RESUMO
Face transplantation has emerged as reconstructive option for the most challenging facial deformities. A comprehensive analysis of functional outcomes, medical complications, incidence of malignancy, and chronic rejection in face transplantation recipients over an extended follow-up period has not yet been published leaving a notable gap in the literature. We retrospectively collected data of morbidity, rejection, vasculopathy, metabolic side effects, as well as functional outcome of sensory return, facial motor function, and speech from 9 patients who underwent face transplantation at Brigham and Women's Hospital between 2009 and 2020. The median follow-up was 120 months (54 and 154 months). Four grafts (40%) developed signs of clinical and histopathologic chronic rejection without evidence of vasculopathy on computed tomography angiograms. Sensory return assessed with Weinstein enhanced sensory testing-monofilament showed an increase in 6 patients (66.7%), and facial expression analysis showed improvement throughout the whole cohort at their most recent follow-up. Speech intelligibility was stable or increasing for 5 patients (55.6%). In conclusion, the long-term outcomes reveal promising results in terms of overall graft retention and functional recovery. Metabolic, malignant, and infectious complications, as well as graft rejection episodes, are expected to occur in this population, and some may be related to patient's age and lifestyle.
RESUMO
Lymphatic reconstruction entails microsurgery of the smallest human vessels with little microsurgical error tolerance. Surgical outcomes are therefore tightly tied to microsurgical performances and can be restricted by physiologic tremor or muscle tiring throughout extensive procedures. Recently introduced highly specialized microsurgical robots are promising to help overcome these human limitations, particularly relevant for lymphatic microsurgery. Ideal indications and setups for these robotic systems, however, are not yet well established. Reviewing the first 5 years of clinical experience with these microsurgical robots revealed a total of 204 robotically performed lymphatic anastomoses. Most reported use cases (84.4%) involved microsurgical reconstructions of lymphatic flow at the upper and lower extremities, of which 42% of patients were treated for breast cancer-related lymphedema. Considering rising cancer incidences and survival rates, these numbers highlight the potential of robotic-assisted microsurgery for this patient group, whereas the concept of robotic-assisted microsurgery per se can aid surgeons to achieve a new level of microsurgical excellence.
RESUMO
Face transplantation is a highly sensationalized procedure in the media. The purpose of this study is to assess the content and readability of online materials that prospective patients/public encounter regarding face transplantation. A search for face transplantation was performed on Google. Sites were categorized under 3 groups: established face transplant programs, informational third-party sources (eg, Wikipedia), and news article/tabloid sites. Each site was assessed for readability using 6 different readability metrics, while quality was assessed utilizing JAMA benchmark criteria and DISCERN instrument. One-way ANOVA with post hoc Tukey's multiple comparisons test was used for analysis. News sources were significantly easier to read than face transplant program sites (10.4 grade reading level vs. 12.4). For the JAMA benchmark, face transplant programs demonstrated the lowest average score relative to third-party sites, and news sources (2.05 vs. 2.91 vs. 3.67, respectively; P<0.001), but had significantly greater DISCERN scores than news sources (53.50 vs. 45.83, P=0.019). News sources were significantly more accessible, readable, and offered greater transparency of authorship compared with reputable sources, despite their lack of expertise on face transplantation. Face transplant programs should update their websites to ensure readability and accessibility of the information provided to the public.
RESUMO
OBJECTIVE: Face transplantation is a groundbreaking and complex surgical intervention offering profound physical and psychological benefits to patients with severe facial disfigurements. This report provides an update on the long-term psychosocial outcome of eight face transplant recipients. METHOD: All transplant recipients were initially transplanted at Brigham and Women´s Hospital (Boston, USA) between 2011 and 2020 and seen as outpatient patients at Yale New Haven Hospital (New Haven, USA). A mixed-methods approach was used to assess the psychological and social well-being of these patients. The Short-Form 12, Brief-COPE, EQ-VAS and CES-D were administered between October 2022 and October 2023. RESULTS: Older age of face transplant recipients was significantly and positively associated with better mental health and increased use of both emotional and instrumental support (Brief-COPE). The initial enhancement in patients' self-reported quality of life, as assessed by the EQVAS, declined on the EQ-VAS score at the last follow-up. Similarly, an increase in depression score was observed (CES-D score) up through the last follow-up assessment. Both of the latter results, however, did not reach statistical significance. CONCLUSIONS: These results underscore the importance of ongoing psychological support throughout the long-term journey of recovery for face transplant recipients. These findings emphasize the need for a comprehensive, patient-centered approach that also addresses the complex psychological dimensions and contributes to our understanding of the mental health dynamics involved in face transplantation, stressing the need for guidelines and continued research in this evolving field.
Assuntos
Transplante de Face , Qualidade de Vida , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Transplante de Face/psicologia , Qualidade de Vida/psicologia , Transplantados/psicologia , Apoio Social , Idoso , Depressão/psicologiaRESUMO
INTRODUCTION: Despite the clinical success in vascularized composite allotransplantation (VCA), systemic immunosuppression remains necessary to prevent allograft rejection. Even with potent immunosuppressive regimens (tacrolimus, mycophenolate mofetil, and steroids), most patients experience several rejection episodes, often within the same year. The risk of systemic side effects must constantly be weighed against the risk of under-immunosuppression and, thus, acute and chronic rejection. In this context, genomic editing has emerged as a potential tool to minimize the need for toxic immunosuppressive regimens and has gained attention in the fields of solid organ transplantation and xenotransplantation. This strategy may also be relevant for the future of VCA. METHODS: We discuss the topic of genetic engineering and review recent developments in this field that justify investigating tools such as clustered regularly interspaced short palindromic repeats/Cas9 in the context of VCA. RESULTS: We propose specific strategies for VCA based on the most recent gene expression data. This includes the well-known strategy of tolerance induction. Specifically, targeting the interaction between antigen-presenting cells and recipient-derived T cells by CD40 knockout may be effective. The novelty for VCA is a discovery that donor-derived T lymphocytes may play a special role in allograft rejection of facial transplants. We suggest targeting these cells prior to transplantation (e.g., by ex vivo perfusion of the transplant) by knocking out genes necessary for the long-term persistence of donor-derived immune cells in the allograft. CONCLUSION: Despite the demonstrated feasibility of VCA in recent years, continued improvements to immunomodulatory strategies using tools like clustered regularly interspaced short palindromic repeats/Cas9 could lead to the development of approaches that mitigate the limitations associated with rejection of this life-giving procedure.
Assuntos
Transplante de Órgãos , Alotransplante de Tecidos Compostos Vascularizados , Humanos , Rejeição de Enxerto/prevenção & controle , Alotransplante de Tecidos Compostos Vascularizados/métodos , Transplante Homólogo , Imunossupressores/uso terapêutico , Engenharia GenéticaRESUMO
Pre-clinical studies are an obligatory tool to develop and translate novel therapeutic strategies into clinical practice. Acute and chronic rejection mediated by the recipient's immune system remains an important limiting factor for the (long-term) survival of vascularized composite allografts (VCA). Furthermore, high intensity immunosuppressive (IS) protocols are needed to mitigate the immediate and long-term effects of rejection. These IS regiments can have significant side-effects such as predisposing transplant recipients to infections, organ dysfunction and malignancies. To overcome these problems, tolerance induction has been proposed as one strategy to reduce the intensity of IS protocols and to thereby mitigate long-term effects of allograft rejection. In this review article, we provide an overview about animal models and strategies that have been used to induce tolerance. The induction of donor-specific tolerance was achieved in preclinical animal models and clinical translation may help improve short and long-term outcomes in VCAs in the future.
Assuntos
Aloenxertos Compostos , Alotransplante de Tecidos Compostos Vascularizados , Animais , Rejeição de Enxerto , Alotransplante de Tecidos Compostos Vascularizados/métodos , Tolerância Imunológica , Transplante Homólogo , Imunossupressores/uso terapêuticoRESUMO
Microtia can have deleterious impacts on the functional, psychological, and aesthetic outcomes of affected young children. Reconstructive procedures can alleviate these negative outcomes and significantly improve the quality of life for patients; however, the cost and length of hospital stay (LOS) for such procedures and the factors that impact them have not been well-characterized. This study seeks to understand the hospital-level (institution type, size, and geographic region) and patient-level factors (race, age, and insurance status) that impact cost and LOS in patients who undergo microtia reconstructive surgery. A retrospective data analysis was conducted utilizing the National Inpatient Sample (NIS) database for the years 2008 to 2015. Inclusion criteria included patients who had an International Classification of Diseases, Ninth Revision (ICD-9) diagnostic code for microtia (744.23) as well as a procedure for microtia correction (186×/187×). A total of 714 microtia repair cases met the inclusion criteria and were sampled from the NIS database. Microtia repair cost was significantly increased on the West Coast compared with the Northeast ($34,947 versus $29,222, P =0.020), increased with patient age ($614/y, P =0.012), and gradually increased from 2008 to 2015 ($25,897-$48,985, P <0.001). Microtia LOS was significantly increased with government-controlled hospitals compared with private hospitals (1.93 versus 1.39 d, P =0.005), increased with patients on Medicaid compared with private insurance (2.33 versus 2.00 d, P =0.036), and overall decreased with patient age (-0.07 d/y, P =0.001). The results not only identify the multifactorial impacts that drive cost and LOS in microtia repair but provide insights into the financial and medical considerations patients and their families must navigate.
Assuntos
Microtia Congênita , Criança , Estados Unidos , Humanos , Pré-Escolar , Tempo de Internação , Estudos Retrospectivos , Microtia Congênita/cirurgia , Qualidade de Vida , Estética Dentária , HospitaisRESUMO
Sex diversity among plastic surgery and its subspecialties faculties lags behind many medical specialties. Despite the significant evidence in favor of diversity in leadership, female presence in high-ranking positions in medicine is lacking across multiple specialties. In this study, we aim to evaluate sex disparity among faculty across craniofacial fellowship programs by comparing the disparities among total number of faculty, program directors, years in practice, and academic rank. Our sample included 354 individuals including 193 craniofacial surgery journal editorial board members, 130 craniofacial surgery academic faculty members, and 31 craniofacial surgery association board members. A significant difference (P-value <0.0001) was seen among male and female craniofacial surgery faculty with 84.6% males. Faculty members were further subdivided by academic rank. A significant difference was found between the number of male and female faculty members at all academic positions (P-value =0.043). Of 41 full professors, 2.4% were female. There were 42 associate professors queried with 14.3% female. Similarly, 43 assistant professors were identified with 32.0% female. Years in practice after completing terminal training were analyzed across the academic faculty. There was a significant difference in the number of male and female faculty members across all experience levels (P-value =0.0037). Among the faculty with <10 years since completion of terminal training, 32.4 % were female. For faculty with 10 to 20 years after post-terminal training, 19.6% were female. For those with 20 to 30 years of experience, 0% were female. Finally, for the faculty with over 30 years since graduation, 5.9% were female. Board membership in 2 craniofacial surgery organizations was analyzed: the American Cleft Palate-Craniofacial Association and the American Society of Maxillofacial Surgeons. Among the 17 board members of the American Cleft Palate-Craniofacial Association, 8 (47.1%) were female. For the American Society of Maxillofacial Surgeons, 5 (35.7%) were female. Data were collected for 193 editorial board members from 2 craniofacial surgery journals. There was a significant difference between the number of male and female members across both journals (χ2 value: 33.3570; P-value <0.0001). Among 56 editorial board members from Cleft Palate-Craniofacial Journal, 26 (46.4%) members were female. In comparison, Journal of Craniofacial Surgery has 24.8% female editorial board members. Sex diversity among faculty members is really important and should be brought into light to highlight and improve areas of particular importance and of tremendous potential impact. Given our results, surgical residencies and fellowship programs should begin to show concrete commitment and increase their efforts to recruit and retain a diverse faculty not only for the educational benefit but more importantly to achieve a higher level of care for all.
Assuntos
Fissura Palatina , Internato e Residência , Cirurgia Plástica , Humanos , Masculino , Estados Unidos , Feminino , Docentes de Medicina , Bolsas de EstudoRESUMO
4-Formylaminooxyvinylglycine (FVG) is an herbicidal and antibacterial nonproteinogenic amino acid produced by several strains of the Pseudomonas fluorescens species complex. It contains a unique vinyl alkoxyamine moiety with an O-N bond, and its biosynthetic origin remains unknown. Here, we show that the gvg cluster from P. fluorescens WH6 is responsible for the biosynthesis of FVG and two additional O-N bond-containing oxyvinylglycines, guanidinooxyvinylglycine and aminooxyvinylglycine. Feeding studies in the producing bacteria indicate that these compounds originate from homoserine. We identify a formyltransferase gvgI that is required for the production of FVG and characterize the activity of this enzyme in vitro toward amino acids with a side chain amine. Sequence similarity network analysis reveals that GvgI and homologues make up a distinct group from the main classes of formyltransferases.
Assuntos
Hidroximetil e Formil Transferases , Pseudomonas fluorescens , Aminas/metabolismo , Aminoácidos/metabolismo , Antibacterianos/metabolismo , Glicina , Homosserina , Hidroximetil e Formil Transferases/metabolismoRESUMO
Abandoned mine lands present persistent environmental challenges to ecosystems and economies; reclamation an important step for overcoming these challenges. Phytostabilization is an elegant and cost-effective reclamation strategy, however, establishing plants on severely degraded soils is problematic, often requiring soil amendment additions. We evaluated whether amendment mixtures composed of lime, biochar, biosolids, and locally effective microbes (LEM) could alleviate the constraints that hinder phytostabilization success. We hypothesized that 1) plants grown in tailings amended with lime, biochar, and biosolids (LBB) would establish faster and grow larger than plants grown in tailings amended with lime only, and 2) the LEM source would influence microbial community function and structure in amended mine tailings. We conducted a greenhouse study that simulated in situ conditions to measure the influence of LBB-LEM amendment blends on plant growth, plant nutrients, metal concentrations, microbial function, and microbial community structure. Blue wildrye [Elymus glaucus Buckley ssp. Jepsonii (Burtt Davy) Gould] was grown in tailings collected from the Formosa mine site amended with various combinations of LBB-LEM. The above and below ground biomass of plants grown in mine tailings amended with LBB was 3 to 4 times larger than the biomass of plants grown in tailings amended only with lime. Although the LEM addition did not influence immediate plant growth, it did affect nutrient content and altered the rhizosphere community membership. As such, it is not yet clear if LEM-driven alterations in microbial membership will advance mine reclamation strategies by improving long-term growth.
RESUMO
BACKGROUND: Hand injuries are common in sports and associated with high dropout rates and costs. Hence, efforts should strive for further risk prevention measures in order to increase safety in sports. This implies knowledge of sports injury risk profiles. So far, major surveillance programs exist mainly in Anglo-American countries, reflecting the specific concerns of sports in this part of the world. Data on sports injuries within Europe are scarce. As sports behaviour appears to vary demographically, we hypothesised that risk injury profiles differ as well. METHODS: To assess whether the described sports injuries of the hand are applicable to the German population, we performed a five-year retrospective, single-centre analysis of sports-related hand injuries, using data from the Enterprise Clinical Research Data Warehouse of the Hannover Medical School. RESULTS: Notable differences in comparison to other data were observed. Ball sports, cycling and equestrian sports caused most of the recorded hand injuries, which were predominantly fractures of the wrist and hand. Hand injuries in equestrian sports were associated with significantly higher operation and hospitalisation rates as well as a significantly longer inpatient treatment. CONCLUSION: Risk profiles for sports-related hand injuries appear to differ not only in terms of age- and sex, but also geographically. Nation- and Europe-wide hand trauma registries as well as a broad registry participation are necessary in order to accurately assess the risk patterns in Europe; henceforth reducing hand injuries and their sequelae.
Assuntos
Traumatismos em Atletas , Traumatismos da Mão , Esportes , Traumatismos em Atletas/diagnóstico , Traumatismos em Atletas/epidemiologia , Europa (Continente) , Traumatismos da Mão/epidemiologia , Humanos , Estudos Retrospectivos , Estados UnidosRESUMO
The genomes of five Cochliobolus heterostrophus strains, two Cochliobolus sativus strains, three additional Cochliobolus species (Cochliobolus victoriae, Cochliobolus carbonum, Cochliobolus miyabeanus), and closely related Setosphaeria turcica were sequenced at the Joint Genome Institute (JGI). The datasets were used to identify SNPs between strains and species, unique genomic regions, core secondary metabolism genes, and small secreted protein (SSP) candidate effector encoding genes with a view towards pinpointing structural elements and gene content associated with specificity of these closely related fungi to different cereal hosts. Whole-genome alignment shows that three to five percent of each genome differs between strains of the same species, while a quarter of each genome differs between species. On average, SNP counts among field isolates of the same C. heterostrophus species are more than 25× higher than those between inbred lines and 50× lower than SNPs between Cochliobolus species. The suites of nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS), and SSP-encoding genes are astoundingly diverse among species but remarkably conserved among isolates of the same species, whether inbred or field strains, except for defining examples that map to unique genomic regions. Functional analysis of several strain-unique PKSs and NRPSs reveal a strong correlation with a role in virulence.
Assuntos
Ascomicetos/genética , Peptídeo Sintases/genética , Doenças das Plantas , Policetídeo Sintases/genética , Polimorfismo de Nucleotídeo Único/genética , Ascomicetos/patogenicidade , Sequência de Bases , Evolução Molecular , Variação Genética , Genoma Fúngico , Filogenia , Doenças das Plantas/genética , Doenças das Plantas/parasitologia , Virulência/genéticaRESUMO
Pyrenophora tritici-repentis Ptr ToxB (ToxB) is a proteinaceous host-selective toxin produced by Pyrenophora tritici-repentis (P. tritici-repentis), a plant pathogenic fungus that causes the disease tan spot of wheat. One feature that distinguishes ToxB from other host-selective toxins is that it has naturally occurring homologs in non-pathogenic P. tritici-repentis isolates that lack toxic activity. There are no high-resolution structures for any of the ToxB homologs, or for any protein with >30% sequence identity, and therefore what underlies activity remains an open question. Here, we present the NMR structures of ToxB and its inactive homolog Ptr toxb. Both proteins adopt a ß-sandwich fold comprising three strands in each half that are bridged together by two disulfide bonds. The inactive toxb, however, shows higher flexibility localized to the sequence-divergent ß-sandwich half. The absence of toxic activity is attributed to a more open structure in the vicinity of one disulfide bond, higher flexibility, and residue differences in an exposed loop that likely impacts interaction with putative targets. We propose that activity is regulated by perturbations in a putative active site loop and changes in dynamics distant from the site of activity. Interestingly, the new structures identify AvrPiz-t, a secreted avirulence protein produced by the rice blast fungus, as a structural homolog to ToxB. This homology suggests that fungal proteins involved in either disease susceptibility such as ToxB or resistance such as AvrPiz-t may have a common evolutionary origin.
Assuntos
Proteínas Fúngicas/química , Interações Hospedeiro-Patógeno/genética , Doenças das Plantas/microbiologia , Triticum/microbiologia , Cristalografia por Raios X , Evolução Molecular , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/toxicidade , Espectroscopia de Ressonância Magnética , Dobramento de Proteína , Estrutura Secundária de Proteína , Soluções/química , Triticum/genéticaRESUMO
The necrotrophic fungus Pyrenophora tritici-repentis is responsible for the disease tan spot of wheat. Ptr ToxB (ToxB), a proteinaceous host-selective toxin, is one of the effectors secreted by P. tritici-repentis. ToxB induces chlorosis in toxin-sensitive wheat cultivars and displays characteristics common to apoplastic effectors. We addressed the hypothesis that ToxB exerts its activity extracellularly. Our data indicate that hydraulic pressure applied in the apoplast following ToxB infiltration can displace ToxB-induced symptoms. In addition, treatment with a proteolytic cocktail following toxin infiltration results in reduction of symptom development and indicates that ToxB requires at least 8 h in planta to induce maximum symptom development. In vitro assays demonstrate that apoplastic fluids extracted from toxin-sensitive and -insensitive wheat cultivars cannot degrade ToxB. Additionally, ToxB can be reisolated from apoplastic fluid after toxin infiltration. Furthermore, localization studies of fluorescently labeled ToxB indicate that the toxin remains in the apoplast in toxin-sensitive and -insensitive wheat cultivars. Our findings support the hypothesis that ToxB acts as an extracellular effector.
Assuntos
Proteínas Fúngicas/metabolismo , Interações Hospedeiro-Patógeno , Doenças das Plantas/microbiologia , Triticum/metabolismo , Espaço Extracelular/metabolismo , Micotoxinas/metabolismo , Folhas de Planta/citologia , Folhas de Planta/metabolismo , Folhas de Planta/microbiologia , Pressão , Transporte Proteico , Triticum/citologia , Triticum/microbiologiaRESUMO
Renin-angiotensin-aldosterone system (RAAS) is recognized as the main regulatory system of hemodynamics in man, and its derangements have a key role in the development and maintenance of arterial hypertension. Classification of the hypertensive states according to different patterns of renin and aldosterone levels ("RAAS profiling") allows the diagnosis of specific forms of secondary hypertension and may identify distinct hemodynamic subsets in essential hypertension. In this review, we summarize the application of RAAS profiling for the diagnostic assessment of hypertensive patients and discuss how the pathophysiological framework provided by RAAS profiling may guide therapeutic decision-making, especially in the context of uncontrolled hypertension not responding to multi-therapy.
Assuntos
Aldosterona/sangue , Hipertensão/diagnóstico , Renina/sangue , Humanos , Hipertensão/sangueRESUMO
BACKGROUND: The GBGT1 gene encodes the globoside alpha-1,3-N-acetylgalactosaminyltransferase 1. This enzyme catalyzes the last step in the multi-step biosynthesis of the Forssman (Fs) antigen, a pentaglycosyl ceramide of the globo series glycosphingolipids. While differential GBGT1 mRNA expression has been observed in a variety of human tissues being highest in placenta and ovary, the expression of GBGT1 and the genes encoding the glycosyltransferases and glycosidases involved in the biosynthesis of Fs as well as the possible involvement of DNA methylation in transcriptional regulation of GBGT1 expression have not yet been investigated. RESULTS: RT-qPCR profiling showed high GBGT1 expression in normal ovary surface epithelial (HOSE) cell lines and low GBGT1 expression in all (e.g. A2780, SKOV3) except one (OVCAR3) investigated ovarian cancer cell lines, a finding that was confirmed by Western blot analysis. Hierarchical cluster analysis showed that GBGT1 was even the most variably expressed gene of Fs biosynthesis-relevant glycogenes and among the investigated cell lines, whereas NAGA which encodes the alpha-N-acetylgalactosaminidase hydrolyzing Fs was not differentially expressed. Bisulfite- and COBRA-analysis of the CpG island methylation status in the GBGT1 promoter region demonstrated high or intermediate levels of GBGT1 DNA methylation in all ovarian cancer cell lines (except for OVCAR3) but marginal levels of DNA methylation in the two HOSE cell lines. The extent of DNA methylation inversely correlated with GBGT1 mRNA and protein expression. Bioinformatic analysis of GBGT1 in The Cancer Genome Atlas ovarian cancer dataset demonstrated that this inverse correlation was also found in primary ovarian cancer tissue samples confirming our cell line-based findings. Restoration of GBGT1 mRNA and protein expression in low GBGT1-expressing A2780 cells was achieved by 5-aza-2'-deoxycytidine treatment and these treated cells exhibited increased helix pomatia agglutinin-staining, reflecting the elevated presence of Fs disaccharide on these cells. CONCLUSIONS: GBGT1 expression is epigenetically silenced through promoter hypermethylation in ovarian cancer. Our findings not only suggest an involvement of DNA methylation in the synthesis of Fs antigen but may also explain earlier studies showing differential GBGT1 expression in various human tissue samples and disease stages.
Assuntos
Metilação de DNA , Regulação Neoplásica da Expressão Gênica , N-Acetilgalactosaminiltransferases/genética , Neoplasias Ovarianas/genética , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Linhagem Celular Tumoral , Decitabina , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ovário/metabolismo , Regiões Promotoras GenéticasRESUMO
In addition to direct tumor cell cytotoxicity, chemotherapy can mediate tumor reduction through immune modulation of the tumor microenvironment to promote anti-tumor immunity. Mature dendritic cells (DCs) play key roles in priming robust immune responses in tumor-bearing hosts. Here, we screened a panel of 21 anticancer agents with defined molecular targets for their ability to induce direct maturation of DCs. We identified ansamitocin P3, a microtubule-depolymerizing agent, as a potent inducer of phenotypic and functional maturation of DCs. Exposure of both murine spleen-derived and human monocyte-derived DCs to ansamitocin P3 triggered up-regulation of maturation markers and production of pro-inflammatory cytokines, resulting in an enhanced T cell stimulatory capacity. Local administration of ansamitocin P3 induced maturation of skin Langerhans cells in vivo and promoted antigen uptake and extensive homing of tumor-resident DCs to tumor-draining lymph nodes. When used as an adjuvant in a specific vaccination approach, ansamitocin P3 dramatically increased activation of antigen-specific T cells. Finally, we demonstrate that ansamitocin P3, due to its immunomodulatory properties, acts in synergy with antibody-mediated blockade of the T cell inhibitory receptors PD-1 and CTLA-4. The combination treatment was most effective and induced durable growth inhibition of established tumors. Mechanistically, we observed a reduced regulatory T cell frequency and improved T cell effector function at the tumor site. Taken together, our study unravels an immune-based anti-tumor mechanism exploited by microtubule-depolymerizing agents, including ansamitocin P3, and paves the way for future clinical trials combining this class of agents with immunotherapy.
Assuntos
Células Dendríticas/efeitos dos fármacos , Maitansina/análogos & derivados , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Moduladores de Tubulina/farmacologia , Animais , Antígeno B7-2/biossíntese , Antígeno B7-2/imunologia , Antígenos CD11/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Humanos , Interferon gama/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Ativação Linfocitária/efeitos dos fármacos , Maitansina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
We report 12 metagenome-assembled genomes (MAGS) of a bioreactor community of acid-tolerant nitrifying bacteria. The MAGS include autotrophs in the Nitrospira genus and heterotrophs in the Xanthomonadales, Ktedonobacterales, Cytophagales, Burkholderiales, and Hyphomicrobiales. These taxonomic and genomic data provide insights into the core community members required for nitrification at low pH.
RESUMO
Background: Recipients of Vascularized Composite Allotransplants require effective immunosuppressive therapy to prevent graft rejection. This systematic review summarizes the current body of literature on immunosuppressive regimens used in face and hand transplants while summarizing their outcome in terms of rejection, renal failure, and infections. Methods: A systematic search of electronic databases was conducted to identify relevant studies from 1998 until July 1st, 2023. We included all studies that discussed immunosuppressive strategies in face and hand transplant recipients according to PRISMA. Results: The standard triple maintenance therapy was mostly adjusted due to nephrotoxicity or high incidence of rejection. The most common alternative treatments utilized were sirolimus (25/91; 27.5%) or everolimus (9/91; 9.9%) following hand- and photophoresis (7/45; 15.6%), sirolimus (5/45; 11.1%) or belatacept (1/45; 2.2%) following face transplantation. Episodes of rejection were reported in 60 (65.9%) of hand- and 33 (73%) of face transplant patients respectively. Graft loss of 12 (13.2%) hand and 4 (8.9%) face transplants was reported. Clinical CMV infection was observed in 6 (6.6%) hand and 7 (15.5%) face transplant recipients. Conclusions: Based on the herein presented data, facial grafts exhibited a heightened incidence of rejection episodes and CMV infections. Facial mucosa adds complexity to the immunological graft composition highlighting the need of individualized immunosuppressive regimens and further research.