A 48-year-old woman presented with a 3-day history of fatigue and abdominal pain 2 weeks after receiving the Ad26.COV2.S vaccine. She had a low platelet count and was found to have cerebral venous ...sinus thrombosis and clots in the right hepatic and splenic veins. Testing for antibody to PF4–polyanion was positive.
BRAF inhibitor therapy may provide profound initial tumor regression in metastatic melanoma with BRAF V600 mutations, but treatment resistance often leads to disease progression. A multi-center ...analysis of BRAF inhibitor resistant patient tissue samples detected genomic changes after disease progression including multiple secondary mutations in the MAPK/Erk signaling pathway, mutant BRAF copy number gains, and BRAF alternative splicing as the predominant putative mechanisms of resistance, but 41.7% of samples had no known resistance drivers.
models of BRAF inhibitor resistance have been developed under a wide variety of experimental conditions to investigate unknown drivers of resistance. Several
models developed genetic alterations observed in patient tissue, but others modulate the response to BRAF inhibitors through increased expression of receptor tyrosine kinases. Both secondary genetic alterations and expression changes in receptor tyrosine kinases may increase activation of MAPK/Erk signaling in the presence of BRAF inhibitors as well as activate PI3K/Akt signaling to support continued growth. Melanoma cells that develop resistance
may have increased dependence on serine or glutamine metabolism and have increased cell motility and metastatic capacity. Future studies of BRAF inhibitor resistance
would benefit from adhering to experimental parameters that reflect development of BRAF inhibitor resistance in patients through using multiple cell lines, fully characterizing the dosing strategy, and reporting the fold change in drug sensitivity.
Abstract
Objectives
To establish the optimal parameters for group testing of pooled specimens for the detection of SARS-CoV-2.
Methods
The most efficient pool size was determined to be five specimens ...using a web-based application. From this analysis, 25 experimental pools were created using 50 µL from one SARS-CoV-2 positive nasopharyngeal specimen mixed with 4 negative patient specimens (50 µL each) for a total volume of 250 µL. Viral RNA was subsequently extracted from each pool and tested using the CDC SARS-CoV-2 RT-PCR assay. Positive pools were consequently split into individual specimens and tested by extraction and PCR. This method was also tested on an unselected group of 60 nasopharyngeal specimens grouped into 12 pools.
Results
All 25 pools were positive with cycle threshold (Ct) values within 0 and 5.03 Ct of the original individual specimens. The analysis of 60 specimens determined that 2 pools were positive followed by identification of 2 individual specimens among the 60 tested. This testing was accomplished while using 22 extractions/PCR tests, a savings of 38 reactions.
Conclusions
When the incidence rate of SARS-CoV-2 infection is 10% or less, group testing will result in the saving of reagents and personnel time with an overall increase in testing capability of at least 69%.
Revisiting Ebola: Lessons learned from the 2014–2015 Koepsell, Scott A.; Fitts, Eric Charles; Roback, John D.
Transfusion (Philadelphia, Pa.),
February 2023, 2023-02-00, 20230201, Letnik:
63, Številka:
2
Journal Article
Myeloid-derived suppressor cells (MDSCs) are pathologically activated immature myeloid cells with immunosuppressive activity that expand during chronic inflammation, such as cancer and prosthetic ...joint infection (PJI). Myeloid-derived suppressor cells can be broadly separated into 2 populations based on surface marker expression and function: monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic myeloid-derived suppressor cells (G-MDSCs). Granulocytic myeloid-derived suppressor cells are the most abundant leukocyte infiltrate during PJI; however, how this population is maintained in vivo and cellular heterogeneity is currently unknown. In this study, we identified a previously unknown population of Ly6G+Ly6C+F4/80+MHCII+ MDSCs during PJI that displayed immunosuppressive properties ex vivo. We leveraged F4/80 and MHCII expression by these cells for further characterization using cellular indexing of transcriptomes and epitopes by sequencing, which revealed a distinct transcriptomic signature of this population. F4/80+MHCII+ MDSCs displayed gene signatures resembling G-MDSCs, neutrophils, and monocytes but had significantly increased expression of pathways involved in cytokine response/production, inflammatory cell death, and mononuclear cell differentiation. To determine whether F4/80+MHCII+ MDSCs represented an alternate phenotypic state of G-MDSCs, Ly6G+Ly6C+F4/80-MHCII- G-MDSCs from CD45.1 mice were adoptively transferred into CD45.2 recipients using a mouse model of PJI. A small percentage of transferred G-MDSCs acquired F4/80 and MHCII expression in vivo, suggesting some degree of plasticity in this population. Collectively, these results demonstrate a previously unappreciated phenotype of F4/80+MHCII+ MDSCs during PJI, revealing that a granulocytic-to-monocytic transition can occur during biofilm infection.
Abstract
The recent SARS-CoV-2 outbreak has placed immense pressure on supply chains, including shortages in nasopharyngeal (NP) swabs. Here, we report our experience of using 3D-printing to rapidly ...develop and deploy custom-made NP swabs to address supply shortages at our healthcare institution.
BACKGROUND
In 2014, passive immunization by transfusion of Ebola convalescent plasma (ECP) was considered for treating patients with acute Ebola virus disease (EVD). Early Ebola virus (EBOV) ...seroconversion confers a survival advantage in natural infection, hence transfusion of ECP plasma with high levels of neutralizing EBOV antibodies is a potential passive immune therapy. Techniques to reduce the risk of other transfusion‐transmitted infections (TTIs) are warranted as recent ECP survivors are ineligible as routine blood donors. As part of an ongoing clinical trial to evaluate the safety and effectiveness of ECP, the impact of amotosalen/UVA pathogen reduction technology (PRT) on EBOV antibody characteristics was examined.
STUDY DESIGN AND METHODS
Serum and plasma samples were collected from EVD‐recovered subjects at multiple timepoints and evaluated by ELISA for antibodies to recombinant EBOV glycoprotein (GP) and irradiated whole EBOV antigen, as well as for EBOV microneutralization, classic plaque reduction neutralization test (PRNT) and EBOV pseudovirion neutralization assay (PsVNA) activity.
RESULTS
Six subjects donated 40 individual ECP units. Substantial antibody titers and neutralizing activity results were demonstrated but were generally lower for the ACD plasma samples compared to the serum samples. Anti‐EBOV titers by all assays remained essentially unchanged after PRT.
CONCLUSION
Treatment of ECP with PRT to reduce the risk of TTI did not significantly reduce EBOV IgG antibody titers or neutralizing activity. Although ECP was used in the treatment of repatriated patients, no PRT units from this study were transfused to EVD patients. This inventory of PRT‐treated ECP is currently available for future clinical evaluation.
Chronic lymphocytic leukemia (CLL) is a clonal mature B‐cell neoplasm with a typically indolent clinical course. Though most clinicians follow these neoplasms through observation alone, an aggressive ...transformation to prolymphocytic leukemia, diffuse large‐B‐cell lymphoma (Richter transformation) or classical Hodgkin lymphoma requires immediate attention. We present a case of extreme leukocytosis (>1 million/μL) in a previously diagnosed CLL patient. Due to symptomatic leukostasis, she was started on cytoreductive therapies including leukocytapheresis. After three rounds of leukocytapheresis (LCP) and concurrent chemotherapy, her white blood cell count decreased from a maximum 1262 × 103/μL to 574 × 103/μL. To our knowledge, CLL with symptomatic leukostasis that required therapeutic LCP is rarely reported in literature. We propose that therapeutic LCP is of value in such rare, yet dangerous settings like our case.
PURPOSE OF REVIEWThe purpose of this review is to discuss the use of convalescent plasma for the treatment of emerging infectious diseases, focusing on the recent use for the treatment of Ebola virus ...disease (EVD).
RECENT FINDINGSEbola convalescent plasma has been used as a therapy for treatment of EVD during the 2014 West Africa epidemic. Several cases from the United States and Europe have been recently published, in addition to multiple ongoing clinical trials in the United States and West Africa. Even more recently, convalescent plasma has been used for treatment of individuals with Middle East respiratory syndrome coronavirus (MERS-CoV) infection.
SUMMARYAlthough the first reports of successful treatment with passive immune therapy date back to the early 1900s, convalescent plasma has materialized as a possible therapy for patients who develop infection from one of the emerging infectious diseases such as EVD or MERS-CoV, although the efficacy of such therapy has yet to be proven in clinical trials.
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