Potentiating adoptive cell therapy using synthetic IL-9 receptors.

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rß-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.

MSC Based Therapies to Prevent or Treat BPD-A Narrative Review on Advances and Ongoing Challenges.

Bronchopulmonary dysplasia (BPD) remains one of the most devastating consequences of preterm birth resulting in life-long restrictions in lung function. Distorted lung development is caused by its inflammatory response which is mainly provoked by mechanical ventilation, oxygen toxicity and bacterial infections. Dysfunction of resident lung mesenchymal stem cells (MSC) represents one key hallmark that drives BPD pathology. Despite all progress in the understanding of pathomechanisms, therapeutics to prevent or treat BPD are to date restricted to a few drugs. The limited therapeutic efficacy of established drugs can be explained by the fact that they fail to concurrently tackle the broad spectrum of disease driving mechanisms and by the huge overlap between distorted signal pathways of lung development and inflammation. The great enthusiasm about MSC based therapies as novel therapeutic for BPD arises from the capacity to inhibit inflammation while simultaneously promoting lung development and repair. Preclinical studies, mainly performed in rodents, raise hopes that there will be finally a broadly acting, efficient therapy at hand to prevent or treat BPD. Our narrative review gives a comprehensive overview on preclinical achievements, results from first early phase clinical studies and challenges to a successful translation into the clinical setting.

Native hepatic T1-time as a non-invasive predictor of diastolic dysfunction and a monitoring tool for disease progression and treatment response in patients with pulmonary hypertension.

AIMS: Hepatic T1-time derived from cardiac magnetic resonance imaging (cMRI) reflects venous congestion and may provide a simple alternative to invasive end-diastolic elastance (Eed) for assessment of right ventricular (RV) diastolic function. We investigated the association of native hepatic T1-time with single-beat Eed and the value of hepatic T1-time for longitudinal monitoring in pulmonary hypertension (PH). METHODS AND RESULTS: We retrospectively enrolled 85 patients with suspected PH (59% female; 78 with PH diagnosed; 7 with PH excluded) who underwent standard right heart catheterization and cMRI within 24 h between 2015 and 2020. Hepatic T1-time showed moderate to strong correlations (rho >0.3, P ≤ 0.002) with pulmonary vascular resistance, native myocardial T1-time, Eed, RV size and function, brain natriuretic peptide (BNP) level, and 6-min walk distance, and a significant association with functional class (Kruskal-Wallis P < 0.001). Eed, myocardial T1-time, and BNP were independently linked to hepatic T1-time in multivariable regression. Hepatic T1-time > 598 ms predicted elevated Eed with 72.9% sensitivity and 82.1% specificity. Hepatic T1-time was superior to Eed in predicting clinical worsening. In 16 patients with follow-up assessments, those with decreasing hepatic T1-time (7 patients) showed significant hemodynamic improvements, whereas those with increasing hepatic T1-time (9 patients) did not. In a second retrospective cohort of 27 patients with chronic thromboembolic PH undergoing balloon pulmonary angioplasty, hepatic T1-time decreased significantly and hemodynamics improved after the procedure. CONCLUSIONS: Hepatic T1-time predicts RV diastolic dysfunction and prognosis, and may be useful for monitoring disease progression and treatment response in PH.

Risk assessment of aquifer storage transfer and recovery with urban stormwater for producing water of a potable quality.

The objective of the Parafield Aquifer Storage Transfer and Recovery research project in South Australia is to determine whether stormwater from an urban catchment that is treated in a constructed wetland and stored in an initially brackish aquifer before recovery can meet potable water standards. The water produced by the stormwater harvesting system, which included a constructed wetland, was found to be near potable quality. Parameters exceeding the drinking water guidelines before recharge included small numbers of fecal indicator bacteria and elevated iron concentrations and associated color. This is the first reported study of a managed aquifer recharge (MAR) scheme to be assessed following the Australian guidelines for MAR. A comprehensive staged approach to assess the risks to human health and the environment of this project has been undertaken, with 12 hazards being assessed. A quantitative microbial risk assessment undertaken on the water recovered from the aquifer indicated that the residual risks posed by the pathogenic hazards were acceptable if further supplementary treatment was included. Residual risks from organic chemicals were also assessed to be low based on an intensive monitoring program. Elevated iron concentrations in the recovered water exceeded the potable water guidelines. Iron concentrations increased after underground storage but would be acceptable after postrecovery aeration treatment. Arsenic concentrations in the recovered water continuously met the guideline concentrations acceptable for potable water supplies. However, the elevated concentration of arsenic in native groundwater and its presence in aquifer minerals suggest that the continuing acceptable residual risk from arsenic requires further evaluation.

MSC Based Therapies-New Perspectives for the Injured Lung.

Chronic lung diseases pose a tremendous global burden. At least one in four people suffer from severe pulmonary sequelae over the course of a lifetime. Despite substantial improvements in therapeutic interventions, persistent alleviation of clinical symptoms cannot be offered to most patients affected to date. Despite broad discrepancies in origins and pathomechanisms, the important disease entities all have in common the pulmonary inflammatory response which is central to lung injury and structural abnormalities. Mesenchymal stem cells (MSC) attract particular attention due to their broadly acting anti-inflammatory and regenerative properties. Plenty of preclinical studies provided congruent and convincing evidence that MSC have the therapeutic potential to alleviate lung injuries across ages. These include the disease entities bronchopulmonary dysplasia, asthma and the different forms of acute lung injury and chronic pulmonary diseases in adulthood. While clinical trials are so far restricted to pioneering trials on safety and feasibility, preclinical results point out possibilities to boost the therapeutic efficacy of MSC application and to take advantage of the MSC secretome. The presented review summarizes the most recent advances and highlights joint mechanisms of MSC action across disease entities which provide the basis to timely tackle this global disease burden.

Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma.

Defects in tumor-intrinsic interferon (IFN) signaling result in failure of immune checkpoint blockade (ICB) against cancer, but these tumors may still maintain sensitivity to T cell-based adoptive cell therapy (ACT). We generated models of IFN signaling defects in B16 murine melanoma observed in patients with acquired resistance to ICB. Tumors lacking Jak1 or Jak2 did not respond to ICB, whereas ACT was effective against Jak2 KO tumors, but not Jak1 KO tumors, where both type I and II tumor IFN signaling were defective. This was a direct result of low baseline class I major histocompatibility complex (MHC I) expression in B16 and the dependency of MHC I expression on either type I or type II IFN signaling. We used genetic and pharmacologic approaches to uncouple this dependency and restore MHC I expression. Through independent mechanisms, overexpression of NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) and intratumoral delivery of BO-112, a potent nanoplexed version of polyinosinic:polycytidylic acid (poly I:C), each restored the efficacy of ACT against B16-Jak1 KO tumors. BO-112 activated double-stranded RNA (dsRNA) sensing (via protein kinase R and Toll-like receptor 3) and induced MHC I expression via nuclear factor κB, independent of both IFN signaling and NLRC5. In summary, we demonstrated that in the absence of tumor IFN signaling, MHC I expression is essential and sufficient for the efficacy of ACT. For tumors lacking MHC I expression due to deficient IFN signaling, activation of dsRNA sensors by BO-112 affords an alternative approach to restore the efficacy of ACT.

Recovery of injected freshwater from a brackish aquifer with a multiwell system.

Herein we propose a multiple injection and recovery well system strategically operated for freshwater storage in a brackish aquifer. With the system we call aquifer storage transfer and recovery (ASTR) by using four injection and two production wells, we are capable of achieving both high recovery efficiency of injected freshwater and attenuation of contaminants through adequately long residence times and travel distances within the aquifer. The usual aquifer storage and recovery (ASR) scheme, in which a single well is used for injection and recovery, does not warrant consistent treatment of injected water due to the shorter minimum residence times and travel distances. We tested the design and operation of the system over 3 years in a layered heterogeneous limestone aquifer in Salisbury, South Australia. We demonstrate how a combination of detailed aquifer characterization and solute transport modeling can be used to maintain acceptable salinity of recovered water for its intended use along with natural treatment of recharge water. ASTR can be used to reduce treatment costs and take advantage of aquifers with impaired water quality that might locally not be otherwise beneficially used.

Cancer on a mammogram is not memorable: readers remember their recalls and not cancers.

AIM: To determine if presence of cancer on a mammogram makes that mammogram more memorable. MATERIALS AND METHODS: A total of 100 mammograms (25 cancers) were grouped into 5 sets of 20 cases. Set pairs were presented in five reads to eight radiologist readers. Readers were asked to 'clear' or 'call back' cases, and at post-baseline reads to indicate whether each case was 'new' or 'old' (remembered from prior read). Two sets were presented only at baseline, to calculate each reader's false recollection rate. For cases presented more than once ('old' cases, 100 presentations) readers could have 'correct memory' or 'memory loss'. Memory performance was defined as odds ratio of correct memory to memory loss. Multivariate logistic data regression analysis identified predictors of memory performance from: reader, set, time since last read, presence of cancer, and whether the case was called back at the last read. RESULTS: Memory performance differed markedly between readers and reader identity was a highly significant predictor of memory performance. Presence of cancer was not a significant predictor of memory performance (odds ratio 0.77, 95% CI: 0.49-1.21). Whether the case was called back at the last read was a highly significant predictor (odds ratio 4.22, 95% CI: 2.70-6.61) for the model incorporating reader variability, and also the model without reader variability (odds ratio 2.67, 95% CI: 1.74-4.08). CONCLUSION: The only statistically significant predictor of radiologist memory for a mammogram was whether the radiologist 'called it back' at a prior reading round. Presence of cancer on a mammogram did not make it memorable.