We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC).
The ...PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected toin vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling.
The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations ofFGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib.
FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited ...response to ICIs remain unclear.
We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients.
Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved.
HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.
•TMB alone is not sufficiently reliable or accurate as a biomarker of response to ICIs in NSCLC.•TMB-based survival prediction is improved by using the HLA-corrected TMB algorithm (TMB in combination with loss of heterozygosity of HLA).•Notably, additional predictive and prognostic value of the HLA-corrected TMB is not limited to certain types of cancer.•The HLA-corrected TMB could be a new strategy for selecting patients who may benefit from immunotherapy.
Background
Patients with fibromyalgia (FM) exhibit significant clinical heterogeneity, in terms of physical, social and psychological functions, as well as therapeutic responses. Here, we examined FM ...patients in terms of pain, physical, social and psychological variables to identify clinical subgroups that may be predictive of treatment patterns.
Methods
A total of 313 FM patients were interviewed using a structured questionnaire that included sociodemographic data, current or past FM symptoms and current use of relevant medications. A K‐means cluster analysis was conducted using variables reflecting tender points, the Fibromyalgia Impact Questionnaire, Beck Depression Inventory, State‐Trait Anxiety Inventor and Social Support Scale.
Results
Four distinct clusters were identified in these patients. Group 1 was characterized by high pain levels, severe physical and mental impairment and low social support. Group 2 had moderate pain and physical impairment, mild mental impairment and moderate social support. Group 3 had moderate pain, low physical and moderate mental impairment and low social support. Group 4 had low pain levels, nearly normal physical and mental function and high social support. Group 1 was more often a current or past smoker, more likely to have a variety of symptoms, including swelling, cognitive dysfunction, dizziness, syncope, oesophageal dysmotility, dyspepsia, irritable bladder, vulvodynia and restless leg syndrome.
Conclusions
We identified four subgroups of FM patients based on pain, physical, social and psychological function. These subgroups had different clinical symptoms and medication profiles, suggesting that FM may be better managed using a more comprehensive assessment of an individual patient's symptoms.
Significance
FM patients can be clustered into four distinct subgroups based on clinically measurable variables – pain, physical involvement, psychological function and social support. These subgroups had different clinical symptoms and medication profiles.
MicroRNAs (miRNAs) are short, non‐coding RNAs that regulate gene expression at the post‐transcriptional level, which can be measured in cells, tissues, and body fluids including plasma. Differences ...in miRNA expression levels suggest an epigenetic mechanism and changed expression levels are emerging as a novel biomarker for various diseases. We attempted to identify circulating miRNAs associated with susceptibility to systemic lupus erythematosus (SLE) in the Korean population and elucidate their significance for clinical phenotype. An expression profiling analysis using miRNA polymerase chain reaction (PCR) array was conducted with pooled miRNA from 10 patients with SLE and 10 healthy controls (HCs). Nine miRNAs were differentially expressed between the SLE and HC. To verify this, we performed quantitative PCR for various miRNA from SLE patients (n = 70) and HCs (n = 40). The hsa‐miR‐30e‐5p, hsa‐miR‐92a‐3p, and hsa‐miR‐223‐3p were significantly up‐regulated in plasma of SLE patients (P = 0.048, P = 0.039, and P = 0.046, respectively). Especially, the hsa‐miR‐223‐3p was significantly associated with oral ulcer (P < 0.001) and lupus anticoagulant (P = 0.031). Thus, plasma hsa‐miR‐30e‐5p, hsa‐miR‐92a‐3p, and hsa‐miR‐223‐3p may be promising novel biomarkers in the diagnosis and clinical manifestation of SLE.
Microbial metabolites, such as short-chain fatty acids (SCFAs), are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in the regulation of ...T-cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T-cell differentiation into T cells producing interleukin-17 (IL-17), interferon-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41 or GPR43, but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17 (T helper type 17), Th1, and IL-10(+) T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during Citrobacter rodentium infection, but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T-cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.
Vaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. In this study we set out to investigate, for the vaccines currently approved in the ...Netherlands, the immunogenicity and reactogenicity of SARS-CoV-2 vaccinations in PLWH.
We conducted a prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S vaccines in adult PLWH without prior COVID-19, and compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response, and reactogenicity. Between 14 February and 7 September 2021, 1,154 PLWH (median age 53 IQR 44-60 years, 85.5% male) and 440 controls (median age 43 IQR 33-53 years, 28.6% male) were included in the final analysis. Of the PLWH, 884 received BNT162b2, 100 received mRNA-1273, 150 received ChAdOx1-S, and 20 received Ad26.COV2.S. In the group of PLWH, 99% were on antiretroviral therapy, 97.7% were virally suppressed, and the median CD4+ T-cell count was 710 cells/μL (IQR 520-913). Of the controls, 247 received mRNA-1273, 94 received BNT162b2, 26 received ChAdOx1-S, and 73 received Ad26.COV2.S. After mRNA vaccination, geometric mean antibody concentration was 1,418 BAU/mL in PLWH (95% CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV status remained associated with a decreased response (0.607, 95% CI 0.508-0.725, p < 0.001). All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+ T-cell count 250-500 cells/μL (2.845, 95% CI 1.876-4.314, p < 0.001) or >500 cells/μL (2.936, 95% CI 1.961-4.394, p < 0.001), whilst a viral load > 50 copies/mL was associated with a reduced response (0.454, 95% CI 0.286-0.720, p = 0.001). Increased IFN-γ, CD4+ T-cell, and CD8+ T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation-induced marker assays, comparable to controls. Reactogenicity was generally mild, without vaccine-related serious adverse events. Due to the control of vaccine provision by the Dutch National Institute for Public Health and the Environment, there were some differences between vaccine groups in the age, sex, and CD4+ T-cell counts of recipients.
After vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH compared to HIV-negative controls. To reach and maintain the same serological responses as HIV-negative controls, additional vaccinations are probably required.
The trial was registered in the Netherlands Trial Register (NL9214). https://www.trialregister.nl/trial/9214.
In common parlance, moral transgressions "leave a bad taste in the mouth." This metaphor implies a link between moral disgust and more primitive forms of disgust related to toxicity and disease, yet ...convincing evidence for this relationship is still lacking. We tested directly the primitive oral origins of moral disgust by searching for similarity in the facial motor activity evoked by gustatory distaste (elicited by unpleasant tastes), basic disgust (elicited by photographs of contaminants), and moral disgust (elicited by unfair treatment in an economic game). We found that all three states evoked activation of the levator labii muscle region of the face, characteristic of an oralnasal rejection response. These results suggest that immorality elicits the same disgust as disease vectors and bad tastes.
There are a few reports regarding the outcome evaluation of balloon-expandable intracranial stent placement (BEICS). The purpose of our study was to evaluate the outcome and factors related to the ...adverse events (AEs) of BEICS.
We evaluated 100 consecutive patients who underwent BEICS. We assessed the procedural success (residual stenosis < 50%), AEs (minor strokes, major strokes, and death), clinical outcome, and restenosis (> 50%) at 6 months. We also analyzed 18 factors including symptom patterns related to AE rate. Symptom patterns revealed 1) stable patients (n = 73) with improving, stationary, or resolved symptoms; and 2) unstable patients (n = 27) with gradual worsening or fluctuating symptoms (National Institutes of Health Stroke Scale NIHSS > or = 4) within 2 days before stent placement.
The procedural success rate was 99%. Overall, there were 10 (10%) AEs within the 6 months: 4 (4%) minor strokes, 3 (3%) major strokes, and 3 (3%) deaths including a death from myocardial infarction. AE rate was 4.1% in stable and 25.9% in unstable patients. Restenosis at 6 months revealed 0% (0/59). Good outcome (modified Rankin Scale < or = 2) at 6 months was 97% (71/73) in stable and 67% (18/27) in unstable patients. Stepwise logistic regression model revealed that symptom pattern (unstable versus stable) was the only significant risk factor (OR, 8.167; 95% CI, 1.933-34.500; P = .004).
BEICS revealed a low AE and good outcome rate at 6 months, especially in the stable patients. Midterm outcome was also favorable in the unstable patient group.
The isolation of various two-dimensional (2D) materials, and the possibility to combine them in vertical stacks, has created a new paradigm in materials science: heterostructures based on 2D ...crystals. Such a concept has already proven fruitful for a number of electronic applications in the area of ultrathin and flexible devices. Here, we expand the range of such structures to photoactive ones by using semiconducting transition metal dichalcogenides (TMDCs)/graphene stacks. Van Hove singularities in the electronic density of states of TMDC guarantees enhanced light-matter interactions, leading to enhanced photon absorption and electron-hole creation (which are collected in transparent graphene electrodes). This allows development of extremely efficient flexible photovoltaic devices with photoresponsivity above 0.1 ampere per watt (corresponding to an external quantum efficiency of above 30%).
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