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Abstract The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

Background: Bone metastases (BM) are uncommon in endometrial carcinoma (EC), without information on the optimal oncologic management of patients with BM in EC. Here, we systematically review clinical characteristics, treatment approaches and prognosis in patients with BM in EC. Methods: We conducted a systematic literature search until 27th March 2022 on PubMed, MEDLINE, Embase and clinicaltrials.gov. Outcomes included treatment frequency and survival after BM with comparators being treatment approaches (local cytoreductive bone surgery, systemic therapy, and local radiotherapy). Risk of bias was assessed using the NIH Quality Assessment Tool and Navigation Guide methodology. Results: We retrieved 1096 records of which 112 retrospective studies (12 cohort studies, 12/12 fair quality; 100 case studies, 100/100 low quality) with a total of 1566 patients were included. The majority had a primary diagnosis of FIGO stage IV, grade 3 endometrioid EC. Singular BM were present in a median of 39.2%, multiple BM in 60.8% and synchronous additional distant metastases in 48.1% of patients respectively. In patients with secondary BM median time to bone recurrence was 14 months. Median survival after BM was 12 months. Local cytoreductive bone surgery was assessed in 7/13 cohorts and performed in a median of 15.8% (interquartile range [IQR] 10.3–43.0) of patients. Chemotherapy was assessed in 11/13 cohorts and administered in a median of 55.5% (IQR 41.0–63.9), hormonal therapy (7/13 cohorts) in 24.7% (IQR 16.3–36.0), and osteooncologic therapy (4/13 cohorts) in 2.7% (IQR 0.0–7.5) of patients respectively. Local radiotherapy was assessed in 9/13 cohorts and performed in a median of 66.7% (IQR 55.6–70.0) of patients. Survival benefits were seen in 2/3 cohorts after local cytoreductive bone surgery, and in 2/7 cohorts after chemotherapy without survival benefits in the remaining cohorts and investigated therapies. Limitations include the lack of controlled intervention studies, the heterogeneity and retrospective nature of the investigated populations. Conclusions: This systematic review shows heterogenous therapeutic approaches in clinical practice without clear evidence for optimal oncologic management for patients with BM in EC.

Objective: The major strengths of surgical treatment of benign prostatic hyperplasia with laser are reduced morbidity compared to endoscopic resec-tion. No studies analysed the different risk of intra/peri-opera-tive events between patients undergoing Thulium and GreenLight procedures. Materials and methods: We retrospectively reviewed 100 con-secutive cases undergoing GreenLight vaporization and Thulium procedures performed during the learning curve of two expert endoscopic surgeons. Pre-operative data, intra and post-opera-tive events at 90 days were analysed. Results: Patients on antiplatelet/anticoagulant therapy were pre-dominant in the Green group (p < 0.0001). Rates of blood trans-fusion (p < 0.0038), use of resectoscope (p < 0.0086), and tran-sient stress urinary incontinence were statistically higher in the Thulium group. On the contrary conversions to TURP (p < 0.023) were more frequent in GreenLight patients. Readmissions were more frequently necessary in GreenLight group (24%) vs. Thulium group (26.6%). The overall complica-tion rate in GreenLight and Thulium groups were 31% and 53%respectively; Clavien 3b complications were 13% in Thulium patients versus 1% in GreenLight patients. Conclusions: GreenLight and Thulium treatments show similar safety profiles. Randomized controlled trial are needed to better clarify the rate of major complications in Thulium group, and the incidence of post-operative storage symptoms in these patients’ populations.

Introduction: In the last years due to miniaturization of endoscopic instruments and percutaneous surgery, endourology has become very popular in paediatric urinary stone managment. We reported our single-centre experience in retrograde endoscopic procedures in children. Results and complications of URS/RIRS are discussed. Materials and methods: We retrospectively reviewed our experience in patients ≤ 16 years old affected by urinary stones who underwent URS/RIRS procedures performed by two surgeons with expertise in endourology. A total of 30 renal Units (RUs) underwent endoscopic procedures (URS, RIRS or both). Surgical complications according to the ClavienDindo’s classification and stone-free rate were evaluated at 3 months follow-up. Success of URS was defined as stone-free status after single procedure while RIRS success rate was considered as presence of residual stone fragments smaller than 4 mm at first procedure. Results: The mean age of our patients was 8 years, range 2- 16 years. A total of 30 renal units (RUs) underwent 40 endourological procedures (23 URS and 17 RIRS; 10 children underwent both procedures at the same time). 17/30 (56.6%) RUs were pre-stented before surgery. The stone-free status was achieved in 23/30 renal units treated, with a 76.6% success rate. The remaining 7 patients had residual stones greater than 4 mm and underwent further treatments. After a second surgery the stone-free rate turned out to be 93.3% (28/30 renal units). Conclusions: Rigid and flexible ureteroscopy (URS/RIRS) is a reliable technique for treatment of < 2 cm urinary stones in paediatric age group. It shows low rate of major complications and promising results in terms of stone-free rate.

Ewing’s sarcoma (EWS), an aggressive pediatric bone and soft-tissue sarcoma, has a very stable genome with very few genetic alterations. Unlike in most cancers, the progression of EWS appears to depend on epigenetic alterations. EWS–FLI1 and CD99, the two hallmarks of EWS, are reported to severely impact the malignancy of EWS cells, at least partly by regulating the expression of several types of non-coding RNAs. Here, we identify miR-214-3p as a common mediator of either EWS-FLI1 or CD99 by in silico analysis. MiR-214-3p expression was lower in EWS cells and in clinical samples than in bone marrow mesenchymal stem cells, and this miRNA was barely expressed in metastatic lesions. Silencing of EWS-FLI1 or CD99 restored the expression of miR-214-3p, leading to a reduced cell growth and migration. Mechanistically, miR-214-3p restoration inhibits the expression of the high-mobility group AT-hook 1 (HMGA1) protein, a validated target of miR-214-3p and a major regulator of the transcriptional machinery. The decrease in HMGA1 expression reduced the growth and the migration of EWS cells. Taken together, our results support that the miR-214-3p is constitutively repressed by both EWS-FLI1 and CD99 because it acts as an oncosuppressor limiting the dissemination of EWS cells.

Background: Plaque composition may predict the evolution of carotid artery stenosis rather than its sole extent. The grey scale median (GSM) value is a reproducible and standardized value to report plaque echogenicity as an indirect measure of its composition. We monitored plaque composition in asymptomatic subcritical carotid stenosis and evaluated the effect of an oral modulating calcification factor (vitamin K2). Methods: Carotid plaque composition was assessed by GSM value. Monitoring the effects of standard therapy (acetylsalicylic acid and low–medium dosage statin) (acetylsalicylic acid (ASA) arm) or standard therapy plus vitamins K2 oral supplementation (ASA + K2 arm) over a 12 months period was conducted using an ultrasound scan in a prospective, open-label, randomized controlled trial (PLAK2). Results: Sixty patients on low–medium dosage statin therapy were enrolled and randomized (30 per arm) to either ASA + K2 or ASA alone. Thirty-seven patients (61.6%) showed at 12 months a stable plaque with a mean increase in the GSM value in respect to the baseline of 2.6% with no differences between the two study arms (p = 0.66). Fifteen patients (25%) showed an 8% GSM value reduction respect the baseline with no differences between the two study arms (p = 0.99). At multivariable analysis, the adjusted mean (95% confidence interval) GSM change per month from baseline was greater in the ASA + K2 arm (−0.55 points, p = 0.048) compared to ASA alone (−0.18 points, p = 0.529). Conclusions: Carotid plaque composition monitoring through GSM value represents a laborious procedure. Although its use may not be applied to everyday practice, a specific application consists in evaluating the effect of pharmacological therapy on plaque composition. This 12 months randomized trial showed that the majority of subcritical asymptomatic carotid plaque on treatment with low–medium dosage statin presented a stable or increased echogenicity. Although vitamin K2 beyond standard therapy did not determine a significant change in plaque composition, for those who presented with GSM reduction it did enhance a GSM monthly decline.

Placental dysfunction is involved in a group of obstetrical conditions including preeclampsia, intrauterine growth restriction, and placental abruption. Their timely and accurate recognition is often a challenge since diagnostic criteria are still based on nonspecific signs and symptoms. The discovering of the role of angiogenic-related factors (sFlt-1/PlGF) in the underlying pathophysiology of placental dysfunction, taking into account that angiogenesis-related biomarkers are not specific to any particular placental insufficiency-related disease, has marked an important step for improving their early diagnosis and prognosis assessment. However, sFlt-1/PlGF has not been yet established as a part of most guidelines. We will review the current evidence on the clinical utility of sFlt-1/PlGF and propose a new protocol for its clinical integration.

Multiple Sclerosis patients run an increased risk of microbial infections, which leads to high rates of hospitalization and infection-related mortality. Although immunotherapy may increase infection risk in some cases, data as to the relationship among microbial factors, immunotherapy and alterations in the innate immunity of these patients are still scanty. On these grounds, this interdisciplinary study aims at investigating the role the functional activity of polymorphonuclear cells (PMNs) play in relapsing remitting multiple sclerosis at different stages. The in vitro ability of PMNs from patients, either untreated or treated with immunosuppressant or immunomodulatory drugs to kill Klebsiella pneumonia or Candida albicans, were investigated and compared to PMNs from healthy subjects. The release of various cytokines was also assessed, as was the production of reactive oxygen species and their ability to regulate apoptosis after microbial stimulation. Our results indicate that although patients have a normal number of PMNs, they have a statistically significant (p

Fifteen mature crossbred sheep were fed different daily amounts (2.5-35g kg-1 bw) of the fresh green leaves of Ateleia glazioviana for different periods of time (1-24 days). One sheep was not fed the plant and served as a control. All 16 sheep were euthanatized at different stages of the experiment, necropsied, and several organs, including heart and brain were evaluated histologically. Samples of five brain regions from three affected sheep were evaluated by electron microscopy. Clinical signs observed in three sheep included depression, anorexia, general weakness, staggering gait and prolonged recumbency. One sheep had signs of congestive heart failure. Necropsy findings included subcutaneous dependent edema and edema of the body cavities in two sheep and nutmeg liver in one. Histopathological findings included degeneration, necrosis and interstitial fibrosis in the myocardium of four sheep and vacuolation of cerebral white matter (spongy degeneration, status spongiosus) in 10 sheep, although this latter change were marked only in two of those 10. The ultrastructure of the brain lesion was morphologically consistent with that found in diseases grouped as spongiform myelinopathies in which vacuolation of the myelin occurs in the absence of significant myelin breakdown or phagocytosis. The morphology and pathogenesis of the chronic cardiomyopathy and of the cerebral spongy degeneration in affected sheep in this experiment are discussed and compared with other similar conditions in domestic ruminants.Quinze ovinos mestiços adultos receberam quantidades variáveis (2,5-35g kg-1 pv), por via oral, das folhas verdes frescas de Ateleia glazioviana durante períodos de tempo que variaram de 1 a 24 dias. Um ovino não recebeu a planta e serviu como controle. Todos os 16 ovinos foram submetidos à eutanásia em diferentes estágios do experimento, necropsiados, e vários órgãos, incluindo coração e encéfalo, foram avaliados histologicamente. Fragmentos de cinco regiões do encéfalo de três ovinos afetados foram avaliados por microscopia eletrônica. Sinais clínicos observados em três ovinos incluíam depressão, anorexia, fraqueza geral, andar vacilante e decúbito prolongado. Um ovino apresentou sinais de insuficiência cardíaca congestiva. Achados de necropsia incluíram edema subcutâneo de declive e das cavidades orgânicas em dois ovinos e fígado de noz-moscada em umdeles. Achados histopatológicos incluíram necrose e fibrose intersticial no miocárdio de quatro ovinos e vacuolização da substância branca (degeneração esponjosa, status spongiosus) em 10 ovinos, embora essa última alteração fosse acentuada em apenas dois ovinos. A ultra-estrutura das lesões encefálicas foi morfologicamente consistente com o que é descrito em um grupo de doenças conhecidas como mielinopatias espongiformes nas quais a vacuolização da mielina ocorre na ausência de degradação significativa da mielina ou fagocitose. A morfologia e patogênese da miocardiopatia crônica e da degeneração esponjosa encefálica nos ovinos deste experimento são discutidas e comparadas com outras condições semelhantes em animais domésticos.

Ten outbreaks of anthrax occurred in cattle from 1978 to 2006 in southern Brazil, in 5 municipalities on the border with Uruguay, a country where the disease is frequent. The 10 outbreaks represented 0.2% of all bovine specimens received during the period by the Regional Diagnostic Laboratory of the Federal University of Pelotas, causing 267 deaths in a risk population of 6,605 head. The disease affected young and adult cattle mainly during summer. Only one farmer reported that sheep and horses were also affected. Clinically the peracute form was more frequent, but in some outbreaks the acute form with a clinical manifestation period of 6-48 hours was also observed. The source of infection was not established; but the reduced rainfall, associated with low, flat, flooded lands used for agriculture followed by animal grazing after harvest was probably related to the disease occurrence. Annual vaccination is an efficient way to prevent the disease.Foi realizado um estudo retrospectivo da ocorrência de carbúnculo hemático em bovinos na área de influência do Laboratório Regional de Diagnóstico (LRD) da Faculdade de Veterinária da Universidade Federal de Pelotas. Entre 1978 e março de 2006, dez surtos da enfermidade ocorreram em cinco municípios da região sul do Rio Grande do Sul, todos localizados na fronteira com o Uruguai. A enfermidade representou 0,2% dos diagnósticos realizados no LRD no período. Ocorre em bovinos jovens e adultos, principalmente em verões quentes e secos, e com menor freqüência em outras épocas do ano. Freqüentemente, a doença se apresenta na forma hiperaguda, entretanto casos de carbúnculo hemático agudo podem ser observados. Não foi possível estabelecer a origem das infecções, mas precipitações pluviométricas menores que as normais, em campos planos, sujeitos a alagamentos freqüentes, utilizados para plantio e posterior uso das restevas (restolhos) para a criação dos animais podem ter favorecido a ocorrência dos surtos. A prática da vacinação anual dos animais é a forma de evitar eficientemente os surtos da doença.

Tra il 1820 e il 1920 immigrarono in America circa 35 milioni di persone (Renshaw 3), la stragrande maggioranza delle quali era entrata nel mondo del lavoro da unskilled, vale a dire senza una qualifica specifica. In questo periodo, infatti, l’industria americana si stava ristrutturando aumentando le sue dimensioni e impiegando nuovi macchinari fino ad allora sconosciuti, che rendevano inutili le competenze degli operai specializzati. Iniziava così a formarsi una forza lavoro senza differenziazioni, senza nessun controllo sulla produzione e facilmente rimpiazzabile. Le molteplici nazionalità erano molto spesso causa di tensioni che frammentavano ulteriormente la classe operaia privandola così di qualsiasi potere contrattuale.

ABSTRACT: Equine pythiosis is an ulcerative and granulomatous disease of the skin, caused by the oomycete Pythium insidiosum (Pythiaceae). The objective of this study was to describe seven cases of equine pythiosis that occurred from 2012 to 2017 in the eastern region of Uruguay. Six of the seven cases occurred in the eastern wetland ecosystems of the Merin basin, and the remaining case occurred in the wetland fluvial plains of the Tacuarembó River. Lesions consisted of a large, rapidly growing ulcerated tumor with abundant granulation tissue, serosanguineous secretion, and fistulous tracts containing large concretions or kunkers. The animals presented intense pruritus, claudication and loss of body condition, with death or euthanasia in extremis in six cases. The main histological lesions consisted of an eosinophilic and pyogranulomatous inflammatory process, with numerous foci of eosinophilic necrosis (kunkers), collagenolysis, and a Splendore-Hoeppli reaction. In all cases, silver coloration (Grocott) showed intralesional hyphae compatible with P. insidiosum, which was confirmed by immunohistochemistry in three cases. A horse in the terminal phase of the disease was treated with triamcinolone acetonide (50mg IM every 15 days), and fully recovered after 1 year. It is concluded that equine pythiosis is prevalent in the wetland ecosystems of eastern Uruguay and that treatment with triamcinolone is auspicious.

Hepatocellular carcinoma is the most prevalent primary liver tumor and is among the top ten cancer that affect the world population. Its development is related, in most cases, to the existence of chronic liver injury, such as in cirrhosis. The knowledge about the correlation between chronic inflammation and cancer has driven new researches with anti-inflammatory agents that have potential for the development of antitumor drugs. Gallic acid is a phenolic acid found in many natural products and have shown anti-inflammatory, anti-tumor, anti-mutagenic and antioxidant actions. The purpose of this study was to investigate the effect of gallic acid on acute and chronic cell proliferation and inflammatory parameters of hepatocellular carcinoma cells (HepG2), as well as to investigate the mechanisms involved. Results showed that the gallic acid decreased the proliferation of HepG2 cells in a dose-dependent manner (Trypan blue exclusion assay), without causing necrosis (LDH assay). We observed a significant increase in the percentage of small and regular nuclei (Nuclear Morphometric Analysis assay), a significant induction of apoptosis by Annexin V-FITC and PI assay and no interference with the cell cycle using the FITC BrdU Flow Kit. We observed a significant reduction in the levels of IL-8 and increased levels of IL-10 and IL-12 (Cytometric Bead Array Human Inflammation Assay). Furthermore, gallic acid caused no cancer cells regrowth at a long term (Cumulative Population Doubling assay). According to these results, gallic acid showed a strong potential as an anti-tumor agent in hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]