Primary CNS lymphoma: update on molecular pathogenesis and therapy.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of extra-nodal non-Hodgkin lymphoma that as a brain tumor poses a unique set of challenges in diagnosis and management. With the advent of next-generation sequencing, we review updates in the understanding of its molecular and genomic pathogenesis. We also highlight key issues in management, with a focus on emerging technologies and new biological therapies including monoclonal antibodies, IMiDs, BTK inhibitors, PD-1 inhibitors, and CAR-T therapy. Integration of these approaches will likely enhance induction and consolidation strategies to suppress NF-κB activation and the anti-tumor immune response, while minimizing the often noxious effects of genotoxic approaches.

Cost-effectiveness analysis of multimodal prognostication in cardiac arrest with EEG monitoring.

OBJECTIVE: To determine cost-effectiveness parameters for EEG monitoring in cardiac arrest prognostication. METHODS: We conducted a cost-effectiveness analysis to estimate the cost per quality-adjusted life-year (QALY) gained by adding continuous EEG monitoring to standard cardiac arrest prognostication using the American Academy of Neurology Practice Parameter (AANPP) decision algorithm: neurologic examination, somatosensory evoked potentials, and neuron-specific enolase. We explored lifetime cost-effectiveness in a closed system that incorporates revenue back into the medical system (return) from payers who survive a cardiac arrest with good outcome and contribute to the health system during the remaining years of life. Good outcome was defined as a Cerebral Performance Category (CPC) score of 1-2 and poor outcome as CPC of 3-5. RESULTS: An improvement in specificity for poor outcome prediction of 4.2% would be sufficient to make continuous EEG monitoring cost-effective (baseline AANPP specificity = 83.9%). In sensitivity analysis, the effect of increased sensitivity on the cost-effectiveness of EEG depends on the utility (u) assigned to a poor outcome. For patients who regard surviving with a poor outcome (CPC 3-4) worse than death (u = -0.34), an increased sensitivity for poor outcome prediction of 13.8% would make AANPP + EEG monitoring cost-effective (baseline AANPP sensitivity = 76.3%). In the closed system, an improvement in sensitivity of 1.8% together with an improvement in specificity of 3% was sufficient to make AANPP + EEG monitoring cost-effective, assuming lifetime return of 50% (USD $70,687). CONCLUSION: Incorporating continuous EEG monitoring into cardiac arrest prognostication is cost-effective if relatively small improvements in sensitivity and specificity are achieved.

Tombusvirus p19 Captures RNase III-Cleaved Double-Stranded RNAs Formed by Overlapping Sense and Antisense Transcripts in Escherichia coli.

Antisense transcription is widespread in bacteria. By base pairing with overlapping sense RNAs, antisense RNAs (asRNA) can form double-stranded RNAs (dsRNA), which are cleaved by RNase III, a dsRNA endoribonuclease. The ectopic expression of plant Tombusvirus p19 in Escherichia coli stabilizes ∼21-nucleotide (nt) dsRNA RNase III decay intermediates, which enabled us to characterize otherwise highly unstable asRNA by deep sequencing of p19-captured dsRNA. RNase III-produced small dsRNA were formed at most bacterial genes in the bacterial genome and in a plasmid. We classified the types of asRNA in genomic clusters producing the most abundant p19-captured dsRNA and confirmed RNase III regulation of asRNA and sense RNA decay at three type I toxin-antitoxin loci and at a coding gene, rsd Furthermore, we provide potential evidence for the RNase III-dependent regulation of CspD protein by asRNA. The analysis of p19-captured dsRNA revealed an RNase III sequence preference for AU-rich sequences 3 nucleotides on either side of the cleavage sites and for GC-rich sequences in the 2-nt overhangs. Unexpectedly, GC-rich sequences were enriched in the middle section of p19-captured dsRNA, suggesting some unexpected sequence bias in p19 protein binding. Nonetheless, the ectopic expression of p19 is a sensitive method for identifying antisense transcripts and RNase III cleavage sites in dsRNA formed by overlapping sense and antisense transcripts in bacteria.

Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine.

Immune checkpoint blockade (ICB) therapies, which potentiate the body's natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient's tumor and immune system must be considered to maximize treatment efficacy. Here, we review the various biological pathways and emerging biomarkers implicated in response to PD-(L)1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapies, including oncogenic signaling pathways, human leukocyte antigen (HLA) variability, mutation and neoantigen burden, microbiome composition, endogenous retroviruses (ERV), and deficiencies in chromatin remodeling and DNA damage repair (DDR) machinery. We also discuss several mechanisms that have been observed to confer resistance to ICB, such as loss of phosphatase and tensin homolog (PTEN), loss of major histocompatibility complex (MHC) I/II expression, and activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta (TGFß) pathways. Clinical trials testing the combination of PD-(L)1 or CTLA-4 blockade with molecular mediators of these pathways are becoming more common and may hold promise for improving treatment efficacy and response. Ultimately, some of the genes and molecular mechanisms highlighted in this review may serve as novel biological targets or therapeutic vulnerabilities to improve clinical outcomes in patients.

Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy.

The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug-polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.