Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory.

Metastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescent and proliferative state in response to systemic and microenvironmental signals including immune-mediated surveillance. Despite its relevance, how intrinsic mechanisms sustain DTCs plasticity has not been addressed. By interrogating the epigenetic state of metastatic cells, we find that tumour progression is coupled with the activation of oncogenic enhancers that are organized in variable interconnected chromatin domains. This spatial chromatin context leads to the activation of a robust transcriptional response upon repeated exposure to retinoic acid (RA). We show that this adaptive mechanism sustains the quiescence of DTCs through the activation of the master regulator SOX9. Finally, we determine that RA-stimulated transcriptional memory increases the fitness of metastatic cells by supporting the escape of quiescent DTCs from NK-mediated immune surveillance. Overall, these findings highlight the contribution of oncogenic enhancers in establishing transcriptional memories as an adaptive mechanism to reinforce cancer dormancy and immune escape, thus amenable for therapeutic intervention.

Chromatin Velocity reveals epigenetic dynamics by single-cell profiling of heterochromatin and euchromatin.

Recent efforts have succeeded in surveying open chromatin at the single-cell level, but high-throughput, single-cell assessment of heterochromatin and its underlying genomic determinants remains challenging. We engineered a hybrid transposase including the chromodomain (CD) of the heterochromatin protein-1α (HP-1α), which is involved in heterochromatin assembly and maintenance through its binding to trimethylation of the lysine 9 on histone 3 (H3K9me3), and developed a single-cell method, single-cell genome and epigenome by transposases sequencing (scGET-seq), that, unlike single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), comprehensively probes both open and closed chromatin and concomitantly records the underlying genomic sequences. We tested scGET-seq in cancer-derived organoids and human-derived xenograft (PDX) models and identified genetic events and plasticity-driven mechanisms contributing to cancer drug resistance. Next, building upon the differential enrichment of closed and open chromatin, we devised a method, Chromatin Velocity, that identifies the trajectories of epigenetic modifications at the single-cell level. Chromatin Velocity uncovered paths of epigenetic reorganization during stem cell reprogramming and identified key transcription factors driving these developmental processes. scGET-seq reveals the dynamics of genomic and epigenetic landscapes underlying any cellular processes.

Nested Stochastic Block Models applied to the analysis of single cell data.

Single cell profiling has been proven to be a powerful tool in molecular biology to understand the complex behaviours of heterogeneous system. The definition of the properties of single cells is the primary endpoint of such analysis, cells are typically clustered to underpin the common determinants that can be used to describe functional properties of the cell mixture under investigation. Several approaches have been proposed to identify cell clusters; while this is matter of active research, one popular approach is based on community detection in neighbourhood graphs by optimisation of modularity. In this paper we propose an alternative and principled solution to this problem, based on Stochastic Block Models. We show that such approach not only is suitable for identification of cell groups, it also provides a solid framework to perform other relevant tasks in single cell analysis, such as label transfer. To encourage the use of Stochastic Block Models, we developed a python library, schist, that is compatible with the popular scanpy framework.

Gel Polymer Electrolytes Based on Silica-Added Poly(ethylene oxide) Electrospun Membranes for Lithium Batteries.

Solid polymer electrolytes, in the form of membranes, offering high chemical and mechanical stability, while maintaining good ionic conductivity, are envisaged as a possible solution to improve performances and safety in different lithium cell configurations. In this work, we designed and prepared systems formed using innovative nanocomposite polymer membranes, based on high molecular weight poly(ethylene oxide) (PEO) and silica nanopowders, produced by the electrospinning technique. These membranes were subsequently gelled with solutions based on aprotic ionic liquid, carbonate solvents, and lithium salt. The addition of polysulfide species to the electrolyte solution was also considered, in view of potential applications in lithium-sulfur cells. The morphology of the electrospun pristine membranes was evaluated using scanning electron microscopy. Stability and thermal properties of pristine and gelled systems were investigated uisng differential scanning calorimetry and thermal gravimetric analysis. Electrochemical impedance spectroscopy was used to determine the conductivity of both swelling solutions and gelled membranes, allowing insight into the ion transport mechanism within the proposed composite electrolytes.

Predicting mortality and cost of hematopoietic stem-cell transplantation.

OBJECTIVE: To evaluate whether the Pretransplantion Assesment of Mortality risk score is associated to transplant costs and can be used not only to predict mortality but also as a cost management tool. METHODS: We evaluated consecutively patients submitted to allogeneic (n = 27) and autologous (n = 89) hematopoietic stem cell-transplantation from 2004 to 2006 at Hospital Israelita Albert Einstein (SP), Brazil. Participants mean age at hematopoietic stem cell-transplantation was 42 (range 1 to 72) years; there were 69 males and 47 females; 30 patients had multiple myeloma; 41 had non-Hodgkin and Hodgkin's lymphomas; 22 had acute leukemia; 6 had chronic leukemia; and 17 had non-malignant disease. The Pretransplantion Assesment of Mortality risk score was applied in all patients using the available web site (http://cdsweb.fhcrc.org/ pam/). RESULTS: Patients could be classified in three risk categories: high, intermediate and low, having significant difference in survival (p = 0.0162). The median cost in US dollars for each group was $ 281.000, $ 73.300 and $ 54.400 for high, intermediate and low risk, respectively. The cost of hematopoietic stem cell-transplantation significantly differed for each Pretransplantin Assesment of Mortality risk group (p = 0.008). CONCLUSION: The validation of the Pretransplantion Assesment of Mortality risk score in our patients confirmed that this system is an important tool to be used in transplantation units, being easy to apply and fully reproducible.

Predicting mortality and cost of hematopoeitic stem-cell transplantation / Preditores de mortalidade e custo de transplante de célula-tronco hematopoéticas

Objective: To evaluate whether the Pretransplantion Assesment of Mortality risk score is associated to transplant costs and can be used not only to predict mortality but also as a cost management tool. Methods: We evaluated consecutively patients submitted to allogeneic (n = 27) and autologous (n = 89) hematopoietic stem cell-transplantation from 2004 to 2006 at Hospital Israelita Albert Einstein (SP), Brazil. Participants mean age at hematopoietic stem cell-transplantation was 42 (range 1 to 72) years; there were 69 males and 47 females; 30 patients had multiple myeloma; 41 had non-Hodgkin and Hodgkin?s lymphomas; 22 had acute leukemia; 6 had chronic leukemia; and 17 had non-malignant disease. The Pretransplantion Assesment of Mortality risk score was applied in all patients using the available web site (http://cdsweb.fhcrc.org/pam/). Results: Patients could be classified in three risk categories: high, intermediate and low, having significant difference in survival (p = 0.0162). The median cost in US dollars for each group was $ 281.000, $ 73.300 and $ 54.400 for high, intermediate and low risk, respectively. The cost of hematopoietic stem cell-transplantation significantly differed for each Pretransplantin Assesment of Mortality risk group (p = 0.008). Conclusion: The validation of the Pretransplantion Assesment of Mortality risk score in our patients confirmed that this system is an important tool to be used in transplantation units, being easy to apply and fully reproducible.

