Diagnostic models of non-small cell lung cancer based on determination of blood cytokines and their receptors

Cytokine biomarkers have been suggested to be a promising tool for detecting lung cancer at the initial stage of its development. However, they have not found wide application in practice due to the low diagnostic sensitivity and specificity. The aim of the work was to develop an original combination of the blood level of proteins that could increase the efficiency of their use in the diagnosis of I and II stages of non-small cell lung cancer (NSCLC).152 patients (93 men and 59 women) with newly diagnosed NSCLC were examined: 91 had adenocarcinoma (AC) and 61 had squamous cell lung cancer (SCLC). As a control, 36 healthy patients and 13 patients with hamartoma were examined. The serum level of CYFRA 21-1, SCC, CXCL5 by the immunoassay procedure, of the C-reactive protein (CRP) by the turbidimetric method, and the fluorescence intensity of CXCR2 (MFI CXCR2) receptors on blood lymphocytes by flow cytometry were evaluated.The diagnostic efficacy of the individually analyzed results of measuring CYFRA 21-1, CXCL5, MFI CXCR2, and CRP in AK patients and the level of SCC, CXCL5, MFI CXCR2, and CRP in SCLC was less than 75 %.Two regression equations were developed using a combination of the values of each 4 markers for the diagnosis of the initial disease phase. The ROC-analysis revealed the optimal values of thresholds. In the range 0.307–0.483, the probability of AC on I and II stages was 97.9 %. In SCLC, the threshold range was 0.321–0.529. The predictive value of a positive result was 96.7 %.The examination groups included 17 patients with AK, 14 patients with SCLC, 9 patients with hamartoma, and 12 healthy people. Checking the model performance on an example sample of patients with AC showed that the diagnostic sensitivity was 76.3 %, and the diagnostic specificity was 82.8 %, in SCLC – 76.3 and 81.5 %, respectively

Effect of Hyperbaric Oxygenation on Blood Cytokines and Arginine Derivatives; No Evidence for Induction of Inflammation or Endothelial Injury

(1) Background: Hyperbaric oxygen therapy (HBOT) uses 100% oxygen delivered at 1.5–3 times the atmospheric pressure in a specialised chamber to achieve supraphysiological oxygen tension in blood and tissues. Besides its target, HBOT may affect inflammation, endothelial function or angiogenesis. This study analysed the effect of HBOT on blood concentrations of factors that may affect these processes in patients with necrotizing soft-tissue infections (NSTI), aseptic bone necrosis (ABN) and idiopathic sudden sensory neural hearing loss (ISSNHL). (2) Methods: Concentrations asymmetric dimethylarginine (ADMA) and other arginine derivatives were measured with liquid chromatography/mass spectrometry, whereas ELISA was used to quantitate vascular endothelial growth factor (VEGF) and cytokines (IL-1, IL-4, IL-6, IL-10, TGF-β) before and after HBOT in 80 patients (NSTI n = 21, ISSNHL n = 53, ABN n = 6). (3) Results: While some differences were noted between patient groups in ADMA and other arginine derivatives as well as in cytokine concentrations, HBOT did not affect any of these parameters. (4) Conclusions: While cytokines and arginine derivatives concentrations were modified by underlying pathology, hyperbaric oxygenation did not immediately modify it suggesting that it is neutral for inflammation and is not inducing endothelial injury.

Inflammatory cytokines, placental pathology, and neurological outcomes in infants born to preterm preeclamptic mothers

Preeclampsia is both a vascular and inflammatory disorder. Since the placenta is a conduit for fetal development, preeclampsia should be a presumed cause of adverse infant outcomes. Yet, the relationship of placental pathology, inflammation and neurological outcomes after preeclampsia are understudied. We prospectively examined a cohort of maternal-infant dyads with preeclampsia for maternal inflammatory cytokines at time of preeclampsia diagnosis and delivery, and fetal cord blood cytokines (IL-1β, IL-6, IL-8, and TNF-α). Placentas were analyzed for inflammatory and vascular pathologies. Neurodevelopmental assessment of infants utilizing the Pediatric Stroke Outcome Measure (PSOM) was conducted at 6-month corrected gestational age. Eighty-one maternal-newborn dyads were examined. Worse neurological outcomes were not associated with elevated maternal / fetal cytokines. Early preterm birth (gestational age ≤ 32 weeks) was associated with worse neurological outcomes at 6-months regardless of maternal/ fetal cytokine levels, placental pathology, or cranial ultrasound findings (OR 1.70, [1.16–2.48], p = 0.006). When correcting for gestational age, elevated IL-6 approached significance as a predictor for worse developmental outcome (OR 1.025 [0.985–1.066], p = 0.221). Pathological evidence of maternal malperfusion and worse outcomes were noted in early preterm, although our sample size was small. Our study did not demonstrate an obvious association of inflammation and placental pathology in preeclampsia and adverse neurodevelopmental outcome at 6-month corrected age but does suggest maternal malperfusion at earlier gestational age may be a risk factor for worse outcome.

PSX-B-30 Study of the effects of gestational and weaning stresses on blood cytokines and analytes in pigs

The effects of the practice of weaning in pigs have been documented, and include changes in organ function and immune mechanisms. However, the effects of weaning following exposure to maternal infection during gestation are incompletely characterized. We hypothesize that the disruption of physiological processes triggered by weaning can be influenced by the exposure of the pig to maternal immune signals elicited by a challenge during gestation. To test our hypothesis, the concentrations of biochemical indicators and cytokines were measured in the blood from 72 female and male pigs distributed across two weaning groups (nursed or weaned), and two gestational challenge groups (gilts infected with porcine reproductive and respiratory virus or healthy controls). Weaning had a significant effect on the concentration of albumin among females born from healthy gilts (P < 0.01). The albumin concentrations were higher in weaned relative to nursed pigs from healthy gilts. This pattern may be associated with the transition to a higher protein diet, whereas no differences were observed among pigs from infected gilts. The interaction between gestation and weaning stresses had a significant effect on the concentration of bicarbonate. The highest levels of bicarbonate were detected among nursed pigs from infected gilts. The lowest levels of bicarbonate were detected among weaned pigs from health gilts, and this could indicate metabolic acidosis. An interaction effect (P < 0.02) was detected for pro-inflammatory interleukin 4. The highest concentrations of interleukin 4 were detected in weaned females from infected gilts, while the lowest levels were detected among weaned males from health gilts. The studied biomarker patterns indicate that the effect of weaning on blood indicators can be influenced by the exposure of the pigs to challenges during gestation. This study is supported by USDA NIFA AFRI, grant number 2018-67015-27413.

Circulating Cytokines Predict 1H-Proton MRS Cerebral Metabolites in Healthy Older Adults

Background: Changes in both circulating cytokines and neurochemical concentrations have been observed in aging. Patterns of change across these factors are associated with age-related pathologies, including neurodegenerative disease. More evidence to define patterns of change that are characteristic of healthy aging is needed, as is an investigation into how age-related changes in blood cytokines and brain neurochemicals may relate to one another in a healthy older adult population.Methods: Single voxel 1H-proton magnetic resonance spectroscopy was collected in medial frontal and medial parietal regions. Phosphocholine and glycerophosphocholine (Cho), myo-inositol (MI), N-acetylaspertate and N-acetylasperglutamate (NAA), creatine and phosphocreatine (Cr), and glutamate and glutamine (Glx) were measured in a sample of 83 healthy, cognitively normal adults aged 52–89. Blood data were collected to quantify 12 cytokines: interleukins (IL-) 2, 5, 6, 7, 8, 10, 12, 13, IL-1 β, tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), and IL-17 α. Correlation analyses were performed to assess age relationships between each of these factors. Backward linear regressions were performed. Cytokine data and age were used as predictors of each cerebrospinal fluid (CSF)-corrected metabolite concentration in both voxels.Results: Associations were identified between a variety of cytokines and concentrations of frontal NAA, Cr, and Glx, and of parietal MI, Cho, NAA, and Cr. In the frontal voxel, NAA was predicted by more IL-1B and less TNF-α, Cr by less TNF-α and more IL-5, and Glx by less TNF-α. In the parietal voxel, MI was predicted by more IL-10 and IL-8 and less IL-2, Cho by more TNF-α and less IL-2, NAA by more IL-1B and TNF-α and less IL-13, IL-2, and IL-7, and Cr by more IL-10 and less IL-2.Conclusions: Associations were identified between circulating cytokines and neurometabolite concentrations in this sample of older adults. The present results serve as the initial evidence of relationships between circulating cytokines and neurophysiology. Findings invite further investigation to understand the physiological consequences of aging, and how peripheral inflammatory markers may relate to neurochemical concentrations in healthy aging.

COM701 with or without nivolumab: Results of an ongoing phase 1 study of safety, tolerability and preliminary antitumor activity in patients with advanced solid malignancies (NCT03667716).

2504 Background: COM701 is a novel first in class humanized IgG4 monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG), blocking its interaction with its ligand, PVRL2. Blocking of PVRIG leads to enhanced activation of T/NK cells and in mouse models inhibits tumor growth. We report new and updated results on safety/tolerability/pharmacokinetics and antitumor activity from this ongoing study including final results in dose escalation combination cohort, monotherapy expansion cohort (MEC). Methods: We enrolled a total of 51 DLT-evaluable pts: Arm A (COM701 mono dose escalation), 16 pts in 8 cohorts (0.01 – 20 mg/kg IV Q3/4 wks); Arm B (COM701 0.3 – 20 mg/kg + nivolumab (NIVO) 360 mg/480 mg IV Q3/Q4 wks), 15 pts in 5 cohorts; 20 pts in MEC (NSCLC, OVCA, breast, endometrial and CRC) at the recommended dose for expansion(RDFE), 20 mg/kg IV Q4 wks. Key inclusion criteria: Age ≥18 yrs, histologically confirmed metastatic solid malignancy, has exhausted available standard tx, ECOG 0-1, prior ICI permissible (except prior tx with a PVRIG inhibitor). Key exclusion criteria: active autoimmune disease requiring systemic tx, hx inflammatory lung disease. Primary objectives – safety/tolerability of COM701 ± NIVO (AEs, CTCAE v4.03), PK, RDFE. Key secondary/exploratory objectives - antitumor activity of COM701 ± NIVO (RECIST v1.1), evaluation of PVRL2 expression in tumor biopsy, blood cytokines and immunophenotyping. Results: No DLTs were reported in Arms A or B. COM701 PK profile similar in Arm A, 20 mg/kg IV Q4 wks (cohort 8) and Arm B cohort 5 (COM701 20 mg/kg + NIVO 480 mg; all IV Q4 wks). Frequency of TEAEs in safety population (N=54 pts): pts on COM701 mono (N=38)- No AE (4), Grade≤2 (21), G3 (11), G4 (1), G5 (1, PD), pts on combo (N=16) - Grade≤2 (8), G3 (7), G5 (1, PD). Serious TEAE: pts on COM701 mono 11/38, pts on combo 6/16. Most frequent AEs in Arm A: Grade ≤2 fatigue 12/38 pts (31%), nausea 9/38 (23%); Arm B: fatigue 7/16 pts (44%) and AST increased 4/16 pts (25%). Antitumor activity - in Arm A (cohort 8), a pt with platinum resistant primary peritoneal cancer had confirmed PR ongoing 14 months. In Arm B (COM701 10 mg/kg + NIVO 480 mg, all IV Q4 wks), a pt with anal SCCA; confirmed CR, ongoing 18 months, last tx with prior PD on NIVO. In addition, a pt with renal cell CA had confirmed SD [ongoing 13 months, COM701 0.3 mg/kg + NIVO 360mg; IV Q3 wks],] In MEC, 30% (6/20 pts) had best response of SD [1-endometrial, 3 NSCLC, 2 OVCA], 2 pts [NSCLC, OVCA] ongoing at 6/4 months. Overall 16pts had prior tx-refractory disease, 9(56%) had best response of ≥SD. Of 18 pts with prior tx with ICI, 13 (72%) had best response of ≥SD. Datacut 14Dec2020. Conclusions: COM701 ± NIVO well tolerated with no new safety signals. Encouraging signal of antitumor activity including in pts with prior tx with ICI or prior tx-refractory disease. Clinical trial information: NCT03667716..

Environmental and Genetic Factors in the Pathogenesis of COPD in the Road-Working Population

Background. Chronic obstructive pulmonary disease (COPD) is a typical heterogeneous condition caused by environmental and genetic risk factors. Objectives. We investigated extrinsic (environmental) and intrinsic (genetic) factors contributing to the development of COPD in a nonsmoker road-working population in Northeast China. Method. The target population was divided into a COPD group and an exposed control group. Another healthy nonroad working nonsmoker control group was also included for environmental factor comparison. Peripheral blood was collected and analyzed using inductively coupled plasma mass spectrometry for inorganic elements of PM2.5, and microarray, rt-PCR, and Multiplex ELISA for genetic factors. Results. Forty-three COPD road workers, thirty-nine non-COPD road workers, and 52 age and gender-matched healthy nonroad workers were enrolled. There were significantly higher levels in all 24 inorganic elements in the COPD group compared with the healthy control group except potassium and manganese, while the majority of inorganic elements were similar between the COPD group and the exposed control group except in aluminum and cobalt. There were 39 genes showing significant differences between the COPD group and the exposed control group. Collagen, type XV, alpha 1 (COL15A1), Meis homeobox 1 (MEIS1), carbonyl reductase 3 (CBR3), and amine oxidase, copper containing 3 (AOC3) were confirmed by rt-PCR to be differentially expressed. Their correlations with blood cytokines were also evaluated. Conclusions. Aluminum might contribute to the development of COPD in the road-working population. CBR3 and AOC3 seem expressed in different patterns than previously reported, evidenced by their correlation with proinflammatory and anti-inflammatory cytokines.