La cadena operativa en la producción de los moldes mochica: una aproximación a partir del análisis de la muestra procedente del taller alfarero del Conjunto Arquitectónico 60, Complejo Arqueológico Huacas de Moche

La imagen de los moldes prehispánicos suele asociarse, muchas veces, con nociones de estandarización, repetitividad y sencillez (de uso y fabricación). Ir más allá de esos lugares comunes supone examinar con mayor profundidad la cadena de gestos técnicos y operaciones necesarias para su confección desde la preparación de las materias primas hasta su cocción. Lejos de perfilarse como un proceso sencillo y rápido, el análisis macroscópico de una muestra de moldes mochicas procedentes de la excavación de un taller recientemente descubierto en el sitio de Huacas de Moche (Trujillo, La Libertad), junto con la información provista por los alfareros modernos de la campiña de Moche, puso de relieve la existencia de una cadena de pasos, compleja y diversificada, cuya realización requirió de conocimientos específicos y de un cierto grado de destreza y habilidad técnica. Al mismo tiempo, a partir de la variabilidad tecnológica observada en la muestra, se examinó la dimensión social e identitaria del contexto de producción alfarera. El cuadro que emerge indica un escenario en el que diversos artesanos, trabajando bajo modalidades tecnológicas ligeramente distintas, compartían un mismo espacio de trabajo y un bagaje de conocimientos y símbolos comunes.The image of pre-Hispanic molds is often associated with notions of standardization, repetitiveness and simplicity (of use and manufacturing). Going beyond these commonplaces means examining in greater depth the chain of technical gestures and operations necessary for its manufacture, from the preparation of the raw materials to its cooking. Far from emerging as a simple and quick process, the macroscopic analysis of a sample of Moche molds from the excavation of a recently discovered workshop at the site of Huacas de Moche (Trujillo, La Libertad), together with the information provided by the potters of the “campiña de Moche”, showed the existence of a complex and diversified chain of steps which implementation required specific knowledge and a certain degree of skill and technical ability. At the same time, based on the technological variability observed in the sample, the social and identitary dimension of the pottery production context is examined. The picture that emerges suggests a scenario in which various artisans, working under slightly different technological modalities, shared the same workspace and a baggage of knowledge and symbols

ROLE OF TOLL-LIKE RECEPTORS-3 AND -4 IN THE INTERACTIONS BETWEEN NEUTROPHILS AND MESENCHYMAL STROMAL CELLS

Le cellule stromali mesenchimali di derivazione midollare (Bone marrow-derived mesenchymal stromal cells, BM-MSC) sono precursori stromali dotati di estese capacit\ue0 immunomodulatorie. Nel presente studio, ci siamo posti l\u2019obiettivo di verificare se le BM-MSC potessero influenzare le risposte biologiche di neutrofili umani in cocultura dopo stimolo dei loro Toll-like receptors (TLR) -3 e -4. Dimostreremo come l\u2019attivazione del TLR3 da parte del suo ligando poly(I:C) determini un drammatico aumento dell\u2019effetto antiapoptotico esercitato costitutivamente su neutrofili in cocultura dalle BM-MSC in condizioni basali, in modo pi\uf9 significativo dell\u2019attivazione del TLR4 da parte del lipopolisaccaride (LPS). Inoltre, le BM-MSC stimolate da TLR3 e TLR4 aumentano il burst respiratorio e l\u2019espressione del CD11b dei neutrofili. La cocultura in assenza di contatto cellulare e l\u2019incubazione dei neutrofili nei supernatanti raccolti da BM-MSC attivate da TLR3 e TLR4 determinano effetti paragonabili in termini di aumento di sopravvivenza e di modifiche immunofenotipiche, fatto che suggerisce il coinvolgimento di fattori solubili endogeni. Esperimenti di blocco con anticorpi monoclonali rivelano come gli effetti biologici esercitati sui neutrofili dalle BM-MSC dopo stimolo del TLR3 siano mediati dall\u2019azione combinata di IL-6, IFN-\u3b2 e GM-CSF, mentre quelli esercitati dopo stimolo del TLR4 siano per lo pi\uf9 dipendenti dalla produzione di GM-CSF. Cellule stromali mesenchimali derivate dal timo, dalla milza e dal tessuto adiposo sottocutaneo hanno mostrato comportamento simile alle BM-MSC. Complessivamente, i nostri risultati evidenziano un nuovo meccanismo biologico tramite cui le cellule stromali mesenchimali sostengono e amplificano le funzioni dei neutrofili in risposta all\u2019attivazione di TLR3 e TLR4, e possono di conseguenza contribuire alla patogenesi di svariate malattie infiammatorie.Bone marrow-derived mesenchymal stromal cells (BM-MSC) are stromal precursors endowed with extensive immunomodulative properties. In this study, we aimed to assess whether Toll-like receptor(TLR)3- and TLR4-activated BM-MSC influence human neutrophil responses under coculture conditions. We show that TLR3 triggering by poly(I:C) dramatically amplifies, in a more significant manner than TLR4 triggering by LPS, the antiapoptotic effects that resting BM-MSC constitutively exert on neutrophils under coculture conditions. In addition, TLR3- and TLR4-activated BM-MSC enhance respiratory burst ability and CD11b expression by neutrophils. The coculture in the absence of cell contact and the incubation of neutrophils in supernatants harvested from TLR3- and TLR4-activated BM-MSC yield comparable results in terms of increased survival and immunophenotypic changes, thus suggesting the involvement of endogenous soluble factors. Neutralizing experiments reveal that the biological effects exerted on neutrophils by TLR3-activated BM-MSC are mediated by the combined action of IL-6, IFN-\u3b2 and GM-CSF, while those exerted by TLR4-activated BM-MSC mostly depend on GM-CSF. MSC isolated from thymus, spleen and subcutaneous adipose tissue behave similarly. Therefore, our data highlight a novel mechanism by which MSC sustain and amplify the functions of neutrophils in response to TLR3- and TLR4-activation and may consequently contribute to inflammatory disorders

Stem Cell Modeling of Core Binding Factor Acute Myeloid Leukemia

Even though clonally originated from a single cell, acute leukemia loses its homogeneity soon and presents at clinical diagnosis as a hierarchy of cells endowed with different functions, of which only a minority possesses the ability to recapitulate the disease. Due to their analogy to hematopoietic stem cells, these cells have been named “leukemia stem cells,” and are thought to be chiefly responsible for disease relapse and ultimate survival after chemotherapy. Core Binding Factor (CBF) Acute Myeloid Leukemia (AML) is cytogenetically characterized by either the t(8;21) or the inv(16)/t(16;16) chromosomal abnormalities, which, although being pathognomonic, are not sufficient per se to induce overt leukemia but rather determine a preclinical phase of disease when preleukemic subclones compete until the acquisition of clonal dominance by one of them. In this review we summarize the concepts regarding the application of the “leukemia stem cell” theory to the development of CBF AML; we will analyze the studies investigating the leukemogenetic role of t(8;21) and inv(16)/t(16;16), the proposed theories of its clonal evolution, and the role played by the hematopoietic niches in preserving the disease. Finally, we will discuss the clinical implications of stem cell modeling of CBF AML for the therapy of the disease

Evolution of populations expanding on curved surfaces

The expansion of a population into new habitat is a transient process that leaves its footprints in the genetic composition of the expanding population. How the structure of the environment shapes the population front and the evolutionary dynamics during such a range expansion is little understood. Here, we investigate the evolutionary dynamics of populations consisting of many selectively neutral genotypes expanding on curved surfaces. Using a combination of individual-based off-lattice simulations, geometrical arguments, and lattice-based stepping-stone simulations, we characterise the effect of individual bumps on an otherwise flat surface. Compared to the case of a range expansion on a flat surface, we observe a transient relative increase, followed by a decrease, in neutral genetic diversity at the population front. In addition, we find that individuals at the sides of the bump have a dramatically increased expected number of descendants, while their neighbours closer to the bump's centre are far less lucky. Both observations can be explained using an analytical description of straight paths (geodesics) on the curved surface. Complementing previous studies of heterogeneous flat environments, the findings here build our understanding of how complex environments shape the evolutionary dynamics of expanding populations.Comment: This preprint has also been posted to http://www.biorxiv.org with doi: 10.1101/406280. Seven pages with 5 figures, plus an appendix containing 3 pages with 1 figur

A proliferation-inducing ligand (APRIL) serum levels predict time to first treatment in patients affected by B-cell chronic lymphocytic leukemia

Purpose: A proliferation-inducing ligand (APRIL), a tumor necrosis factor superfamily member involved inB-lymphocytes differentiation and survival, plays a role in protecting B-Cell Chronic lymphocytic leukemia(B-CLL) cells from apoptosis. Having observed that APRIL serum (sAPRIL) levels were higher in B-CLLpatients with CLL at diagnosis as compared to healthy donors (14.61 \ub1 32.65 vs. 4.19 \ub1 3.42 ng \u2044 mL;P < 0.001), we tested the correlation existing in these patients between sAPRIL, clinical\u2013biological parametersand disease progression. Experimental design: sAPRIL levels were measured by ELISA in 130patients with B-CLL at diagnosis and in 25 healthy donors. Results: sAPRIL levels did not correlate withgender, age, clinical stage, blood cell counts, b2-microglobulin (b2M) levels, ZAP-70 and CD38 expression.Using median sAPRIL natural logarithm (ln) as cutoff, we distinguished two groups of patients (APRILLOWand APRILHIGH) who were comparable with regard to clinical\u2013biological parameters and overall survival, butdifferent with regard to time to the first treatment (TTFT; P = 0.035). According to univariate analysis, highlymphocyte count, high b2M, Binet stage B\u2013C, ZAP-70 expression and ln(sAPRIL) above median wereassociated with earlier TTFT. Advanced clinical stage, high b2M, ZAP-70 expression and ln(sAPRIL) abovemedian remained independently predictive of shorter TTFT at multivariate analysis. Moreover, sAPRILincreased its prognostic significance when patients were stratified according to independent favorable clinical\u2013biological characteristics (low b2M, stage A and lack of ZAP-70 expression). Conclusions: sAPRIL is anovel indicator of shorter TTFT in B-CLL and a predictor of progression especially in patients otherwiseconsidered at low risk according to validated prognostic factors

Endothelin-1 receptor blockade as new possible therapeutic approach in multiple myeloma.

New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasmacells (PCs) represent attractive new therapeutic targets. The endothelin-1(EDN1) axis, consisting of EDN1 acting through EDN-receptor A(EDNRA) and B (EDNRB), was previously shown to be overexpressed inseveral tumours, including MM. However, there is incomplete understand-ing of how EDN1 axis regulates MM growth and response to therapy.Besides EDNRA, the majority of MM cell lines and primary malignant PCsexpress high levels of EDNRB and release EDN1. Similarly, bone-marrowmicroenvironment cells also secrete EDN1. Investigating the extent of epi-genetic dysregulation of EDNRB gene in MM, we found that hypermethyla-tion of EDNRB promoter and subsequent down-regulation of EDNRB genewas observed in PCs or B lymphocytes from healthy donors compared toEDNRB-expressing malignant PCs. Pharm acological blockade with the dualEDN1 receptor antagonist bosentan decreased cell viability and MAPK acti-vation of U266 and RPMI-8226 cells. Interestingly, the combination ofbosentan and the proteasome inhibitor bortezomib, currently approved forMM treatment, resulted in synergistic cytotoxic effects. Overall, our datahas uncovered EDN1-mediated autocrine and paracrine mechanisms thatregulate malignant PCs growth and drug response, and support EDN1receptors as new therapeutic targets in MM

Venetoclax in combination with hypomethylating agents in previously untreated patients with acute myeloid leukemia ineligible for intensive treatment: a real-life multicenter experience

The addition of venetoclax to hypomethylating agents (HMA-V) improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive treatment. The aim of our study was to confirm data reported in literature, in a real-life multicenter experience. We retrospectively evaluated 56 naive AML patients who received HMA-V at 8 different collaborating Hematology Units in the North-East of Italy, from September 2018 to October 2020. Patients received azacitidine or decitabine at standard dose, adding venetoclax starting from cycle 1-3. The median time-to-response was 2 cycles and composite complete remission rate (CCR) was 67.9%. Thirteen out of 38 responders (34.2%) relapsed, with a median response duration of 13.7 months. Transfusion independence (TI) was obtained in 27 (87.0%) and 28 (90.3%) out of 31 patients for red blood cells and platelets, respectively. Median OS was 12.3 months (95% CI, 8.1-16.5), and median PFS was 11.3 months (95% CI, 4.6-17.9). Cytogenetic risk was the only variable impacting on survival, while no differences were observed stratifying patients by age, bone marrow blasts, WHO classification or type of HMA. In conclusion, our real-life multicenter experience indicates that HMA-V treatment allows achieving good response rates in naive AML patients, ineligible for intensive chemotherapy

Efficacy assessment of interferon-alpha-engineered mesenchymal stromal cells in a mouse plasmacytoma model

Bone marrow mesenchymal stromal cells (BM-MSCs) may survive and proliferate in the presence of cycling neoplastic cells. Exogenously administered MSCs are actively incorporated in the tumor as stromal fibroblasts, thus competing with the local mesenchymal cell precursors. For this reason, MSCs have been suggested as a suitable carrier for gene therapy strategies, as they can be genetically engineered with genes encoding for biologically active molecules, which can inhibit tumor cell proliferation and enhance the anti-tumor immune response. We used BM-MSCs engineered with the murine interferon-alpha (IFN-alpha) gene (BM-MSCs/IFN-alpha) to assess in a mouse plasmacytoma model the efficacy of this approach towards neoplastic plasma cells. We found that IFN-alpha can be efficiently produced and delivered inside the tumor microenvironment. Subcutaneous multiple administration of BM-MSCs/IFN-alpha significantly hampered the tumor growth in vivo and prolonged the overall survival of mice. The anti-tumor effect was associated with enhanced apoptosis of tumor cells, reduction in microvessel density, and ischemic necrosis. By contrast, intravenous administration of BM-MSCs/IFN-alpha did not significantly modify the survival of mice, mainly as a consequence of an excessive entrapment of injected cells in the pulmonary vessels. In conclusion, BM-MSCs/IFN-alpha are effective in inhibiting neoplastic plasma cell growth; however, systemic administration of engineered MSCs still needs to be improved to make this approach potentially suitable for the treatment of multiple myeloma

ERK1/2 phosphorylation is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia

Abstract Extracellular signal-regulated kinase-1/2 (ERK1/2) is frequently found constitutively activated (p-ERK1/2) in hematopoietic diseases, suggesting a role in leukemogenesis. The aim of this study was to assess the expression and clinical role of p-ERK1/2 in adult acute lymphoblastic leukemia (ALL). In 131 primary samples from adult de novo ALL patients enrolled in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) Leucemia Acute Linfoide (LAL) 2000 protocol and evaluated by flow cytometry, constitutive ERK1/2 activation was found in 34.5% of cases; these results were significantly associated with higher white blood cell (WBC) values (P = .013). In a multivariate analysis, p-ERK1/2 expression was an independent predictor of complete remission achievement (P = .027). Effective approaches toward MEK inhibition need to be explored in order to evaluate whether this may represent a new therapeutic strategy for adult ALL patients

Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy

Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of &gt;70-year patients who completed intensive therapy (induction + &gt;3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age &gt;70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=&lt;.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies