Concordant palliative care delivery in advanced head and neck cancer.

OBJECTIVES: To describe the palliative care consultation practices in an academic head and neck surgery practice. METHODS: This is a retrospective review of a palliative care database and the health record for all palliative care consultations of patients suffering from advanced stage head and neck cancer within a 21-month period. RESULTS: Ten head and neck cancer patients received palliative care consults while on the otolaryngology service. One consultation occurred preoperatively; nine occurred postoperatively, on a median of hospital day 9. At the time of referral, seven patients were in the ICU and three were on a surgical floor. Code status de-escalation occurred in six patients and psycho-socio-spiritual suffering was supported in all consultations. Nine patients died within six months, with a median post-consultation survival of 35 days. Of these, two died in an ICU, five were discharged to hospice, one to a SNF, and one to a LTACH. CONCLUSION: Palliative care consultation in this advanced head and neck cancer cohort was commonly late, however, significant suffering was mitigated following most consults. Palliative care specialists are experts at eliciting patient values, determining acceptable tradeoffs and suffering limitations by employing a shared decision-making process that ends with a patient-centered value-congruent treatment recommendation. Oftentimes, this embraces curative-intent or palliative surgery, along with contingency plans for unacceptable value-incongruent postoperative outcomes. Enhanced awareness of the benefits of embracing concordant palliative care in advanced head and neck cancer patients may help overcome the significant barriers to involving palliative care experts earlier.

VEXAS syndrome: lessons learnt from an early Australian case series.

VEXAS is a newly recognised adult-onset autoinflammatory syndrome resulting from a somatic mutation in the UBA1 gene. Herein, we present three cases of VEXAS syndrome in Sydney, Australia, that capture key clinical features and the refractory nature of the condition. They highlight the importance of multidisciplinary collaboration for early diagnosis and the need for new therapeutic options.

The effects on bronchial epithelial mucociliary cultures of coarse, fine, and ultrafine particulate matter from an underground railway station.

We have previously shown that underground railway particulate matter (PM) is rich in iron and other transition metals across coarse (PM10-2.5), fine (PM2.5), and quasi-ultrafine (PM0.18) fractions and is able to generate reactive oxygen species (ROS). However, there is little knowledge of whether the metal-rich nature of such particles exerts toxic effects in mucus-covered airway epithelial cell cultures or whether there is an increased risk posed by the ultrafine fraction. Monolayer and mucociliary air-liquid interface (ALI) cultures of primary bronchial epithelial cells (PBECs) were exposed to size-fractionated underground railway PM (1.1-11.1 µg/cm(2)) and release of lactate dehydrogenase and IL-8 was assayed. ROS generation was measured, and the mechanism of generation studied using desferrioxamine (DFX) and N-acetylcysteine (NAC). Expression of heme oxygenase-1 (HO-1) was determined by RT-qPCR. Particle uptake was studied by transmission electron microscopy. Underground PM increased IL-8 release from PBECs, but this was diminished in mucus-secreting ALI cultures. Fine and ultrafine PM generated a greater level of ROS than coarse PM. ROS generation by ultrafine PM was ameliorated by DFX and NAC, suggesting an iron-dependent mechanism. Despite the presence of mucus, ALI cultures displayed increased HO-1 expression. Intracellular PM was observed within vesicles, mitochondria, and free in the cytosol. The results indicate that, although the mucous layer appears to confer some protection against underground PM, ALI PBECs nonetheless detect PM and mount an antioxidant response. The combination of increased ROS-generating ability of the metal-rich ultrafine fraction and ability of PM to penetrate the mucous layer merits further research.

Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease.

OBJECTIVE: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up. DESIGN: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis. RESULTS: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (p(FDR)=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-κB regulator CYLD. This resulted in IκB-α degradation and NF-κB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly. CONCLUSIONS: Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors.

Targeting pan-resistant bacteria with antibodies to a broadly conserved surface polysaccharide expressed during infection.

BACKGROUND: New therapeutic targets for antibiotic-resistant bacterial pathogens are desperately needed. The bacterial surface polysaccharide poly-ß-(1-6)-N-acetyl-glucosamine (PNAG) mediates biofilm formation by some bacterial species, and antibodies to PNAG can confer protective immunity. By analyzing sequenced genomes, we found that potentially multidrug-resistant bacterial species such as Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, and the Burkholderia cepacia complex (BCC) may be able to produce PNAG. Among patients with cystic fibrosis patients, highly antibiotic-resistant bacteria in the BCC have emerged as problematic pathogens, providing an impetus to study the potential of PNAG to be targeted for immunotherapy against pan-resistant bacterial pathogens. METHODS: The presence of PNAG on BCC was assessed using a combination of bacterial genetics, microscopy, and immunochemical approaches. Antibodies to PNAG were tested using opsonophagocytic assays and for protective efficacy against lethal peritonitis in mice. RESULTS: PNAG is expressed in vitro and in vivo by the BCC, and cystic fibrosis patients infected by the BCC species B. dolosa mounted a PNAG-specific opsonophagocytic antibody response. Antisera to PNAG mediated opsonophagocytic killing of BCC and were protective against lethal BCC peritonitis even during coinfection with methicillin-resistant Staphylococcus aureus. CONCLUSIONS: Our findings raise potential new therapeutic options against PNAG-producing bacteria, including even pan-resistant pathogens.

Eph-2B, acting as an extracellular ligand, induces differentiation markers in epidermal keratinocytes.

In the bi-directional signaling system comprising ephrins (EFNs) and ephrin receptors (Ephs), both EFNs and Ephs simultaneously function both as ligands and as receptors. Importantly, the EFN/Eph system is deregulated in human cancers and has been implicated in the metastatic processes because of its effects on the adhesion and migration of epithelial cells. The idiosyncratic function of Ephs, membrane-bound receptor kinases, as extracellular signaling ligands, has not been extensively studied. This prompted us to explore the transcriptional targets regulated by Ephs acting solely as ligands. To define the ligand function of EphB2 in human epidermal keratinocytes, we treated these cells with EphB2 as Fc-conjugate dimmers, which thus act exclusively as extracellular ligands. We compared the EphB2 and EFNA4 effects during a 48 h time course, using transcriptional profiling. We found that EphB2, acting as a ligand, promotes epidermal differentiation. For example, EphB2 induces expression of markers of epidermal differentiation, including keratins KRT1 and KRT10, SPRRs, desmosomal proteins and cell cycle inhibitors, while suppressing basal layer markers, integrins and cell cycle proteins. The effects of EphB2 are delayed relative to those of EFNA4. Unlike EFNA4, EphB2 did not induce lipid metabolism proteins, this particular aspect of epidermal differentiation seems not to be regulated by EphB2. Our results define the transcriptional targets of the reverse signaling by EphB2 acting exclusively as a ligand and begin to characterize this intriguing function of Ephs.

Specific and shared targets of ephrin A signaling in epidermal keratinocytes.

Both ephrins (EFNs) and their receptors (Ephs) are membrane-bound, restricting their interactions to the sites of direct cell-to-cell interfaces. They are widely expressed, often co-expressed, and regulate developmental processes, cell adhesion, motility, survival, proliferation, and differentiation. Both tumor suppressor and oncogene activities are ascribed to EFNs and Ephs in various contexts. A major conundrum regarding the EFN/Eph system concerns their large number and functional redundancy given the promiscuous cross-activation of ligands and receptors and the overlapping intracellular signaling pathways. To address this issue, we treated human epidermal keratinocytes with five EFNAs individually and defined the transcriptional responses in the cells. We found that a large set of genes is coregulated by all EFNAs. However, although the responses to EFNA3, EFNA4, and EFNA5 are identical, the responses to EFNA1 and EFNA2 are characteristic and distinctive. All EFNAs induce epidermal differentiation markers and suppress cell adhesion genes, especially integrins. Ontological analysis showed that all EFNAs induce cornification and keratin genes while suppressing wound healing-associated, signaling, receptor, and extracellular matrix-associated genes. Transcriptional targets of AP1 are selectively suppressed by EFNAs. EFNA1 and EFNA2, but not the EFNA3, EFNA4, EFNA5 cluster, regulate the members of the ubiquitin-associated proteolysis genes. EFNA1 specifically induces collagen production. Our results demonstrate that the EFN-Eph interactions in the epidermis, although promiscuous, are not redundant but specific. This suggests that different members of the EFN/Eph system have specific, clearly demarcated functions.

Evaluating the care of patients with malignant spinal cord compression at a regional cancer centre.

The consequences of malignant spinal cord compression (MSCC) can be devastating. If not detected early, MSCC can result in paralysis and significant bowel and bladder dysfunction that is not improved by treatment. Patients have to cope with sudden and unexpected disability alongside a diagnosis of advanced cancer. A multidisciplinary group was established within a cancer centre to review the care of patients with MSCC. Two linked studies were carried out: a staff questionnaire sent to senior medical staff and all nurses and an audit of documentation. The documentation audit reviewed the notes of 50 patients who had received radiotherapy for MSCC. The symptoms patients presented with on admission and before discharge demonstrated that many experienced significant physical problems as a consequence of developing MSCC. Usually, these symptoms were either unaffected by treatment, or had deteriorated further by the time of their discharge from hospital. The average number of days between admission with MSCC and death was 58.6 days (range 2 to 319 days). The project identified variations in practice in a range of aspects of care and provided clear evidence for the need to develop interventions in relation to specific concerns.

Nexus between epidermolysis bullosa and transcriptional regulation by thyroid hormone in epidermal keratinocytes.

Abstract Thyroid hormone, T3, through the interaction of its receptor with the recognition sequences in the DNA, regulates gene expression. This regulation includes the promoter activity of keratin genes. The receptor shares coregulators with other members of the nuclear receptor family, including RXR. Intending to define the transcriptional effects of thyroid hormones in keratinocytes, we used Affymetrix microarrays to comprehensively compare the genes expressed in T3-treated and untreated human epidermal keratinocytes. The transcriptomes were compared at 1, 4, 24, 48, and 72 hours. Surprisingly, T3 induced only 9 and suppressed 28 genes, much fewer than expected. Significantly, genes associated with epidermolysis bullosa, a set of inherited blistering skin diseases, were found statistically highly overrepresented among the suppressed genes. These genes include Integrin beta4, Plectin, Collagen XVII, MMP1, MMP3, and MMP14. The data imply that in keratinocytes T3 could suppresses the remodeling by, attachment to, and production of extracellular matrix. The results suggest that topical treatment with T3 may be effective for alleviation of symptoms in patients with epidermolysis bullosa.