The use of dynamic probing tests and cone penetration tests to verify the effectiveness of expanding polyurethane resin injections for ground improvement

Injection of expanding polyurethane resins is a popular method to improve both the stiffness and the shear strength of the ground below existing foundations. The effect of the polyurethane resin expansion is to increase the soil confining stress and density around the injection holes. An estimation of the horizontal stress and volumetric strain changes that are induced within the ground is derived from the theory of cavity expansion in elasto-plastic materials. A series of case-histories is presented to document the feasibility of different in-situ tests to evaluate the achieved ground improvement. The tests have been performed before and after the injection of polyurethane resins and the obtained results have been compared with theoretical predictions. The considered investigation methods include the dynamic probing tests and the cone penetration tests. The preliminary results that have been achieved using an experimental miniature cone penetration test are also illustrated. The advantages and limitations of different test methods are discussed and practical indications for conducting such verifications of polyurethane resin injection effectiveness are provided

Coagulation factor X promotes resistance to androgen-deprivation therapy in prostate cancer

Although hypercoagulability is commonly associated with malignancies, whether coagulation factors directly affect tumor cell proliferation remains unclear. Herein, by performing single-cell RNA sequencing (scRNA-seq) of the prostate tumor microenvironment (TME) of mouse models of castration-resistant prostate cancer (CRPC), we report that immunosuppressive neutrophils (PMN-MDSCs) are a key extra-hepatic source of coagulation factor X (FX). FX activation within the TME enhances androgen-independent tumor growth by activating the protease-activated receptor 2 (PAR2) and the phosphorylation of ERK1/2 in tumor cells. Genetic and pharmacological inhibition of factor Xa (FXa) antagonizes the oncogenic activity of PMN-MDSCs, reduces tumor progression, and synergizes with enzalutamide therapy. Intriguingly, F10$^{high}$ PMN-MDSCs express the surface marker CD84 and CD84 ligation enhances F10 expression. Elevated levels of FX, CD84, and PAR2 in prostate tumors associate with worse survival in CRPC patients. This study provides evidence that FXa directly promotes cancer and highlights additional targets for PMN-MDSCs for cancer therapies

National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy

BACKGROUND: We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period. METHODS: Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs. RESULTS: We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0-75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were SCN1A (16%), followed by KCNQ2 (5.6%) and SCN2A (5%). CONCLUSION: Our study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies

AML1/ETO Oncoprotein Is Directed to AML1 Binding Regions and Co-Localizes with AML1 and HEB on Its Targets

A reciprocal translocation involving chromosomes 8 and 21 generates the AML1/ETO oncogenic transcription factor that initiates acute myeloid leukemia by recruiting co-repressor complexes to DNA. AML1/ETO interferes with the function of its wild-type counterpart, AML1, by directly targeting AML1 binding sites. However, transcriptional regulation determined by AML1/ETO probably relies on a more complex network, since the fusion protein has been shown to interact with a number of other transcription factors, in particular E-proteins, and may therefore target other sites on DNA. Genome-wide chromatin immunoprecipitation and expression profiling were exploited to identify AML1/ETO-dependent transcriptional regulation. AML1/ETO was found to co-localize with AML1, demonstrating that the fusion protein follows the binding pattern of the wild-type protein but does not function primarily by displacing it. The DNA binding profile of the E-protein HEB was grossly rearranged upon expression of AML1/ETO, and the fusion protein was found to co-localize with both AML1 and HEB on many of its regulated targets. Furthermore, the level of HEB protein was increased in both primary cells and cell lines expressing AML1/ETO. Our results suggest a major role for the functional interaction of AML1/ETO with AML1 and HEB in transcriptional regulation determined by the fusion protein

The acute phase management of spinal cord injury affecting polytrauma patients: the ASAP study

Background: Few data on the management of acute phase of traumatic spinal cord injury (tSCI) in patients suffering polytrauma are available. As the therapeutic choices in the first hours may have a deep impact on outcome of tSCI patients, we conducted an international survey investigating this topic. Methods: The survey was composed of 29 items. The main endpoints of the survey were to examine: (1) the hemodynamic and respiratory management, (2) the coagulation management, (3) the timing of magnetic resonance imaging (MRI) and spinal surgery, (4) the use of corticosteroid therapy, (5) the role of intraspinal pressure (ISP)/spinal cord perfusion pressure (SCPP) monitoring and (6) the utilization of therapeutic hypothermia. Results: There were 171 respondents from 139 centers worldwide. A target mean arterial pressure (MAP) target of 80–90 mmHg was chosen in almost half of the cases [n = 84 (49.1%)]. A temporary reduction in the target MAP, for the time strictly necessary to achieve bleeding control in polytrauma, was accepted by most respondents [n = 100 (58.5%)]. Sixty-one respondents (35.7%) considered acceptable a hemoglobin (Hb) level of 7 g/dl in tSCI polytraumatized patients. An arterial partial pressure of oxygen (PaO2) of 80–100 mmHg [n = 94 (55%)] and an arterial partial pressure of carbon dioxide (PaCO2) of 35–40 mmHg [n = 130 (76%)] were chosen in most cases. A little more than half of respondents considered safe a platelet (PLT) count > 100.000/mm3 [n = 99 (57.9%)] and prothrombin time (PT)/activated partial thromboplastin time (aPTT) < 1.5 times the normal control [n = 85 (49.7%)] in patients needing spinal surgery. MRI [n = 160 (93.6%)] and spinal surgery [n = 158 (92.4%)] should be performed after intracranial, hemodynamic, and respiratory stabilization by most respondents. Corticosteroids [n = 103 (60.2%)], ISP/SCPP monitoring [n = 148 (86.5%)], and therapeutic hypothermia [n = 137 (80%)] were not utilized by most respondents. Conclusions: Our survey has shown a great worldwide variability in clinical practices for acute phase management of tSCI patients with polytrauma. These findings can be helpful to define future research in order to optimize the care of patients suffering tSCI

The acute phase management of spinal cord injury affecting polytrauma patients : the ASAP study

Publisher Copyright: © 2022, The Author(s).Background: Few data on the management of acute phase of traumatic spinal cord injury (tSCI) in patients suffering polytrauma are available. As the therapeutic choices in the first hours may have a deep impact on outcome of tSCI patients, we conducted an international survey investigating this topic. Methods: The survey was composed of 29 items. The main endpoints of the survey were to examine: (1) the hemodynamic and respiratory management, (2) the coagulation management, (3) the timing of magnetic resonance imaging (MRI) and spinal surgery, (4) the use of corticosteroid therapy, (5) the role of intraspinal pressure (ISP)/spinal cord perfusion pressure (SCPP) monitoring and (6) the utilization of therapeutic hypothermia. Results: There were 171 respondents from 139 centers worldwide. A target mean arterial pressure (MAP) target of 80–90 mmHg was chosen in almost half of the cases [n = 84 (49.1%)]. A temporary reduction in the target MAP, for the time strictly necessary to achieve bleeding control in polytrauma, was accepted by most respondents [n = 100 (58.5%)]. Sixty-one respondents (35.7%) considered acceptable a hemoglobin (Hb) level of 7 g/dl in tSCI polytraumatized patients. An arterial partial pressure of oxygen (PaO2) of 80–100 mmHg [n = 94 (55%)] and an arterial partial pressure of carbon dioxide (PaCO2) of 35–40 mmHg [n = 130 (76%)] were chosen in most cases. A little more than half of respondents considered safe a platelet (PLT) count > 100.000/mm3 [n = 99 (57.9%)] and prothrombin time (PT)/activated partial thromboplastin time (aPTT) < 1.5 times the normal control [n = 85 (49.7%)] in patients needing spinal surgery. MRI [n = 160 (93.6%)] and spinal surgery [n = 158 (92.4%)] should be performed after intracranial, hemodynamic, and respiratory stabilization by most respondents. Corticosteroids [n = 103 (60.2%)], ISP/SCPP monitoring [n = 148 (86.5%)], and therapeutic hypothermia [n = 137 (80%)] were not utilized by most respondents. Conclusions: Our survey has shown a great worldwide variability in clinical practices for acute phase management of tSCI patients with polytrauma. These findings can be helpful to define future research in order to optimize the care of patients suffering tSCI.Peer reviewe

B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements

The B cell receptor (BCR) is critical for mature B cell lymphomas, serving as a therapeutic target. We show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) differ from IGH+ counterparts in germinal center-zone programs, MYC expression, and immune infiltrate. While IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IGH isotype switching and IG-Lambda rearrangements. IGHUND lymphomas retain productive IGHV rearrangements and require IGH for optimal fitness. BCR silencing, caused by accelerated IGH turnover and reduced IGH expression, precedes HGBCL-DH-BCL2 onset, inducing RAG1/2-dependent IG light chain editing and facilitating t(8;22)/IGL::MYC translocations. IGHUND HGBCL-DH-BCL2 models exhibit reduced sensitivity to the CD79B-targeting antibody-drug conjugate Polatuzumab-vedotin. Collectively, HGBCL-DH-BCL2 commonly arises from isotype-switched t(14;18)+ germinal center B cells, which edit IG light chains, fueling intra-clonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Non-AIDS defining cancers in the D:A:D Study - time trends and predictors of survival : A cohort study

Background: Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.Methods: Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.Results: Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.Conclusions: The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC. © 2013 Worm et al.; licensee BioMed Central Ltd