Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether, a marine algae derived bromophenol, inhibits the growth of Botrytis cinerea and interacts with DNA molecules.

Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) is a bromophenol isolated from marine algae. Previous reports have shown that BDDE possesses cytotoxic and antibacterial activity. In the present study, we demonstrate that BDDE displays broad-spectrum antifungal activities, especially on Botrytis cinerea. BDDE inhibits the growth of B. cinerea cultured on a solid medium of potato dextrose agar (PDA) as well as on the potato dextrose broth (PDB) medium. Moreover, BDDE decreases the incidence of fruit decay and severity of strawberries infected with B. cinerea. Further studies have revealed that BDDE decreases the germination rate and inhibits the mycelial growth of B. cinerea. The inhibition mechanisms are related to the disruption of the cell membrane integrity in B. cinerea spores and newly formed germ tubes. This study also suggests that BDDE possibly interacts with DNA via intercalation and minor groove binding. The studies provide evidence that BDDE has potential application in the control of gray mold after fruit harvest and the compound could serve as a candidate or lead template for rational drug design and for the development of antifungal agents.

PD-L1 Expression Is Increased in LPS-Induced Acute Respiratory Distress Syndrome by PI3K-AKT-Egr-1/C/EBPδ Signaling Pathway.

The role of programmed death ligand 1 (PD-L1) has been extensively investigated in adaptive immune system. However, increasing data show that innate immune responses are also affected by the immune checkpoint molecule. It has been demonstrated that regulation of PD-L1 signaling in macrophages may be a potential therapeutic method for acute respiratory distress syndrome (ARDS). However, the PD-L1 expression pattern in local macrophages and whole lung tissues remains mysterious, hindering optimization of the potential treatment program. Therefore, we aim to determine the PD-L1 expression pattern during ARDS. Our findings show that PD-L1 levels are markedly increased in lipopolysaccharide (LPS)-stimulated lung tissues, which might be attributable to an increase in the gene expression by immune cells, including macrophages and neutrophils. In vitro experiments are performed to explore the mechanism involved in LPS-induced PD-L1 production. We find that PD-L1 generation is controlled by transcription factors early growth response 1 (Egr-1) and CCAAT/enhancer binding protein delta (C/EBPδ). Strikingly, PD-L1 production is enhanced by phosphoinositide-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway via up-regulation of Egr-1 and C/EBPδ expressions. Additionally, we observe that expressions of Egr-1 and C/EBPδ mutually reinforce each other. Moreover, we observe that PD-L1 is protective for ARDS due to its regulatory role in macrophage-associated inflammatory response. In summary, during LPS-induced ARDS, PD-L1 expression, which is beneficial for the disease, is increased via the PI3K-AKT1-Egr-1/C/EBPδ signaling pathway, providing theoretical basis for application of methods controlling PD-L1 signaling in macrophages for ARDS treatment in clinic.

Time­dependent changes in NLRP3 and Nrf2 levels in lipopolysaccharide­induced acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe clinical conditions with a high mortality rate. Nucleotide­binding oligomerization domain (NOD)­like receptor containing pyrin domain 3 (NLRP3) and nuclear factor E2­related factor 2 (Nrf2) have been reported to be associated with ALI. However, the dynamic changes in the levels of these factors in lipopolysaccharide (LPS)­induced lung injury remain unclear. Thus, the present study aimed to determine the LPS­induced activation of immunological cascades, as well as the NLRP3/Nrf2 signaling pathway at different stages of lung injury. For this purpose, mice were divided into six groups as follows: The control, LPS­4 h, LPS­24 h, LPS­48 h, LPS­96 h and LPS­144 h groups. LPS (4 mg/kg) was administered intratracheally to induce lung injury. Flow cytometry was used to determine the changes in macrophages, neutrophils and T­cell subsets in lung tissue, hematoxylin and eosin staining were used to measure the histopathological changes in lung tissues, ELISA was performed to evaluate the levels of cytokines, western blot analysis was used to measure the levels of inflammatory proteins, and reverse transcription­quantitative PCR used to determine the mRNA level of a target gene. Following LPS administration, evident histopathological damage with neutrophil infiltration was observed which peaked at 48 h. The levels of interleukin­1ß, keratinocyte­derived chemokine, macrophage inflammatory protein 2 and tumor necrosis factor a were markedly increased in bronchoalveolar lavage fluid and serum from the mice, and these levels peaked at 4 h. Moreover, LPS promoted Toll like receptor­4 expression and reactive oxygen species production, thus activating NLRP3/Nrf2 signaling and pyroptosis. Collectively, the present study demonstrates that LPS triggers multiple inflammatory molecules and immune cells during ALI, which may be closely involved in the irregular redox status, NLRP3/Nrf2 pathway and pyroptosis.

Identification of factors related to immunotherapy efficacy and prognosis in patients with advanced head and neck squamous cell carcinoma.

BACKGROUND: Immunotherapy is an important treatment in oncology, but only a fraction of patients with head and neck squamous cell carcinoma (HNSCC) benefit from it. Therefore, the aim of this study was to identify predictive biomarkers of immunotherapy response for HNSCC in order to improve treatment outcomes. METHODS: Survival analyses and comparative efficacy evaluation were performed to investigate prognostic and therapeutic impact factors in patients with advanced HNSCC following immunotherapy, and to examine the effects of factors including gene mutations, tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), and immune cell infiltration on the survival and efficacy. RESULTS: Anti-PD-1 treatment led to a prolonged overall survival (OS) in HNSCC patients with gene mutations compared with those without the mutations, while no significant difference in the OS was found between the two groups of patients. And no marked association between the MATH value and OS was detected in HNSCC patients, whereas patients with either high TMB scores in tissues and blood or high immune cell infiltration displayed a significantly longer OS. Further analysis with efficacy as the primary endpoint revealed no significant differences in the tissue TMB, blood TMB, and MATH value between the patients who responded to immunotherapy and those who did not. Moreover, no significant differences in the expression percentages of positive immune cells in tumor, stroma, and total regions were identified between the above two groups of patients. CONCLUSION: HNSCC is characterized by high mutation rate, high mutation burden, and high level of immune cell infiltration, and a subset of HNSCC patients respond to immunotherapy. Here, we showed that high mutation burden and immune cell infiltration may improve the prognosis of HNSCC patients with immunotherapy, while there was no remarkable effect on the efficacy.

Manifestation of severe pneumonia in anti-PL-7 antisynthetase syndrome and B cell lymphoma: A case report.

BACKGROUND: Antisynthetase syndrome (ASS) is characterized by the presence of antisynthetase antibodies coupled with clinical findings such as fever, polymyositis-dermatomyositis and interstitial lung disease. It is, however, rare to observe ASS association with B cell lymphoma presenting severe pneumonia as the first clinical manifestation. CASE SUMMARY: We evaluated a 59-year-old male patient who presented with cough with sputum, shortness of breath and fever for 13 d. A chest computed tomography radiograph revealed bilateral diffuse ground-glass infiltrates in both upper fields, left lingual lobe and right middle lobe. Initially, the patient was diagnosed with severe community-acquired pneumonia and respiratory failure. He was empirically treated with broad-spectrum antibiotics, without improvement. Further analysis showed an ASS panel with anti-PL7 antibodies. Besides, electromyography evaluation demonstrated a manifestation of myogenic damage, while deltoid muscle biopsy showed irregular muscle fiber bundles especially abnormal lymphocyte infiltration. In addition, bone marrow biopsy revealed high invasive B cell lymphoma. Thus, the patient was diagnosed with a relatively rare anti-PL7 antibody positive ASS associated with B cell lymphoma. CONCLUSION: This case highlights that rapidly progressive lung lesions and acute hypoxemic respiratory failure associated with heliotrope rash and extremely high lactate dehydrogenase level should be considered as the characteristics of non-infectious diseases, especially ASS and B cell lymphoma.

Noncoplanar Versus Coplanar Intensity-Modulated Radiation Therapy (IMRT) for Protection of the Lip and Buccal Mucosa.

OBJECTIVE: In this study, by comparing coplanar and noncoplanar intensity-modulated radiation therapy (IMRT) treatment planning in treating tongue cancer, the significance of noncoplanar fields in the protection of the lip and buccal mucosa was determined, and a reasonable solution was selected. METHODS: Forty-eight tongue cancer patients treated from June 2019 to February 2021 were selected and randomly divided into a coplanar field group and a noncoplanar field group. The mucosal dose limit changed from 15 Gy to 45 Gy for comparison of the two treatment plans. The evaluation indicators (conformal index (CI); homogeneity index (HI); D5, D50, and D98 of the target volume; and the dose of normal tissues) were calculated under different mucosal dose limits. The clinical observation of the lip and buccal mucosa of 48 cases was monitored and graded carefully according to NCI-CTCAE V4.0. Statistical analyses were performed. RESULTS: The differences in CI, HI, D98, D50 and D5 between the two groups in the target volume tended to decrease when the mucosal dose limit was less than 30 Gy, with a significant difference (P < 0.05). When the limit exceeded 30 Gy, significant differences in other indicators except CI (P < 0.05) were still noted. In normal tissue, differences in doses between the two groups existed when the mucosal limit was less than 20 Gy, with a significant difference (P < 0.05). When the limit exceeded 20 Gy, no significant difference was noted. Patients in the noncoplanar group showed significantly better results than those in the other group in terms of the radiation-related toxicity of the lip and cheek membrane(P < 0.001). CONCLUSIONS: Compared with coplanar field radiotherapy, noncoplanar field radiotherapy can effectively reduce the exposure dose to the lip and buccal mucosa. The application of noncoplanar treatment plans exhibits good clinical significance and deserves to be promoted.

Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with bevacizumab for advanced non-squamous non-small-cell lung cancer patients with gradual progression on EGFR-TKI treatment: A cohort study.

ABSTRACT: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve outcomes of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, acquired resistance inevitably emerges and remains a major challenge. The present study aimed to evaluate the efficacy of EGFR-TKIs plus bevacizumab in advanced non-squamous NSCLC patients with gradual progression on EGFR-TKIs.Advanced non-squamous EGFR-mutated NSCLC patients with gradual progression on EGFR-TKIs were administered bevacizumab while EGFR-TKIs were continued until disease progression occurred. Tumor lesions were assessed, and blood samples were collected at the start of the combination treatment and every 6 weeks until disease progression.Among the 15 included patients, there were no grade 3 or higher adverse events (AEs). Partial response (PR) and stable disease (SD) were achieved in 1 and 13 patients, respectively, with an objective response rate (ORR) of 6.7% and a disease control rate (DCR) of 93.3%. The median progression-free survival 2 (PFS2), defined as the time from the initiation of combination treatment to disease progression, was 5.0 (95% confidence interval [CI]: 4.0-6.0) months. Additionally, Spearman correlation analysis revealed that PFS2 was positively correlated with the serum vascular endothelial growth factor (VEGF) level at baseline (r = 0.7212, P = .0234). Patients with high baseline serum VEGF levels showed a better median PFS2 than those with low baseline serum VEGF levels (5.5 months vs 3.6 months, P = .0333).EGFR-TKIs plus bevacizumab led to a durable prolongation of PFS in non-squamous NSCLC patients with gradual progression on EGFR-TKIs. This therapeutic regimen was well tolerated and could be a promising strategy for these patients. Serum VEGF could be a potential biomarker to predict a subset of patients who are likely to benefit from EGFR-TKIs combined with bevacizumab.

Lower circulating adiponectin is associated with higher risk of renal cell carcinoma: A meta-analysis.

BACKGROUND: Changes in circulating adiponectin have been related to the risks of various cancers. However, the association between circulating adiponectin and the risk of renal cell carcinoma has not been fully determined. A meta-analysis was performed to evaluate the relationship between circulating adiponectin and renal cell carcinoma risk. METHODS: Observational studies that evaluated the association between circulating adiponectin and renal cell carcinoma risk were identified via a systematic search of PubMed and Embase databases. The difference between circulating adiponectin in renal cell carcinoma cases and healthy controls, and the multivariable adjusted association between circulating adiponectin and renal cell carcinoma risk were evaluated. A random effects model was used if significant heterogeneity existed; otherwise a fixed effects model was applied. RESULTS: Eight case-control studies with 2624 renal cell carcinoma cases and 2904 healthy controls were included. Pooled results showed that circulating adiponectin was significantly lower in renal cell carcinoma cases than in healthy controls (mean difference = -1.08 ug/mL; 95% confidence interval (CI) -1.62, -0.54; P < 0.001). Higher circulating adiponectin was independently associated with a significantly lowered risk of renal cell carcinoma (adjusted odds ratio for 1 SD increment of adiponectin = 0.78; 95% CI: 0.63, 0.96; P = 0.02). Subgroup analyses according to characteristics including study design, ethnics of participants, blood samples, numbers of participants, mean ages of participants, and study quality showed consistent results. CONCLUSIONS: Lower circulating adiponectin is associated with increased risk of renal cell carcinoma. The potential pathophysiological mechanisms underlying the role of circulating adiponectin in the pathogenesis of renal cell carcinoma deserve further investigation.

Positron imaging for verification of irradiation field during radiotherapy.

AIM OF STUDY: The present study was designed to investigate the application of positron images from photonuclear reactions to verify the location of targeted radiation in vivo. MATERIALS AND METHODS: The phantom study was conducted with distilled water, porcine muscle, porcine adipose tissue, and graphite; these subjects were irradiated separately with 50 MV photons generated by an MM50 Racetrack Microtron. The positron emission activity was measured using a Geiger counter, and the radioactive decay curves for each of the irradiated materials were then established. The positron emission tomography (PET) images of the three tissue models were also achieved using the same radiation conditions. The in vivo PET imaging study was also conducted in tumor-bearing rabbits. RESULTS: Our results demonstrated that the PET imaging could be used to verify the position of the irradiation field in vivo. The dose distribution images of photonuclear reactions of 11 C and 15 O were uniform, using 2-Gy 50 MV photons. CONCLUSIONS: The factors influencing the half-life of radiation activity in various tissues were different from the first order kinetic reaction in physics.

Clinical Analysis of Percutaneous Computed Tomography-Guided Hook Wire Localization of 168 Small Pulmonary Nodules.

BACKGROUND: The aim of this study was to evaluate the correlation of clinical and radiologic characteristics and pathologic features in small pulmonary nodules and to evaluate the success rate and safety of a computed tomography (CT)-guided hook wire system. METHODS: One hundred sixty-eight pulmonary nodules that were 20 mm or less in diameter in 161 patients were percutaneously localized by a CT-guided hook wire system, followed by pulmonary resection. The general clinical data, computed tomographic characteristics, and pathologic findings were evaluated, and the major side effects during the localization procedure were reviewed. RESULTS: Of the targeted nodules, 71 (42.3%) nodules were pure ground-glass opacities (GGOs), 59 (35.1%) nodules were partially solid GGOs, and 38 (22.6%) nodules were solid lesions. Pathologically, 49.3% of the pure GGOs were atypical adenomatous hyperplasia (AAH), 54.2% of the partially solid GGOs were lung cancer, and 65.8% of the solid nodules were benign lesions. Lung cancer tended to develop in older patients with larger nodule diameters. Subsolid nodules greater than 10 mm showed a statistically significant correlation with malignancy (p < 0.001). The hook wires were successfully placed in 164 (97.6%) nodules, and no serious complications occurred. CONCLUSIONS: In resected specimens with a CT-guided hook wire, pulmonary subsolid nodules tend to be AAH or lung cancer, whereas small solid nodules tend to be benign lesions. Pulmonary subsolid nodules larger than 10 mm are more frequently malignant. Preoperative localization of small pulmonary nodules with a hook wire system has a high success rate and acceptable utility.

Mannose prevents acute lung injury through mannose receptor pathway and contributes to regulate PPARγ and TGF-ß1 level.

Mannose has been reported to prevent acute lung injury (ALI), and mannose receptor (MR) has been demonstrated to have a role. The rationale for this study is to characterize the mechanism by which mannose and MR prevent lipopolysaccharide (LPS)-induced ALI. Male ICR mice were pretreated mannose by intravenous injection 5 min before and 3 h after intratracheal instillation of LPS. Pathological changes, proinflammatory mediator, peroxisome proliferator activated receptor gamma (PPARγ), MR, and transforming growth factor ß1 (TGF-ß1) levels were determined. The RAW264.7 cells were pretreated with mannose and stimulated with LPS for 3 h. Proinflammatory mediator and TGF-ß1 in the culture media, PPARγ, MR, and TGF-ß1 expression in RAW 264.7 cells were measured. Mannose markedly attenuated the LPS-induced histological alterations and inhibited the production of proinflammatory mediator in mice and in RAW 264.7 cells. Mannose increased PPARγ and MR expression, and inhibited TGF-ß1 stimulated by LPS. Interestingly, competitive inhibition of MR with mannan was associated with elimination of the anti-inflammatory effects of mannose, and reversed effects of mannose of regulation to PPARγ and TGF-ß1. MR is important in increasing PPARγ and decreasing TGF-ß1 expression and plays a critical role in mannose's protection against ALI.

[Effect of "Xinjingjie mouthrinse" on prevention and treatment of radiation-induced oral mucositis].

PURPOSE: To investigate the effect of "Xinjingjie compound lysostaphin antibacterial collutorium" on prevention and treatment of radiation-induced oral mucositis in a prospective, randomized and double-blind clinical trial. METHODS: Sixty patients with oral cancer to be treated with radiotherapy were randomized into the experimental and control group. The experimental group (30 patients) was treated with "Xinjingjie mouthrinse" during the full course of radiotherapy, 4 times daily with 5 mL and 5 min each time. The control group (30 patients) rinsed the mouth in the same way with normal saline. Oral mucositis was assessed according to the RTOG criteria. The severity of mucositis and the degree of pain were recorded and photographed. Patients shouldn't be treated with other drugs until the level of oral mucositis reached above grade III. The results were statistically analyzed using Stata 12.0 software packages. RESULTS: Age, gender, radiotherapy techniques and dose showed no significant difference between the 2 groups (P>0.05). The first onset of oral mucositis in the experimental group was later than that in the control group (11.0 times:9.1 times,P<0.05), and the incidence of pain at the early time of radiotherapy was lower (36.7%: 70.0%, P<0.05). Also, the onset time of grade III oral mucositis in the emperimental group was later than that in the control group (18.9 times:15.9 times,P<0.05), and the incidence of grade III oral mucositis in the experimental group was lower (63.3% vs. 90.0%, P<0.05). CONCLUSIONS: "Xinjingjie mouthrinse" is worthwhile to be used in clinic because it can delay the occurrence time of radiation-induced oral mucositis, alleviate pain and reduce the indication of grade III oral mucositis.

A case of bilateral pleural effusion as the first sign of multiple myeloma.

Multiple myeloma (MM) is a type of hematological malignancy that can affect all types of tissues in human. However, it is extremely rare that pleural effusion presents as the first sign in MM patients. A 54-year-old male patient attended our department of respiratory medicine complaining of shortness of breath for the past 3 months. A chest computer tomography (CT) radiograph revealed a bilateral pleural effusion, which was further assessed as exudative type. Sinus spiral CT scan demonstrated diffuse bone destruction of craniofacial bone. A broad reduction of the lumbar bone signal was confirmed by MRI. Furthermore, pleural biopsy showed abnormal proliferation of plasmocytes whereas bone marrow biopsy showed active hyperplasia of plasmacytoid cells. Interestingly, Bence-Jones protein in urine and serum protein electrophoresis was negative. The patient was diagnosed as non-secretory MM. He then underwent chemotherapy with vincristine, adriamycin and dexamethasone. Partial regression of the pleural effusion was achieved after two rounds of chemotherapy, and the patient has been followed for more than one year.

Involvement of mannose receptor in the preventive effects of mannose in lipopolysaccharide-induced acute lung injury.

Although macrophage mannose receptor contributes to the anti-inflammatory procedure, its mechanisms of action are incompletely understood in acute lung injury. We recently found that mannose which could bind to mannose receptor, prevented acute lung injury in rats. Here, we profiled the involvement of mannose receptor in the preventive effects of mannose in lipopolysaccharide-induced acute lung injury in mice. We found that pulmonary edema, protein exudation, and lung histopathology were significantly improved in a dose-dependent manner among the mannose (50, 150, and 450 mg/kg) mice (a bolus tail vein injection of mannose 5 min before and 3h after intratracheal instillation of LPS) compared to the LPS mice. Mannose also prevented the inflammatory cell accumulation, and inhibited production of cytokines. Further, in the in vitro alveolar macrophages, treatment with mannose resulted in decreased phagocytic activity and production of cytokines, and its anti-inflammatory effects were associated with up-regulation of mannose receptor. Importantly, we found that competitive inhibition of mannose receptor (mannan 2mg/ml) or targeted short interfering RNA-mediated gene suppression of mannose receptor mRNA was associated with the elimination of the anti-inflammatory effects of mannose. Furthermore, the up-regulation of mannose receptor by mannose administration was associated with inhibited NF-kappaB nuclear translocation. Taken together, these studies reveal involvement of mannose receptor and impaired NF-kappaB activation in the mannose prevention of acute lung injury, and implicate mannose receptor as a potential therapeutic target during acute lung injury.

An in vitro rat diaphragmatic fatigue model induced by combined hypoxic and hypercapnic acidosis and the effect of salmeterol.

Hypoxia or hypercapnia impairs diaphragmatic contractility and induces fatigue. However, little is known about the combined effect of hypoxic and hypercapnic acidosis (HHA) on diaphragmatic fatigue. In this study, a gas mixture (21% O2, 12% CO2 and 67% N2) was used to produce HHA-induced rat diaphragmatic fatigue. Force-frequency relationships and twitch characteristics including peak twitch tension (PTT), time to peak tension (TPT), half relaxation time (1/2RT), maintaining tension (MT) and direct-muscle-stimulation tension (MST) were measured in diaphragm preparations from male SD rats. The HHA gas mixture attenuated force at all frequencies (5-120 Hz) and decreased PTT, MT and MST significantly. Aminophylline, a positive control drug, blocked the negative inotropic effect of HHA in a dose-dependent manner. Moreover, salmeterol, a long-acting beta2-adrenoceptor agonist, inhibited the harmful effect of HHA at high frequencies (40-120 Hz), but without effect on MT and MST. These results suggest that an in vitro HHA-induced rat diaphragmatic fatigue model could be established by aerating with the gas mixture, which may be an optimal model to screen effective drugs for diaphragmatic fatigue. Furthermore, salmeterol may play a protective role in HHA-induced impairment.