Humana , Células-Tronco/metabolismo , Sinaptotagminas
15.
Pharmacotherapy ; 42(8): 594-598, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35810342

RESUMO

Advances in maintenance immunosuppression over the past three decades have improved solid organ transplantation outcomes dramatically. Uninterrupted access to immunosuppression is paramount to minimize rejection and maintain allograft and patient survival. Agents used vary based on transplanted organ, center-specific protocol, provider expertise, insurance formularies, ability to cover co-pays, recipient characteristics and tolerability. Published data reflects this heterogeneity. Despite these obstacles, the information about maintenance immunosuppression use cross pollinates between organ groups with standard of care agents often being used off-label, making medication access a challenge for many transplant recipients. A multidisciplinary panel of American transplant clinicians was formed to review published literature on maintenance immunosuppression with the goal to formulate consensus recommendations for their use in specific organ groups. These consensus recommendations are intended to provide transplant clinicians with a summary of literature on maintenance immunosuppression in the modern era, and to support transplant team members working to secure medication access for patients.


Assuntos
Transplante de Pulmão , Transplante de Órgãos , Farmácia , Consenso , Rejeição de Enxerto , Humanos , Terapia de Imunossupressão , Imunossupressores
16.
Transplant Direct ; 8(5): e1315, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35415214

RESUMO

Background: The use of pediatric grafts for liver transplantation (LT) into adult recipients is rare, and reported outcomes are conflicting. The aim of this study is to evaluate the outcomes in adult recipients following LT with grafts from deceased pediatric donors. Methods: A retrospective study identifying adult LT between 2010 and 2020 using pediatric deceased donor liver grafts was conducted. Adults undergoing LT with deceased donor pediatric grafts (age ≤ 12) were identified and matched 1:2 with adults receiving adult grafts (age ≥ 18) based on recipient age (±10 y), model for end-stage liver disease (MELD) score at transplant (±5 points) and etiology of liver disease. To assess real liver size differences between the pediatric-donor and adult-donor groups, patients receiving a graft from a donor between 13 and 17 y were excluded from the main analysis and studied independently. Outcomes between the groups were compared. Complication rates were identified and graded using Clavien-Dindo classification. Graft and patient survival were assessed by Kaplan-Meier curves. Results: Twelve adult LT recipients with whole liver grafts from deceased pediatric donors were matched with 24 adult recipients of adult donors. Recipient age and MELD score were similar between groups. Recipients of pediatric grafts were more likely to be female (66.7% versus 16.7%, P = 0.007) and leaner (body mass index = 24.4 versus 29.9, P = 0.013). Alcohol-related cirrhosis was the most prevalent liver disease etiology in both groups (P = 0.96). There was no significant difference in length of stay, readmissions, early complications, or major complications between groups. Vascular and biliary complication rates were similar. Actuarial graft and patient survival at 1, 3, and 5 y were 100/100/100 versus 96/96/96 (P = 0.48). Conclusions: Excellent patient and graft survival is achievable with LT using young pediatric deceased donor grafts in smaller adult recipients. Outcomes are comparable with recipients of age and MELD-matched adult donors. Careful donor MELD-score recipient matching and close monitoring for potential biliary and vascular complications are crucial to achieve acceptable outcomes.

17.
Transpl Int ; 36: 10437, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35391900

RESUMO

Split and LDLT in pediatric patients have the potential to decrease wait times and waitlist mortality. Using UNOS-STAR data, we compared outcomes of pediatric patients undergoing LDLT and SLT using LLS grafts. The baseline characteristics and post-operative outcomes were compared between groups. Actuarial graft and patient survival were analyzed with Kaplan-Meier curves. Between 2010 and 2019, 911 pediatric LT were included in the analysis (LD graft group, n = 508, split graft group, n = 403). LD graft recipients spent more time on the waitlist vs. the split graft group (60 (22-138) days vs. 46 (16-108) days; p = 0.007). LD recipients had a lower rate of graft failure, found in 9.8% of patients compared with 14.6% in the split graft group (p = 0.02). HAT was the most common graft failure cause, with similar rates. Graft and patient survival at 1-, 3-, and 5-years was comparable between LDLT and SLT. In subgroup analyses, patients with biliary atresia, those ≤10 kg or ≤10 years old receiving an LD graft showed improved graft survival. In conclusion, LDLT is associated with a lower rate of graft failure in pediatric patients. The use of LLS regardless of the type of donor is a safe way to facilitate access to transplantation to pediatric patients with acceptable short and long-term outcomes.


