A number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint ...inhibitors (ICIs), but the results remain controversial.
Under the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and efficacy of ICIs in patients with cancer. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Subgroup analyses involving the cancer type, class of ICIs, combination therapy, sample size, model, landmark analysis, and approach used to extract the data were performed. Specific analyses of the type and grade of irAEs were also performed.
This meta-analysis included 30 studies including 4971 individuals. Patients with cancer who developed irAEs experienced both an OS benefit and a PFS benefit from ICI therapy compared to patients who did not develop irAEs (OS: hazard ratio (HR), 0.54, 95% confidence interval (CI), 0.45-0.65; p < 0.001; PFS: HR, 0.52, 95% CI, 0.44-0.61, p < 0.001). Subgroup analyses of the study quality characteristics and cancer types recapitulated these findings. Specific analyses of endocrine irAEs (OS: HR, 0.52, 95% CI, 0.44-0.62, p < 0.001), dermatological irAEs (OS: HR, 0.45, 95% CI, 0.35-0.59, p < 0.001), and low-grade irAEs (OS: HR, 0.57, 95% CI, 0.43-0.75; p < 0.001) yielded similar results. The association between irAE development and a favorable benefit on survival was significant in patients with cancer who were undergoing treatment with programmed cell death-1 inhibitors (OS: HR, 0.51, 95% CI, 0.42-0.62; p < 0.001), but not cytotoxic T-lymphocyte antigen-4 inhibitors (OS: HR, 0.89, 95% CI, 0.49-1.61; p = 0.706). Additionally, the association was significant in patients with cancer who were treated with ICIs as a monotherapy (OS: HR, 0.53, 95% CI, 0.43-0.65; p < 0.001), but not as a combination therapy (OS: HR, 0.62, 95% CI, 0.36-1.05; p = 0.073).
The occurrence of irAEs was significantly associated with a better ICI efficacy in patients with cancer, particularly endocrine, dermatological, and low-grade irAEs. Further large-scale prospective studies are warranted to validate our findings.
PROSPERO CRD42019129310.
Experimental evidence suggest that breast tumors originate from breast cancer stem cells (BCSCs), and that mitochondrial biogenesis is essential for the anchorage-independent clonal expansion and ...survival of CSCs, thus rendering mitochondria a significant target for novel treatment approaches. One of the recognized side effects of the FDA-approved drug, doxycycline is the inhibition of mitochondrial biogenesis. Here we investigate the mechanism by which doxycycline exerts its inhibitory effects on the properties of breast cancer cells and BCSCs, such as mammosphere forming efficiency, invasion, migration, apoptosis, the expression of stem cell markers and epithelial-to-mesenchymal transition (EMT) related markers of breast cancer cells. In addition, we explored whether autophagy plays a role in the inhibitory effect of doxycycline on breast cancer cells. We find that doxycyline can inhibit the viability and proliferation of breast cancer cells and BCSCs, decrease mammosphere forming efficiency, migration and invasion, and EMT of breast cancer cells. Expression of stem cell factors Oct4, Sox2, Nanog and CD44 were also significantly downregulated after doxycycline treatment. Moreover, doxycycline could down-regulate the expression of the autophagy marker LC-3BI and LC-3BII, suggesting that inhibiting autophagy may be responsible in part for the observed effects on proliferation, EMT and stem cell markers. The potent inhibition of EMT and cancer stem-like characteristics in breast cancer cells by doxycycline treatment suggests that this drug can be repurposed as an anti-cancer drug in the treatment of breast cancer patients in the clinic.
Autoimmune connective tissue diseases (ACTDs) are a family of consistent systemic autoimmune inflammatory disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic ...sclerosis (SSc) and Sjögren's syndrome (SS). IL-1R-like receptors (TLRs) are located on various cellular membranes and sense exogenous and endogenous danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), playing a critical role in innate immune responses. During the past decade, the investigation of TLRs in inflammatory autoimmune diseases has been fruitful. In this report, we review the significant biochemical, physiological and pathological studies of the key functions of TLRs in ACTDs. Several proteins in the TLR signaling pathways (e.g., IKK-2 and MyD88) have been identified as potential therapeutic targets for the treatment of ACTDs. Antibodies, oligodeoxyribonucleotides (ODNs) and small molecular inhibitors (SMIs) have been tested to modulate TLR signaling. Some drug-like SMIs of TLR signaling, such as RDP58, ST2825, ML120B and PHA-408, have demonstrated remarkable potential, with promising safety and efficacy profiles, which should warrant further clinical investigation. Nonetheless, one should bear in mind that all TLRs exert both protective and pathogenic functions; the function of TLR4 in inflammatory bowel disease represents such an example. Therefore, an important aspect of TLR modulator development involves the identification of a balance between the suppression of disease-inducing inflammation, while retaining the beneficiary host immune response.
We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and ...healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.
Abstract
Objectives
This randomized, controlled clinical trial aims to compare the efficacy and safety of glucocorticoid combined with MMF and glucocorticoid monotherapy for patients with ...IgG4-related disease.
Methods
Sixty-nine patients newly diagnosed with IgG4-related disease were randomly divided into two groups (35 patients in Group I and 34 patients in Group II). Patients in Group I received glucocorticoid monotherapy (0.6-0.8 mg/(kg·day) and tapered gradually); patients in Group II received glucocorticoid combined with MMF therapy (1-1.5 g/day). All the patients were followed up at 1, 3, 6 and 12 months. The primary endpoint was response rate in 12 months and the secondary endpoints were relapse, remission rate and adverse reactions.
Results
Group I and Group II shared almost the same efficacy at the 1 month treatment, but during the follow-up, the complete response rate in Group II was much higher than that in Group I at different time points, and the cumulative relapse rate during 1 year of therapy was much higher in Group I than that in Group II (40.00 vs 20.59%). The remission rate was lower in Group I (51.42 vs 76.47%). Relapses were more likely to happen in lung, lacrimal gland, salivary gland, paranasal sinus and kidney. MMF could reduce relapse, especially organs recurrence. No serious adverse reactions occurred in the two groups.
Conclusion
Combination treatment with glucocorticoid and MMF was more effective than the monotherapy, and the relapse of IgG4-related disease might be associated with the elevated levels of serum IgG4 and the low glucocorticoid maintenance dose.
Trial registration
ClinicalTrials.gov, www.clinicaltrials.gov, NCT02458196.
Little evidence exists on the safety and efficacy of the rechallenge of immune checkpoint inhibitors (ICIs) after immune-related adverse events (irAEs) in patients with cancer.
We searched PubMed, ...Web of Science, Embase, and Cochrane for articles on ICI rechallenge after irAEs for systemic review and meta-analysis. The outcomes included the incidence and associated factors for safety and objective response rate (ORR) and disease control rate (DCR) for efficacy.
A total of 789 ICI rechallenge cases from 18 cohort studies, 5 case series studies, and 54 case reports were included. The pooled incidence of all-grade and high-grade irAEs after rechallenge in patients with cancer was 34.2% and 11.7%, respectively. Compared with initial ICI treatment, rechallenge showed a higher incidence for all-grade irAEs (OR, 3.81; 95% CI, 2.15-6.74;
< 0.0001), but similar incidence for high-grade irAEs (
> 0.05). Types of initial irAEs (pneumonitis and global irAEs) and cancer (non-small cell lung cancer and multiple cancer) recapitulated these findings. Gastrointestinal irAEs and time interval between initial irAEs and ICI rechallenge were associated with higher recurrence of high-grade irAEs (
< 0.05), whereas initial anti-PD-1/PD-L1 antibodies were associated with a lower recurrence (
< 0.05). Anti-PD-1/PD-L1 antibodies rechallenge was associated with a lower all-grade irAE recurrence (
< 0.05). The pooled ORR and DCR after rechallenge were 43.1% and 71.9%, respectively, showing no significant difference compared with initial ICI treatment (
> 0.05).
ICI rechallenge after irAEs showed lower safety and similar efficacy outcomes compared with initial ICI treatment.
PROSPERO, identifier CRD42020191405.
Abstract
Since the total number of the antenna elements can be up to hundreds in a massive multiple‐input multiple‐output (MIMO) system, subarray‐structured base station (BS) array configurations are ...widely adopted to achieve a good cell coverage and to reduce the required number of radio frequency chains at the same time. It is crucial for any BS product to ensure that the antenna elements perform correctly as expected. Therefore, the necessity of array diagnosis is evident, especially for large BS arrays. Furthermore, it is essential that the diagnosis can be achieved in a compact and cost‐effective setup with high measurement efficiency (i.e. only a few measurement samples are required). The principle of the diagnosis method presented in this article is to obtain the S‐parameters between the subarrays and the probe via solving linear equations. In the simulation, a BS array composed of 16 subarrays with each containing 3 elements is used to validate the diagnosis method at 3.5 GHz. An array composed of 4 subarrays with each containing 3 elements was used in the measurements to verify the diagnosis method with two different phase tuning matrices at 3 GHz. Successful diagnosis results have been achieved in both the simulations and the measurements.
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