Objetivo: Avaliar se o escore de risco Avaliação de Mortalidade Pré-Transplante está associado aos custos de transplante e pode ser usado não apenas para predizer a mortalidade, mas também como ferramenta de gerenciamento de custos. Métodos: Foram avaliados consecutivamente 27 pacientes submetidos a transplante alogênico e 89 a transplante autólogo de células tronco hematopoéticas no período de 2004 a 2006 no Hospital Israelita Albert Einstein (SP). A média de idade dos pacientes por ocasião do transplante foi de 42 anos (variação de 1 a 72 anos); 69 eram do gênero masculino e 47 feminino; 30 pacientes tinham mieloma múltiplo, 41 linfoma não Hodgkin e linfoma de Hodgkin; 22 tinham leucemia aguda; 6 tinham leucemia crônica; e 17 doença não maligna. O escore de risco Avaliação de Mortalidade Pré-Transplante foi aplicado a todos os pacientes usando um web site fornecido pelos autores (http://cdsweb.fhcrc.org/pam/). Resultados: Classificaram-se os pacientes em três categorias de risco: alto, intermediário e baixo, apresentando diferença significativa de sobrevivência (p = 0,0162). O custo médio, em dólares, foi de U$ 281.000, U$ 73.300 e U$ 54.400 para risco alto, intermediário e baixo, respectivamente. O custo do transplante de células tronco hematopoéticas diferiu significantemente para cada grupo de risco segundo o escore Avaliação de Mortalidade Pré-Transplante (p = 0,008). Conclusão: A validação do escore de risco Avaliação de Mortalidade Pré-transplante em nossos pacientes confirmou que esse sistema é uma importante ferramenta a ser usada em unidades de transplante, sendo facilmente aplicável e inteiramente reprodutível.

Oral care in Brazilian bone marrow transplant centers

BACKGROUND: Oral care is a fundamental procedure for the success of the hematopoietic stem cell transplantation, particularly regarding the control of oral infectious diseases. Information about oral care protocols and the inclusion of dental professionals in transplantation medical staff is poorly known. OBJECTIVE: The aim of this study was to carry out a survey about the protocols of Brazilian dental professionals with regard to oral care of HSCT patients. METHODS: A questionnaire was mailed to 36 Brazilian transplant centers with questions about basic oral care protocols, the indication of specific mouthwashes, antibiotic therapy regimens, laser therapy, and treatment of oral mucositis and graft-versus-host disease. All the respondent centers (n = 12) have dentists as members of the HSCT medical staff. RESULTS: The majority indicate non-alcoholic chlorhexidine (n = 9; 75.0 percent) and sodium bicarbonate (n = 5; 41.7 percent) as routine mouthwashes. Laser therapy was frequently indicated (n= 9; 75.0 percent), mainly in the prevention of oral mucositis and in oral pain control. In the post-transplant period, antibiotic therapy was only indicated for invasive dental treatments (n= 8; 66.7 percent). Several treatments for graft-versus-host disease were mentioned without a trend towards establishing a standard protocol. CONCLUSION: Basic oral care constitutes regular assessment in the routine treatment of hematopoietic stem cell transplantation patients in Brazilian centers.

Oral care in Brazilian bone marrow transplant centers.

BACKGROUND: Oral care is a fundamental procedure for the success of the hematopoietic stem cell transplantation, particularly regarding the control of oral infectious diseases. Information about oral care protocols and the inclusion of dental professionals in transplantation medical staff is poorly known. OBJECTIVE: The aim of this study was to carry out a survey about the protocols of Brazilian dental professionals with regard to oral care of HSCT patients. METHODS: A questionnaire was mailed to 36 Brazilian transplant centers with questions about basic oral care protocols, the indication of specific mouthwashes, antibiotic therapy regimens, laser therapy, and treatment of oral mucositis and graft-versus-host disease. All the respondent centers (n = 12) have dentists as members of the HSCT medical staff. RESULTS: The majority indicate non-alcoholic chlorhexidine (n = 9; 75.0%) and sodium bicarbonate (n = 5; 41.7%) as routine mouthwashes. Laser therapy was frequently indicated (n= 9; 75.0%), mainly in the prevention of oral mucositis and in oral pain control. In the post-transplant period, antibiotic therapy was only indicated for invasive dental treatments (n= 8; 66.7%). Several treatments for graft-versus-host disease were mentioned without a trend towards establishing a standard protocol. CONCLUSION: Basic oral care constitutes regular assessment in the routine treatment of hematopoietic stem cell transplantation patients in Brazilian centers.