Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis.

Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induced proinflammatory IRE1α hyperactivation in myeloid cells that led to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor dectin-1 by C. albicans induced NADPH oxidase-driven generation of ROS, which caused ER stress and IRE1α-dependent overexpression of key inflammatory mediators such as IL-1ß, IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 (PGE2), and TNF-α. Selective ablation of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1α hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis.

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E2. Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.

Effective primary care management of type 2 diabetes for indigenous populations: A systematic review.

BACKGROUND: Indigenous peoples in high income countries are disproportionately affected by Type 2 Diabetes. Socioeconomic disadvantages and inadequate access to appropriate healthcare are important contributors. OBJECTIVES: This systematic review investigates effective designs of primary care management of Type 2 Diabetes for Indigenous adults in Australia, Canada, New Zealand, and the United States. Primary outcome was change in mean glycated haemoglobin. Secondary outcomes were diabetes-related hospital admission rates, treatment compliance, and change in weight or Body Mass Index. METHODS: Included studies were critically appraised using Joanna Briggs Institute appraisal checklists. A mixed-method systematic review was undertaken. Quantitative findings were compared by narrative synthesis, meta-aggregation of qualitative factors was performed. RESULTS: Seven studies were included. Three reported statistically significant reductions in means HbA1c following their intervention. Seven components of effective interventions were identified. These were: a need to reduce health system barriers to facilitate access to primary care (which the other six components work towards), an essential role for Indigenous community consultation in intervention planning and implementation, a need for primary care programs to account for and adapt to changes with time in barriers to primary care posed by the health system and community members, the key role of community-based health workers, Indigenous empowerment to facilitate community and self-management, benefit of short-intensive programs, and benefit of group-based programs. CONCLUSIONS: This study synthesises a decade of data from communities with a high burden of Type 2 Diabetes and limited research regarding health system approaches to improve diabetes-related outcomes. Policymakers should consider applying the seven identified components of effective primary care interventions when designing primary care approaches to mitigate the impact of Type 2 Diabetes in Indigenous populations. More robust and culturally appropriate studies of Type 2 Diabetes management in Indigenous groups are needed. TRAIL REGISTRATION: Registered with PROSPERO (02/04/2021: CRD42021240098).

Precision and consistency of the passive leg raising maneuver for determining fluid responsiveness with bioreactance non-invasive cardiac output monitoring in critically ill patients and healthy volunteers.

OBJECTIVE: The passive leg raising (PLR) maneuver has become standard practice in fluid resuscitation. We aim to investigate the precision and consistency of the PLR for determining fluid responsiveness in critically ill patients and healthy volunteers using bioreactance non-invasive cardiac output monitoring (NiCOM™, Cheetah Medical, Inc., Newton Center, Massachusetts, USA). METHODS: This study is prospective, single-center, observational cohort with repeated measures in critically ill patients admitted to the medical intensive care unit and healthy volunteers at a tertiary academic medical center. Three cycles of PLR were performed, each at 20-30 minutes apart. Fluid responsiveness was defined as a change in stroke volume index (ΔSVI) > 10% with each PLR as determined by NiCOM™. Precision was the variability in ΔSVI after the 3 PLR's, and determined by range, average deviation and standard deviation. Consistency was the same fluid responsiveness determination of "Yes" (ΔSVI > 10%) or "No" (ΔSVI ≤ 10%) for all 3 PLR's. RESULTS: Seventy-five patients and 25 volunteers were enrolled. In patients, the precision was range of 17.2±13.3%, average deviation 6.5±4.0% and standard deviation 9.0±5.2%; and for volunteers, 17.4±10.3%, 6.6±3.8% and 9.0±6.7%, respectively. There was no statistical difference in the precision measurements between patients and volunteers. Forty-nine (65.3%) patients vs. twenty-four (96.0%) volunteers had consistent results, p < 0.01. Among those with consistent results, twenty-four (49.0%) patients and 24 (100%) volunteers were fluid responsive. CONCLUSIONS: The precision and consistency of determining ΔSVI with NiCOM™ after PLR may have clinical implication if ΔSVI > 10% is the absolute cutoff to determine fluid responsiveness.

IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.

Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE2), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human PTGS2 and PTGES genes to enable optimal PGE2 production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE2-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.

IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1-4. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies5-8-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.

A multi-center evaluation of a disposable catheter to aid in correct positioning of the endotracheal tube after intubation in critically ill patients.

PURPOSE: To demonstrate that use of a minimally invasive catheter reduces endotracheal tube (ETT) malposition rate after intubation. MATERIALS AND METHODS: This study is a multi-center, prospective observational cohort of intubated patients in the medical intensive care unit. The catheter was inserted into the ETT immediately after intubation. The ETT was adjusted accordingly based on qualitative color markers on the catheter. A confirmatory chest radiograph was obtained to determine the ETT position. Malposition of the ETT was defined by the distal ETT not being within 2-5 cm above the carina. RESULTS: Sixty-nine patients were enrolled, age 56.2 ±â€¯19.5 years, body mass index 31.0 ±â€¯13.8 kg/m2. The catheter prompted repositioning of the ETT in 39 (56.5%) patients. Using the catheter, the rate of malposition decreased to 7.2%, with the distal ETT position at 3.7 ±â€¯1.2 cm above the carina. Without the catheter, the ETT malposition rate would have been 39.1%. The time for catheter use and chest radiograph completion at our institutions was 1.7 ±â€¯1.5 and 44.4 ±â€¯36.4 min, respectively. CONCLUSIONS: With use of an ETT positioning catheter after intubation, the ETT malposition rate was reduced by 82%. This catheter-based system was safe, and its use may perhaps decrease the need for the post-intubation chest radiograph.

TumorMap: Exploring the Molecular Similarities of Cancer Samples in an Interactive Portal.

Vast amounts of molecular data are being collected on tumor samples, which provide unique opportunities for discovering trends within and between cancer subtypes. Such cross-cancer analyses require computational methods that enable intuitive and interactive browsing of thousands of samples based on their molecular similarity. We created a portal called TumorMap to assist in exploration and statistical interrogation of high-dimensional complex "omics" data in an interactive and easily interpretable way. In the TumorMap, samples are arranged on a hexagonal grid based on their similarity to one another in the original genomic space and are rendered with Google's Map technology. While the important feature of this public portal is the ability for the users to build maps from their own data, we pre-built genomic maps from several previously published projects. We demonstrate the utility of this portal by presenting results obtained from The Cancer Genome Atlas project data. Cancer Res; 77(21); e111-4. ©2017 AACR.

A Community Challenge for Inferring Genetic Predictors of Gene Essentialities through Analysis of a Functional Screen of Cancer Cell Lines.

We report the results of a DREAM challenge designed to predict relative genetic essentialities based on a novel dataset testing 98,000 shRNAs against 149 molecularly characterized cancer cell lines. We analyzed the results of over 3,000 submissions over a period of 4 months. We found that algorithms combining essentiality data across multiple genes demonstrated increased accuracy; gene expression was the most informative molecular data type; the identity of the gene being predicted was far more important than the modeling strategy; well-predicted genes and selected molecular features showed enrichment in functional categories; and frequently selected expression features correlated with survival in primary tumors. This study establishes benchmarks for gene essentiality prediction, presents a community resource for future comparison with this benchmark, and provides insights into factors influencing the ability to predict gene essentiality from functional genetic screens. This study also demonstrates the value of releasing pre-publication data publicly to engage the community in an open research collaboration.

ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.

Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum (ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy.