Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia.

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets.

Ultrasensitive plasma-based monitoring of tumor burden using machine-learning-guided signal enrichment.

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment.

Dorsal hippocampus to nucleus accumbens projections drive reinforcement via activation of accumbal dynorphin neurons.

The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli.

Bradykinin receptor expression and bradykinin-mediated sensitization of human sensory neurons.

Bradykinin is a peptide implicated in inflammatory pain in both humans and rodents. In rodent sensory neurons, activation of B1 and B2 bradykinin receptors induces neuronal hyperexcitability. Recent evidence suggests that human and rodent dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons, differ in the expression and function of key GPCRs and ion channels; whether bradykinin receptor expression and function are conserved across species has not been studied in depth.

Cortical stimulation leads to shortened myelin sheaths and increased axonal branching in spared axons after cervical spinal cord injury.

Neural activity and learning lead to myelin sheath plasticity in the intact central nervous system (CNS), but this plasticity has not been well-studied after CNS injury. In the context of spinal cord injury (SCI), demyelination occurs at the lesion site and natural remyelination of surviving axons can take months. To determine if neural activity modulates myelin and axon plasticity in the injured, adult CNS, we electrically stimulated the contralesional motor cortex at 10 Hz to drive neural activity in the corticospinal tract of rats with sub-chronic spinal contusion injuries.

Bradykinin receptor expression and bradykinin-mediated sensitization of human sensory neurons.

Bradykinin is a peptide implicated in inflammatory pain in both humans and rodents. In rodent sensory neurons, activation of B1 and B2 bradykinin receptors induces neuronal hyperexcitability. Recent evidence suggests that human and rodent dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons, differ in the expression and function of key GPCRs and ion channels; whether BK receptor expression and function are conserved across species has not been studied in depth.

Immune-Related Adverse Events Among COVID-19-Vaccinated Patients With Cancer Receiving Immune Checkpoint Blockade.

Background: Whether COVID-19 vaccination and the associated immune response increases susceptibility to immune-related adverse events (irAEs) among patients treated with immune checkpoint inhibition (ICI) remains unknown. Short-term follow-up can assess the safety of concurrent administration of the vaccine and ICI treatment.

Methods: We conducted an electronic health record analysis of a cohort of 408 patients with cancer receiving ICI therapy and who were vaccinated for COVID-19 between January 16 and March 27, 2021.

CD8 T cells contribute to survival in patients with COVID-19 and hematologic cancer.

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses.

CD8 T cells compensate for impaired humoral immunity in COVID-19 patients with hematologic cancer.

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center.

Effects of ketamine and other rapidly acting antidepressants on hippocampal excitatory and inhibitory transmission.

A single sub-anesthetic intravascular dose of the use-dependent NMDAR antagonist, ketamine, improves mood in patients with treatment resistant depression within hours that can last for days, creating an entirely new treatment strategy for the most seriously ill patients. However, the psychomimetic effects and abuse potential of ketamine require that new therapies be developed that maintain the rapid antidepressant effects of ketamine without the unwanted side effects. This necessitates a detailed understanding of what cellular and synaptic mechanisms are immediately activated once ketamine reaches the brain that triggers the needed changes to elicit the improved behavior.

Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring.

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance.

Rats bred for high anxiety exhibit distinct fear-related coping behavior, hippocampal physiology, and synaptic plasticity-related gene expression.

The hippocampus is essential for learning and memory but also regulates emotional behavior. We previously identified the hippocampus as a major brain region that differs in rats bred for emotionality differences. Rats bred for low novelty response (LRs) exhibit high levels of anxiety- and depression-like behavior compared to high novelty responder (HR) rats.

Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH.

The production of melanin increases skin pigmentation and reduces the risk of skin cancer. Melanin production depends on the pH of melanosomes, which are more acidic in lighter-skinned than in darker-skinned people. We showed that inhibition of soluble adenylyl cyclase (sAC) controlled pigmentation by increasing the pH of melanosomes both in cells and in vivo.

Intravascular Ketamine Increases Theta-Burst but Not High Frequency Tetanus Induced LTP at CA3-CA1 Synapses Within Three Hours and Devoid of an Increase in Spine Density.

In the past 20 years, ketamine has become a promising treatment for Major Depressive Disorder (MDD) due to its rapid and sustain antidepressant effects in patients. A single ketamine treatment causes improvement in depressive symptoms within hours and can last weeks, long after it is eliminated. Previous studies have demonstrated increased synaptic plasticity at CA3-CA1 synapses in hippocampus (HPC) 24 h post ketamine treatment suggesting increased activity-dependent hippocampal function may underlie the antidepressant effects of ketamine.

Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy.

Low-dose ketamine, an open-channel -methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated.

The genetic landscape of programmed death ligand-1 (PD-L1) alterations in head and neck cancer.

Objectives: Nivolumab has recently been shown in the phase III clinical trial CheckMate-141 to have superior survival rates compared to the current standard of care chemotherapy for recurrent or metastatic platinum-resistant head and neck squamous cell carcinoma (HNSCC). Nivolumab targets the immune inhibitory receptor programmed cell death 1 (PD-1). Programmed cell death ligand 1 (PD-L1) genomics have been poorly characterized in the context of HNSCC, including expression levels of PD-L1 in individual tumors as well as related up or down-regulated genes that might function as co-targets.

Increased hepatic expression of miRNA-122 in patients infected with HCV genotype 3.

Hepatitis C virus (HCV) infection affects approximately 3 % of the world population. HCV targets hepatic tissue, and most infected patients develop a chronic infection. Currently, studies have demonstrated an association between HCV-RNA replication and miR-122, the most abundant microRNA in the liver.

Driving for patients in palliative care-a reality?

Objective: Very little is known about car driving in palliative patients. We have asked patients in at home palliative care environments about their driving habits during palliative care.

Methods: At admittance to the palliative care program and at regular visits the patients were asked a few questions about age, diagnosis, sex, driving license, driving, medication and functional status.

PTEN knockdown alters dendritic spine/protrusion morphology, not density.

Mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology by using fluorescent dye confocal imaging.

Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission.

The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms. We have now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain.

Interdisciplinary approach for the management of peg lateral incisors in adolescents.

When faced with the presence of peg laterals in adolescent patients, the problem is, how do you correct the laterals in order to obtain an esthetic smile result? This case study describes a procedure to produce an esthetic smile for an adolescent patient. The procedure represented in this case report is only a temporary way to create an esthetic smile until the patient becomes an adult, when a more permanent solution addressing the peg laterals can be accomplished.

Generation of CD8+ T cell-mediated immunity against idiotype-negative lymphoma escapees.

We investigated the ability of CpG-oligodeoxynucleotide to generate an anti-tumor CD8+ T-cell immune response and to synergize with passive antibody therapy. For these studies, we generated an antibody against the idiotype on the A20 B-cell lymphoma line. This antibody caused the regression of established tumors, but ultimately the tumors relapsed.

Clinical and histological characteristics of HIV and hepatitis C virus-co-infected patients in Brazil: a case series study.

Unlabelled: Hepatitis C virus (HCV) is an important factor contributing to morbidity and mortality in patients co-infected with HIV and HCV. In addition, liver biopsy is an important tool in the clinical management of these patients. Although liver biopsy is controversial, it is recommended for all patients.