Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population.

BACKGROUND: A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. METHODS: We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. RESULTS: After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 (p-value = 3.81 × 10-14), ABO rs582094 (p-value = 1.16 × 10-10) and newly reported locus FABP2 rs1799883 (p-value = 7.59 × 10-17). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G(rs1799883) promoted the transcription and protein expression of FABP2. Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. CONCLUSIONS: We identified FABP2, related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.

Progress in the study of cancer-associated venous thromboembolism.

OBJECTIVE: Venous thromboembolism is a major cause of morbidity, mortality, and increased medical costs in tumor patients. In the current review, we summarize the progress made in the study of cancer-associated venous thromboembolism. METHODS: By searching cancer-associated venous thromboembolism-related literature on PubMed, the epidemiology, pathological mechanisms, risk factors, risk prediction models, and prevention and treatment of cancer-associated venous thromboembolism were reviewed. RESULTS: The pathophysiological mechanisms of cancer-associated venous thromboembolism are multifactorial. Various blood cell counts (such as platelets and white blood cells) and biomarkers (such as D-dimer and sP-selectin) were considered predictors of thrombosis in cancer patients and were incorporated into the venous thromboembolism risk stratification models. Thromboprophylaxis is currently recommended for all hospitalized cancer patients. In addition, outpatient thromboprophylaxis can be used for selected high-risk patients. Low-molecular-weight heparin was the preferred treatment for cancer-associated venous thromboembolism, but some issues arose in the long-term treatment. In this case, direct oral anticoagulants were a treatment option for tumor patients. The efficacy of direct oral anticoagulant in treating cancer patients is not inferior to low-molecular-weight heparin, but is associated with a higher risk of bleeding. Therefore, there were concerns regarding their safety. CONCLUSION: Since thrombocytopenia, thrombosis recurrence, and bleeding are common in tumor patients, the selection of anticoagulants in this circumstance is a considerable challenge for clinicians.

Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy.

Aging is a major risk factor for most chronic disorders, for which cellular senescence is one of the central hallmarks. Senescent cells develop the pro-inflammatory senescence-associated secretory phenotype (SASP), which significantly contributes to organismal aging and age-related disorders. Development of senotherapeutics, an emerging class of therapeutic agents to target senescent cells, allows to effectively delay aging and alleviate chronic pathologies. Here we report preliminary outputs from screening of a natural medicinal agent (NMA) library for senotherapeutic candidates and validated several agents with prominent potential as senomorphics. Rutin, a phytochemical constituent found in a number of plants, showed remarkable capacity in targeting senescent cells by dampening expression of the full spectrum SASP. Further analysis indicated that rutin restrains the acute stress-associated phenotype (ASAP) by specifically interfering with the interactions of ATM with HIF1α, a master regulator of cellular and systemic homeostasis activated during senescence, and of ATM with TRAF6, part of a key signaling axis supporting the ASAP development toward the SASP. Conditioned media produced by senescent stromal cells enhanced the malignant phenotypes of prostate cancer cells, including in vitro proliferation, migration, invasion, and more importantly, chemoresistance, while rutin remarkably downregulated these gain-of-functions. Although classic chemotherapy reduced tumor progression, the treatment outcome was substantially improved upon combination of a chemotherapeutic agent with rutin. Our study provides a proof of concept for rutin as an emerging natural senomorphic agent, and presents an effective therapeutic avenue for alleviating age-related pathologies including cancer.

PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.

Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.

Early use of noninvasive positive pressure ventilation for acute lung injury: a multicenter randomized controlled trial.

OBJECTIVE: Noninvasive positive pressure ventilation is beneficial for patients with acute respiratory failure. However, its possible benefit for patients with acute lung injury (200 mm Hg < PaO(2)/FIO(2) ≤300 mm Hg) remains unclear. Our aim was to assess the safety and efficacy of noninvasive positive pressure ventilation for patients with acute lung injury and compare this with high-concentration oxygen therapy. DESIGN: A multicentered randomized controlled trial. SETTING: Ten multipurpose intensive care units. PATIENTS: Forty patients who fulfilled the criteria for acute lung injury were included in this study. INTERVENTIONS: Patients were randomly allocated to receive either noninvasive positive pressure ventilation (noninvasive positive pressure ventilation group) or high-concentration oxygen therapy through a Venturi mask (control group). MEASUREMENTS AND MAIN RESULTS: Twenty-one patients were assigned to the noninvasive positive pressure ventilation group and 19 were in the control group. At study entry, the patients' characteristics in the two groups were similar. Noninvasive positive pressure ventilation application decreased the respiratory rate and improved PaO(2)/FIO(2) with time. The proportion of patients requiring intubation and the actual number of intubations in the noninvasive positive pressure ventilation group were significantly less than in the control group (one of 21 vs. seven of 19; p = .02, and one of 21 vs. four of 19; p = .04, respectively). Noninvasive positive pressure ventilation showed a trend for reducing inhospital mortality (one of 21 vs. five of 19; p = .09). The total number of organ failures in the noninvasive positive pressure ventilation group was significantly lower than in the control group (three vs. 14; p < .001). CONCLUSIONS: Noninvasive positive pressure ventilation is safe for selected patients with acute lung injury. However, a larger randomized trial with need for intubation and mortality as the outcomes of interest is required.

Metagenomic Next-Generation Sequencing Is Highly Efficient in Diagnosing Pneumocystis Jirovecii Pneumonia in the Immunocompromised Patients.

Purposes: To explore the value of metagenomic next-generation sequencing (mNGS) in diagnosing pneumocystis jiroveciipneumonia (PJP) in the immunocompromised patients. Methods: Data of 122 patients with PJP in an immunosuppressed state and 67 non-PJP patients were collected. The diagnostic efficacy of mNGS was compared with the conventional methods, including Gomori methenamine silver (GMS) staining and serum (1,3)-ß-D-glucan (BDG). Changes of anti-microbial therapy for patients with PJP based on mNGS results were also reviewed. Results: The diagnostic sensitivity of mNGS to PJP was higher than that of GMS and BDG (100% vs. 15 and 74.5%, p < 0.001). The diagnostic specificity (91.%) was lower than that of GMS (100%), and similar with BDG (89.6%). In addition to P. jirovecii, mNGS revealed co-pathogens like human ß-herpesvirus 5, human γ-pesvirus 4, and some other opportunistic pathogens. The reads of mNGS were remarkably higher in BALF than in blood samples. Initial antimicrobial treatment was modified in 89.3% patients based on the mNGS results, and 74 cases (60.7%) were treated with anti-P. jirovecii therapy. Conclusion: mNGS is highly efficient in diagnosing PJP and good at identifying pathogens in mixed infections.

Acute Respiratory Distress Syndrome Caused by Occupational Exposure to Waterproofing Spray: A Case Report and Literature Review.

Background: Acute respiratory distress syndrome (ARDS) is a serious respiratory disease, caused by severe infection, trauma, shock, inhalation of harmful gases and poisons and presented with acute-onset and high mortality. Timely and accurate identification will be helpful to the treatment and prognosis of ARDS cases. Herein, we report a case of ARDS caused by occupational exposure to waterproofing spray. To our knowledge, inhalation of waterproofing spray is an uncommon cause of ARDS, and what makes our case special is that we ruled out concurrent infections with some pathogens by using metagenomic next-generation sequencing (mNGS) as an auxiliary diagnosis, which presents the most comprehensive etiological examination of similar reports. Case Presentation: A previously healthy 25 years old delivery man developed hyperpyrexia, chest tightness, cough and expectoration. The symptoms occurred and gradually exacerbated after exposure to a waterproofing spray. The chest computed tomography (CT) finding showed diffuse ground glass and infiltrative shadows in both lungs. The diagnosis of ARDS related to waterproofing spray was established on the basis of comprehensive differential diagnosis and etiological examination. The patient achieved good curative effect after proper systemic glucocorticoid therapy. Conclusions: The diagnosis and differential diagnosis of acute respiratory failure for outdoor workers, such as delivery drivers or hikers, should be considered whether toxic aerosol exposure exists from daily contacts. The case can educate the public that more attention should be paid to avoid exposure to these chemicals by aerosols/ingestion mode and some preventive strategies should be taken in occupational environment. The treatment effect of glucocorticoids is significant in ARDS patients with general chemical damage caused by inhaling toxic gases and substances.

Targeting epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance.

The tumor microenvironment (TME) represents a milieu enabling cancer cells to develop malignant properties, while concerted interactions between cancer and stromal cells frequently shape an "activated/reprogramed" niche to accelerate pathological progression. Here we report that a soluble factor epiregulin (EREG) is produced by senescent stromal cells, which non-cell-autonomously develop the senescence-associated secretory phenotype (SASP) upon DNA damage. Genotoxicity triggers EREG expression by engaging NF-κB and C/EBP, a process supported by elevated chromatin accessibility and increased histone acetylation. Stromal EREG reprograms the expression profile of recipient neoplastic cells in a paracrine manner, causing upregulation of MARCHF4, a membrane-bound E3 ubiquitin ligase involved in malignant progression, specifically drug resistance. A combinational strategy that empowers EREG-specific targeting in treatment-damaged TME significantly promotes cancer therapeutic efficacy in preclinical trials, achieving response indices superior to those of solely targeting cancer cells. In clinical oncology, EREG is expressed in tumor stroma and handily measurable in circulating blood of cancer patients post-chemotherapy. This study establishes EREG as both a targetable SASP factor and a new noninvasive biomarker of treatment-damaged TME, thus disclosing its substantial value in translational medicine.

Mitochondrial dysfunction: A potential target for Alzheimer's disease intervention and treatment.

Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder which manifests as a progressive decline in cognitive function. Mitochondrial dysfunction plays a critical role in the early stages of AD, and advances the progression of this age-related neurodegenerative disorder. Therefore, it can be a potential target for interventions to treat AD. Several therapeutic strategies to target mitochondrial dysfunction have gained significant attention in the preclinical stage, but the clinical trials performed to date have shown little progress. Thus, we discuss the mechanisms and strategies of different therapeutic agents for targeting mitochondrial dysfunction in AD. We hope that this review will inspire and guide the development of efficient AD drugs in the future.

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice.

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype.

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of prostate cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq, and expression profiling through RNA-seq, reveal global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment (TME), and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a novel therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies including cancer.

[The DNA binding activity of nuclear factor-ΚB in patients with severe pneumonia and the intervention effects of Xuebijing injection].

OBJECTIVE: To investigate the role of nuclear factor-ΚB (NF-ΚB) in severe pneumonia and observe the effects of Xuebijing injection in its treatment. METHODS: Thirty hospitalized patients with severe pneumonia were divided into the routine therapy group (n=14) and Xuebijing therapy group (n=16) in whom with Xuebijing injection 100 ml was given once daily for 7 days besides routine therapies, according to the random numeral. The DNA binding activity of NF-ΚB in human monocytes was detected before and 3 days and 7 days after administration, the contents of tumor necrosis factor-α (TNF-α), procalcitonin (PCT) and C-reactive protein (CRP) were determined, and the changes in coagulatory and fibrinolytic parameters were assayed at the same time. Acute physiology and chronic health evaluationII (APACHEII) score was also recorded. Ten healthy volunteers served as the healthy control group. RESULTS: The DNA binding activities of NF-ΚB, the contents of TNF-α, PCT, CRP, fibrinogen (Fib), D-dimer in hospitalized subjects with severe pneumonia were higher before treatment than those in healthy control group, while the prothrombin time (PT), thrombin time (TT) were significantly lower (P<0.05 or P<0.01). Compared with the routine therapy group, the DNA binding activity of NF-ΚB (grey level) at the 7 days (66.60±36.23 vs. 79.90±39.11) was notably decreased in Xuebijing therapy group; the levels of TNF-α (ng/L, 25.81±11.67 vs. 33.78±13.36), PCT (µg/L, 1.91±1.09 vs. 2.96±1.80), CRP (mg/L, 20.01±7.21 vs. 26.59±10.66), Fib (g/L, 4.02±1.26 vs. 5.09±1.43), D-dimer (mg/L, 0.24±0.06 vs. 0.31±0.11) were significantly lower in Xuebijing therapy group, and APACHEII score (15.81±3.47 vs. 17.93±3.05) was obviously lowered (all P<0.05). There was statistical difference of the TT (s) between two groups at 3 days (15.68±1.89 vs. 14.65±1.33,P<0.05). There was a significant positive correlation between NF-ΚB DNA binding activity and the levels of TNF-α (r(1)=0.373, r(2)=0.362, r(3)=0.419), PCT (r (1)=0.800, r(2)=0.716, r(3)=0.920) or CRP (r(1)=0.368, r(2)=0.441, r(3)=0.366, all P<0.05) before and 3 days and 7 days after the treatment. CONCLUSION: NF-ΚB activation and coagulopathy were observed in patients with severe pneumonia, and NF-ΚB was involved in the process of inflammatory response. Inflammatory response was partly alleviated by Xuebijing injection. These effects of Xuebijing injection may be mediated by inhibition of the activation of NF-ΚB and its anticoagulation property.

Senescent Stromal Cells Promote Cancer Resistance through SIRT1 Loss-Potentiated Overproduction of Small Extracellular Vesicles.

Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype, which is implicated in age-related pathologies including cancer. Here, we report that senescent cells actively synthesize and release small extracellular vesicles (sEV) with a distinctive size distribution. Mechanistically, SIRT1 loss supported accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly altered the expression profile of recipient cancer cells and enhanced their aggressiveness, specifically drug resistance mediated by expression of ATP-binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with agonist SRT2104 prevented development of cancer resistance by restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients were readily detectable by routine biotechniques, presenting an exploitable biomarker to monitor therapeutic efficacy and predict long-term outcome. Together, this study identifies a distinct mechanism supporting pathologic activities of senescent cells and provides a potent avenue to circumvent advanced human malignancies by cotargeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells. SIGNIFICANCE: Senescent stromal cells produce a large number of sEVs to promote cancer resistance in therapeutic settings, a process driven by SIRT1 decline in stromal cells and ABCB4 augmentation in cancer cells.See related commentary by Wiley, p. 3193 GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/16/3383/F1.large.jpg.

[Clinical features of patients with venous thromboembolism: 177 case analysis in 10 years].

OBJECTIVE: To analyze the clinical characteristics and risk factors of patients with confirmed venous thromboembolism (VTE) in order to improve recognition of VTE, and reduce the rate of missed diagnosis and wrong diagnosis. METHODS: A retrospectively review was performed for 205 patients diagnosed with VTE confirmed by CT pulmonary angiography (CTPA), radionuclide pulmonary ventilation/perfusion (V/Q) imaging, lower extremity deep vein ultrasound or venography in the First Affiliated Hospital of Bengbu Medical College from January 2009 to December 2018. The clinical manifestations, laboratory examination results, imaging results, treatment and prognosis of patients diagnosed with VTE were analyzed. The clinical possibility was assessed by pulmonary thromboembolism (PTE) simplified Wells score and deep venous thrombosis (DVT) Wells score. 130 non-VTE patients admitted in the same period were enrolled as controls, and the risk factors of VTE were screened by multivariate Logistic regression analysis. RESULTS: Among 205 VTE patients, 14 cases had incomplete data, 2 cases were complicated with other diseases deteriorated, 2 cases were excluded because of economic reasons, 10 cases abandoned treatment because of serious illness, and finally 177 cases were included in the analysis. The main clinical symptoms of VTE patients were chest tightness (36.16%), followed by chest pain (29.94%), dyspnea (29.38%) and hemoptysis (24.29%). Swelling or tenderness of unilateral/bilateral lower extremities (38.98%) and lung moist rale (20.90%) were the most common signs. ST-T changes were the main changes in electrocardiogram (ECG, 49.15%), followed by SIQIIITIII or QIIITIII changes (35.03%). Only 5.65% of the patients had plasma D-dimer less than 0.5 mg/L. 31.07% (55/177) patients had normal arterial blood gas results. Of the 177 VTE patients, 175 were diagnosed as PTE by CTPA, with bilateral/multi-lobar pulmonary artery embolism and its branches being the main type [44.57% (78/175)]. Two cases were diagnosed as PTE by V/Q imaging. Among them, 112 cases were received lower extremity deep venous ultrasound or lower extremity deep venography, 51 cases were diagnosed as lower extremity DVT, with thrombosis of popliteal and above vein as common [68.63% (35/51)]. The clinical possibility assessment showed that 67.23% (119/177) patients might have PTE (PTE simplified Wells score greater than or equal to 2), 38.98% (69/177) patients might have lower extremity DVT (DVT Wells score greater than or equal to 2). Multivariate Logistic regression analysis showed that operation less than 4 weeks [odds ratio (OR) = 5.503, 95% confidence interval (95%CI) = 1.577-19.206, P = 0.007], trauma or fracture less than 3 months (OR = 6.771, 95%CI = 1.510-30.370, P = 0.012), VTE history (OR = 0.072, 95%CI = 0.009-0.549, P = 0.011) were independent risk factors for VTE occurrence. Thrombolytic therapy was administered in 13 cases while anticoagulant therapy alone was prescribed in 164 cases. 176 patients recovered, while 1 case died. CONCLUSIONS: VTE clinical manifestations are not specific. Patients with risk factors should be vigilant, be strengthen with diagnostic awareness, paid attention to the evaluation of clinical possibilities. Timely thrombolytic or anticoagulant treatment after diagnosis, can improve the survival rate.

Alterations to the Lung Microbiome in Idiopathic Pulmonary Fibrosis Patients.

Lung microbiome ecosystem homeostasis in idiopathic pulmonary fibrosis (IPF) remains uncharacterized. The aims of this study were to identify unique microbial signatures of the lung microbiome and analyze microbial gene function in IPF patients. DNA isolated from BALF samples was obtained for high-throughput gene sequencing. Microbial metagenomic data were used for principal component analysis (PCA) and analyzed at different taxonomic levels. Shotgun metagenomic data were annotated using the KEGG database and were analyzed for functional and metabolic pathways. In this study, 17 IPF patients and 38 healthy subjects (smokers and non-smokers) were recruited. For the PCA, the first and the second principal component explained 16.3 and 13.4% of the overall variability, respectively. The ß diversity of microbiome was reduced in the IPF group. Signature of IPF's microbes was enriched of Streptococcus, Pseudobutyrivibrio, and Anaerorhabdus. The translocation of lung microbiome was shown that 32.84% of them were from oral. After analysis of gene function, ABC transporter systems, biofilm formation, and two-component regulatory system were enriched in IPF patients' microbiome. Here we shown the microbiology characteristics in IPF patients. The microbiome may participate in altering internal conditions and involving in generating antibiotic resistance in IPF patients.

Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression.

Aging is characterized by a progressive loss of physiological integrity, while cancer represents one of the primary pathological factors that severely threaten human lifespan and healthspan. In clinical oncology, drug resistance limits the efficacy of most anticancer treatments, and identification of major mechanisms remains a key to solve this challenging issue. Here, we highlight the multifaceted senescence-associated secretory phenotype (SASP), which comprises numerous soluble factors including amphiregulin (AREG). Production of AREG is triggered by DNA damage to stromal cells, which passively enter senescence in the tumor microenvironment (TME), a process that remarkably enhances cancer malignancy including acquired resistance mediated by EGFR. Furthermore, paracrine AREG induces programmed cell death 1 ligand (PD-L1) expression in recipient cancer cells and creates an immunosuppressive TME via immune checkpoint activation against cytotoxic lymphocytes. Targeting AREG not only minimized chemoresistance of cancer cells, but also restored immunocompetency when combined with classical chemotherapy in humanized animals. Our study underscores the potential of in vivo SASP in driving the TME-mediated drug resistance and shaping an immunosuppressive niche, and provides the proof of principle of targeting major SASP factors to improve therapeutic outcome in cancer medicine, the success of which can substantially reduce aging-related morbidity and mortality.

[Effects of prone position ventilation combined with recruitment maneuver on oxygenation and shunt in canines with acute respiratory distress syndrome].

OBJECTIVE: To evaluate the effects of prone position ventilation (PPV) combined with recruitment maneuver (RM) on oxygenation and intrapulmonary shunting in oleic acid-induced acute respiratory distress syndrome (ARDS) in canines while ventilated with lung protective ventilation strategy. METHODS: ARDS was induced by oleic acid in 24 dogs, and the animals were ventilated with volume controlled ventilation (VCV), 16 cm H2O (1 cm H2O = 0.098 kPa) of positive end-expiratory pressure (PEEP) and small tidal volumes (V(T) 10 ml/kg). All the dogs were randomly divided by random digit table into 4 groups (6 each), a control group (supine position, SP group), a prone position group (PP group), a supine position + RM group (SPRM group), and a prone position + RM group (PPRM group), and then were ventilated by VCV for 4 h. Arterial and mixed venous blood gas analyses were measured. Data were analyzed using the SPSS for windows (version 11.5). Results were expressed as x +/- s. Homogeneity of variance test was performed. The differences in means were calculated using one-way ANOVA. Post-hoc multiple comparisons of means were performed using Least Significant Difference. Nonparametric tests for several independent samples were performed to compare differences between the ranks in the groups studied. P value of < 0.05 was considered statistically significant. RESULTS: (1) At 15 min, PaO2/FiO2 in the SPRM group, the PP group and the PPRM group [(368 +/- 45) mm Hg (1 mm Hg = 0.133 kPa), (349 +/- 80) mm Hg, ( 423 +/- 43) mm Hg, respectively] was significantly higher than that in the SP group [(269 +/- 72) mm Hg, q = 2.77, 2.23, 4.31, respectively, all P < 0.05]. At 2 h, PaO2/FiO2 in the PP group and the PPRM group [(401 +/- 82) mm Hg, (416 +/- 23) mm Hg, respectively] was significantly higher than that in the SP group [(232 +/- 40) mm Hg, q = 3.99, 4.35, respectively, all P < 0.05]. At 4 h, PaO2/FiO2 in the PPRM group [(384 +/- 68) mm Hg] was significantly higher than that in the SP group [(256 +/- 75) mm Hg], that in the SPRM group [(267 +/-92) mm Hg] and that in the PP group [(284 +/- 83) mm Hg, q = 2.75, 2.56, 2.17, respectively, all P < 0.05]. (2) Intrapulmonary shunt (Q(S)/Q(T)) in the PP group was significantly decreased compared with that in the SP group from 30 min to 2 h [30 min (9.9 +/- 4.4)% vs (15.0 +/- 1.6)%, 1 h (9.7 +/- 4.5)% vs (16.0 +/- 2.0)%, 2 h (8.3 +/- 4.6)% vs (16.2 +/- 1.8)%, q = 2.86, 3.00, 3.65, respectively, all P < 0.05]. The Q(S)/Q(T), in the PPRM group was significantly decreased compared with that in the SP group from 30 min to 4 h [30 min (10.0 +/- 1.0)% vs (15.0 +/- 1.6)%, 1 h (10.4 +/- 2.7)% vs (16.0 +/- 2.0)%, 2 h (10.2 +/- 0.7)% vs (16.2 +/- 1.8)%, 4 h (10.1 +/- 1.1)% vs (15.7 +/- 1.7)%, q = 2.80, 2.67, 2.75, 2.99, respectively, all P < 0.05]. CONCLUSIONS: On the basis of small tidal volume lung and PEEP protective ventilation strategy, combining prone position and recruitment maneuver was more effective and showed a synergistic effect on improving oxygenation and intrapulmonary shunt.