Circulating biomarkers predictive of tumor response to cancer immunotherapy

Introduction: The advent of checkpoint blockade immunotherapy has revolutionized cancer treatment, but clinical response to immunotherapies is highly heterogeneous among individual patients and between cancer types. This represents a challenge to oncologists when choosing specific immunotherapies for personalized medicine. Thus, biomarkers that can predict tumor responsiveness to immunotherapies before and during treatment are invaluable. Areas covered: We review the latest advances in 'liquid biopsy' biomarkers for noninvasive prediction and in-treatment monitoring of tumor response to immunotherapy, focusing primarily on melanoma and non-small cell lung cancer. We concentrate on high-quality studies published within the last five years on checkpoint blockade immunotherapies, and highlight significant breakthroughs, identify key areas for improvement, and provide recommendations for how these diagnostic tools can be translated into clinical practice. Expert opinion: The first biomarkers proposed to predict tumor response to immunotherapy were based on PD1/PDL1 expression, but their predictive value is limited to specific cancers or patient populations. Recent advances in single-cell molecular profiling of circulating tumor cells and host cells using next-generation sequencing has dramatically expanded the pool of potentially useful predictive biomarkers. As immunotherapy moves toward personalized medicine, a composite panel of both genomic and proteomic biomarkers will have enormous utility in therapeutic decision-making

Sensory Prioritization in Rats: Behavioral Performance and Neuronal Correlates

Operating with some finite quantity of processing resources, an animal would benefit from prioritizing the sensory modality expected to provide key information in a particular context. The present study investigated whether rats dedicate attentional resources to the sensory modality in which a near-threshold event is more likely to occur. We manipulated attention by controlling the likelihood with which a stimulus was presented from one of two modalities. In a whisker session, 80% of trials contained a brief vibration stimulus applied to whiskers and the remaining 20% of trials contained a brief change of luminance. These likelihoods were reversed in a visual session. When a stimulus was presented in the high-likelihood context, detection performance increased and was faster compared with the same stimulus presented in the low-likelihood context. Sensory prioritization was also reflected in neuronal activity in the vibrissal area of primary somatosensory cortex: single units responded differentially to the whisker vibration stimulus when presented with higher probability compared with lower probability. Neuronal activity in the vibrissal cortex displayed signatures of multiplicative gain control and enhanced response to vibration stimuli during the whisker session. In conclusion, rats allocate priority to the more likely stimulus modality and the primary sensory cortex may participate in the redistribution of resources

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on the mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ binding proteins, polymerase delta interaction protein 46 (PDIP46) and polymerase delta interaction protein 38 (PDIP38), both of which are multi-functional proteins. PDIP46 is a novel activator of Pol δ4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol δ3 and Pol δ4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the spliceosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, mouse double minute 2 homolog (Mdm2) alternative splicing and the regulation of the NADPH oxidase 4 (Nox4)

Telehealth Solutions for In-hospital Communication with Patients Under Isolation During COVID-19

The coronavirus disease 2019 (COVID-19) pandemic is a public health crisis that has quickly overwhelmed our healthcare system. It has led to significant shortages in personal protective equipment (PPE), ventilators, and intensive care unit beds across the nation. As the initial entry point for patients with suspected COVID illness, emergency departments (ED) have had to adapt quickly to prioritize the safety of patients and providers while still delivering optimal, timely patient care. COVID-19 has presented many challenges for the ED that also extend to all inpatient services. Some of these key challenges are the fundamental tasks of communicating with patients in respiratory isolation while minimizing PPE usage and enabling all patients who have been affected by hospitals’ visitor restrictions to connect with their families. We discuss the design principles behind implementing a robust in-hospital telehealth system for patient-provider and patient-family communication, provide a review of the strengths and weaknesses of potential videoconferencing options, and deliver concise, step-by-step guides for setting up a secure, low-cost, user-friendly solution that can be rapidly deployed

Phosphorylation Alters the Properties of Pol eta: Implications for Translesion Synthesis

There are significant ambiguities regarding how DNA polymerase eta is recruited to DNA lesion sites in stressed cells while avoiding normal replication forks in non-stressed cells. Even less is known about the mechanisms responsible for Pol eta-induced mutations in cancer genomes. We show that there are two safeguards to prevent Pol eta from adventitious participation in normal DNA replication. These include sequestration by a partner protein and low basal activity. Upon cellular UV irradiation, phosphorylation enables Pol eta to be released from sequestration by PDIP38 and activates its polymerase function through increased affinity toward monoubiquitinated proliferating cell nuclear antigen (Ub-PCNA). Moreover, the high-affinity binding of phosphorylated Pol eta to Ub-PCNA limits its subsequent displacement by Pol delta. Consequently, activated Pol eta replicates DNA beyond the lesion site and potentially introduces clusters of mutations due to its low fidelity. This mechanism could account for the prevalence of Pol eta signatures in cancer genome

Circulating biomarkers predictive of tumor response to cancer immunotherapy

Introduction: The advent of checkpoint blockade immunotherapy has revolutionized cancer treatment, but clinical response to immunotherapies is highly heterogeneous among individual patients and between cancer types. This represents a challenge to oncologists when choosing specific immunotherapies for personalized medicine. Thus, biomarkers that can predict tumor responsiveness to immunotherapies before and during treatment are invaluable. Areas covered: We review the latest advances in 'liquid biopsy' biomarkers for noninvasive prediction and in-treatment monitoring of tumor response to immunotherapy, focusing primarily on melanoma and non-small cell lung cancer. We concentrate on high-quality studies published within the last five years on checkpoint blockade immunotherapies, and highlight significant breakthroughs, identify key areas for improvement, and provide recommendations for how these diagnostic tools can be translated into clinical practice. Expert opinion: The first biomarkers proposed to predict tumor response to immunotherapy were based on PD1/PDL1 expression, but their predictive value is limited to specific cancers or patient populations. Recent advances in single-cell molecular profiling of circulating tumor cells and host cells using next-generation sequencing has dramatically expanded the pool of potentially useful predictive biomarkers. As immunotherapy moves toward personalized medicine, a composite panel of both genomic and proteomic biomarkers will have enormous utility in therapeutic decision-making

PDIP46 (DNA Polymerase Delta Interacting Protein 46) Is an Activating Factor for Human DNA Polymerase Delta

PDIP46 (SKAR, POLDIP3) was discovered through its interaction with the p50 subunit of human DNA polymerase δ (Pol δ). Its functions in DNA replication are unknown. PDIP46 associates with Pol δ in cell extracts both by immunochemical and protein separation methods, as well as by ChIP analyses. PDIP46 also interacts with PCNA via multiple copies of a novel PCNA binding motif, the APIMs (AlkB homologue-2 PCNA-Interacting Motif). Sites for both p50 and PCNA binding were mapped to the N-terminal region containing the APIMs. Functional assays for the effects of PDIP46 on Pol δ activity on singly primed ssM13 DNA templates revealed that it is a novel and potent activator of Pol δ. The effects of PDIP46 on Pol δ in primer extension, strand displacement and synthesis through simple hairpin structures reveal a mechanism where PDIP46 facilitates Pol δ4 synthesis through regions of secondary structure on complex templates. In addition, evidence was obtained that PDIP46 is also capable of exerting its effects by a direct interaction with Pol δ, independent of PCNA. Mutation of the Pol δ and PCNA binding region resulted in a loss of PDIP46 functions. These studies support the view that PDIP46 is a novel accessory protein for Pol δ that is involved in cellular DNA replication. This raises the possibility that altered expression of PDIP46 or its mutation may affect Pol δ functions in vivo, and thereby be a nexus for altered genomic stability

Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation

Pathological self-assembly is a concept that is classically associated with amyloids, such as amyloid-β (Aβ) in Alzheimer's disease and α-synuclein in Parkinson's disease. In prokaryotic organisms, amyloids are assembled extracellularly in a similar fashion to human amyloids. Pathogenicity of amyloids is attributed to their ability to transform into several distinct structural states that reflect their downstream biological consequences. While the oligomeric forms of amyloids are thought to be responsible for their cytotoxicity via membrane permeation, their fibrillar conformations are known to interact with the innate immune system to induce inflammation. Furthermore, both eukaryotic and prokaryotic amyloids can self-assemble into molecular chaperones to bind nucleic acids, enabling amplification of Toll-like receptor (TLR) signaling. Recent work has shown that antimicrobial peptides (AMPs) follow a strikingly similar paradigm. Previously, AMPs were thought of as peptides with the primary function of permeating microbial membranes. Consistent with this, many AMPs are facially amphiphilic and can facilitate membrane remodeling processes such as pore formation and fusion. We show that various AMPs and chemokines can also chaperone and organize immune ligands into amyloid-like ordered supramolecular structures that are geometrically optimized for binding to TLRs, thereby amplifying immune signaling. The ability of amphiphilic AMPs to self-assemble cooperatively into superhelical protofibrils that form structural scaffolds for the ordered presentation of immune ligands like DNA and dsRNA is central to inflammation. It is interesting to explore the notion that the assembly of AMP protofibrils may be analogous to that of amyloid aggregates. Coming full circle, recent work has suggested that Aβ and other amyloids also have AMP-like antimicrobial functions. The emerging perspective is one in which assembly affords a more finely calibrated system of recognition and response: the detection of single immune ligands, immune ligands bound to AMPs, and immune ligands spatially organized to varying degrees by AMPs, result in different immunologic outcomes. In this framework, not all ordered structures generated during multi-stepped AMP (or amyloid) assembly are pathological in origin. Supramolecular structures formed during this process serve as signatures to the innate immune system to orchestrate immune amplification in a proportional, situation-dependent manner

Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation

Pathological self-assembly is a concept that is classically associated with amyloids, such as amyloid-β (Aβ) in Alzheimer's disease and α-synuclein in Parkinson's disease. In prokaryotic organisms, amyloids are assembled extracellularly in a similar fashion to human amyloids. Pathogenicity of amyloids is attributed to their ability to transform into several distinct structural states that reflect their downstream biological consequences. While the oligomeric forms of amyloids are thought to be responsible for their cytotoxicity via membrane permeation, their fibrillar conformations are known to interact with the innate immune system to induce inflammation. Furthermore, both eukaryotic and prokaryotic amyloids can self-assemble into molecular chaperones to bind nucleic acids, enabling amplification of Toll-like receptor (TLR) signaling. Recent work has shown that antimicrobial peptides (AMPs) follow a strikingly similar paradigm. Previously, AMPs were thought of as peptides with the primary function of permeating microbial membranes. Consistent with this, many AMPs are facially amphiphilic and can facilitate membrane remodeling processes such as pore formation and fusion. We show that various AMPs and chemokines can also chaperone and organize immune ligands into amyloid-like ordered supramolecular structures that are geometrically optimized for binding to TLRs, thereby amplifying immune signaling. The ability of amphiphilic AMPs to self-assemble cooperatively into superhelical protofibrils that form structural scaffolds for the ordered presentation of immune ligands like DNA and dsRNA is central to inflammation. It is interesting to explore the notion that the assembly of AMP protofibrils may be analogous to that of amyloid aggregates. Coming full circle, recent work has suggested that Aβ and other amyloids also have AMP-like antimicrobial functions. The emerging perspective is one in which assembly affords a more finely calibrated system of recognition and response: the detection of single immune ligands, immune ligands bound to AMPs, and immune ligands spatially organized to varying degrees by AMPs, result in different immunologic outcomes. In this framework, not all ordered structures generated during multi-stepped AMP (or amyloid) assembly are pathological in origin. Supramolecular structures formed during this process serve as signatures to the innate immune system to orchestrate immune amplification in a proportional, situation-dependent manner