Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry

The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype.     

The DNA of murine sarcoma-leukemia virus

A DNA wih a sedimentation coefficient of 7 S (ρc_s2so₄: = 1.423) was isolated from DNase- and RNase-treated purified virions of each of three different oncogenic RNA viruses: murine sarcoma virus, Rauscher murine leukemia virus, and avian myeloblastosis virus. The naturally occurring DNA of murine sarcoma virus constituted about 2.5% of the total viral nucleic acid and resolved into two components (ρ = 1.698 and ρ = 1.678) when centrifuged to equilibrium in a CsCl density gradient. The viral DNA was complementary to the 18 S viral RNA subunit, but not to the 37 S or 4 S subunits.     

MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells

The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors.     

Adverse events related to the new psychoactive substance 3-fluorophenmetrazine – results from the Swedish STRIDA project

Background: New psychoactive substances (NPS) are often poorly pharmacologically documented and the production is unregulated, implying high risks for toxic side effects. This report from the STRIDA project describes analytically confirmed non-fatal intoxications involving the phenmetrazine analogue 3-fluorophenmetrazine (3-FPM).

Study design and methods: Observational case series of patients with suspected acute NPS exposure requiring hospital care. Blood and urine samples were collected from patients presenting in emergency departments (ED) or intensive care units (ICU), after consultation with the Swedish Poisons Information Centre (PIC). Laboratory analysis was performed by multi-component liquid chromatography–mass spectrometry. Clinical data were collected during PIC consultations and retrieved from medical records.

Results: From November 2014 to October 2015, eight cases were registered as 3-FPM or “phenmetrazine” intoxications at the PIC after consultation. During the same period, analysis of STRIDA project samples confirmed 3-FPM use in a total of 19 patients (84% men) aged 22–54 (median 30) years. 3-FPM was detected in 15 out of 19 serum (2.7–1416?ng/mL) and in 14 out of 14 urine (1.0–6857?μg/mmol creatinine) samples. All patients were also tested positive for other psychoactive substances, with benzodiazepines being most common (57% of the cases). Ten patients were monitored in the ED for <4?h, while six needed ICU monitoring of which five were graded as severe intoxications (Poisoning Severity Score 3). Prominent clinical signs were tachycardia (47%), depressed consciousness (42%), agitation/anxiety (37%), delirium (37%), dilated pupils (26%), and seizures (16%). All patients survived.

Conclusion: In 19 patients testing positive for 3-FPM, a high incidence of severe clinical features was demonstrated. However, as all patients had also used other psychoactive substances, it was difficult to identify a unique toxidrome for 3-FPM. The results further showed that many 3-FPM intoxications would have been missed, if relying solely on information from PIC consultations. These results emphasize the importance of performing bioanalytical investigation in cases of suspected NPS intoxication.     

Superiority of Higher-Volume Fresh Feces Compared to Lower-Volume Frozen Feces in Fecal Microbiota Transplantation for Recurrent Clostridioides Difficile Colitis

Digestive Diseases and Sciences - To compare the clinical outcomes of different protocols for fecal microbiota transplantation (FMT) in two community hospitals with similar patient demographics....     

Characterizing patient-oncologist communication in genomic tumor testing: The 21-gene recurrence score as an exemplar

ObjectiveWomen with early-stage, ER + breast cancer are recommend to receive genomic profiling tests, such as the 21-gene Recurrence Score (RS) test, to guide treatment decisions. We examined test- and treatment-related information discussed and the associations between RS categories and aspects of communication during patient-oncologist clinical encounters.MethodsAs part of a larger trial, clinical encounters (N = 46) were audiorecorded and coded for 1) RS- and treatment-related information, 2) shared decision making, 3) patient active participation, and 4) oncologist patient-centered communication. We examined differences by RS category using mixed models, adjusting for nesting within oncologist.ResultsPatients with a high RS were more likely to receive a chemotherapy recommendation (p < .01), hear about the risks/side effects of chemotherapy (p < .01), and offer their preferences (p = .02) than those with intermediate or low RS. Elements of shared decision making increased with RS. Oncologist patient-centered communication (M = 4.09/5, SD = .25) and patient active participation (M = 3.5/4, SD = 1.0) were high across RS.ConclusionFindings suggest that disease severity, rather than clinical uncertainty, impact treatment recommendations and shared decision making.Practice implicationsOncologists adjust test- and treatment-related information and shared decision making by disease severity. This information provides a framework to inform decision making in complex cancer and genomics settings.     

ACTN3's R577X Single Nucleotide Polymorphism Allele Distribution Differs Significantly in Professional Football Players according to Their Field Position

IntroductionFootball is characterised by intermittent high-intensity efforts varying according to the field position of a player. We aimed to ascertain whether polymorphisms in the ACTN3 gene are associated with different playing positions in elite professional football players.Subjects and MethodsGenotyping of the ACTN3 gene was conducted in 43 elite professional football players of a single team. Playing position was recorded based on the player''s most frequent position.ResultsThe genotype distribution was not significant between positions (p = 0.057), while the allele distribution differed significantly (p = 0.035). Goalkeepers (p = 0.04, p = 0.03), central defenders (p = 0.03, p = 0.01), and central midfielders (p = 0.01, p = 0.00) had a significantly different allele distribution compared with wide midfielders and forward players.ConclusionsGenetic biomarkers may be important when analysing performance capability in elite professional football. Identifying the genetic characteristics of a player to adapt his playing position may lead to orientation of positions based on physical capabilities and tissue quality in young football players, and also to performance enhancement in those who are already playing in professional teams.     

COMPLEMENTARY NUCLEAR RNA''S OF MURINE SARCOMA-LEUKEMIA VIRUS COMPLEX IN TRANSFORMED CELLS

The high molecular weight RNA (S(20,w) = 69S) of murine sarcomaleukemia virus (MSV-MLV) complex dissociated into 37S subunits when heated to 95 degrees C for 2 minutes. Specific annealing tests revealed that the viral RNA had complementarity with two heterogeneous RNA species from the nuclei of cells (78 A1) transformed by and chronically infected with this virus complex. The two nuclear RNA species that hybridized with the viral RNA had sedimentation constants ranging from 31-36S and 18-22S, respectively. There was no specific annealing between viral RNA and the cytoplasmic RNA of the 78 A1 cells. The detection of the complementary RNA strands of MSV-MLV suggests that this oncogenic virus complex may replicate in a fashion similar to that of the non-oncogenic RNA viruses, but may differ in that the complementary strands are found in the nucleus rather than in the cytoplasm of the transformed cells.