Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy

Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD)

Multimodal sensory evaluation of neuropathic spinal cord injury pain ::an experimental study

Study design : An experimental study. Objectives : To investigate the changes in somatosensory functions using the combined application of quantitative sensory testing (QST), contact heat-evoked potentials (CHEPs) and laser-evoked potentials (LEPs) studies in individuals with spinal cord injury (SCI) in relation to neuropathic pain (NeP). Setting : Centre for Pain Medicine, Swiss Paraplegic Centre, Nottwil, Switzerland. Methods : Individuals with SCI were compared: 12 with NeP (SCI NeP) and 12 without NeP (SCI no NeP). Tools used were QST, CHEPs, LEPs and self-reported questionnaires. Tests were applied to the control (hand) and test (dermatome of altered sensation) sites, and compared to the able-bodied group. Results: QST, LEPs and CHEPs assessments showed abnormalities both on the test and control sites, which did not differ between the groups with SCI. QST showed higher prevalence of allodynia in SCI NeP. CHEPs and LEPs demonstrated diminished amplitudes in both groups with SCI in comparison to able-bodied individuals. Only reaction time (RT) analysis revealed the difference of SCI NeP from the other two groups, expressed in partially preserved responses to the laser C-fibre stimulations. Conclusions : Combination of assessments in our study allowed to examine spinothalamic and dorsal column functions in individuals with SCI. Changes in QST, CHEPs and LEPs were detected below the level of injury independent of NeP and at the control site indicating modifications in sensory processing rostral to the spinal lesion. Analysis of RT during laser stimulation could be an essential component when evaluating the somatosensory functions related to NeP in persons with SCI

Usefulness of laser-evoked potentials and quantitative sensory testing in the diagnosis of neuropathic spinal cord injury pain ::a multiple case study

Objectives: The aim of this study was to investigate the contribution of laser-evoked potentials (LEPs) and quantitative sensory testing (QST) to the diagnosis of neuropathic pain in patients with spinal cord injury (SCI) and inconclusive magnetic resonance imaging (MRI) findings. Setting: A multidisciplinary pain center. Methods: QST (DFNS protocol) and Tm-YAG-laser stimulation of the skin were applied within the pain site corresponding with dermatomes of altered sensation. Available MRI scans were reviewed. Results: Thirteen individuals (50±16 years) with SCI were examined. In four cases with no detectable neural lesion on MRI, all QST but three LEP were abnormal. In four patients with poorly defined spinal lesion on MRI, all QST but three LEP only were abnormal. In four cases where pain was not matching adequately with MRI lesions, all patients had abnormal LEP and QST. In one patient showing a spinal cord atrophy, LEP was normal but QST was abnormal. Findings supported the diagnoses at-level (n=5) and below-level (n=8) SCI pain. Spinothalamic tract function assessed by LEP was normal in three cases, but QST was abnormal in all cases. Conclusions: As QST is a psychophysical examination depending on patient cooperation, we suggest that the combination of QST and LEP might be a valuable diagnostic tool to detect lesions of the somatosensory system in a subgroup of patients with neuropathic spinal cord injury pain and inconclusive MRI findings

Acute kidney injury in patients with COVID-19: a retrospective cohort study from Switzerland

BACKGROUND Data about patients in Europe with corona virus disease-2019 (COVID-19) and acute kidney injury (AKI) are scarce. We examined characteristics, presentation and risk factors of AKI in patients hospitalised with COVID-19 in a tertiary hospital in Switzerland. METHODS We reviewed health records of patients hospitalised with a positive nasopharyngeal polymerase chain reaction test for SARS-CoV2 between 1 February and 30 June 2020, at the University Hospital of Basel. The nadir creatinine of the hospitalisation was used as baseline. AKI was defined according the KDIGO guidelines as a 1.5× increase of baseline creatinine and in-hospital renal recovery as a discharge creatinine <1.25× baseline creatinine. Least absolute shrinkage and selection operator (LASSO) regression was performed to select predictive variables of AKI. Based on this a final model was chosen. RESULTS Of 188 patients with COVID-19, 41 (22%) developed AKI, and 11 (6%) required renal replacement therapy. AKI developed after a median of 9 days (interquartile range [IQR] 5-12) after the first symptoms and a median of 1 day (IQR 0-5) after hospital admission. The peak AKI stages were stage 1 in 39%, stage 2 in 24% and stage 3 in 37%. A total of 29 (15%) patients were admitted to the intensive care unit and of these 23 (79%) developed AKI. In-hospital renal recovery at discharge was observed in 61% of all AKI episodes. In-hospital mortality was 27% in patients with AKI and 10% in patients without AKI. Age (adjusted odds ratio [aOR] 1.04, 95% confidence interval [CI] 1.01–1.08; p = 0.024), history of chronic kidney disease (aOR 3.47, 95% CI 1.16–10.49;p = 0.026), C-reactive protein levels (aOR 1.09, 95% CI 1.03–1.06; p = 0.002) and creatinine kinase (aOR 1.03, 95% CI 1.01–1.06; p = 0.002) were associated with development of AKI. CONCLUSIONS AKI is common in hospitalised patients with COVID-19 and more often seen in patients with severe COVID-19 illness. AKI is associated with a high in-hospital mortality

Le cenote d'Ani-e-wee(Lifou, Nouvelle-Calédonie) et son gisement exceptionnel de Nautilus macromphalus

International audienceLe cénote d'Ani-e-Wee renferme un gisement exceptionnel des plus anciens nautiles endémiques de Nouvelle-Calédonie. Son étude depuis la mission Namaka en décembre 2011, livre des indices sur l'origine de ces nautiles et sur la formation des karsts de Lifou. Sur 37 spécimens aperçus, 20 coquilles ont été observées et certaines d'entre elles échantillonnées. Elles se situent entre 35m et 40m de profondeur dans l'eau de mer, sous la lentille d'eau douce de surface. La halocline, qui semble limiter le toit du gisement, a été précisée par des mesures physiques et chimiques et corrélée avec les sédiments déposés dans la cavité. Les coquilles montrent par leur état de conservation, leur position et leur datation, que durant plus de 700 ans des nautiles ont fréquenté le cénote depuis la mer et y sont morts piégés. Depuis 6400 ans, vers la fin de la dernière remontée du niveau marin, le milieu karstique les a conservés quasiment intacts, les laissant progressivement se fossiliser. Les résultats de cette première mission apportent également des perspectives d'études des paléoclimats dans cette zone du Pacifique Sud, et de la karstification à Lifou conduite à la fois par la tectonique régionale et par les variations de niveau marin au Pléistocène

Venovenous extracorporeal membrane oxygenation to treat hypercapnia in a morbidly obese patient

Morbid obesity plays an increasingly important role in healthcare. Patients who are severely obese often suffer from a range of medical problems. One problem is obesity-related hypoventilation syndrome with its resulting hypercapnia. We report a case of a 33-year-old female patient who was in an extraordinarily bad medical state, with severe hypercapnia (pCO2 15.1 kPa), sepsis, acute anuric kidney failure and resulting acidosis (pH 6.96). Her body mass index was 84 kg/m2. Her chances of survival were considered very low after failed attempts at noninvasive ventilation. Based on prior research, we refrained from intubation and chose venovenous extracorporeal membrane oxygenation to treat the hypercapnia. In the entire medical literature, we are not aware of a similarly extraordinary case of obesity-related hypoventilation syndrome that could finally be treated successfully. The idea behind this case report is to consider venovenous extracorporeal membrane oxygenation as an alternative to intubation in this patient collective

Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease.

BACKGROUND: Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored. METHODS: The phenotypic and functional properties of CD4+CD25+CD127lo/- Tregs isolated from patients with LC were compared to healthy controls (HC). Treg redox state was investigated by characterizing intracellular reactive oxygen species (ROS), NADPH oxidase-2 (Nox2) activity, mitochondrial function, morphology, and nuclear factor-erythroid 2-related factor (Nrf2) antioxidant signalling. The relevance of Nrf2 and its downstream target, Heme-oxygenase-1 (HO-1), in Treg function, stability, and survival, was further assessed using mouse models and CRISPR/Cas9-mediated HO-1 knock-out. FINDINGS: Circulating Tregs from LC patients displayed a reduced suppressive function, correlating with liver disease severity, associated with phenotypic abnormalities and increased apoptosis. Mechanistically, this was linked to a dysregulated Nrf2 signalling with resultant lower levels of HO-1, enhanced Nox2 activation, and impaired mitochondrial respiration and integrity. The functional deficit in LC Tregs could be partially recapitulated by culturing control Tregs in patient sera. INTERPRETATION: Our findings reveal that Tregs rely on functional redox homeostasis for their function, stability, and survival. Targeting Treg specific anti-oxidant pathways may have therapeutic potential to reverse the Treg impairment in conditions of oxidative damage such as advanced liver disease. FUNDING: This study was funded by the Wellcome Trust (211113/A/18/Z)