Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8 T Cells in Immunotherapy-Resistant and Metastatic Cancers.

Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease.

Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans.

The diversity of circulating human B cells is unknown. We use single-cell RNA sequencing (RNA-seq) to examine the diversity of both antigen-specific and total B cells in healthy subjects and malaria-exposed individuals. This reveals two B cell lineages: a classical lineage of activated and resting memory B cells and an alternative lineage, which includes previously described atypical B cells.

Targeting Nuclear LSD1 to Reprogram Cancer Cells and Reinvigorate Exhausted T Cells via a Novel LSD1-EOMES Switch.

Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical for the development of breast cancer stem cells. Here we show that circulating tumor cells isolated from immunotherapy-resistant metastatic melanoma patients express higher levels of nLSD1p compared to responders, which is associated with co-expression of stem-like, mesenchymal genes.

Relation of postoperative pain medication to return for unplanned care after ureteroscopy.

To determine whether the US Drug Enforcement Agency (DEA) class of narcotics prescribed to patients after ureteroscopy impacts their rate of return for unplanned care, a retrospective analysis of patients from February 2014 through March 2016 was performed. Data were collected for the first 90 days after surgery. Patients were divided into groups based on the narcotics schedule prescribed after surgery.

Comparison of utilization of pressurized automated versus manual hand irrigation during ureteroscopy in the absence of ureteral access sheath.

This study compared patient outcomes following irrigation applied using an automated pressure system (AP) to hand irrigation utilizing a syringe (HI) during ureteroscopy. Retrospective chart review was performed to evaluate ureteroscopy procedures without a ureteral access sheath. Procedures in which irrigation was applied by AP were compared to those with HI.

Cervical spine kinematics during machine-based and live scrummaging.

The aim of this study was to compare cervical spine kinematics in rugby union front row players during machine-based and "live" scrummaging. Cervical spine kinematics was measured via electromagnetic tracking of sensors attached to the head and thorax. Joint angles were extracted from each trial at two time points ("bind" prior to engagement and instant of impact) for comparison between scrummaging conditions.

Comparison of Recurrence and Postoperative Complications Between 3 Different Techniques for Surgical Repair of Idiopathic Hydrocele.

Objective: To determine if recurrence rates and complication rates differ between 3 different techniques for treatment of idiopathic hydrocele: Jaboulay's bottleneck, hydrocelectomy, or Lord's technique.

Methods: All surgeries for idiopathic hydrocele in the health system were reviewed from 2000 to 2011. Recurrence rate, complication rate, and other surgical data were collected and analyzed.

Ex-vivo ureteroscopy of deceased donor kidneys.

Introduction: When encountered, the ideal management of lithiasis in deceased donor kidneys is not well-defined. With advances in endourological techniques, minimally invasive treatments are becoming an increasingly viable option. We set out to describe our experience performing ex-vivo ureteroscopy on cadaveric donor kidneys, including one in which the procedure was completed on-pump.

Mantle cell lymphoma of the prostate gland treated with holmium laser enucleation.

Mantle cell lymphoma of the prostate is rare and is seldom encountered in general urologic practice. It either arises primarily from the prostate or is a result of metastatic spread from another site. This specific type of lymphoma has an aggressive course and may respond poorly to traditional chemotherapy with frequent relapses.

Physical characteristics associated with neck pain and injury in rugby union players.

Background: Neck pain and injury are common in rugby union. Physical characteristics predisposing players to neck injury are largely unknown. This study aimed to determine physical characteristics associated with neck pain and injury in rugby union players.

Durability of Artificial Urinary Sphincter With Prior Radiation Therapy.

Background: The aim of this study was to investigate the effect of prior radiation therapy on artificial urinary sphincter.

Methods: Group 1 was comprised of 63 men who underwent prior radical prostatectomy, and Group 2 was comprised of 31 men who received prior radiation therapy with or without prior radical prostatectomy. Social incontinence was defined as requiring to use > 1 pad per day and/or catheter-dependent at the time of last follow-up.

Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation.

Memory T cells are characterized by their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4(+) T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation.

The B subunit of Escherichia coli heat-labile toxin alters the development and antigen-presenting capacity of dendritic cells.

Escherichia coli's heat-labile enterotoxin (Etx) and its non-toxic B subunit (EtxB) have been characterized as adjuvants capable of enhancing T cell responses to co-administered antigen. Here, we investigate the direct effect of intravenously administered EtxB on the size of the dendritic and myeloid cell populations in spleen. EtxB treatment appears to enhance the development and turnover of dendritic and myeloid cells from precursors within the spleen.

Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome.

Background: Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases.

Methods: The DNA of eight patients affected by MAS [all of whom presenting with Sjögren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES.

Chromatinized protein kinase C-θ directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells.

Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. Signal transduction kinases play a pivotal role as chromatin-anchored proteins in eukaryotes. Here we report for the first time that protein kinase C-theta (PKC-θ) promotes EMT by acting as a critical chromatin-anchored switch for inducible genes via transforming growth factor β (TGF-β) and the key inflammatory regulatory protein NF-κB.

Regional bone geometry of the tibia in triathletes and stress reactions--an observational study.

Objectives: The association between tibial morphology and tibial stress fractures or tibial stress syndrome was examined in triathletes with an unusually high incidence of these injuries.

Design: A cross-sectional study design examined associations between tibial geometry from MRI images and training and injury data between male and female triathletes and between stress fracture (SF) and non-stress fracture (NSF) groups.

Methods: Fifteen athletes (7 females, 8 males) aged 17-23 years who were currently able to train and race were recruited from the New Zealand Triathlete Elite Development Squad.

Chromatinized Protein Kinase C-θ: Can It Escape the Clutches of NF-κB?

We recently provided the first description of a nuclear mechanism used by Protein Kinase C-theta (PKC-θ) to mediate T cell gene expression. In this mode, PKC-θ tethers to chromatin to form an active nuclear complex by interacting with proteins including RNA polymerase II, the histone kinase MSK-1, the demethylase LSD1, and the adaptor molecule 14-3-3ζ at regulatory regions of inducible immune response genes. Moreover, our genome-wide analysis identified many novel PKC-θ target genes and microRNAs implicated in T cell development, differentiation, apoptosis, and proliferation.

Chromatin-associated protein kinase C-θ regulates an inducible gene expression program and microRNAs in human T lymphocytes.

Studies in yeast demonstrate that signaling kinases have a surprisingly active role in the nucleus, where they tether to chromatin and modulate gene expression programs. Despite these seminal studies, the nuclear mechanism of how signaling kinases control transcription of mammalian genes is in its infancy. Here, we provide evidence for a hitherto unknown function of protein kinase C-theta (PKC-θ), which physically associates with the regulatory regions of inducible immune response genes in human T cells.

The interaction between skill, postures, forces and back pain in wool handling.

Wool handling is an important rural occupation where workers process 200 or more fleeces daily, separating them into various quality components. Loads and postures they experience carry substantial risk of low back pain (LBP). Although a formal skill training structure exists, interaction with loads and LBP is unknown.

Cognitive performance and leukocyte telomere length in two narrow age-range cohorts: a population study.

Background: Cognitive function and telomere length both decline with age. A correlation between these two measures would suggest that they may be influenced by the same underlying age-related biological process. Several studies suggest telomere length may be positively correlated with cognitive performance but the evidence is equivocal.

No associations between telomere length and age-sensitive indicators of physical function in mid and later life.

Telomere length, which declines with age, has been hypothesized to act as an indicator of biological aging. If it fulfills this purpose, shorter telomere length should correlate with age-related loss of physical function, independent of age. In this cross-sectional Australian population study, the associations between peripheral blood leukocyte telomere length and age-sensitive indicators of physical function (lung function, blood pressure, and grip strength) were examined in two narrow age range cohorts aged 44-49 years (n = 351) and 64-70 years (n = 295).

Match and training injuries in rugby league: a review of published studies.

Rugby league is an international collision sport played by junior, amateur, semiprofessional and professional players. The game requires participants to be involved in physically demanding activities such as running, tackling, passing and sprinting, and musculoskeletal injuries are common. A review of injuries in junior and senior rugby league players published in Sports Medicine in 2004 reported that injuries to the head and neck and muscular injuries were common in senior rugby league players, while fractures and injuries to the knee were common in junior players.

Women's rugby league injury claims and costs in New Zealand.

Aim: There is scarce information on rugby league injuries in female players. This paper provides an overview of the epidemiology of women's rugby league injuries requiring medical treatment and associated costs in New Zealand.

Method: New Zealand Accident Compensation Corporation injury data for the period 1999-2007 were searched for rugby league injury cases occurring in females.

Rugby league injuries in New Zealand: a review of 8 years of Accident Compensation Corporation injury entitlement claims and costs.

Aim: This paper provides an overview of the epidemiology of rugby league injuries and associated costs in New Zealand requiring medical treatment.

Method: New Zealand national Accident Compensation Corporation injury data for the period 1999 to 2007 were searched for rugby league injury cases. Data were analysed by demographics, body region, nature/severity of injury, and medical procedure and costs.