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To describe the clinical findings in patients with incidental prostatic amyloidosis.Retrospective search in the database of the Department of Pathology, Hospital de Bellvitge, for prostate specimens with amyloid. Congo red and immunohistochemical staining of the sections. Review of the patients' clinical charts for symptoms attributable to systemic amyloidosis.Amyloid deposition in the prostate was identified and reported in 40 patients between 2001 and 2022. Median age was 76.5 years (range = 62-90 years). Prostate cancer was diagnosed in 25 patients. Only four patients had a previous diagnosis of amyloidosis. In the remaining 36 the prostate sample (31 needle biopsies, two transurethral resections (TUR), two simple prostatectomies, one radical cystectomy for bladder cancer) provided the initial diagnosis. Amyloid deposits were mainly located in the wall of small vessels and rarely in the prostatic stroma. Immunohistochemistry was available in 32 cases, 26 of which were positive for TTR. All patients showed at least one symptom indicative of systemic amyloidosis, the most frequent being hearing loss (55%), carpal tunnel syndrome (42,5%) or other osteoarticular symptoms (tendinopathies, osteoarthritis), cataracts (37.5%) and cardiac symptoms (32.5%), among others.The prostate is a target tissue for amyloid deposition. The incidental finding of amyloid in prostate corresponds, in the majority of cases, to previously undiagnosed systemic TTR amyloidosis in patients lacking signs of heart involvement but having mainly osteoarticular symptoms, hearing and visual impairment.

In this article we have attempted to develop a synthesis of the kinship systems through which this type of society has achieved its adaptation to the environment.The study is based on the basic methodologies in the development of anthropological work. The main tool was on-field work including participative observation and opera interviews, which cannot be detailed due to space limitations. A basic bibliography was also used to frame the work in the scope of Social Anthropology and specifically in kinship studies.The approach to subject was based on the features of the two basic types of family -trunk and nuclear family- and the inheritance systems based on male primogeniture in the former type.We focus on the trunk family due to its clear preeminence in the valley over the nuclear type and to the fact that this type of family is extremely infrequent among kinship systems today. We perform an indepth study of the system of inheritance showing the different types of entailment through history. Lastly we have attempted to state clearly the differences and affinities between these historical types and the current inheritance system.

The role of Rad53 in response to a DNA lesion is central for the accurate orchestration of the DNA damage response. Rad53 activation relies on its phosphorylation by Mec1 and its own autophosphorylation in a manner dependent on the adaptor Rad9. While the mechanism behind Rad53 activation has been well documented, less is known about the processes that counteract its activity along the repair of a DNA adduct. Here, we describe that PP4 phosphatase is required to avoid Rad53 hyper-phosphorylation during the repair of a double-strand break, a process that impacts on the phosphorylation status of multiple factors involved in the DNA damage response. PP4-dependent Rad53 dephosphorylation stimulates DNA end resection by relieving the negative effect that Rad9 exerts over the Sgs1/Dna2 exonuclease complex. Consequently, elimination of PP4 activity affects resection and repair by single-strand annealing, defects that are bypassed by reducing Rad53 hyperphosphorylation. These results confirm that Rad53 phosphorylation is controlled by PP4 during the repair of a DNA lesion and demonstrate that the attenuation of its kinase activity during the initial steps of the repair process is essential to efficiently enhance recombinational DNA repair pathways that depend on long-range resection for their success., Ministerio de Economía y Competitividad [BFU2013-41216-P, BFU2016-77081-P and PGC2018-097963-B-100 (MCIU/AEI/FEDER, UE) granted to A.C.-B.]; The IBFG is supported in part by an institutional grant from the ‘Junta y Castilla y León’ (Programa ‘Escalera de Excelencia’ de la Junta de Castilla y León, Ref. CLU-2017-03 cofinanciado por el P.O. FEDER de Castilla y León 14–20); M.T.V. was recipient of a predoctoral fellowship from the ‘Junta de Castilla y León’; F.R. was recipient of a predoctoral fellowship from the ‘Ministerio de Economía y Competitividad’. Funding for open access charge: Ministerio de Economía y Competitividad Grand [Reference 1: BFU2016-77081-P, Grand Reference 2: PGC2018-097963-B-100].

Background: More than half of patients with multimorbidity require intravenous therapy during their hospital stay. The aims of this study are to describe difficult intravenous access (DIVA) and vascular access care provided to this patient population and to explore the differences between easy and DIVA groups. Methods: A cohort study was conducted in patients with multimorbidity admitted to 2 hospitals between March and November 2013. The variables used to describe vascular care included choice and placement of devices, catheter swell time, and occurrence of adverse events. The incidence of adverse events was expressed as number cases per 1000 catheter days and χ2, Student's t, or Mann-Whitney U tests were used to compare the care provided between both groups. Odds rates were calculated to determine the risk of complications associated with DIVA. Results: We recruited 135 patients, of whom 34.8% were women. Overall, 59.3% had DIVA. A total of 224 catheters were inserted, patients with difficult access requiring a mean of 1.71 catheters and those with easy access 1.58 catheters. Two or more attempts were required to place catheters in 23% of cases in the difficult access group versus 2.50% in the easy access group. Mean catheter dwell time was 3.84 days and 3.99 days, and the adverse event rate was 111/1000 and 83.6/1000 catheter days, respectively. The odds ratio for complications was 1.596. Conclusions: Multimorbid patients with DIVA have a higher rate of complications as well as requiring more catheters and more placement attempts.

Difficulties in the collection of hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients have limited the gene therapy in this disease. We have investigated (ClinicalTrials.gov, NCT02931071) the safety and efficacy of filgrastim and plerixafor for mobilization of HSPCs and collection by leukapheresis in FA patients. Nine of eleven enrolled patients mobilized beyond the threshold level of 5 CD34+ cells/μL required to initiate apheresis. A median of 21.8 CD34+ cells/μL was reached at the peak of mobilization. Significantly, the oldest patients (15 and 16 years old) were the only ones who did not reach that threshold. A median of 4.27 million CD34+ cells/kg was collected in 2 or 3 aphereses. These numbers were markedly decreased to 1.1 million CD34+ cells/kg after immunoselection, probably because of weak expression of the CD34 antigen. However, these numbers were sufficient to facilitate the engraftment of corrected HSPCs in non-conditioned patients. No procedure-associated serious adverse events were observed. Mobilization of CD34+ cells correlated with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher proportion of CD34+ cells in bone marrow (BM). All these values offer crucial information for the enrollment of FA patients for gene therapy protocols., Graphical abstract, Mobilization and collection of HSPCs from FA patients with sufficient HSPC reserve is a safe and efficient procedure, incorporating filgrastim and plerixafor as mobilization agents. Adequate HSPC mobilization correlates with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher BM CD34+ cell numbers.

Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date1,2. Mutations in FANCA account for more than 60% of FA cases worldwide3,4. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70–80% of patients with FA during the first decade of life5,6. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder. In an early-phase lentiviral gene therapy trial, gene-corrected autologous hematopoietic stem cells show sustained engraftment and phenotypic correction in non-conditioned patients with Fanconi anemia.

Haploidentical hematopoietic stem cell transplantation using T-cell-depleted grafts is a valid option for pediatric patients with hematological malignancies in need of an allogeneic transplantation and lacking an HLA-identical donor. Seventy-five transplantations were performed in 70 patients. Thirty-eight patients had ALL, 32 had AML, 3 had advanced myelodysplastic syndromes and 2 juvenile myelomonocytic leukemia; 19 were in first CR, 30 in second CR, 12 in greater than second CR and 14 were considered to be in refractory disease at time of transplantation. Four patients developed graft failure. Among engrafted patients, the median time to neutrophil and platelet recovery was 13 (range 8-20) and 10 days (range 8-70), respectively. In 64 (85%) cases, ⩾1 infections were diagnosed after transplant. The probability of nonrelapse mortality by day +100 after transplantation was 10±4%. With a median follow-up of 22 months, the probability of relapse was 32±6% and disease-free survival was 52±6%. Haploidentical transplantation using CD3/CD19 depletion is associated with encouraging results especially in patients in early phase of disease. Killer-cell Ig-like receptor B haplotype donors confer a rapid natural killer cells expansion early after transplantation, resulting in lower probability of relapse and suggesting a GvL effect apart from graft-versus-host reactions. Donor infusion of high numbers of CD34+ cells is recommended in order to improve T-cell reconstitution.

The role of Rad53 in response to a DNA lesion is central for the accurate orchestration of the DNA damage response. Rad53 activation relies on its phosphorylation by the Mec1 kinase and its own auto-phosphorylation in a manner dependent on the adaptor Rad9. While the mechanism behind Rad53 phosphorylation and activation has been well documented, less is known about the processes that counteract its kinase activity during the response to DNA damage. Here, we describe that PP4 phosphatase dephosphorylates Rad53 during the repair of a double-strand break, a process that impacts on the phosphorylation status of multiple factors involved in the DNA damage response. PP4-dependent Rad53 dephosphorylation stimulates DNA end resection by relieving the negative effect that Rad9 exerts over the Sgs1/Dna2 exonuclease complex. Consequently, elimination of PP4 activity affects DNA resection and repair by single-strand annealing, defects that are bypassed by reducing the hyper-phosphorylation state of Rad53 observed in the absence of the phosphatase. These results confirm that Rad53 is one of the main targets of PP4 during the repair of a DNA lesion and demonstrate that the attenuation of its kinase activity during the initial steps of the repair process is essential to efficiently enhance recombinational DNA repair pathways that depend on long-range resection.

Nine Fanconi anemia patients complementation group A (FA-A), age 2-6 years, have been infused with autologous hematopoietic cells after genetic correction with the therapeutic PGK-FANCA.Wpre* lentiviral vector. In all instances patients underwent CD34+ cell mobilization with G-CSF and plerixafor and were subsequently infused in the absence of any pre-conditioning regimen, in order to avoid genotoxic side effects in a population characterized by DNA repair defects and cancer predisposition. The first four patients were treated between January 2016 and March 2017 and were infused with an estimated number of 170,000 and 410,000 transduced CD34+ cells/Kg. The other five patients were treated more recently with cell numbers that ranged between 50,000 to 1.6x106 corrected CD34+ cells/kg. The analyses of the first four patients showed the presence of corrected cells both in BM and PB after six months post-infusion and progressive increases of gene marking were observed thereafter in all these patients until the most recent follow-up (2 to >3 years post-infusion). Gene marking in BM CD34+ cells correlated with the survival of the CFCs to mitomycin-C, with levels up to 70% at 3 years post-infusion. Additionally, progressive decreases in the percentage of PB T cells with diepoxybutane-induced chromosomal breaks were observed in the patients with higher levels of gene marking. Similarly, stabilized PB cell counts have been observed in patients with higher percentages of gene corrected cells. Insertion site analyses revealed the absence of genotoxic events, and demonstrated the engraftment of pluripotent HSCs and a pattern of oligoclonal reconstitution, consistent with the number of infused corrected CD34+ cells and the absence of conditioning. In the five additional patients treated more recently, the presence of gene corrected PB cells has been confirmed; levels of gene marking have been consistent with data observed in the first four treated patients and with the number of infused CD34+ cells. Our results confirm the engraftment of gene corrected HSCs in non-conditioned FA-A patients, in some cases through more than 3 years of follow-up, suggesting the relevance of this therapeutic approach in FA. Disclosures Rio: Rocket Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding. Navarro:Rocket Pharmaceuticals, Inc.: Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents. Segovia:Rocket Pharmaceuticals, Inc.: Equity Ownership, Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding. Wang:GeneWerk: Employment. Casado:Rocket Pharmaceuticals, Inc.: Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents. Galy:Genethon: Employment. Cavazzana:SmartImmune: Other: Founder. Schwartz:Rocket Pharmaceuticals: Employment, Equity Ownership. Schmidt:GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership; German Cancer Research Center, Heidelberg, Germany: Employment. Díaz de Heredia:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sevilla:Rocket Pharmaceuticals, Inc.: Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rocket: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Honoraria. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding.

BACKGROUND Only little detailed information has been published by a small number of centers on experiences with the technical aspects of "in vitro" large-scale graft manipulation technologies. METHODS We report our experiences with the graft engineering procedures performed and the results obtained after T cell depletion. We have analyzed data from 212 procedures (108 CD34+ cell selection and 104 CD3+/CD19+ cell depletion). RESULTS We conclude that the final cell products after selection or depletion were completely different with regard to CD34+ cell purity (95.8% vs. 1.52%). The CD34+ cell recovery after CD34+ cell selection is negatively affected when the initial leukocyte and/or CD34+ cell counts exceed the threshold defined by the manufacturer (68.9% vs. 45.2%, p < 0.01). However, the cell count threshold defined for the depletion technique could be exceeded without seriously affecting final results (86.1% vs. 86.4% for those with more or less than 40 x 109 leukocyte before the procedure; p = 0.7). Another important conclusion from this study is that in both CD34+ cell selection and CD3+/CD19+ cell depletion better results were reached after having gained experience by performing the procedures several times. This means that a learning process can be expected when using these in vitro graft manipulation procedures. CONCLUSIONS It is extremely important to have experienced staff to perform these procedures. The expected results are different with each procedure so the decision on which of these T cell depletion approaches are used should be based on the characteristics of the final product wanted.

Fanconi anemia (FA) is a DNA repair syndrome characterized by bone marrow failure, congenital abnormalities and cancer predisposition. Based on previous experimental results showing the in vivo proliferative advantage of gene corrected FA patients' hematopoietic stem cells (HSCs; Rio, Navarro et al. Blood 2017) a gene therapy trial in non-conditioned FA-A patients was initiated in 2016. Six patients have been treated to-date using fresh and cryopreserved CD34+ cells mobilized to peripheral blood with G-CSF and plerixafor, and transduced with the PGK-FANCA.Wpre* lentiviral vector. Cell doses infused in four patients with a follow-up of at least 12 months varied from 0.6 to 1.4 million CD34+ cells/kg. Transduction efficacies of these samples, determined as vector copies per cell, ranged from 0.17 to 0.53 copies/cell. Despite the absence of patients' conditioning, a marked in vivo expansion of gene-corrected cells was observed in all hematopoietic cell lineages analyzed in BM and PB. Significantly, up to 44% of corrected cells were determined in total PB cells at the most recent follow-up visit (24 month) in the first treated patient. Insertion site analyses in PB cells showed an oligoclonal pattern of hematopoietic reconstitution, and revealed engraftment of multipotent corrected HSCs and no evidence of insertion-site mediated clonal expansion. Functional studies showed significant increases in the resistance of BM progenitors to mitomycin C in all treated patients. Additionally, patients with higher levels of corrected cells also showed significant increases in the chromosomal stability of T cells exposed to diepoxybutane. Finally, analyses discriminating the presence of corrected and uncorrected PB cells in these patients showed marked increases in the total number of corrected leukocytes, contrasting to progressive decreases of uncorrected cells. Our studies demonstrate for the first time that lentiviral-mediated gene therapy results in progressive engraftment and phenotypic correction of HSCs in non-conditioned FA patients, suggesting that this gene therapy approach may constitute a low-toxicity option for the treatment and prevention of BMF in patients with FA. Disclosures Bueren: Rocket Pharmaceuticals Inc: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Navarro:Rocket Pharmaceuticals Inc: Equity Ownership, Patents & Royalties, Research Funding. Segovia:Rocket Pharmaceuticals Inc: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Casado:Rocket Pharmaceuticals Inc: Patents & Royalties. Schwartz:Rocket Pharmaceuticals: Employment, Equity Ownership. Schmidt:GeneWerk GmbH: Employment; German Cancer Research Center: Employment; bluebird bio: Consultancy. Rio:Rocket Pharmaceuticals Inc: Equity Ownership, Patents & Royalties, Research Funding. Sevilla:Rocket Pharmaceuticals Inc: Honoraria, Patents & Royalties.

El cambio en los objetivos y en los instrumentos de intervención de las políticas públicas no siempre comporta el desarrollo de nuevas perspectivas y metodologías para su evaluación. El caso de las políticas culturales ejemplifica esta realidad. Por un lado, han adquirido un rol fundamental en el desarrollo territorial que busca integrar una economía del conocimiento con la cohesión social, la gobernanza y la sostenibilidad. Sin embargo, su perspectiva de evaluación continúa centrada en criterios estéticos, de consumo cultural o, simplemente, en las externalidades de la cultura. Así, este artículo contribuye al desarrollo de metodologías para evaluar de forma científica el retorno social de las políticas culturales, su valor público y los beneficios producidos para la ciudadanía. Palabras clave: políticas públicas; evaluación de políticas; políticas culturales; valor público de la cultura. Abstract. New Policies, New Perspectives, and Methodologies of Evaluation: How to Evaluate the Social Return of Cultural Policies? Change in policy objectives and instruments does not always entail the development of new perspectives and strategies for policy evaluation. Cultural policies exemplify these circumstances. On the one hand, they have achieved a crucial role in the territorial development which tries to integrate knowledge economy with social cohesion, governance, and sustainability but on the other hand, their policy evaluation perspectives remain focused on aesthetic and cultural consumption criteria, or simply in culture externalities. Thus, this article contributes to the development of methodologies that evaluate scientifically the social return of cultural policies, their public value and benefits for citizens. Key words: public policy; policy evaluation; cultural policy; public value of culture.