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"Waldmann, David A"
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In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer
Mitochondria are essential regulators of cellular energy and metabolism, and have a crucial role in sustaining the growth and survival of cancer cells. A central function of mitochondria is the synthesis of ATP by oxidative phosphorylation, known as mitochondrial bioenergetics. Mitochondria maintain oxidative phosphorylation by creating a membrane potential gradient that is generated by the electron transport chain to drive the synthesis of ATP
1
. Mitochondria are essential for tumour initiation and maintaining tumour cell growth in cell culture and xenografts
2
,
3
. However, our understanding of oxidative mitochondrial metabolism in cancer is limited because most studies have been performed in vitro in cell culture models. This highlights a need for in vivo studies to better understand how oxidative metabolism supports tumour growth. Here we measure mitochondrial membrane potential in non-small-cell lung cancer in vivo using a voltage-sensitive, positron emission tomography (PET) radiotracer known as 4-[
18
F]fluorobenzyl-triphenylphosphonium (
18
F-BnTP)
4
. By using PET imaging of
18
F-BnTP, we profile mitochondrial membrane potential in autochthonous mouse models of lung cancer, and find distinct functional mitochondrial heterogeneity within subtypes of lung tumours. The use of
18
F-BnTP PET imaging enabled us to functionally profile mitochondrial membrane potential in live tumours.
A positron emission tomography imaging tracer is developed to image mitochondrial function in vivo, and application of this tracer to a mouse model of lung cancer identifies distinct functional mitochondrial heterogeneity between tumour cells.
Journal Article
Adverse outcome pathways: opportunities, limitations and open questions
Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.
Journal Article
Electrical Impedance Tomography Can Identify Ventilation and Perfusion Defects: A Neonatal Case
Case Report A 34-weeks' gestation male infant (birth weight, 2,720 g; Apgar score, 8 and 8 at 5 and 10 min) developed tachypnea and 25% oxygen requirement over the first 6 hours of life requiring continuous positive airway pressure in a regional hospital. EIT holds potential in monitoring ventilation and perfusion development in conditions characterized by unilateral lung differences and altered pulmonary blood flow, such as congenital diaphragmatic hernia and after cardiac surgery, over longer time periods. To date, the use of EIT to measure lung perfusion has been limited to human observations in which the perfusion state was not known (2) or animal models with selective occlusion of a single pulmonary artery and injection of an electrical impedance contrast agent (3).
Journal Article
IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages
The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 μg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors. We investigated combination therapy of IL-15 with rituximab in a syngeneic mouse model of lymphoma transfected with human CD20 and with alemtuzumab (Campath-1H) in a xenograft model of human adult T cell leukemia (ATL). IL-15 greatly enhanced the therapeutic efficacy of both rituximab and alemtuzumab in tumor models. The additivity/synergy was shown to be associated with augmented ADCC. Both NK cells and macrophages were critical elements in the chain of interacting effectors involved in optimal therapeutic responses mediated by rituximab with IL-15. We provide evidence supporting the hypothesis that NK cells interact with macrophages to augment the NK-cell activation and expression of FcγRIV and the capacity of these cells to become effectors of ADCC. The present study supports clinical trials of IL-15 combined with tumor-directed monoclonal antibodies.
Journal Article
EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer
Recent findings suggested a benefit of anti-EGFR therapy for basal-like muscle-invasive bladder cancer (MIBC). However, the impact on bladder cancer with substantial squamous differentiation (Sq-BLCA) and especially pure squamous cell carcinoma (SCC) remains unknown. Therefore, we comprehensively characterized pure and mixed Sq-BLCA (n = 125) on genetic and protein expression level, and performed functional pathway and drug-response analyses with cell line models and isolated primary SCC (p-SCC) cells of the human urinary bladder. We identified abundant EGFR expression in 95% of Sq-BLCA without evidence for activating EGFR mutations. Both SCaBER and p-SCC cells were sensitive to EGFR tyrosine kinase inhibitors (TKIs: erlotinib and gefitinib). Combined treatment with anti-EGFR TKIs and varying chemotherapeutics led to a concentration-dependent synergism in SCC cells according to the Chou-Talalay method. In addition, the siRNA knockdown of EGFR impaired SCaBER viability suggesting a putative “Achilles heel” of Sq-BLCA. The observed effects seem Sq-BLCA-specific since non-basal urothelial cancer cells were characterized by poor TKI sensitivity associated with a short-term feedback response potentially attenuating anti-tumor activity. Hence, our findings give further insights into a crucial, Sq-BLCA-specific role of the ERBB signaling pathway proposing improved effectiveness of anti-EGFR based regimens in combination with chemotherapeutics in squamous bladder cancers with wild-type EGFR-overexpression.
Journal Article
Superior T memory stem cell persistence supports long-lived T cell memory
Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (TSCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a TSCM phenotype and stem cell-like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific TSCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of TSCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of TSCM cells.
Journal Article
Lung volume distribution in preterm infants on non-invasive high-frequency ventilation
IntroductionNon-invasive high-frequency oscillatory ventilation (nHFOV) is an extension of nasal continuous positive airway pressure (nCPAP) support in neonates. We aimed to compare global and regional distribution of lung volumes during nHFOV versus nCPAP.MethodsIn 30 preterm infants enrolled in a randomised crossover trial comparing nHFOV with nCPAP, electrical impedance tomography data were recorded in prone position. For each mode of respiratory support, four episodes of artefact-free tidal ventilation, each comprising 30 consecutive breaths, were extracted. Tidal volumes (VT) in 36 horizontal slices, indicators of ventilation homogeneity and end-expiratory lung impedance (EELI) for the whole lung and for four horizontal regions of interest (non-gravity-dependent to gravity-dependent; EELINGD, EELImidNGD, EELImidGD, EELIGD) were compared between nHFOV and nCPAP. Aeration homogeneity ratio (AHR) was determined by dividing aeration in non-gravity-dependent parts of the lung through gravity-dependent regions.Main resultsOverall, 228 recordings were analysed. Relative VT was greater in all but the six most gravity-dependent lung slices during nCPAP (all p<0.05). Indicators of ventilation homogeneity were similar between nHFOV and nCPAP (all p>0.05). Aeration was increased during nHFOV (mean difference (95% CI)=0.4 (0.2 to 0.6) arbitrary units per kilogram (AU/kg), p=0.013), mainly due to an increase in non-gravity-dependent regions of the lung (∆EELINGD=6.9 (0.0 to 13.8) AU/kg, p=0.028; ∆EELImidNGD=6.8 (1.2 to 12.4) AU/kg, p=0.009). Aeration was more homogeneous during nHFOV compared with nCPAP (mean difference (95% CI) in AHR=0.01 (0.00 to 0.02), p=0.0014).ConclusionAlthough regional ventilation was similar between nHFOV and nCPAP, end-expiratory lung volume was higher and aeration homogeneity was slightly improved during nHFOV. The aeration difference was greatest in non-gravity dependent regions, possibly due to the oscillatory pressure waveform. The clinical importance of these findings is still unclear.
Journal Article
Prophylactic surfactant nebulisation for the early aeration of the preterm lung: a randomised clinical trial
ObjectiveThe effect of prophylactic surfactant nebulisation (SN) is unclear. We aimed to determine whether prophylactic SN improves early lung aeration.DesignParallel, randomised clinical trial, conducted between March 2021 and January 2022.SettingDelivery room (DR) of a tertiary neonatal centre in Zurich, Switzerland.PatientsPreterm infants between 26 0/7 and 31 6/7 weeks gestationInterventionsInfants were randomised to receive positive distending pressure alone or positive distending pressure and additional SN (200 mg/kg; poractant alfa) using a customised vibrating membrane nebuliser. SN commenced with the first application of a face mask immediately after birth.Main outcome measuresPrimary outcome was the difference in end-expiratory lung impedance from birth to 30 min after birth (∆EELI30min). EELI correlates well with functional residual capacity. Secondary outcomes included physiological and clinical outcomes.ResultsData from 35 infants were collected, and primary outcome data were analysed from 32 infants (n=16/group). Primary outcome was not different between intervention and control group (median (IQR): 25 (7–62) vs 10 (0–26) AU/kg, p=0.21). ∆EELI was slightly higher in the intervention group at 6 and 12 hours after birth, particularly in the central areas of the lung. There were no differences in cardiorespiratory and clinical parameters. Two adverse events were noted in the intervention group.ConclusionsProphylactic SN in the DR did not significantly affect ∆EELI30min and showed only minimal effects on lung physiology. Prophylactic SN in the DR was feasible. There were no differences in clinical outcomes.Trial registration number NCT04315636.
Journal Article
miR-155 augments CD8⁺ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines
Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic “cytokine sinks.” These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumor-specific CD8 ⁺ T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic γc cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serine-threonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers.
Significance We describe here a strategy based on microRNA therapeutics to augment the efficacy of T-cell–based therapies without the requirement of toxic maneuvers such as lymphodepletion preconditioning and the administration of high doses of exogenous cytokines. These findings can lead to the development of safer and more effective T-cell–based therapies for the treatment of patients with advanced cancer.
Journal Article