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Apples (Malus domestica) are one of the most consumed fruits globally. It is a relevant crop in Argentina and Spain, and one of the main fruits for export and industrialization in these countries. Quality control of apples, fundamentally in the postharvest stage, is critical to prevent fungal diseases. The blue mould, caused by Penicillium expansum , is responsible for great economic losses due to the deterioration of the fruit and mycotoxin production. Many studies have characterized this pathogen; however, little is known about the differences between populations from distant geographical origins. The objective of the present study was to characterize two P. expansum populations, from Argentina and Spain, through morphological, metabolomic and molecular approaches, and to evaluate the existence of differences related to their geographical source. A total of 103 isolates, 53 from Argentina and 50 from Spain were studied. Their morphological features were consistent with the species description. The secondary metabolite profiles revealed low chemical diversity. All 103 isolates shared the production of 13 compounds, namely andrastins, aurantioclavine, chaetoglobosins, communesins, expansolides, roquefortine C and patulin. Penostatins and citrinin were produced by 102 and 101 isolates, respectively. A region of the β-tubulin gene was selected to analyse the diversity of the P. expansum isolates. No substantial differences were observed between isolates of different geographical origins through morphology, patulin accumulation, secondary metabolite profiles and phylogenetic analysis. However, the analysis of polymorphisms revealed 29 haplotypes with a relative separation between isolates of both populations; 13 haplotypes contained Argentinean isolates, while Spanish isolates were separated into 16 haplotypes. The diversity indices of Shannon (H'= 2.075; H'= 2.402) and Simpson (Si D = 0.850; Si D = 0.895) for isolates from Argentina and Spain, respectively, indicated that the diversity of P. expansum is greater in Spain than in Argentina. This distribution could be explained both by the existence of haplotype exchange between both countries, with the ancestral haplotypes originating in Spain, and the subsequent adaptation to the environmental conditions or apples varieties grown in each region. • Penicillium expansum populations from Argentinean and Spanish apples were compared. • P. expansum populations showed low secondary metabolite diversity. • Phylogenetic analyses did not allow establishing evolutionary relationships. • Relative separation was revealed by analysis of polymorphisms in the β-tub fragment. • A significant geographical genetic structure was found in the populations. [ABSTRACT FROM AUTHOR]

Wheat is one of the most important crops in Argentina and worldwide. One of the major diseases affecting the crop is the Fusarium Head Blight (FHB). It is an endemic disease caused mainly by Fusarium graminearum , the most common agent of FHB around the world. The infection is strongly influenced by environmental parameters and occurs mostly when there are favourable conditions of moisture and temperature during wheat anthesis or flowering. This destructive disease affects wheat, barley and other small grains and has the capability of destroying crops, causing great economic losses due to reduced grain quality, and the accumulation of significant levels of mycotoxins such as trichothecenes. The aim of this study was to evaluate the influence of temperature on mycotoxin biosynthesis, on three strains of F. graminearum of 15-ADON genotype and one of 3-ADON genotype, with different capacity of synthesizing DON, 3-ADON and 15-ADON. Trichothecene production of the strains at different temperatures (5, 10, 15, 20, 25, 30 and 35 °C) was evaluated after 7, 14, 21, 28 and 35 d of incubation. The optimum temperature to produce DON and 3-ADON was between 25 and 30 °C, but the maximum production of 15-ADON occurred at a lower temperature (10 °C) for all the strains. Conversely, the minimum production of DON and 3-ADON was recorded between 5 and 10 °C and of 15-ADON between 30 and 35 °C. A possible explanation for the similar accumulation of both acetyl derivatives by strains of different chemotype and genotypes could be that the acetyl derivatives biosynthesis is regulated by temperature. • Genotyping and chemical analyses were not coincident for DON acetyl derivatives. • High temperatures (30 °C) favour the synthesis of 3-ADON. • Low temperatures (10 °C) are optimum for the production of 15-ADON. • The minimum production of 3-ADON occurred at 5–10 °C and of 15-ADON at 30–35 °C. • Regulation of acetyl derivatives biosynthesis is influenced by temperature. [ABSTRACT FROM AUTHOR]

Abstract The group of the small-spored Alternaria species is particularly relevant in foods due to its high frequency and wide distribution in different crops. These species are responsible for the accumulation of mycotoxins and bioactive secondary metabolites in food. The taxonomy of the genus has been recently revised with particular attention on them; several morphospecies within this group cannot be segregated by phylogenetic methods, and the most recent classifications proposed to elevate several phylogenetic species-groups to the taxonomic status of section. The purpose of the present study was to compare the new taxonomic revisions in Alternaria with secondary metabolite profiles with special focus on sections Alternaria and Infectoriae and food safety. A total of 360 small-spored Alternaria isolates from Argentinean food crops (tomato fruit, pepper fruit, blueberry, apple, wheat grain, walnut, pear, and plum) was morphologically identified to species-group according to Simmons (2007), and their secondary metabolite profile was determined. The isolates belonged to A. infectoria sp.-grp. (19), A. tenuissima sp.-grp. (262), A. arborescens sp.-grp. (40), and A. alternata sp.-grp. (7); 32 isolates, presenting characteristics overlapping between the last three groups, were classified as Alternaria sp. A high chemical diversity was observed; 78 different metabolites were detected, 31 of them of known chemical structure. The isolates from A. infectoria sp.-grp. (= Alternaria section Infectoriae) presented a specific secondary metabolite profile, different from the other species-groups. Infectopyrones, novae-zelandins and phomapyrones were the most frequent metabolites produced by section Infectoriae. Altertoxin-I and alterperylenol were the only compounds that these isolates produced in common with members of section Alternaria. None of the well-known Alternaria toxins, considered relevant in foods, namely alternariol (AOH), alternariol monomethyl ether (AME), tenuazonic acid (TeA), tentoxin (TEN) or altenuene (ALT), were produced by isolates of this section. On the other hand, strains from section Alternaria (A. tenuissima , A. arborescens , and A. alternata sp.-grps.) shared a common metabolite profile, indistinguishable from each other. AOH, AME, ALT, TEN, and TeA were the most frequently mycotoxins produced, together with pyrenochaetic acid A and altechromone A. Alternaria section Alternaria represents a substantial risk in food, since their members in all types of crops are able to produce the toxic metabolites. Highlights • Metabolite profiling of small-spored Alternaria segregates isolates into sections. • Secondary metabolite profiles agree with phylogenetic organization. • Alternaria section Alternaria poses the highest health risk in food. • Alternaria section Infectoriae is relevant in cereal crops. [ABSTRACT FROM AUTHOR]

Here, we present a case of a patient with Ph-like ALL who achieved a hematologic and molecular remission after treatment with the pan-tyrosine kinase inhibitor (TKI) ponatinib, even in the absence of the ABL-class gene rearrangement. Philadelphia chromosome (Ph)-like (or I BCR/ABL1 i -like) acute lymphoblastic leukemia (ALL) is a subtype of B-cell precursor acute lymphoblastic leukemia (B-ALL) with a transcriptional profile that resembles that of true I BCR/ABL1 i -positive ALL, but without the presence of the I BCR/ABL1 i fusion gene. Indeed, the genomic hallmark of Ph-like ALL suggests the use of ABL-inhibitors in cases with ABL-class gene aberrations and the use of JAK-inhibitors in patients with JAK-STAT signaling pathway activation, as supported by several experimental models [[1]],[10]]. As a matter of fact, sporadic clinical reports show that patients with relapsed/refractory Ph-like ALL with ABL-class gene alterations can be successfully treated with TKIs, mainly imatinib [[1], [11]] or dasatinib [[1]],[10],[15]]. [Extracted from the article]

Alternaria arborescens has been reported as a common fungal species invading tomatoes and is capable of producing several mycotoxins in infected plants, fruits and in agricultural commodities. Alternariol (AOH), alternariol monomethyl ether (AME), and tenuazonic acid (TeA) are some of the main Alternaria mycotoxins that can be found as contaminants of food. This species can produce these toxic metabolites together with AAL toxins ( Alternaria alternata f. sp. lycopersicum toxins), which can act as inhibitors of sphingolipid biosynthesis. The objective of this study was to determine the effect of water activity (a w , 0.995, 0.975, 0.950) and temperature (6, 15, 20, 25 and 30 °C) on mycotoxin production by A. arborescens on a synthetic tomato medium. The optimum production of AOH and AME occurred at 0.975 a w after 40 days of incubation at 30 °C. The maximum TeA accumulation was observed at 0.975 a w and 25 °C and at 0.950 a w and 30 °C. AAL TA was produced in higher quantities at 0.995 a w and 30 °C. At 6 °C no quantifiable levels of AOH or AME were detected, but significant amounts of TeA were produced at 0.975 a w . In general, high a w levels and high temperatures were favorable for mycotoxin production. The greatest accumulation of all four toxins occurred at 0.975 a w and 30 °C. The results obtained here could be extrapolated to evaluate the risk of tomato fruits and tomato products contamination caused by these toxins. [ABSTRACT FROM AUTHOR]

Alternaria species are common saprophytes or pathogens of a wide range of plants pre- and post-harvest. This review considers the relative importance of Alternaria species, their ecology, competitiveness, production of mycotoxins and the prevalence of the predominant mycotoxins in different food products. The available toxicity data on these toxins and the potential future impacts of Alternaria species and their toxicity in food products pre- and post-harvest are discussed. The growth of Alternaria species is influenced by interacting abiotic factors, especially water activity (aw), temperature and pH. The boundary conditions which allow growth and toxin production have been identified in relation to different matrices including cereal grain, sorghum, cottonseed, tomato, and soya beans. The competitiveness of Alternaria species is related to their water stress tolerance, hydrolytic enzyme production and ability to produce mycotoxins. The relationship between A. tenuissima and other phyllosphere fungi has been examined and the relative competitiveness determined using both an Index of Dominance (ID) and the Niche Overlap Index (NOI) based on carbon-utilisation patterns. The toxicology of some of the Alternaria mycotoxins have been studied; however, some data are still lacking. The isolation of Alternaria toxins in different food products including processed products is reviewed. The future implications of Alternaria colonization/infection and the role of their mycotoxins in food production chains pre- and post-harvest are discussed. [ABSTRACT FROM AUTHOR]

The influence of a w on DON and its acetyl derivatives biosynthesis by a strain of Fusarium graminearum s.s. (ITEM 4606) which produces DON, 3-ADON and 15-ADON was evaluated. Trichothecene production was studied on agar wheat 2% at 0.95 and 0.99 a w at different temperatures (10, 15, 20, 25 and 30 °C) and incubation times (7, 14, 21 and 28 days). Statistical analysis (ANOVA) showed that a w , temperature, incubation time and their interactions were significant on the production of DON, 3-ADON and 15-ADON (p < 0.0001). The pattern of toxin production was influenced by a w , showing differences for the three toxins. The maximum accumulation of DON occurred at 30 °C at 0.99 a w (14 d) and at 25 °C at 0.95 a w (7 and 21 d). The highest concentration of 3-ADON at 0.95 a w was observed at 25 °C and 7 days, and it was significantly higher than all the other values registered. At 0.99 a w , the maximum occurred at 30 °C and 21 days, but another significantly high accumulation was observed at 28 days at the same temperature. For 15-ADON, at 0.95 a w , the highest amount of toxin was accumulated at 10 °C, both at 7 and 28 days. At 0.99 a w , a maximum was observed at 10 °C and 7 days, significantly different from the values observed at the other conditions. The toxin accumulated at a higher concentration at 0.95 a w was 15-ADON (173.2 μg/g) and at 0.99 a w , 3-ADON (370.6 μg/g). A marked influence of a w on the maximum toxin accumulation with respect to temperature and time was observed for trichothecene production. This is an important fact to consider when designing predictive models to prevent toxin contamination, both in the field and during storage, especially in intermediate drying stages. • A w influence on DON, 3- and 15-ADON production by Fusarium graminearum was evaluated. • Interactions between a w , temperature and time on toxin production were observed. • The production pattern for DON differed from the acetyl derivatives. • At 0.95 a w , 15-ADON was the prevalent toxin, while at 0.99 a w it was 3-ADON. [ABSTRACT FROM AUTHOR]

Alternaria arborescens is the causal agent of tomato stem canker, a disease frequently responsible of substantial economic losses. A. arborescens can produce several mycotoxins, such as alternariol, alternariol monomethyl ether and tenuazonic acid and phytotoxins such as the AAL toxins. The objective of this study was to determine the effect of water activity (aw, 0.950, 0.975, 0.995) and temperature (6, 15, 20, 25 and 30°C) on the germination and radial growth rate of A. arborescens on a synthetic tomato medium. Germination followed by growth was observed at all temperatures and aw levels analyzed. The shortest germination time (0.5days) was observed at 0.995 aw, both at 25°C and at 30°C. The germination time increased with a reduction of aw and temperature. The highest growth rate was registered at 0.995 aw and 30°C (7.21mm/day) while the lowest occurred at 0.950 aw and 6°C (0.52mm/day), conditions at which the longest lag phase was observed (8days). Growth rates increased with aw and temperature. Knowledge of the ecophysiology of the fungus in this substrate is necessary to formulate future strategies to prevent its development and evaluate the consumer health risk posed by potential exposure to the toxins. [ABSTRACT FROM AUTHOR]

High-throughput DNA sequence analysis was used to screen for TET2 mutations in peripheral blood derived DNA from 97 patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). Overall six mutations in the coding region of the gene were identified in 7 patients with an overall mutational frequency of 7.2%. In polycythemia vera patients (n = 25) 2 mutations were identified (8%), and in those with essential thrombocythemia (n = 55) 2 mutations (3.6%); in those with unclassifiable MPN (n = 8) 3 mutations (37.5%). No primary myelofibrosis patients (n = 6) harboured TET2 mutations. Three unreported mutations were identified (p.P177fs, p.C1298del, and p.P411del), the first two in patients with unclassifiable MPN, the last in a patient with essential thrombocythemia. On multivariate analysis the diagnosis of an unclassifiable MPN was significantly related to the presence of TET2 mutations (P = 0.02; OR: 2.81; 95% CI 1.11-7.06). We conclude that TET2 mutations occur in both JAK2 V617F-positive and -negative MPNs and are more frequent in MPN-U patients. This could represent the biological link between the different classes of myeloid malignancies. [ABSTRACT FROM AUTHOR]

Aspergillus section flavi strains isolated from peanuts, wheat and soybean grown in Argentina were screened for aflatoxins (type B and G) and cyclopiazonic acid (CPA) production. Aspergillus flavus was the predominant species in all substrates, although there was almost the same proportion of A. flavus and Aspergillus parasiticus in peanuts. Aspergillus nomius was not found. Incidence of aflatoxigenic A. flavus strains was higher in peanuts (69%) than in wheat (13%) or soybeans (5%) while the ratio of CPA producers A. flavus isolated from all substrates was very high (94% in peanuts, 93% in wheat and 73% in soybeans). Isolates of A. flavus able to produce simultaneously aflatoxins type B and CPA were detected in all substrates, suggesting the possibility of co-occurrence of these toxins. Almost all isolates of A. parasiticus resulted aflatoxins (type B and G) producers but did not produce CPA. Five of sixty-seven strains isolated from peanuts showed an unusual pattern of mycotoxin production (aflatoxins type B and G simultaneously with CPA). These strains also produced numerous small sclerotia like S strains of A. flavus detected in cottonseed in Arizona and in soils of Thailand and West Africa. The atypical strains are not widely distributed in Argentina and were found uniquely in peanuts. [Copyright &y& Elsevier]

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries, with an incidence of approximately 5.1/100,000 new cases per year. Some patients may never require treatment, whereas others relapse early after front line therapeutic approaches. Recent whole genome and whole exome sequencing studies have allowed a better understanding of CLL pathogenesis and the identification of genetic lesions with potential clinical relevance. Consistently, precision medicine plays a pivotal role in the treatment algorithm of CLL, since the integration of molecular biomarkers with the clinical features of the disease may guide treatment choices. Most CLL patients present at the time of diagnosis with an early stage disease and are managed with a watch and wait strategy. For CLL patients requiring therapy, the CLL treatment armamentarium includes both chemoimmunotherapy strategies and biological drugs. The efficacy of these treatment strategies relies upon specific molecular features of the disease. TP53 disruption (including both TP53 mutation and 17p deletion) is the strongest predictor of chemo-refractoriness, and the assessment of TP53 status is the first and most important decisional node in the first line treatment algorithm. The presence of TP53 disruption mandates treatment with biological drugs that inhibit the B cell receptor or, alternatively, the B-cell lymphoma 2 (BCL2) pathway and can, at least in part, circumvent the chemorefractoriness of TP53-disrupted patients. Beside TP53 disruption, the mutational status of immunoglobulin heavy variable (IGHV) genes also helps clinicians to improve treatment tailoring. In fact, patients carrying mutated IGHV genes in the absence of TP53 disruption experience a long-lasting and durable response to chemoimmunotherapy after fludarabine, cyclophosphamide, and rituximab (FCR) treatment with a survival superimposable to that of a matched general population. In contrast, patients with unmutated IGHV genes respond poorly to chemoimmunotherapy and deserve treatment with B cell receptor inhibitors. Minimal residual disease is also emerging as a relevant biomarker with potential clinical implications. Overall, precision medicine is now a mainstay in the management and treatment stratification of CLL. The identification of novel predictive biomarkers will allow further improvements in the treatment tailoring of this leukemia. [ABSTRACT FROM AUTHOR]

Evans syndrome (ES) is rare and mostly treated on a “case‐by‐case” basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP‐NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work‐up and management. Thirty clinicians who had followed a median of 5 patients (1–45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti‐platelets and anti‐neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization. [ABSTRACT FROM AUTHOR]

Dormancy of hematopoietic stem cells and formation of progenitors are directed by signals that come from the bone marrow microenvironment. Considerable knowledge has been gained on the murine hematopoietic stem cell microenvironment, while less so on the murine progenitor microenvironment and even less so on these microenvironments in humans. Characterization of these microenvironments is decisive for understanding hematopoiesis and finding new treatment modalities against bone marrow malignancies in the clinic. However, it is equally challenging, because hematopoietic stem cells are difficult to detect in the complex bone marrow landscape. In the present study we are characterizing the human hematopoietic stem cell and progenitor microenvironment. We obtained three adjacent bone marrow sections from ten healthy volunteers. One was used to identify a population of CD34+/CD38- "hematopoietic stem cells and multipotent progenitors" and a population of CD34+/CD38+ "progenitors" based on immunofluorescence pattern/intensity and cellular morphology. The other two were immunostained respectively for CD34/CD56 and for CD34/SMA. Using the combined information we performed a non-computer-assisted quantification of nine bone marrow components (adipocytes, megakaryocytes, bone surfaces, four different vessel types (arteries, capillaries, sinusoids and collecting sinuses), other "hematopoietic stem cells and multipotent progenitors" and other "progenitors") within 30 μm of "hematopoietic stem cells and multipotent progenitors", "progenitors", and "random cell profiles". We show that the microenvironment of the "hematopoietic stem cells and multipotent progenitors" is significantly enriched in sinusoids and megakaryocytes, while the microenvironment of the "progenitors" is significantly enriched in capillaries, other "progenitors", bone surfaces and arteries. [ABSTRACT FROM AUTHOR]

Health-related quality of life (HRQOL) assessment is important to facilitate decisions in the current treatment landscape of chronic myeloid leukemia (CML). Therefore, the availability of a validated HRQOL questionnaire, specifically developed for CML patients treated with tyrosine kinase inhibitors (TKIs), may enhance quality of research in this area. We performed an international study including 782 CML patients to assess the validity of the EORTC QLQ-CML 24 questionnaire, and to generate HRQOL reference values to facilitate interpretation of results in future studies. Internal consistency, assessed with Cronbach's alpha coefficients, ranged from 0.66 to 0.83. In the confirmatory factor analysis, all standardized factor loadings exceeded the threshold of 0.40 (range 0.49–0.97), confirming the hypothesized scale structure. Reference values stratified by age and sex were also generated. Our findings support the use of the EORTC QLQ-CML 24, in conjunction with the EORTC QLQ-C30, as a valuable measure to assess HRQOL in CML patients. [ABSTRACT FROM AUTHOR]

Background: The authors assessed the clinical utility of patient‐reported symptom monitoring in the setting of newly diagnosed chronic myeloid leukemia (CML). The primary objective was to evaluate adherence to therapy. Methods: The authors conducted an international prospective study that included patients with newly diagnosed, chronic‐phase CML. Before clinical consultation, patients were provided a tablet computer to self‐rate their symptoms, and the results were available in real time to each physician during the patient's visit. Adherence was assessed by pill count and with a validated self‐reported questionnaire. The proportions of optimal responders at 3 and 6 months were assessed according to the European LeukemiaNet criteria. Results: Between July 2020 and August 2021, 94 patients with a median age of 57 years were enrolled. Pill count adherence analysis indicated that 86 of 93 evaluable patients (92.5%) took at least 90% of prescribed tyrosine kinase inhibitor therapy during the 6‐month observation period. The online platform was well accepted by patients and physicians. An optimal response was achieved by 69 of 79 patients (87.3%) at 3 months and by 61 of 81 patients (75.3%) at 6 months. Conclusions: Patient‐reported symptom monitoring from the beginning of therapy in patients with CML may be critical to improve adherence to therapy and early molecular response rates (ClinicalTrials.gov identifier NCT04384848). Optimal adherence to tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia is critical to attain and maintain an optimal clinical response. The current findings suggest that systematic monitoring of patient‐reported symptoms is associated with high adherence rates. [ABSTRACT FROM AUTHOR]

Abstract Alternaria spp. are major contaminants of wheat crops, causing both economic losses for producers and health risk for consumers due to the accumulation of toxic metabolites. The application of synthetic fungicides in the field may trigger mycotoxin accumulation, since fungistatic levels of those compounds might cause fungal responses to stress. Hence, new alternatives are needed for its control. The aim of this work was to compare the effects of a natural antifungal compound, the antifungal protein PgAFP, and a synthetic commercial one, on Alternaria tenuissima sp.-grp. growth, mycotoxin biosynthesis (tenuazonic acid and alternariols) and the expression of a stress-related gene associated with cell wall integrity (CWI) pathway, in a wheat-based medium at two water activities (a w ; 0.95 and 0.98 a w) conditions associated with the ripening of this grain. The application of both antifungals produced comparable fungistatic effects on Alternaria spp. growth. However, the presence of PgAFP produced a significant reduction in mycotoxins accumulation, whereas this effect was not observed with the commercial antifungal. To our knowledge, this is the first study on the influence of fungicides on the expression of a key gene involved in CWI stress-related pathway in relation to Alternaria mycotoxins accumulation. This information is useful when developing new antifungal methods for foods. The application of PgAFP would be a promising natural strategy for its application in wheat for the control of Alternaria spp. Highlights • The antifungal protein PgAFP reduced Alternaria growth on a wheat-based medium. • PgAFP caused a reduction in mycotoxin accumulation at both 0.95 and 0.98 a w. • A commercial fungicide applied at fungistatic level triggered mycotoxin production. • The stress-related CWI pathway and alternariols accumulation may be associated. • PgAFP is a promising natural strategy for the control of Alternaria spp. in wheat. [ABSTRACT FROM AUTHOR]

Simple Summary: The association of venetoclax (VEN) with hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DECI) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy. However, it is not clear how applicable the results of clinical trials are in a real-world setting. For this reason, we conducted a systematic review and meta-analysis of real-world studies on this type of AML patient. Overall, AML patients treated with VEN+HMAs had a lower survival rate than was reported in the pivotal VIALE-A trial. Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment. Future studies are warranted to investigate whether this discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy. In recent years, the association of venetoclax (VEN) with hypomethylating agents (HMAs) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy and became the standard of care after the publication of the pivotal RCT VIALE-A. However, it is still not clear to what extent the results observed in the VIALE-A apply to a real-world setting. For this reason, we carried out a systematic review and meta-analysis of real-world studies on newly diagnosed patients with AML, ineligible for intensive induction chemotherapy, receiving first-line VEN+HMA. We then compared their results in term of survival with those from the VIALE-A. Kaplan-Meier curves were extracted from all included studies and individual survival data was reconstructed. We then estimated a pooled survival curve and compared it with the results of the VIALE-A using the log-rank test. We also conducted a secondary analysis including only studies considering VEN plus azacytidine (AZA) as treatment, as this was the schedule originally used in the VIALE-A. Nineteen real-world studies met the inclusion criteria and were included in the systematic review. Most of them reported a worse survival than the VIALE-A. The pooled survival curve was similar to that reported in the VIALE-A during the first three months of treatment but diverged thereafter (p-value = 0.0001). The pooled median survival among the real-world studies was 9.37 months (95%CI 8.81–10.5), substantially lower than that reported in the VIALE-A (14.7 months; 95%CI 11.9–18.7). Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment (median survival: 11.5 months; 95%CI 10.2–14.8). Survival of newly diagnosed AML patients treated with VEN+HMAs in a real-world setting seems to be lower than previously reported in the VIALE-A, while the effect of VEN+AZA is more in line with expected results. Future studies are needed to evaluate whether this apparent discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy, and whether alternative regimens can provide better results in terms of safety and effectiveness. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is characterized by high molecular and clinical heterogeneity. Autophagy, a lysosome-driven catabolic process devoted to macromolecular turnover, is fundamental in maintaining normal hematopoietic stem cells and progenitors homeostasis, and its dysregulation plays a critical role in the initiation and progression of hematological malignancies. One main regulator of autophagy is BECLIN-1, which may interact alternatively with either BCL-2, thus allowing apoptosis, or PI3KC3, thus promoting autophagy. The altered expression of BCL2 and BECN1 correlates with lymphoma outcomes, but whether this is associated with dysregulated cross-talk between autophagy and apoptosis remains to be elucidated. Analysis of the TCGA database revealed that BCL2 and BECN1 mRNA expression were inversely correlated in DLBCL patients. In representative DLBCL cell lines exposed to doxorubicin, the cells highly expressing BCL-2 were resistant, while the ones highly expressing BECLIN-1 were sensitive, and this correlated with low and high autophagy flux, respectively. Venetoclax targeting of BCL-2 increased while the spautin-1-mediated inhibition of BECLIN-1-dependent autophagy reversed doxorubicin sensitivity in the former and in the latter, respectively. By interrogating the TCGA DLBCL dataset, we found that BCL2 and BECN1 acted as negative and positive prognostic markers for DLBCL, respectively. The differentially expressed gene analysis in the respective cohorts revealed that BCL2 positively correlated with oncogenic pathways (e.g., glucose transport, HIF1A signaling, JAK-STAT signaling, PI3K-AKT-mTOR pathway) and negatively correlated with autophagy-related transcripts, while BECN1 showed the opposite trend. Notably, patients with high BECN1 expression displayed longer survival. Our data reveal, for the first time, that the modulation of BECLIN-1-dependent autophagy influences the prognosis of DLBCL patients and provide a mechanistic explanation supporting the therapeutic use of drugs that, by stimulating autophagy, can sensitize lymphoma cells to chemotherapy. [ABSTRACT FROM AUTHOR]

In addition, the cancer status at the time of vaccine administration influenced the levels of anti-s IgG titres as these were generally higher in patients belonging to the "watch and wait" group (median: 1040.4, IQR: 431.9-4712.7) and "complete/partial response" group (median: 913.0, IQR: 233.8-2542.5) compared to "stable/progressive disease" patients (median: 500, IQR: 155.0-1436.9), albeit the difference was not statistically significant ( I p i = 0.38) (Figure 1A). Patterns of neutralizing humoral response to SARS-CoV-2 infection among hematologic malignancy patients reveal a robust immune response in anti-cancer therapy-naive patients. Violin plots depicting (A) anti-s IgG titres and (B) anti-SARS-CoV-2 neutralising activity in HM patients with prior SARS-CoV-2 infection analysed after completing the SARS-CoV-2 vaccination. In contrast, when patients were stratified according to cancer diagnosis, the anti-s IgG antibody titre was significantly higher in patients with myeloid neoplasms (median: 1896.7, interquartile range [IQR]: 818.8-4712.7) than in patients with lymphoid malignancies or plasma cell disorders (median: 715.0; IQR: 42.6-1755.9 and median: 685.3; IQR: 186.0-1602.5 respectively; I p i = 0.0031). [Extracted from the article]

Alternaria is a frequent contaminant of apple fruit, causing severe economic losses. It can produce external lesions and mouldy core, characterised by a rotten area in the apple core. In the present study, morphological and chemical characterization of Alternaria from apples was performed, evaluating differences related to agricultural practices and type of disease. A low morphological diversity was observed; most of the isolates were identified as A. tenuissima sp.-grp. (95 %). A. arborescens sp.-grp. and A. gaisen sp.-grp. were present in a proportion of 1 %, and 3 % of the isolates showed intermediate characteristics between these sp.-grps. and were identified as Alternaria sp. The chemical diversity was greater; 27 secondary metabolites were produced by the apple isolates. The most frequents were altertoxin-I (85 %), altechromone A (76 %), tentoxin (69 %), and tenuazonic acid (68 %). The alternariols were produced in a lower frequency when comparing with isolates from other crops; alternariol, 58 % and alternariol monomethyl ether, 57 %. The predominant secondary metabolite profile included compounds from different chemical families, such as dibenzopyrones, tetramic acids, perylene quinones, and cyclic tetrapeptides. A wider metabolomic capacity was observed in isolates from conventional apples when compared to those from organic fruit, with the predominance of strong producers of altertoxins and alternariols. The isolates from mouldy core showed higher ability to produce metabolites from different chemical families than those from external lesions. The wide chemical diversity of the Alternaria apple population should be considered to assess the health risk associated with apple by-products. • The Alternaria isolates from apple showed low morphological diversity. • Conventional agriculture isolates had more diverse secondary metabolite profiles. • Mouldy core isolates showed higher chemical diversity. • Alternaria main mycotoxins were produced in high proportion by the apple isolates. [ABSTRACT FROM AUTHOR]

Abstract: Food decay by spoilage fungi causes considerable economic losses and constitutes a health risk for consumers due to the potential for fungi to produce mycotoxins. The indiscriminate use of synthetic antifungals has led to the development of resistant strains which has necessitated utilization of higher concentrations, with the consequent increase in toxic residues in food products. Numerous studies have demonstrated that plant extracts contain diverse bioactive components that can control mould growth. The metabolites produced by plants are a promising alternative because plants generate a wide variety of compounds, either as part of their development or in response to stress or pathogen attack. The aim of this article is to summarize the results from the literature on in vitro and in vivo experiments regarding the effects of plant-derived products for controlling fungal growth. Data from research work on the mode of action of these metabolites inside the fungal cell and the influence of abiotic external factors such as pH and temperature are also covered in the present review. Furthermore, an analysis on how the stress factor derived from the presence of plant extracts and essential oils affects secondary metabolism of the fungus, specifically mycotoxin synthesis, is developed. Finally, the effectiveness of using plant-derived compounds in combination with other natural antimicrobials and its application in food using novel technologies is discussed. [Copyright &y& Elsevier]

Abstract: Growth rate, lag phase and OTA production of a mixed inoculum of four Aspergillus carbonarius strains were compared to the behaviour of the single strains at 30°C on Czapek Yeast Extract Agar. Significant differences between radial growth rates and lag phases of the different isolates were observed; however, no significant differences between growth rates of each strain and the mixed inoculum were detected. When the four strains were inoculated simultaneously, the lag phase was the same than the higher value obtained for individual strains, suggesting mycelial interactions between the A. carbonarius isolates. The four strains differed in maximum OTA yield, and the toxin accumulation by the mixed inoculum showed intermediate levels at each time point. The effects of water activity (0.83, 0.85, 0.87, 0.89, 0.90, 0.93 and 0.95) and temperature (15, 20, 25, 30, and 35°C) on OTA production by the mixed inoculum were studied at 7, 14, 21 and 28days of incubation. The limiting water activity for OTA production by the mixed inoculum was 0.87, showing xerotolerant behaviour of the strains isolated from dried vine fruits. Results obtained were similar to those reported for single A. carbonarius strains from European countries, Israel, Australia and South America. The similar trend in the response of the different isolates to the variation of environmental parameters may be of interest for the building of predictive models. [Copyright &y& Elsevier]

Summary: We aimed at molecularly dissecting the anatomical heterogeneity of small lymphocytic lymphoma (SLL), by analysing a cohort of 12 patients for whom paired DNA from a lymph node biopsy and circulating cells, as well as plasma‐circulating tumour DNA (ctDNA) was available. Notably, the analyses of the lymph node biopsy and of circulating cells complement each other since a fraction of mutations (20·4% and 36·4%, respectively) are unique to each compartment. Plasma ctDNA identified two additional unique mutations. Consistently, the different synchronous sources of tumour DNA complement each other in informing on driver gene mutations in SLL harbouring potential prognostic and/or predictive value. [ABSTRACT FROM AUTHOR]

Summary: Up to 30% immune thrombocytopenia (ITP) patients achieve a sustained remission off‐treatment (SROT) after discontinuation of thrombopoietin receptor agonists (TPO‐RAs). Factors predictive of response are lacking. Patients aged ≥18 years with newly diagnosed or persistent ITP were treated with eltrombopag for 24 weeks. Primary end‐point was SROT: the proportion of responders that were able to taper and discontinue eltrombopag maintaining the response during a period of observation (PO) of six months. Secondary end‐points included the association between some immunological parameters (TPO serum levels, cytokines and lymphocyte subsets) and response. Fifty‐one patients were evaluable. Primary end‐point was achieved in 13/51 (25%) treated patients and 13/34 (38%) patients who started the tapering. Baseline TPO levels were not associated with response at week 24 nor with SROT. Higher baseline levels of IL‐10, IL‐4, TNF‐α and osteopontin were negative factors predictive of response (P = 0·001, 0·008, 0·02 and 0·03 respectively). This study confirms that SROT is feasible for a proportion of ITP patients treated with eltrombopag. Some biological parameters were predictive of response. [ABSTRACT FROM AUTHOR]

Hematologists are frequently involved in the diagnostic pathway of Gaucher disease type 1 (GD1) patients since they present several hematological signs. However, GD1 is mainly underdiagnosed because of a lack of awareness. In this multicenter study, we combine the use of a diagnostic algorithm with a simple test (β-glucosidase activity on Dried Blood Spot) in order to facilitate the diagnosis in a population presenting to the hematologist with splenomegaly and/or thrombocytopenia associated with other hematological signs. In this high-risk population, the prevalence of GD1 is 3.3%. We propose an equation that predicts the probability of having GD1 according to three parameters that are routinely evaluated: platelet count, ferritin, and transferrin saturation. [ABSTRACT FROM AUTHOR]

This case report highlights the challenges in controlling bleeding and correcting coagulation tests through the use of bypassing agents in patients with FV inhibitors. [ABSTRACT FROM AUTHOR]

BACKGROUND: Barley (Hordeum vulgare L.) is one of the most important cereals worldwide, and its quality is affected by fungal contamination such as species of the genus Alternaria. No information is available about the occurrence of Alternaria mycotoxins in Argentinean barley grains, which is of concern, because they can be transferred into malt and beer. The aim of this study was to analyze the occurrence of alternariol (AOH), alternariol monomethyl ether (AME) and tenuazonic acid (TeA) in malting barley grains from the main producing region of Argentina during the 2014 and 2015 growing seasons. RESULTS: The most frequent mycotoxin was AOH (64%), which was detected at higher levels (712 μg kg−1) compared with other studies, followed by TeA (37%, 1522 μg kg−1), while AME was present in five samples in the 2015 growing season only, with a mean of 4876 μg kg−1. A similar frequency of mycotoxin occurrence was observed in both years (80.8 vs 85.3%), but more diverse contamination was found in 2015, which was characterized by lower accumulated precipitation. Nevertheless, AOH was more frequently found in 2014 than in 2015 (80.8 and 47.1% respectively). A negative correlation between AOH concentration and temperature was observed. The susceptibility of different barley varieties to mycotoxin accumulation varied with the mycotoxin, geographical location and meteorological conditions. CONCLUSION: The results obtained in the present work represent a tool for risk assessment of exposition to these mycotoxins and could be used by food safety authorities to determine the need for their regulation. Furthermore, the establishment of a hazard analysis and critical control point (HACCP) system to minimize fungal and mycotoxin contamination in barley from farm to processing could be apply to ensure food safety. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

BACKGROUND: Tomato fruit is susceptible to Alternaria spp. spoilage. Correct postharvest management is necessary to prevent mold growth and mycotoxin accumulation, temperature being one of the main factors associated with these problems. The effect of different postharvest temperatures (5, 12, 25, and 35 °C) on growth, mycotoxin production, and stress‐related gene expression by two Alternaria spp. was assessed. RESULTS: Growth rates decreased rapidly when temperature was higher than the optimum (25 °C), while a gradual reduction was detected at lower temperatures. Tenuazonic acid (TeA) was strongly synthesized at all the temperatures that were evaluated, with a maximum between 12 and 25 °C. Alternariol monomethyl ether (AME) was produced only at the two lowest temperatures, with a peak at 12 °C. Regarding the expression of the stress‐related RHO1 gene, during active fungal growth both Alternaria spp. showed more copies of the gene as temperature increased. At the stationary phase, RHO1 gene expression was significantly higher at 12 °C, coinciding with the highest accumulation of AME. CONCLUSION: Changes in temperature related to different postharvest stages of tomato fruits markedly affect toxigenic Alternaria spp. The highest levels of both mycotoxins were recorded at 12 °C, a common storage temperature for tomato fruit. An association between alternariol biosynthesis and the cell wall integrity pathway was also noticed in relation to temperature, suggesting that temperature may act as a stressor stimulating the RHO1 gene expression, which in turn triggers this mycotoxin synthesis. These results will be useful in developing new strategies to control Alternaria spoilage efficiently in tomato fruit and by‐products. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Eltrombopag (ELT), an oral thrombopoietin receptor agonist, has recently emerged as a promising new drug for the treatment of aplastic anemia (AA). How ELT is used outside of clinical trials in the real-world setting and results of this treatment are not known. We conducted therefore a retrospective survey on the use of ELT in AA among EBMT member centers. We analyzed the 134 patients reported in our survey together with 46 patients recently published by Lengline et al. The median follow-up from start of ELT treatment was 15.3 months, with 85.6% patients alive at last follow-up. Importantly, only 28.9% of our patients received ELT according to the FDA/EMA label as monotherapy in the relapsed/refractory setting, whereas 16.7% received ELT upfront. The overall response rate in our cohort was 62%, very similar to the results of the pivotal ELT trial. In multivariate analysis, combination therapy with ELT/cyclosporine/ATG and response to previous therapy were associated with response. Overall survival was favorable with a 1-year survival from ELT start of 87.4%. We identified age, AA severity before ELT start and response to ELT as variables significantly associated with OS. Two patients transformed to MDS; other adverse events were mostly benign. In sum, ELT is used widely in Europe to treat AA patients, mostly in the relapsed/refractory setting. Response to ELT is similar to the clinical trial data across different age groups, treatment lines, and treatment combinations and results in favorable survival. [ABSTRACT FROM AUTHOR]

Although Alternaria toxins are still considered emerging, their occurrence has been reported in different food, both commodities and raw materials. Tomato products have been identified among the most relevant contributors to human exposure to these toxins. However, no current data are available on their incidence in tomato products in Argentina. A total of 79 samples were collected from the Argentinean market during 2019–2021, including tomato puree, whole peeled tomatoes, crushed tomatoes, concentrated tomato paste, tomato sauce, and tomato pulp. Six Alternaria toxins, altenuene (ALT), alternariol (AOH), alternariol monomethyl ether (AME), altertoxin-I (ATX-I), tentoxin (TEN), and tenuazonic acid, were quantified by HPLC-MS. Natural occurrence of at least one of the toxins was observed in 29 samples. TeA and TEN were the predominant toxins (14%), followed by AOH (13%). A low incidence of ALT (4%), AME (4%) and ATX-I (3%) was detected. TeA was the toxin quantified at the highest levels (211.4–495.7). ATX-I, which is rarely reported in food, was present in 2 samples in relatively high concentrations (146.8 and 233.9 μg/kg). Tomato purees were the products with higher incidence and the only samples contaminated with the six Alternaria toxins. As 11% of the products analysed exceeded the levels recommended by EFSA for AOH and 4% for AME, future risk assessments should be performed to evaluate the consumers' exposure to these toxins. • Alternaria toxins were determined in tomato products from the Argentinean market. • Natural occurrence was detected in 40% of the samples analysed. • TeA and TEN were the predominant toxins (14%), followed by AOH (13%). • Tomato purees showed the highest frequency of contamination (47%). • The six Alternaria toxins were detected in tomato puree samples. [ABSTRACT FROM AUTHOR]

Small-spored Alternaria have been isolated from a wide variety of food crops, causing both economic losses and human health risk due to the metabolites produced. Their taxonomy has been discussed widely, but no scientific consensus has been established in this field to date. Argentina is a major exporter of agricultural products, so it is essential to thoroughly understand the physiological behaviour of this pathogen in a food safety context. Thus, the objective of this work was to characterize small-spored Alternaria spp. obtained from tomato fruits, pepper fruits, wheat grains and blueberries from Argentina by a polyphasic approach involving metabolomic and phylogenetic analyses based on molecular and morphological characters. Morphological analysis divided the population studied into three groups; A. arborescens sp.-grp., A. tenuissima sp.-grp., and A. alternata sp.-grp. However, when these characters were simultaneously analysed with molecular data, no clearly separated groups were obtained. Haplotype network and phylogenetic analysis (both Bayesian and maximum parsimony) of a conserved region yielded the same result, suggesting that all isolates belong to the same species. Furthermore, no correlation could be established between morphological species-groups and a metabolite or group of metabolites synthesized. Thus, the whole set of analyses carried out in the present work supports the hypothesis that these small-spored Alternaria isolates from food belong to the same species. Identification at species level through classical morphology or modern molecular techniques does not seem to be a useful tool to predict toxicological risk in food matrices. The detection of any small-spored Alternaria from Section Alternaria (D.P. Lawr., Gannibal, Peever & B.M. Pryor 2013) in food implies a potential toxicological risk. [ABSTRACT FROM AUTHOR]

Sweet pepper ( Capsicum annuum ) is an important crop cultivated worldwide, with Argentina being one of the major producers in South America. The fruit is susceptible to several fungal diseases, leading to severe economic losses for producers. In this study, Alternaria was found as the prevalent genus in mouldy peppers (50% fruits infected). Morphological identification revealed that all 64 Alternaria isolates belonged to small-spored species, most of them corresponding to A. tenuissima, A. arborescens and A. alternata species-groups. Their secondary metabolite profile was evaluated in vitro ; alternariols were synthesized by most of the isolates (91% for alternariol and 92% for alternariol monomethyl ether). A high number of Alternaria spp. also produced tenuazonic acid (64%), altenuene (84%) and tentoxin (72%). In addition, damaged pepper fruits were analysed for the presence of tenuazonic acid and alternariols. A total 32 out of 48 spoiled pepper fruits were contaminated with at least one of these metabolites. Half of the samples were positive for tenuazonic acid (range 8–11,422 μg/kg), while alternariol and its monomethyl ether were less frequently detected (21 and 29%, respectively) and at lower concentrations. This is the first report on the natural occurrence of Alternaria mycotoxins in Argentinean sweet pepper, and highlights a consumer risk when mouldy fruits are used in industrialized products because these compounds are not destroyed by conventional heat treatments. [ABSTRACT FROM AUTHOR]

Several biosimilar versions of recombinant human erythropoietin are currently approved for use in Europe, including a biosimilar epoetin-α. The aim of this the study was to verify that biosimilar epoetin-α is similar in terms of efficacy, safety and cost to originator epoetin-α for the treatment of refractory anemia in patients with myelodysplastic syndrome. A total of 92 patients with myelodysplasia and refractory anemia were investigated. The patients received either originator (group A) or biosimilar (group B) epoetin-α. In addition, they received liposomal iron (Sideral®), calcium levofolinate and vitamin B12. Moreover, the median monthly overall costs were calculated for each group. The results demonstrated that hemoglobin (Hb) levels increased by 1 g/dl after a median time of 5 weeks in group A and 4 weeks in group B. In group A, a Hb level of >12 g/dl was achieved after 12 weeks, while in group B after 10.5 weeks. The median cost of therapy was 1,536 euros/month in group A and 1,354 euros/month in group B. A total of 5 patients required transfusion support in group A and 7 in group B. In conclusion, biosimilar epoetin-α appears to be comparable to originator epoetin-α in terms of efficacy and safety for the treatment of refractory anemia. [ABSTRACT FROM AUTHOR]

Alternaria species have the ability to produce a variety of secondary metabolite, which plays important roles in food safety. Argentina is the second largest exporter of fresh and processed food products to Europe, however, few studies on Alternaria mycotoxins and other bioactive secondary metabolites have been carried out on Argentinean cereals, fruit and vegetables. Knowing the full chemical potential and the distribution of Alternaria spp. on crops, it is necessary to establish a toxicological risk assessment for food products for human consumption. In the present study, 87 Alternaria strains from different substrates (tomato, wheat, blueberries and walnuts) were characterized according to morphology and metabolite production. Aggressive dereplication (accurate mass, isotopic patterns and lists of all described compounds from Alternaria ) was used for high-throughput evaluation of the chemical potential. Four strains belonged to the Alternaria infectoria sp.-grp., 6 to the Alternaria arborescens sp.-grp., 6 showed a sporulation pattern similar to that of “M” according to Simmons, 1 to that of Alternaria vaccinii , and the remaining 70 constituted a diverse group belonging to morphological groups “G” and “H”. The cluster analysis yielded 16 almost identical dendrograms and grouped the Alternaria strains into four clusters and 11 singletons and outlier groups. The chemical analysis showed that AOH and AME were the most common metabolites produced, followed by TEN, ALXs and TeA. The A. infectoria sp.-grp. had no metabolites in common with the rest of the strains. Several secondary metabolites isolated from large-spored Alternaria species or other fungal genera were detected, such as dehydrocurvularin, pyrenochaetic acid and alternarienonic acid. The strains isolated from tomato produced lower amounts of metabolites than strains from blueberries, walnut and wheat, although individual strains from tomato produced the highest amount of some metabolites. The A. infectoria sp.-grp. was unique to cereals, whereas strains classified as belonging to the A. arborescens sp.-grp or having sporulation pattern “M” were only isolated from tomatoes. Otherwise, no clear association between substrate and identity could be found. The analyses in the study show that at least 75% of the Argentinean strains are able to produce potential mycotoxins. [ABSTRACT FROM AUTHOR]

Abstract: Fusarium graminearum is one of the most important pathogens isolated from small cereal grains with Fusarium Head Blight symptoms. The presence of this fungus is often linked to the occurrence of several mycotoxins in barley and wheat. The aim of our study was to characterize trichothecene genotypes and production profiles of F. graminearum sensu stricto isolates obtained from barley grains in Argentina. A total of 110 F. graminearum s.s. isolates were analyzed by PCR assays to predict deoxynivalenol (DON), 15-acetyldeoxynivalenol (15-ADON), 3-acetyldeoxynivalenol (3-ADON) and nivalenol (NIV) production, and all isolates were found to belong to the same molecular 15-ADON genotype. Trichothecene production in autoclaved rice was analyzed by using gas chromatography (GC) and confirmed by GC–MS. Of the 110 isolates, 95% were able to produce DON, 71% produced 15-ADON, 63% 3-ADON and 52% NIV. With the exception of a single isolate, all isolates that produced NIV, also produced DON. However, the NIV production was very low, ranging from 0.13 to 0.30μg/g. Six different production profiles of DON and its acetyl-derivatives were detected, the predominant being simultaneous production of DON, 3-ADON and 15-ADON, followed by DON production, and DON and 15-ADON co-production. This work is the first attempt to characterize the trichothecene genotypes and production profiles of F. graminearum s.s. isolates from Argentinean barley. [Copyright &y& Elsevier]

Key Clinical Message: Patients with B‐lineage acute lymphoblastic leukemia treated with pegasparaginase‐containing regimens can develop hepatotoxicity related to it. The systemic hyperbilirubinemia due to hepatotoxicity can lead to the development of CSF xanthochromia. [ABSTRACT FROM AUTHOR]

Alternaria is one of the main fungal genera affecting the quality of barley grains. In this study, a polyphasic approach was carried out to characterise the Alternaria population infecting different cultivars of barley grains from the major producing regions of Argentina in the 2014 and 2015 seasons. Its relationship with Fusarium and correlations between predominant species, barley cultivars, and climatic conditions in the growing regions were evaluated. Alternaria incidence exceeded that of Fusarium in all the barley samples and was higher in the drier season (21% in 2014 and 42% in 2015 vs. 6% and 4%, respectively). The main Alternaria species-groups identified were present in both growing seasons in similar frequencies (A. tenuissima sp.-grp. , 83.4% in 2014 and 81.7% in 2015; A. infectoria sp.-grp. , 11.7% in 2014 and 11.3% in 2015). The dominant Alternaria species-group isolated and identified based on morphological characteristics, DNA sequencing, and metabolite profile was A. tenuissima (72.9%) , followed by A. infectoria (14.6%). An association between their frequency and field temperature was observed; A. tenuissima sp.-grp. was more frequent in northern localities, where higher temperatures were registered, while the opposite was observed for A. infectoria sp.-grp. A smaller percentage of A. arborescens sp.-grp. (5%), A. alternata sp.-grp. (3.9%) and A. vaccinii (1.4%) were also identified. Both secondary metabolite profiles and phylogenetic analysis were useful to distinguish isolates from Alternaria section Alternaria and section Infectoriae. Regarding metabolite profiles, alternariol was the most frequent compound produced by isolates of the section Alternaria. Infectopyrones and novae-zelandins were produced by most of the isolates from section Infectoriae. The barley cultivars analysed in this study did not show a particular susceptibility regarding the Alternaria population composition, except for Andreia, which presented the highest frequency of contamination with A. tenuissima sp.-grp. The rest of the cultivars, when grown in different regions, showed different proportion of the Alternaria sp.-grps., suggesting that other factors were determinant in their distribution. The results obtained in the present study will be a valuable tool for health authorities to assess the need for regulations on Alternaria mycotoxins, given the high incidence of Alternaria spp. in barley and the diversity of metabolites that might contaminate the grains. • Alternaria sect. Alternaria and Infectoriae were the main barley contaminants. • The incidence of Alternaria spp. was much higher than that of Fusarium spp. • Barley cultivars showed a similar susceptibility to contamination by Alternaria. • The distribution of Alternaria sections was related to temperature. • Mycotoxigenic species were associated with higher temperatures. [ABSTRACT FROM AUTHOR]

Tomato fruit is susceptible to Alternaria spp. spoilage, which poses a health risk due to their mycotoxin production. Biopreservation relies on the use of whole microorganisms or their metabolites to manage spoilage microorganisms including filamentous fungi. However, the use of treatments at fungistatic level might activate intracellular pathways, which can cause an increment in mycotoxin accumulation. The objective of this work was to evaluate the effect of two strains of Debaryomyces hansenii and the antifungal protein PgAFP at 10 and 40 μg/mL. Both growth and production of two of the most common mycotoxins (tenuazonic acid and alternariol monomethyl ether) by Alternaria tenuissima sp.-grp. and Alternaria arborescens sp.-grp. on a tomato-based matrix, were analysed at 12 °C. Additionally, the impact of these biocontrol agents on the stress-related RHO1 gene expression was assessed. All treatments reduced mycotoxin accumulation (from 27 to 92% of inhibition). Their mode of action against Alternaria spp. in tomato seems unrelated to damages to fungal cell wall integrity at the genomic level. Therefore, the two D. hansenii strains (CECT 10352 and CECT 10353) and the antifungal protein PgAFP at 10 μg/mL are suggested as biocontrol strategies in tomato fruit at postharvest stage. • D. hansenii and the antifungal protein PgAFP were tested against Alternaria spp. • Effects on growth reduction varied with Alternaria strain and treatment. • Both strategies caused a marked reduction in mycotoxin accumulation. • Efficacy of treatments seems to be unrelated to Alternaria -CWI in tomato medium. • D. hansenii and PgAFP are promising strategies to control Alternaria toxins on tomato. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) arising in the context of inherited bone marrow failure syndromes (IBMFS) differ in terms of prognosis and treatment strategy compared to MDS occurring in the adult population without an inherited genetic predisposition. The main molecular pathways affected in IBMFS involve telomere maintenance, DNA repair, biogenesis of ribosomes, control of proliferation and others. The increased knowledge on the genes involved in MDS pathogenesis and the wider availability of molecular diagnostic assessment have led to an improvement in the detection of IBMFS genetic predisposition in MDS patients. A punctual recognition of these disorders implies a strict surveillance of the patient in order to detect early signs of progression and promptly offer allogeneic hematopoietic stem cell transplantation, which is the only curative treatment. Moreover, identifying an inherited mutation allows the screening and counseling of family members and directs the choice of donors in case of need for transplantation. Here we provide an overview of the most recent data on MDS with genetic predisposition highlighting the main steps of the diagnostic and therapeutic management. In order to highlight the pitfalls of detecting IBMFS in adults, we report the case of a 27-year-old man affected by MDS with an underlying telomeropathy. [ABSTRACT FROM AUTHOR]

Mouldy core is a frequent apple fungal disease, mainly caused by toxigenic Alternaria species. Mouldy core is hardly detected in pre-selection procedures when the apples are destined for industrialization, and to date no information is available on the fate of Alternaria toxins during apple concentrate production. Therefore, we evaluated the effect of this process on the natural contamination levels of 10 Alternaria metabolites: alternariol (AOH), alternariol monomethyl ether (AME), altenuene (ALT), tenuazonic acid (TeA), tentoxin (TEN), altertoxin-I (ATX-I), alternariol 3-sulfate (AOH-3-S), alternariol 3-glucoside (AOH-3-G), alternariol monomethyl ether 3-sulfate (AME-3-S), and alternariol monomethyl ether 3-glucoside (AME-3-G). Six stages (grinding, turbos, decanter muds, pre-concentration, concentrate and rejection) of five independent Red Delicious and one of Granny Smith apple concentrate processes were sampled. Four out of the six processes included clarification, while two did not. The Granny Smith raw material was the least contaminated one, both in quality and quantity of Alternaria mycotoxins. Quantifiable levels of AOH, AME, TeA and TEN, were observed in the ground apples of the Red Delicious processes. Regarding the modified mycotoxins, only AME-3-S was present in the raw material; nevertheless, AOH-3-S and AOH-3-G were detected along the process. ALT, ATX-I, and AME-3-G were not detected at any stage. Clear and cloudy processes showed similar variations on mycotoxin quantities until the clarification step, in which all the mycotoxins analysed underwent a significant reduction to non-quantifiable levels. Only TeA remained at detectable levels in one of the clarified final products. The concentration in the final cloudy product increased with respect to the raw material for AOH (301%), AME (221%), TEN (872%) and TeA (1024%). This is the first report of AOH-3-S and AME-3-S in apple-by-products. The clarification stage in apple concentrate production has a relevant role in reducing Alternaria toxins to safe levels in the final products. A major risk might be associated with cloudy apple-by-products. • Alternaria mycotoxins were present in the Red Delicious apple cloudy concentrate. • This is the first report of AOH-3-S and AME-3-S in apple by-products. • The clarification step is key to reduce Alternaria toxins in the apple concentrate. • A major risk is associated with cloudy apple by-products. • Alternaria toxins are stable but can be reduced during apple concentrate process. [ABSTRACT FROM AUTHOR]

Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options. [ABSTRACT FROM AUTHOR]

Apple is a major crop in Argentina where 50% of the production is derived to by-products. Industries process either recently harvested apples or fruit stored for up to 9 months. This crop is susceptible to fungal diseases both external and internal, such as mouldy core (MC). The incidence of fungal pathogens changes during storage, as well as the risk associated with their presence since some contaminants belong to mycotoxigenic genera. The objective of this study was to characterize the fungal contaminants of Red Delicious apple fruit in Argentina evaluating their evolvement from field to process, with main interest on MC causal agents and mycotoxigenic species. A total of 240 apples were analysed; 140, recently harvested and intended for fresh consumption (C), and 100 stored for 9 months in a refrigerated chamber (0–3 °C) and destined to industrialization (I). The 86% of fresh consumption apples showed external fungal lesions, and only 14% were undamaged; MC incidence was 34%. High biodiversity was observed; Penicillium was the predominant genus (54%), followed by Alternaria spp. (41%). Only 3% of industrialization fruit were undamaged, 48% had external lesions and 51% MC. However, biodiversity was lower in these apples. Alternaria spp. was recovered from 60% of apples, mainly causing MC, while Penicillium spp. took second place (34%). All the Alternaria isolates belonged to Section Alternaria with A. tenuissima as the predominant species-group. Alternariol was synthesised by 75% of the isolates, while both alternariol monomethyl-ether and tenuazonic acid by 76%. From the 100 I apples, 93 were contaminated with at least one of these mycotoxins. Alternaria was the main causal agent of MC in Argentinean Red Delicious apples, and fruit affected by this disease might be incorporated into the process line, with a consequent risk of mycotoxin contamination in apple by-products. Effect of postharvest storage on fungal populations of apples and selection of toxigenic Alternaria species with consequent higher risk of by-products contamination. Unlabelled Image • Penicillium and Alternaria were the main spoilage genera in Argentinean apples. • Alternaria was the main causal agent of apple mouldy core in Argentina. • Apple mouldy core incidence increased after 9 months of refrigerated storage. • The Alternaria isolates causing mouldy core showed high toxigenic capacity. • The risk of processing apples contaminated with Alternaria toxins is high. [ABSTRACT FROM AUTHOR]