Assuntos
Transplante de Fígado , Criança , Sobrevivência de Enxerto , Humanos , Doadores Vivos , Estudos Retrospectivos , Resultado do Tratamento
18.
Sci Adv ; 8(9): eabm1032, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35235346

RESUMO

Proinflammatory cytokines have been approved by the Food and Drug Administration for the treatment of metastatic melanoma and renal carcinoma. However, effective cytokine therapy requires high-dose infusions that can result in antidrug antibodies and/or systemic side effects that limit long-term benefits. To overcome these limitations, we developed a clinically translatable cytokine delivery platform composed of polymer-encapsulated human ARPE-19 (RPE) cells that produce natural cytokines. Tumor-adjacent administration of these capsules demonstrated predictable dose modulation with spatial and temporal control and enabled peritoneal cancer immunotherapy without systemic toxicities. Interleukin-2 (IL2)-producing cytokine factory treatment eradicated peritoneal tumors in ovarian and colorectal mouse models. Furthermore, computational pharmacokinetic modeling predicts clinical translatability to humans. Notably, this platform elicited T cell responses in NHPs, consistent with reported biomarkers of treatment efficacy without toxicity. Combined, our findings demonstrate the safety and efficacy of IL2 cytokine factories in preclinical animal models and provide rationale for future clinical testing in humans.


Assuntos
Interleucina-2 , Melanoma , Animais , Citocinas , Imunoterapia , Interleucina-2/farmacologia , Melanoma/tratamento farmacológico , Camundongos , Estados Unidos
19.
Acta Biomater ; 137: 172-185, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34634509

RESUMO

Cell encapsulation in alginate microbeads is a promising approach to provide immune isolation in cell therapy without immunosuppression. However, the efficacy is hampered by pericapsular fibrotic overgrowth (PFO), causing encapsulated cells to lose function. Stability of the microbeads is important to maintain immune isolation in the long-term. Here, we report alginate microbeads with minimal PFO in immunocompetent C57BL/6JRj mice. Microbead formulations included either alginate with an intermediate (47 %) guluronate (G) content (IntG) or sulfated alginate (SA), gelled in Ca2+/Ba2+ or Sr2+. A screening panel of eleven microbead formulations were evaluated for PFO, yielding multiple promising microbeads. Two candidate formulations were evaluated for 112 days in vivo, exhibiting maintained stability and minimal PFO. Microbeads investigated in a human whole blood assay revealed low cytokine and complement responses, while SA microbeads activated coagulation. Protein deposition on microbeads explanted from mice investigated by confocal laser scanning microscopy (CLSM) showed minimal deposition of complement C3. Fibrinogen was positively associated with PFO, with a high deposition on microbeads of high G (68 %) alginate compared to IntG and SA microbeads. Overall, stable microbeads containing IntG or SA may serve in long-term therapeutic applications of cell encapsulation. STATEMENT OF SIGNIFICANCE: Alginate-based hydrogels in the format of micrometer size beads is a promising approach for the immunoisolation of cells in cell therapy. Clinical trials in type 1 diabetes have so far had limited success due to fibrotic responses that hinder the diffusion of nutrients and oxygen to the encapsulated cells, resulting in graft failure. In this study, minimal fibrotic response towards micrometer size alginate beads was achieved by chemical modification of alginate with sulfate groups. Also, the use of alginate with intermediate guluronic acid content resulted in minimally fibrotic microbeads. Fibrinogen deposition was revealed to be a good indicator of fibrosis. This study points to both new microsphere developments and novel insight in the mechanisms behind the fibrotic responses.


Assuntos
Alginatos , Sulfatos , Alginatos/farmacologia , Animais , Fibrose , Ácido Glucurônico , Ácidos Hexurônicos , Camundongos , Camundongos Endogâmicos C57BL , Microesferas
20.
Ann Surg ; 275(3): 591-595, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32657945

RESUMO

OBJECTIVE: To review outcomes after laparoscopic, robotic-assisted living donor nephrectomy (RLDN) in the first, and largest series reported to date. SUMMARY OF BACKGROUND DATA: Introduction of minimal invasive, laparoscopic donor nephrectomy has increased live kidney donation, paving the way for further innovation to expand the donor pool with RLDN. METHODS: Retrospective chart review of 1084 consecutive RLDNs performed between 2000 and 2017. Patient demographics, surgical data, and complications were collected. RESULTS: Six patients underwent conversion to open procedures between 2002 and 2005, whereas the remainder were successfully completed robotically. Median donor age was 35.7 (17.4) years, with a median BMI of 28.6 (7.7) kg/m2. Nephrectomies were preferentially performed on the left side (95.2%). Multiple renal arteries were present in 24.1%. Median operative time was 159 (54) minutes, warm ischemia time 180 (90) seconds, estimated blood loss 50 (32) mL, and length of stay 3 (1) days. The median follow-up was 15 (28) months. Complications were reported in 216 patients (19.9%), of which 176 patients (81.5%) were minor (Clavien-Dindo class I and II). Duration of surgery, warm ischemia time, operative blood loss, conversion, and complication rates were not associated with increase in body mass index. CONCLUSION: RLDN is a safe technique and offers a reasonable alternative to conventional laparoscopic surgery, in particular in donors with higher body mass index and multiple arteries. It offers transplant surgeons a platform to develop skills in robotic-assisted surgery needed in the more advanced setting of minimal invasive recipient operations.


Assuntos
Transplante de Rim , Laparoscopia , Nefrectomia , Procedimentos Cirúrgicos Robóticos , Coleta de Tecidos e Órgãos/métodos , Adolescente , Adulto , Feminino , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
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