A human lung alveolus-on-a-chip model of acute radiation-induced lung injury.

Acute exposure to high-dose gamma radiation due to radiological disasters or cancer radiotherapy can result in radiation-induced lung injury (RILI), characterized by acute pneumonitis and subsequent lung fibrosis. A microfluidic organ-on-a-chip lined by human lung alveolar epithelium interfaced with pulmonary endothelium (Lung Alveolus Chip) is used to model acute RILI in vitro. Both lung epithelium and endothelium exhibit DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6 h of radiation exposure, although greater damage is observed in the endothelium. The radiation dose sensitivity observed on-chip is more like the human lung than animal preclinical models. The Alveolus Chip is also used to evaluate the potential ability of two drugs - lovastatin and prednisolone - to suppress the effects of acute RILI. These data demonstrate that the Lung Alveolus Chip provides a human relevant alternative for studying the molecular basis of acute RILI and may be useful for evaluation of new radiation countermeasure therapeutics.

MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis.

Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.

The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.

Pilot clinical and pharmacokinetic study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain.

This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD, was 1.71 ng mL.h-1 (1.1, 6.6) and 0.65 ng mL.h-1 (0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.

Rapid transition from in-person to videoconferencing psychotherapy in a counselor training clinic: A safety and feasibility study during the COVID-19 pandemic.

Due to the COVID-19 pandemic, many counselor training clinics rapidly transitioned in-person (IP) services to videoconferencing psychotherapy (VCP). Because VCP is a relatively new technology, more research is needed to establish whether this delivery format is a safe and acceptable substitute for IP services in counselor training clinics. The purpose of this study is to explore questions related to how clients perceive VCP versus IP in terms of credibility and expectancy. Results from this investigation demonstrate that clients who participate in VCP, without first meeting their counselor in person, may initially question the credibility and effectiveness of VCP. However, results demonstrated improvement, in both groups, across the duration of therapy. These findings provide both initial support for the safety of VCP in counselor training clinics and justification for further research.

Tetrahydrocannabinol and cannabidiol medicines for chronic pain and mental health conditions.

Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells. The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain. THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.

Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.

Rationale: Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear. Methods: We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype. Results: We identified and validated THBS2, at multi-omic levels, as a tumor size-independent biomarker that robustly predicted post-surgical survival in multiple independent clinical cohorts of early-stage LUAD. Furthermore, scRNA-seq data revealed that THBS2 is exclusively derived from a specific cancer-associated fibroblast (CAF) subset that is distinct from CAFs defined by classical markers. Interestingly, our data demonstrated that THBS2 was preferentially secreted via exosomes in early-stage LUAD tumors with high aggressiveness, and its levels in the peripheral plasma associated with short recurrence-free survival. Further characterization showed that THBS2-high early-stage LUAD was characterized by suppressed antitumor immunity. Specifically, beyond tumor cells, THBS2+ CAFs mainly interact with B and CD8+ T lymphocytes as well as macrophages within tumor microenvironment of early-stage LUAD, and THBS2-high LUAD was associated with decreased immune cell infiltrates but increased immune exhaustion marker. Clinically, high THBS2 expression predicted poor response to immunotherapies and short post-treatment survival of patients. Finally, THBS2 recombinant protein suppressed ex vivo T cells proliferation and promoted in vivo LUAD tumor growth and distant micro-metastasis. Conclusions: Our multi-level analyses uncovered tumor-specific THBS2+ CAFs as a key orchestrator promoting aggressiveness in early-stage LUAD.

Functional and molecular characterization of PD1+ tumor-infiltrating lymphocytes from lung cancer patients.

Antibody-mediated cancer immunotherapy targets inhibitory surface molecules, such as PD1, PD-L1, and CTLA-4, aiming to re-invigorate dysfunctional T cells. We purified and characterized tumor-infiltrating lymphocytes (TILs) and their patient-matched non-tumor counterparts from treatment-naïve NSCLC patient biopsies to evaluate the effect of PD1 expression on the functional and molecular profiles of tumor-resident T cells. We show that PD1+ CD8+ TILs have elevated expression of the transcriptional regulator ID3 and that the cytotoxic potential of CD8 T cells can be improved by knocking down ID3, defining it as a potential regulator of T cell effector function. PD1+ CD4+ memory TILs display transcriptional patterns consistent with both helper and regulator function, but can robustly facilitate B cell activation and expansion. Furthermore, we show that expanding ex vivo-prepared TILs in vitro broadly preserves their functionality with respect to tumor cell killing, B cell help, and TCR repertoire. Although purified PD1+ CD8+ TILs generally maintain an exhausted phenotype upon expansion in vitro, transcriptional analysis reveals a downregulation of markers of T-cell dysfunction, including the co-inhibitory molecules PD1 and CTLA-4 and transcription factors ID3, TOX and TOX2, while genes involved in cell cycle and DNA repair are upregulated. We find reduced expression of WNT signaling components to be a hallmark of PD1+ CD8+ exhausted T cells in vivo and in vitro and demonstrate that restoring WNT signaling, by pharmacological blockade of GSK3ß, can improve effector function. These data unveil novel targets for tumor immunotherapy and have promising implications for the development of a personalized TIL-based cell therapy for lung cancer.

Intestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH), which may then progress to the development of cirrhosis and hepatocarcinoma. NASH is characterized by both steatosis and inflammation. Control of inflammation in NASH is a key step for the prevention of disease progression to severe sequalae. Intestinal dysbiosis has been recognized to be an important causal factor in the pathogenesis of NASH, involving both the accumulation of lipids and aggravation of inflammation. The effects of gut dysbiosis are mediated by adverse shifts of various intestinal commensal bacterial genera and their associated metabolites such as butyrate, tryptophan, and bile acids. In this review, we focus on the roles of tryptophan and its metabolites in NASH in association with intestinal dysbiosis and discuss possible therapeutic implications.

Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma.

Rationale: Despite evidence suggesting that the tumor microenvironment (TME) in malignant pleural mesothelioma (MPM) is linked with poor prognosis, there is a lack of studies that functionally characterize stromal cells and tumor-infiltrating lymphocytes (TILs). Here, we aim to characterize the stromal subsets within MPM, investigate their relationship to TILs, and explore the potential therapeutic targets. Methods: We curated a core set of genes defining stromal/immune signatures expressed by mesenchymal cells within the TME using molecular analysis of The Cancer Genome Atlas (TCGA) MPM cohort. Stromal and immune profiles were molecularly characterized using flow cytometry, immunohistochemistry, microarray, and functionally evaluated using T cell-activation/expansion, coculture assays and drug compounds treatment, based on samples from an independent MPM cohort. Results: We found that a high extracellular matrix (ECM)/stromal gene signature, a high ECM score, or the ratio of ECM to an immune activation gene signature are significantly associated with poor survival in the MPM cohort in TCGA. Analysis of an independent MPM cohort (n = 12) revealed that CD8+ and CD4+ TILs were characterized by PD1 overexpression and concomitant downregulation in degranulation and CD127. This coincided with an increase in CD90+ cells that overexpressed PD-L1 and were enriched for ECM/stromal genes, activated PI3K-mTOR signaling and suppressed T cells. Protein array data demonstrated that MPM samples with high PD-L1 expression were most associated with activation of the mTOR pathway. Further, to reactivate functionally indolent TILs, we reprogrammed ex vivo TILs with Ibrutinib plus Rapamycin to block interleukin-2-inducible kinase (ITK) and mTOR pathways, respectively. The combination treatment shifted effector memory (TEM) CD8+ and CD4+ TILs towards T cells that re-expressed CD45RA (TEMRA) while concomitantly downregulating exhaustion markers. Gene expression analysis confirmed that Ibrutinib plus Rapamycin downregulated coinhibitory and T cell signature pathways while upregulating pathways involved in DNA damage and repair and immune cell adhesion and migration. Conclusions: Our results suggest that targeting the TME may represent a novel strategy to redirect the fate of endogenous TILs with the goal of restoring anti-tumor immunity and control of tumor growth in MPM.

Enhancing Endocannabinoid Control of Stress with Cannabidiol.

The stress response is a well-defined physiological function activated frequently by life events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and increase the risk of somatic and mental health disorders. There is a need for a more effective and safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabinoid system is one of the main regulators of the stress response. A basal endocannabinoid tone inhibits the stress response, modulation of this tone permits/curtails an active stress response, and chronic deficiency in the endocannabinoid tone is associated with the pathological complications of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid system that could be a useful treatment for stress. There have been seven double-blind placebo controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially controlled study on 120 participants. All showed that CBD was effective in significantly reducing the stress response and was non-inferior to pharmaceutical comparators, when included. The clinical trial results are supported by the established mechanisms of action of CBD (including increased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the effectiveness of CBD for treating stress.

Smoking signature is superior to programmed death-ligand 1 expression in predicting pathological response to neoadjuvant immunotherapy in lung cancer patients.

BACKGROUND: There is a paucity of biomarkers that can predict the degree of pathological response [e.g., pathological complete response (pCR) or major response (pMR)] to immunotherapy. Neoadjuvant immunotherapy provides an ideal setting for exploring responsive biomarkers because the pathological responses can be directly and accurately evaluated. METHODS: We retrospectively collected the clinicopathological characteristics and treatment outcomes of non-small cell lung cancer (NSCLC) patients who received neoadjuvant immunotherapy or chemo-immunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center. Clinicopathological factors associated with pathological response were analyzed. RESULTS: A total of 39 patients (35 males and 4 females) were included. The most common histological subtype was lung squamous cell carcinoma (LUSC) (n=28, 71.8%), followed by lung adenocarcinoma (LUAD) (n=11, 28.2%). After neoadjuvant treatment, computed tomography (CT) scan-based evaluation showed poor agreement with the postoperatively pathological examination (weighted kappa =0.0225; P=0.795), suggesting the poor performance of CT scans in evaluating the response to immunotherapy. Importantly, we found that the smoking signature displayed a better performance than programmed death-ligand 1 (PD-L1) expression in predicting the pathological response (area under the curve: 0.690 vs. 0.456; P=0.0259), which might have resulted from increased tumor mutational burden (TMB) and/or microsatellite instability (MSI) relating to smoking exposure. CONCLUSIONS: These findings suggest that CT scan-based evaluation is not able to accurately reflect the pathological response to immunotherapy and that smoking signature is a superior marker to PD-L1 expression in predicting the benefit of immunotherapy in NSCLC patients.

Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer.

BACKGROUND: Although T cell abundance in solid tumours is associated with better outcomes, it also correlates with a stroma-mediated source of immune suppression driven by TGFß1 and poor overall survival. Whether this also is observed in non-small cell lung cancer (NSCLC) is unknown. METHODS: We utilized molecular analysis of The Cancer Genome Atlas (TCGA) NSLCC cohort to correlate immune activation (IA) gene expression and extracellular matrix/stromal (ECM/stromal) gene expression with patient survival. In an independent cohort of NSCLC samples, we used flow cytometry to identify mesenchymal subsets and ex vivo functional studies to characterize their immune regulatory function. FINDINGS: We observed a high enrichment in a core set of genes defining an IA gene expression signature in NSCLC across TCGA Pan-cancer cohort. High IA signature score correlates with enrichment of ECM/stromal gene signature across TCGA NSCLC datasets. Importantly, a higher ratio of ECM/stromal to IA gene signature score was associated with shorter overall survival. In tumours resected from a separate cohort of NSCLC patients, we identified CD90+CD73+ peritumoral cells that were enriched in the ECM/stromal gene signature, which was amplified by TGFß1. IFNγ and TNFα-primed peritumoral CD90+CD73+ cells upregulate immune checkpoint molecules PD-L1 and IDO1 and secrete an array of cytokines/chemokines including TGFß1. Finally, immune primed peritumoral CD90+CD73+ cells suppress T cell function, which was relieved following combined blockade of PD-L1 and TGFß1 with IDO1 inhibition but not PD-L1 or anti-CD73 alone. INTERPRETATION: Our findings suggest that targeting PD-L1 together with independent biological features of the stroma may enhance host antitumor immunity in NSCLC. FUNDING: LW and HY are supported by a 4-year China Scholarship Council award. This work was funded, in part, by a grant from the Cancer League of Bern, Switzerland to SRRH. Laser scanning microscopy imaging was funded by the R'Equip grant from the Swiss National Science Foundation Nr. 316030_145003.

The intestinal microbiota and improving the efficacy of COVID-19 vaccinations.

Most COVID-19 cases are mild or asymptomatic and recover well, suggesting that effective immune responses ensue, which successfully eliminate SARS-CoV-2 viruses. However, a small proportion of patients develop severe COVID-19 with pathological immune responses. This indicates that a strong immune system balanced with anti-inflammatory mechanisms is critical for the recovery from SARS-CoV-2 infections. Many vaccines against SARS-CoV-2 have now been developed for eliciting effective immune responses to protect from SARS-CoV-2 infections or reduce the severity of the disease if infected. Although uncommon, serious morbidity and mortality have resulted from both COVID-19 vaccine adverse reactions and lack of efficacy, and further improvement of efficacy and prevention of adverse effects are urgently warranted. Many factors could affect efficacy of these vaccines to achieve optimal immune responses. Dysregulation of the gut microbiota (gut dysbiosis) could be an important risk factor as the gut microbiota is associated with the development and maintenance of an effective immune system response. In this narrative review, we discuss the immune responses to SARS-CoV-2, how COVID-19 vaccines elicit protective immune responses, gut dysbiosis involvement in inefficacy and adverse effects of COVID-19 vaccines and the modulation of the gut microbiota by functional foods to improve COVID-19 vaccine immunisations.

The renin-angiotensin system in central nervous system tumors and degenerative diseases.

Despite their differences, central nervous system (CNS) tumors and degenerative diseases share important molecular mechanisms underlying their pathologies, due to their common anatomy. Here we review the role of the renin-angiotensin system (RAS) in CNS tumors and degenerative diseases, to highlight common molecular features and examine the potential merits in repurposing drugs that inhibit the RAS, its bypass loops, and converging signaling pathways. The RAS consists of key components, including angiotensinogen, (pro)renin receptor (PRR), angiotensin-converting enzyme 1 (ACE1), angiotensin-converting enzyme 2 (ACE2), angiotensin I (ATI), angiotensin II (ATII), ATII receptor 1 (AT1R), ATII receptor 2 (AT2R) and the Mas receptor (MasR). The RAS is integral to systemic and cellular pathways that regulate blood pressure and body fluid equilibrium and cellular homeostasis. The main effector of the RAS is ATII which exerts its effect by binding to AT1R and AT2R through two competitive arms: an ACE1/ATII/AT1R axis, which is involved in regulating oxidative stress and neuroinflammation pathways, and an ATII/AT2R and/or ATII/ACE2/Ang(1-7)/MasR axis that potentiates neuroprotection pathways. Alterations of these axes are associated with cellular dysfunction linked to CNS diseases. The generation of ATII is also influenced by proteases that constitute bypass loops of the RAS. These bypass loops include cathepsins B, D and G and chymase and aminopeptidases. The RAS is also influenced by converging pathways such as the Wnt/ß-catenin pathway which sits upstream of the RAS via PRR, a key component of the RAS. We also discuss the co-expression of components of the RAS and markers of pluripotency, such as OCT4 and SOX2, in Parkinson's disease and glioblastoma, and their potential influences on transduction pathways involving the Wnt/ß-catenin, MAPK/ERK, PI3K/AKT and vacuolar (H+) adenosine triphosphatase (V-ATPase) signaling cascades. Further research investigating modulation of the ACE1/ATII/AT1R and ACE2/Ang(1-7)/MasR axes with RAS inhibitors may lead to novel treatment of CNS tumors and degenerative diseases. The aim of this review article is to discuss and highlight experimental and epidemiological evidence for the role of the RAS, its bypass loops and convergent signaling pathways in the pathogenesis of CNS tumors and degenerative diseases, to direct research that may lead to the development of novel therapy.

Altered gut microbial metabolites could mediate the effects of risk factors in Covid-19.

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is now pandemic. While most Covid-19 patients will experience mild symptoms, a small proportion will develop severe disease, which could be fatal. Clinically, Covid-19 patients manifest fever with dry cough, fatigue and dyspnoea, and in severe cases develop into acute respiratory distress syndrome (ARDS), sepsis and multi-organ failure. These severe patients are characterized by hyperinflammation with highly increased pro-inflammatory cytokines including IL-6, IL-17 and TNF-alpha as well as C-reactive protein, which are accompanied by decreased lymphocyte counts. Clinical evidence supports that gut microbiota dysregulation is common in Covid-19 and plays a key role in the pathogenesis of Covid-19. In this narrative review, we summarize the roles of intestinal dysbiosis in Covid-19 pathogenesis and posit that the associated mechanisms are being mediated by gut bacterial metabolites. Based on this premise, we propose possible clinical implications. Various risk factors could be causal for severe Covid-19, and these include advanced age, concomitant chronic disease, SARS-CoV-2 infection of enterocytes, use of antibiotics and psychological distress. Gut dysbiosis is associated with risk factors and severe Covid-19 due to decreased commensal microbial metabolites, which cause reduced anti-inflammatory mechanisms and chronic low-grade inflammation. The preconditioned immune dysregulation enables SARS-CoV-2 infection to progress to an uncontrolled hyperinflammatory response. Thus, a pre-existing gut microbiota that is diverse and abundant could be beneficial for the prevention of severe Covid-19, and supplementation with commensal microbial metabolites may facilitate and augment the treatment of severe Covid-19.

A pilot safety, tolerability and pharmacokinetic study of an oro-buccal administered cannabidiol-dominant anti-inflammatory formulation in healthy individuals: a randomized placebo-controlled single-blinded study.

BACKGROUND: The cannabis plant presents a complex biochemical unit of over 500 constituents of which 70 or more molecules have been classified as cannabinoids binding to cannabinoid receptors. The study aimed to investigate the safety, tolerability, and preliminary pharmacokinetics of a nanoparticle CBD formulation. METHODS: The cannabis-based medicine was elaborated with a micellular technology, to produce a water-soluble nanoparticle CBD-dominant anti-inflammatory cannabis medicine (MDCNB-02). On day one, 12 participants administered 2 sprays and on day 2 administered 6 sprays to alternating right and left cheeks [18 mg of CBD and 0.72 mg of THC]. Four other participants administered 2 and 6 sprays on days 1 and 2, respectively of a nanoparticle placebo. RESULTS: The study met the primary outcomes of safety, tolerability, and preliminary pharmacokinetics of a standardized CBD-dominant anti-inflammatory extract for oro-buccal administration. Bioavailability of a 6 mg and 18 mg dose of CBD (median IQR) was 0.87 and 8.9 ng h mL-1, respectively. The maximum concentration of CBD for the low and high doses administered once per day occurred at 60 min for both concentrations. The median half-life of the 6 mg and 18 mg CBD dose was 1.23 and 5.45 h, respectively. The apparent clearance of CBD was 115 and 34 L min-1 for a 6 mg and 18 mg dose, respectively. CONCLUSION: The oro-buccal nanoparticle formulation achieved plasma concentrations that were largely comparable to other commercial and investigated formulations relative to the concentrations administered. Moreover, there were no reports of adverse effects associated with unfavorable inflammatory sequalae.

Pulmonary mesenchymal stem cells are engaged in distinct steps of host response to respiratory syncytial virus infection.

Lung-resident (LR) mesenchymal stem and stromal cells (MSCs) are key elements of the alveolar niche and fundamental regulators of homeostasis and regeneration. We interrogated their function during virus-induced lung injury using the highly prevalent respiratory syncytial virus (RSV) which causes severe outcomes in infants. We applied complementary approaches with primary pediatric LR-MSCs and a state-of-the-art model of human RSV infection in lamb. Remarkably, RSV-infection of pediatric LR-MSCs led to a robust activation, characterized by a strong antiviral and pro-inflammatory phenotype combined with mediators related to T cell function. In line with this, following in vivo infection, RSV invades and activates LR-MSCs, resulting in the expansion of the pulmonary MSC pool. Moreover, the global transcriptional response of LR-MSCs appears to follow RSV disease, switching from an early antiviral signature to repair mechanisms including differentiation, tissue remodeling, and angiogenesis. These findings demonstrate the involvement of LR-MSCs during virus-mediated acute lung injury and may have therapeutic implications.

Pharmaco-transcriptomic correlation analysis reveals novel responsive signatures to HDAC inhibitors and identifies Dasatinib as a synergistic interactor in small-cell lung cancer.

BACKGROUND: Histone acetylation/deacetylase process is one of the most studied epigenetic modifications. Histone deacetylase inhibitors (HDACis) have shown clinical benefits in haematological malignancies but failed in solid tumours due to the lack of biomarker-driven stratification. METHODS: We perform integrative pharmaco-transcriptomic analysis by correlating drug response profiles of five pan-HDACis with transcriptomes of solid cancer cell lines (n=659) to systematically identify generalizable gene signatures associated with HDACis sensitivity and resistance. The established signatures are then applied to identify cancer subtypes that are potentially sensitive or resistant to HDACis, and drugs that enhance the efficacy of HDACis. Finally, the reproductivity of the established HDACis signatures is evaluated by multiple independent drug response datasets and experimental assays. FINDINGS: We successfully delineate generalizable gene signatures predicting sensitivity (containing 46 genes) and resistance (containing 53 genes) to all five HDACis, with their reproductivity confirmed by multiple external sources and independent internal assays. Using the gene signatures, we identify low-grade glioma harbouring isocitrate dehydrogenase 1/2 (IDH1/2) mutation and non-YAP1-driven subsets of small-cell lung cancer (SCLC) that particularly benefit from HDACis monotherapy. Further, based on the resistance gene signature, we identify clinically-approved Dasatinib as a synthetic lethal drug with HDACi, synergizing in inducing apoptosis and reactive oxygen species on a panel of SCLC. Finally, Dasatinib significantly enhances the therapeutic efficacy of Vorinostat in SCLC xenografts. INTERPRETATION: Our work establishes robust gene signatures predicting HDACis sensitivity/resistance in solid cancer and uncovers combined Dasatinib/HDACi as a synthetic lethal combination therapy for SCLC. FUNDING: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun).