Background
Viral pathogen–associated molecular patterns, such as dsRNA, disrupt airway tolerance to inhaled allergens. Specifically, the Th2 and Th17 cell responses are induced by low‐dose dsRNA and ...the Th1‐dominant response by high‐dose dsRNA.
Objective
In this model, we evaluate the role of TNF‐α in the development of adaptive immune dysfunction to inhaled allergens induced by airway sensitization with dsRNA‐containing allergens.
Methods
A virus‐associated asthma mouse model was generated via simultaneous airway administration of ovalbumin (OVA) and low (0.1 μg) or high (10 μg) doses of polyinosine–polycytidylic acid (polyI:C). The effect of TNF‐α on Th2 airway inflammation was evaluated using TNF‐α‐deficient mice and recombinant TNF‐α.
Results
TNF‐α production was enhanced by airway exposure to low and high doses of polyI:C. After airway sensitization with OVA plus low‐dose polyI:C, TNF‐α‐deficient mice exhibited less OVA‐induced airway inflammation than did wild‐type (WT) mice. However, this did not occur upon sensitization with high‐dose polyI:C. In terms of T‐cell response, the production of IL‐4 from lung T cells after OVA challenge was enhanced by airway sensitization with OVA plus low‐dose polyI:C in WT mice, and this phenotype was inhibited by the absence of TNF‐α. Moreover, the Th2 cell response induced by sensitization with OVA plus low‐dose polyI:C, which was abolished in TNF‐α‐deficient mice, was restored in these mice upon addition of recombinant TNF‐α.
Conclusion
The results of this study suggest that TNF‐α produced by airway exposure to low‐dose dsRNA is a key mediator in the development of Th2 cell response to inhaled allergens.
Summary
Background
Many bacterial components in indoor dust can evoke inflammatory pulmonary diseases. Bacteria secrete nanometre‐sized vesicles into the extracellular milieu, but it remains to be ...determined whether bacteria‐derived extracellular vesicles in indoor dust are pathophysiologically related to inflammatory pulmonary diseases.
Objective
To evaluate whether extracellular vesicles (EV) in indoor air are related to the pathogenesis of pulmonary inflammation and/or asthma.
Methods
Indoor dust was collected from a bed mattress in an apartment. EV were prepared by sequential ultrafiltration and ultracentrifugation. Innate and adaptive immune responses were evaluated after airway exposure of EV.
Results
Repeated intranasal application of indoor‐dust‐induced neutrophilic pulmonary inflammation accompanied by lung infiltration of both Th1 and Th17 cells. EV 50–200 nm in diameter were present (102.5 μg protein concentration/g dust) in indoor dust. These vesicles were internalized by airway epithelial cells and alveolar macrophages, and this process was blocked by treatment of polymyxin B (an antagonist of lipopolysaccharide, an outer‐membrane component of Gram‐negative bacteria). Intranasal application of 0.1 or 1 μg of these vesicles for 4 weeks elicited neutrophilic pulmonary inflammation. This phenotype was accompanied by lung infiltration of both Th1 and Th17 cells, which were reversed by treatment of polymyxin B. Serum dust EV‐reactive IgG1 levels were significantly higher in atopic children with asthma than in atopic healthy children and those with rhinitis or dermatitis.
Conclusion & Clinical Relevance
Indoor dust EV, especially derived from Gram‐negative bacteria, is a possible causative agent of neutrophilic airway diseases.
Aim
To evaluate the anti‐inflammatory effects of glutamine and the underlying signal pathway mechanisms in lipopolysaccharide (LPS)‐stimulated human dental pulp cells (HDPCs).
Methods
Human dental ...pulp cells were exposed to 10 μg mL−1 LPS and various concentrations of glutamine for 24 h. The production of PGE2 and nitric oxide was determined by enzyme‐linked immunosorbent assay (ELISA) and Griess reagent kit, respectively. Cytokines were examined by ELISA, reverse transcriptase‐polymerase chain reaction (RT‐PCR) and real‐time PCR. iNOS and COX protein expression as well as signal pathways were accessed by Western blot. The data were analysed by anova with Bonferroni's test (α = 0.05).
Results
Glutamine reduced LPS‐induced iNOS and COX‐2 protein expression as well as production of NO and PGE2 in a dose‐dependent fashion. Additionally, glutamine suppressed the production and mRNA expression of inflammatory cytokines including interleukin‐1β (IL‐1β), TNF‐α, and IL‐8. Furthermore, glutamine attenuated phosphorylation of extracellular signal‐regulated kinase (ERK), p38, c‐Jun N‐terminal kinase (JNK) and IκB‐α, and nuclear translocation of NF‐kB p65, but enhanced mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) expression in LPS‐treated HDPCs.
Conclusion
Glutamine exerted an anti‐inflammatory effect via activation of MKP‐1 and inhibition of the NF‐kB and MAPK pathways in LPS‐treated HDPCs.
Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, ...and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure.
Patients were randomized 1:1 to DHP107 (200mg/m2 orally twice daily days 1, 8, 15 every 4weeks) or i.v. paclitaxel (175mg/m2 day 1 every 3weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25.
Baseline characteristics were balanced in the 236 randomized patients (n=118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7–4.0) months for DHP107 and 2.6 (95% CI 1.8–2.8) months for paclitaxel (hazard ratio HR=0.85; 95% CI 0.64–1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR=0.93; 95% CI 0.70–1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1−11.5) months for DHP107 versus 8.9 (95% CI 7.1–12.2) months for paclitaxel (HR=1.04; 95% CI 0.76–1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%).
DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC.
NCT01839773.
The survival of patients with head and neck squamous cell carcinoma (HNSCC) can be affected by noncancer health events (NCHE) as well as by index cancer progression and second primary cancer (SPC). ...This study aimed to investigate the risk factors for NCHE and noncancer mortality (NCM) in patients with advanced-stage HNSCC.
This cohort study involved 600 consecutive patients with overall stage III to IV HNSCC who were treated between 2001 and 2010 at our tertiary referral hospital. NCHE was defined as re-admission (i.e. after the primary treatments for the index tumors) due to noncancer-related causes. The incidences of NCHE and NCM and their risk factors were analyzed by using cumulative incidence and cause-specific hazard functions.
During a median follow-up period of 54 months, 224 (37.3%) and 55 (9.2%) of the 600 patients had NCHE and NCM, respectively. The 5-year index cancer mortality, SPC mortality, and NCM rates were 23.8%, 4.2%, and 8.9%, respectively. Multivariate analyses revealed that body mass index <20 kg/m2 (P = 0.018), Charlson comorbidity index (CCI) ≥1 (P < 0.001), tumor recurrence (P < 0.001), SPC occurrence (P < 0.001), and initial chemotherapy (P = 0.049) were independent NCHE predictors. Older age (P < 0.001), CCI ≥1 (P = 0.008), tumor recurrence (P < 0.001), and SPC occurrence (P = 0.047) were independent NCM predictors. Patients with respiratory NCHE were at a higher risk of NCM than patients with other NCHE types (P < 0.001).
One or more comorbidities, tumor recurrence, and SPC occurrence were independent predictors of both NCHE and NCM. Patients with respiratory NCHE had a particularly high risk of NCM.
Background and Purpose
Spinal astrocytes have emerged as important mechanistic contributors to the genesis of mechanical allodynia (MA) in neuropathic pain. We recently demonstrated that the spinal ...sigma non‐opioid intracellular receptor 1 (σ1 receptor) modulates p38 MAPK phosphorylation (p‐p38), which plays a critical role in the induction of MA in neuropathic rats. However, the histological and physiological relationships among σ1, p‐p38 and astrocyte activation is unclear.
Experimental Approach
We investigated: (i) the precise location of σ1 receptors and p‐p38 in spinal dorsal horn; (ii) whether the inhibition of σ1 receptors or p38 modulates chronic constriction injury (CCI)‐induced astrocyte activation; and (iii) whether this modulation of astrocyte activity is associated with MA development in CCI mice.
Key Results
The expression of σ1 receptors was significantly increased in astrocytes on day 3 following CCI surgery. Sustained intrathecal treatment with the σ1 antagonist, BD‐1047, attenuated CCI‐induced increase in GFAP‐immunoreactive astrocytes, and the treatment combined with fluorocitrate, an astrocyte metabolic inhibitor, synergistically reduced the development of MA, but not thermal hyperalgesia. The number of p‐p38‐ir astrocytes and neurons, but not microglia was significantly increased. Interestingly, intrathecal BD‐1047 attenuated the expression of p‐p38 selectively in astrocytes but not in neurons. Moreover, intrathecal treatment with a p38 inhibitor attenuated the GFAP expression, and this treatment combined with fluorocitrate synergistically blocked the induction of MA.
Conclusions and Implications
Spinal σ1 receptors are localized in astrocytes and blockade of σ1 receptors inhibits the pathological activation of astrocytes via modulation of p‐p38, which ultimately prevents the development of MA in neuropathic mice.
Background and purpose
We investigated the effect of celecoxib, a selective inhibitor of cyclo‐oxygenase 2, in patients with intracerebral hemorrhage (ICH).
Methods
We conducted a multicenter, ...randomized, controlled, and open with blinded end‐point trial of 44 Korean patients 18 years or older with ICH within 24 h of onset. The intervention group (n = 20) received celecoxib (400 mg twice a day) for 14 days. The control group (n = 24) received the standard medical treatment for ICH. The primary end‐point was the number of patients with a change in the volume of perihematomal edema (PHE) from the 1st to the 7th ± 1 day (cut‐off value, 20%).
Results
The time from onset to computed tomography scan slightly differed between groups (177 ± 160 min for control vs. 297 ± 305 min for the celecoxib group; P = 0.10). In the primary end‐point analysis using cut‐off values, there was a significant shift to reduced expansion of PHE in the celecoxib group (P = 0.005). With respect to the secondary end‐points, there was also a significant shift to reduced expansion of ICH in the celecoxib group (P = 0.046). In addition, the expansion rate of PHE at follow‐up tended to be higher in the control group than in the celecoxib group (90.6 ± 91.7% vs. 44.4 ± 64.9%; P = 0.058).
Conclusions
In our small, pilot trial, administration of celecoxib in the acute stage of ICH was associated with a smaller expansion of PHE than that observed in controls.
Objectives
Postoperative surgical site infection (SSI) is a frequent postoperative complication in patients with oral cancer and significantly affects patient recovery and medical expenses. The aim ...of this study was to examine the predictors of SSI in patients undergoing major surgery for oral or oropharyngeal squamous cell carcinoma (OSCC) and to determine the relationship between perioperative albumin and the development of SSI.
Subjects and methods
In 337 consecutive patients who underwent clean‐contaminated surgery for OSCC, serum albumin, glucose, and hemoglobin levels were perioperatively measured. Differences between the groups were examined using Fisher's exact test, Mann–Whitney U‐test, and multiple logistic regression analysis.
Results
Surgical site infection was detected in 88 (26.1%) patients with median time to development of 10 (2–25) days. Multiple logistic regression analysis showed that only postoperative serum albumin < 2.5 g dl−1 was an independent variable predictive of SSI (P = 0.003). The duration of hospital stay was negatively correlated with postoperative albumin (R2 = –0.302, P < 0.001).
Conclusion
Early postoperative hypoalbuminemia <2.5 g dl−1 is an independent risk factor for the development of SSI in patients undergoing oral cancer surgery. Clinicians should be aware of the implications of postoperative hypoalbuminemia and consider more intensive postoperative care in these patients.
Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy.
A clinical association analysis was performed to examine the three ...single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway.
For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively.
LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.
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