We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC ...expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II-deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of
mutations in both MHC-I- and MHC-II-negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant
. Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in
-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming. SIGNIFICANCE: We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin-specific context. Specifically,
mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination.
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This is the first introductory textbook on Spin, the only requirement is a background in programming. Spin models are written in the Promela language which is easily learned by students and ...programmers. Spin is easy to install and use.
A pump coupled to a conserved density generates long-range modulations, resulting from the non-equilibrium nature of the dynamics. We study how these modulations are modified at the critical point ...where the system exhibits intrinsic long-range correlations. To do so, we consider a pump in a diffusive fluid, which is known to generate a density profile in the form of an electric dipole potential and a current in the form of a dipolar field above the critical point. We demonstrate that while the current retains its form at the critical point, the density profile changes drastically. At criticality, in d<4 dimensions, the deviation of the density from the average is given by sgncos(θ)|cos(θ)/r^{(d-1)}|^{1/δ} at large distance r from the pump and angle θ with respect to the pump's orientation. At short distances, there is a crossover to a cos(θ)/r^{d-3+η} profile. Here δ and η are Ising critical exponents. The effect of the local pump on the domain wall structure below the critical point is also considered.
This is open access book provides plenty of pleasant mathematical surprises. There are many fascinating results that do not appear in textbooks although they are accessible with a good knowledge of ...secondary-school mathematics. This book presents a selection of these topics including the mathematical formalization of origami, construction with straightedge and compass (and other instruments), the five- and six-color theorems, a taste of Ramsey theory and little-known theorems proved by induction. Among the most surprising theorems are the Mohr-Mascheroni theorem that a compass alone can perform all the classical constructions with straightedge and compass, and Steiner's theorem that a straightedge alone is sufficient provided that a single circle is given. The highlight of the book is a detailed presentation of Gauss's purely algebraic proof that a regular heptadecagon (a regular polygon with seventeen sides) can be constructed with straightedge and compass. Although the mathematics used in the book is elementary (Euclidean and analytic geometry, algebra, trigonometry), students in secondary schools and colleges, teachers, and other interested readers will relish the opportunity to confront the challenge of understanding these surprising theorems.
•The decrease in pediatric trauma cases necessitating immediate surgery facilitates the optimization of surgical resource allocation.•The study aimed to create a decision support tool to rapidly ...identify children unlikely to need emergency surgery upon hospital arrival.•Among children with blunt trauma mechanism, normal GCS, and low-risk heart rate, only 0.02 % required emergent surgery.•A limited set of physiological parameters available at hospital admission can effectively identify children at a low risk for emergent surgery.
The number of pediatric trauma patients requiring surgical interventions has been steadily decreasing allowing for a judicious approach to immediately available resources. This study aimed to derive and validate a prediction rule that reliably identifies injured children who are at very low risk for requiring emergency surgery upon emergency department (ED) arrival.
A retrospective cohort study of data included in the Israeli National Trauma Registry from January 1, 2011, through December 31, 2020, was conducted. We included children aged 0–14 years who presented to EDs from the scene of injury and were hospitalized. We excluded patients transferred between facilities or with isolated burns. The primary outcome was emergency operative intervention (EOI) performed within one hour of ED arrival. We tested mechanism, GCS, heart rate, and blood pressure as candidate predictors. We then randomized patients to two cohorts, derived and internally validated a prediction rule.
During the study period, 83,859 children met enrollment criteria. The median age was 6 years (IQR 2–10) and 56,867 (67.8 %) were male; 75,450 (90.0 %) sustained blunt trauma. One hundred sixty-nine (0.20 %) children underwent EOI. In the derivation and validation cohorts, 34,138 (81.4 %) and 34,271 (81.7 %) patients, were classified as low risk based on blunt trauma mechanism, normal GCS (15), and low-risk heart rate (according to age). Of those, 8 (0.02 %) and 13 (0.04 %) required an EOI, respectively. In the validation cohort, the prediction rule for EOI had a sensitivity of 84 % (95 % CI 75–91), a specificity of 82 % (95 % CI 81–82), and a negative predictive value of 99.96 % (95 % CI 99.94–99.98). Among children with an Injury Severity Score>15, the sensitivity was 87 % (95 % CI 77–94), the specificity of 57 % (95 % CI 54–59), and the negative predictive value was 98.97 % (95 % CI 98.13–99.44).
A limited set of physiologic parameters, readily available at hospital admission can effectively identify injured children at very low risk for emergent surgery. For these children, immediate deployment of surgical resources may not be necessary.
PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma ...(DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.
Current guidelines advocate prehospital endotracheal intubation (ETI) in patients with suspected severe head injury and impaired level of consciousness. However, the ability to identify patients with ...traumatic brain injury (TBI) in the prehospital setting is limited and prehospital ETI carries a high complication rate. We investigated the prevalence of significant TBI among patients intubated in the field for that reason.
Data were retrospectively collected from emergency medical services and hospital records of trauma patients for whom prehospital ETI was attempted and who were transferred to Rambam Health Care Campus, Israel. The indication for ETI was extracted. The primary outcome was significant TBI (clinical or radiographic) among patients intubated due to suspected severe head trauma.
In 57.3% (379/662) of the trauma patients, ETI was attempted due to impaired consciousness. 349 patients were included in the final analysis: 82.8% were male, the median age was 34 years (IQR 23.0–57.3), and 95.7% suffered blunt trauma. 253 patients (72.5%) had significant TBI. In a multivariable analysis, Glasgow Coma Scale>8 and alcohol intoxication were associated with a lower risk of TBI with OR of 0.26 (95% CI 0.13–0.51, p < 0.001) and 0.16 (95% CI 0.06–0.46, p < 0.001), respectively.
Altered mental status in the setting of trauma is a major reason for prehospital ETI. Although most of these patients had TBI, one in four of them did not suffer a significant TBI. Patients with a higher field GCS and those suffering from intoxication have a higher risk of misdiagnosis. Future studies should explore better tools for prehospital assessment of TBI and ways to better define and characterize patients who may benefit from early ETI.
Background
Prehospital endotracheal intubation (PEI) of head injured children with impaired level of consciousness (LOC) aims to minimize secondary brain injury. However, PEI is controversial in ...otherwise stable children. We aimed to investigate the indications for PEI among pediatric trauma patients and the prevalence of clinically significant traumatic brain injury (csTBI) among those intubated solely due to impaired consciousness.
Methods
This is a multicenter retrospective cohort study of children who underwent PEI in northern Israel between January 2014 and December 2020 by six EMS agencies and were transported to two trauma centers in the area. We extracted data from EMS records and trauma registries.
Results
PEI was attempted in 179/986 (18.2%) patients and was successful in 92.2% of cases. Common indications for PEI were hypoxemia not corrected by supplemental oxygen (
n
= 30), traumatic cardiac arrest (
n
= 16), and facial injury compromising the airway (
n
= 13). 112 patients (62.6%) were intubated solely due to impaired or deteriorating LOC. Among these patients, 68 (62.4%) suffered csTBI. The prevalence of csTBI among those with field Glasgow Coma Scale (GCS) of 3, 4–8, and > 8 was 81.4%, 55.8%, and 28.6%, respectively (
p
< 0.001). Among children ≤ 10 years old intubated due to impaired LOC, 50% had csTBI.
Conclusion
Impaired LOC is a major indication for PEI. However, a significant proportion of these patients do not suffer csTBI. Older age and lower pre-intubation GCS are associated with more accurate field classification. Our data indicate that further investigation and better characterization of patients who may benefit from PEI is necessary.
Accelerating international trade and climate change make pathogen spread an increasing concern. Hymenoscyphus fraxineus, the causal agent of ash dieback, is a fungal pathogen that has been moving ...across continents and hosts from Asian to European ash. Most European common ash trees (Fraxinus excelsior) are highly susceptible to H. fraxineus, although a minority (~5%) have partial resistance to dieback. Here, we assemble and annotate a H. fraxineus draft genome, which approaches chromosome scale. Pathogen genetic diversity across Europe and in Japan, reveals a strong bottleneck in Europe, though a signal of adaptive diversity remains in key host interaction genes. We find that the European population was founded by two divergent haploid individuals. Divergence between these haplotypes represents the ancestral polymorphism within a large source population. Subsequent introduction from this source would greatly increase adaptive potential of the pathogen. Thus, further introgression of H. fraxineus into Europe represents a potential threat and Europe-wide biological security measures are needed to manage this disease.
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