Enteral lorlatinib after immune hyperprogression as a treatment option for anaplastic lymphoma kinase­positive non­small cell lung cancer: A case report.

Fusion of the anaplastic lymphoma kinase (ALK) gene is a rare driver in non-small cell lung cancer (NSCLC). Lorlatinib is a third-generation ALK inhibitor approved for the treatment of locally advanced or metastatic ALK+ NSCLC. The traditional administration method of lorlatinib is whole tablet ingestion, while the efficacy effect of gastric tube injection after water dissolution remains unclear. In the present report, a marked response to lorlatinib in a 49-year-old patient with ALK+ NSCLC who was administered lorlatinib through a gastric tube, was described. The patient had received chemotherapy combined with immune checkpoint inhibitors prior to targeted drug therapy and developed hyperprogression, which was mainly manifested as rapid enlargement of the primary lesion with multiple new systemic metastases, accompanied by poor performance status score, esophageal compression and difficulty eating. The patient was injected with pre-dissolved lorlatinib through the nasogastric tube. After 6 days, related symptoms, such as dyspnea and dysphagia, were relieved. After 18 days, the esophageal stenosis was significantly alleviated, and the gastric tube was removed. In conclusion, gastric tube injection be used as a means of lorlatinib administration in patients with ALK+ NSCLC with dysphagia, regardless of previous immunotherapy-associated hyperprogression.

A small-molecule inhibitor of Keap1-Nrf2 interaction attenuates sepsis by selectively augmenting the antibacterial defence of macrophages at infection sites.

BACKGROUND: Macrophages at infection sites are considered as the promising therapeutic targets to prevent sepsis development. The Nrf2/Keap1 system acts as a critical modulator of the antibacterial activity of macrophages. Recently, Keap1-Nrf2 protein-protein interaction (PPI) inhibitors have emerged as safer and stronger Nrf2 activators; however, their therapeutic potential in sepsis remains unclear. Herein, we report a unique heptamethine dye, IR-61, as a Keap1-Nrf2 PPI inhibitor that preferentially accumulates in macrophages at infection sites. METHODS: A mouse model of acute lung bacterial infection was used to investigate the biodistribution of IR-61. SPR study and CESTA were used to detect the Keap1 binding behaviour of IR-61 in vitro and in cells. Established models of sepsis in mice were used to determine the therapeutic effect of IR-61. The relationship between Nrf2 levels and sepsis outcomes was preliminarily investigated using monocytes from human patients. FINDINGS: Our data showed that IR-61 preferentially accumulated in macrophages at infection sites, enhanced bacterial clearance, and improved outcomes in mice with sepsis. Mechanistic studies indicated that IR-61 potentiated the antibacterial function of macrophages by activating Nrf2 via direct inhibition of the Keap1-Nrf2 interaction. Moreover, we observed that IR-61 enhanced the phagocytic ability of human macrophages, and the expression levels of Nrf2 in monocytes might be associated with the outcomes of sepsis patients. INTERPRETATIONS: Our study demonstrates that the specific activation of Nrf2 in macrophages at infection sites is valuable for sepsis management. IR-61 may prove to be a Keap1-Nrf2 PPI inhibitor for the precise treatment of sepsis. FUNDING: This work was supported by the National Natural Science Foundation of China (Major program 82192884), the Intramural Research Project (Grants: 2018-JCJQ-ZQ-001 and 20QNPY018), and the Chongqing National Science Foundation (CSTB2022NSCQ-MSX1222).

Clinical diagnostic algorithm in defining tuberculous unilateral pleural effusion in high tuberculosis burden areas short of diagnostic tools.

Background: Empirical treatment was introduced when pathological or microbiological results of tuberculosis (TB) were not available. This report was designed to evaluate an algorithm based on empirical treatment in defining tuberculous pleural effusion (TPE) in high burden areas but short of diagnostic tools. Methods: In this retrospective study, a total of 924 eligible patients were enrolled and 203 (22.0%) were primarily diagnosed as TPE by our diagnostic algorithm based on effusion characteristics [adenosine deaminase (ADA) and exudate] and immunoassays [purified protein derivative (PPD), M. tuberculosis antibody (TB-Ab) and interferon-gamma release assay (IGRA)]. All diagnosed cases received World Health Organization (WHO) standard anti-TB treatment and 187 of them had at least one year of follow-up. The final diagnosis and prognosis of these patients were traced and recorded. Results: A total of 177 (94.65%) cases benefited from standard treatment, 5 (2.67%) failed due to early termination or drug resistance, and 5 (2.67%) were finally confirmed as misdiagnosis. Regarding diagnostic efficacy, 72 (30.13%) patients received four TB tests, and the combination of the four tests could increase the diagnosis of TPE. Besides, receiving operating characteristics curve (ROC) analysis revealed that our algorithm was the best method to differentiate TPE from malignant pleural effusion (MPE) with higher sensitivity and specificity than other serum markers. Conclusions: This clinical diagnostic algorithm was an efficient and available method for the diagnosis of TPE. This diagnostic algorithm should be implemented in regions with high TB prevalence but short of diagnostic tools.

Multiple sclerosing hemangioma of the right lung in a 23-year-old female patient: A case report and review of the literature.

Pulmonary sclerosing hemangioma (PSH) is a relatively uncommon benign tumor of the lung, predominantly affecting young and middle-aged women. In the majority of the patients, PSH is incidentally found on physical examination and typically presents as a solitary nodule with smooth borders, as it is generally asymptomatic or lacks typical symptoms. In the present case, a 23-year-old woman was incidentally diagnosed with pulmonary nodules during routine physical examination and reported suffering from intermittent fevers for >2 months. The patient received antituberculosis therapy for 1 year; however, a computed tomography imaging examination revealed that the lesions had progressed. Finally, the patient underwent thoracoscopic lung biopsy followed by histopathological examination and the lesions were diagnosed as multiple sclerosing hemangioma. The aim of the present study was to review the relevant literature in order to improve our understanding of PSH.

Lung tissue extracellular matrix-derived hydrogels protect against radiation-induced lung injury by suppressing epithelial-mesenchymal transition.

This study aimed to examine whether lung tissue extracellular matrix (ECM) hydrogels have protective effects on radiation-induced lung injury (RILI). The cytocompatibility and histocompatibility were tested for the obtained ECM-derived hydrogel. Sprague-Dawley rats were randomly divided into three groups (n = 18): control group (control); rats receiving irradiation and intratracheal injection of normal saline (IR + NS); and rats receiving irradiation and intratracheal injection of lung ECM-derived hydrogel (IR + ECM). The wet/dry weight ratio was used to evaluate the congestion and edema of the lungs. Histopathological analysis of lung tissues was performed using hemotoxylin and eosin staining and Masson's trichrome staining. Immunohistochemical staining and western blot analyses were carried out to determine the expression of epithelial-mesenchymal transition (EMT)-related proteins in lung tissues (E-cadherin, α-smooth muscle actin [α-SMA], and vimentin). In addition, tumor necrosis factor-α (TNF-α), transforming growth factor-ß1 (TGF-ß1) and interleukin-6 (IL-6), hydroxyproline, malondialdehyde (MDA), and superoxide dismutase (SOD) levels were also evaluated. The ECM-derived hydrogels had good cytocompatibility and histocompatibility. ECM-derived hydrogel treatment improved lung histopathology injury and pulmonary edema. Higher expression of E-cadherin and lower expression of vimentin and α-SMA were found in the IR + ECM group compared with those in the IR + NS group. Hydroxyproline levels were reduced by ECM-derived hydrogel treatment compared with those in the IR + NS group. Obvious increases of TNF-α, IL-6, and TGF-ß1 were identified following irradiation. Marked reductions in MDA content and increases in SOD were induced by ECM-derived hydrogel treatment in rats after radiation. ECM-derived hydrogels were shown to protect against RILI, potentially by reducing EMT, inflammation, and oxidative damage.

Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non­small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway.

Gallic acid (3,4,5­trihydroxybenzoic acid; GA), a plant­derived natural phenolic compound, has been reported to prevent the development and progression of various types of cancers. However, there has been little elaboration of the anticancer effects and underlying mechanisms of GA alone and/or in combination with cisplatin in non­small cell lung cancer (NSCLC). The aim of the present study was to investigate the anticancer effects of GA on NSCLC A549 cells and its auxiliary effects on the anticancer activity of cisplatin. The results revealed that GA inhibited the proliferation and induced the apoptosis of NSCLC A549 cells in dose­ and time­dependent manners, which was associated with upregulated B­cell lymphoma 2 (Bcl­2)­associated X protein (Bax) and downregulated Bcl­2. Notably, the results also indicated that GA enhanced the anticancer effects of cisplatin in the inhibition of cancer cell proliferation and the induction of cell apoptosis following elevated Bax expression and suppressed Bcl­2 expression. Furthermore, the results of the present study also demonstrated that GA exerted independent anticancer effects on NSCLC A549 cells, and facilitated the anticancer effects of cisplatin by modulating the JAK/STAT3 signaling pathway and downstream apoptotic molecules. These results may serve as a rationale for further basic studies and preclinical investigations on the anticancer effects of GA and its auxiliary effects on cisplatin function in human NSCLC.

Expression and clinical significance of lncRNA RP11-259P1.1 in small cell lung cancer tissues / 中国肿瘤生物治疗杂志

@#Objective: To explore the expression of long non-coding RNA RP11-259P1.1 (lncRNA RP11-259P1.1) in small cell lung cancer (SCLC) tissues and to analyze the relationship between lncRNARP11-259P1.1 expression and SCLC clinicopathological characteristics, as well as to investigate its effect in chemoresistance. Methods: Tissue samples, including 158 cases of tumor tissues from SCLC patients, who underwent bronchoscopic biopsy, puncture biopsy and surgical resection, 48 cases of para-cancerous tissues and 40 cases of normal lung tissues, collected from January 2012 to December 2016 in the Sixth People’s Hospital of Chengdu and General Hospital of Chengdu Military Region，were used in this study. The expression of lncRNARP11-259P1.1 was detected by Real-time fluorescence quantitative PCR (qPCR). χ2 test was used to analyze the relationship between the expression of lncRNA RP11-259P1.1 and the clinicopathological characteristics as well as chemotherapeutic resistance in SCLC patients. Relationship between lncRNA RP11259P1.1 expression and prognosis of SCLC patients was analyzed by univariate and multivariate Cox regression analysis. Results: The expression of lncRNA RP11-259P1.1 in SCLC tissues was significantly higher than that in para-cancerous tissues and normal lung tissues (all P < 0.01). The expression of lncRNA RP11-259P1.1 in cancer tissues of chemosensitive group was significantly lower than that of chemoresistant group (P<0.05). The expression of lncRNA RP11-259P 1.1 was not correlated with gender and age, but significantly correlated with tumor stage, metastasis and chemosensitivity (all P<0.05). PFS and OS in patients with high lncRNA RP11-259P 1.1 expression were significantly shorter than those in patients with low expression ([12.25±1.83] vs [22.29±1.58] months, [23.55±1.35] vs [31.75±2.43] months, all P<0.01). The expression of lncRNA RP11-259P 1.1, tumor stage and distant metastasis were the independent prognostic factors in SCLC patients (all P<0.05). Conclusion: The high expression of lncRNA RP11-259P1.1 in SCLC tissues is associated with chemosensitivity and prognosis of SCLC patients, and may be a potential biomarker for prognosis evaluation in SCLC patients.

Effect of carbocisteine on patients with COPD: a systematic review and meta-analysis.

BACKGROUND: COPD is the fourth leading cause of death in the world. It is a common, progressive, treatable and preventable disease. The exacerbation of COPD is associated with the peripheral muscle force, forced expiratory volume in 1 second (FEV1), the quality of life and mortality. Many studies indicated that the mucoactive medicines could reduce the exacerbations of COPD. This study summarized the efficacy of carbocisteine as a treatment for COPD. METHODS: We searched the randomized controlled trials (RCTs) following electronic bibliographic databases: MedLine, Embase, Cochrane Library and Web of Science. We additionally searched gray literature database: OpenSIGLE. We also additionally searched the clinical trial registers: ClinicalTrials.gov register and International Clinical Trials Registry Platform Search Portal. We used RCTs to assess the efficacy of the treatments. We included studies of adults (older than 18 years) with COPD. We excluded studies that were published as protocol or written in non-English language (Number 42016047078). FINDINGS: Our findings included data from four studies involving 1,357 patients. There was a decrease in the risk of the rate of total number of exacerbations with carbocisteine compared with placebo (-0.43; 95% confidence interval [CI] -0.57, -0.29, P<0.01). Carbocisteine could also improve the quality of life (-6.29; 95% CI -9.30, -3.27) and reduce the number of patients with at least one exacerbation (0.86; 95% CI 0.78, 0.95) compared with placebo. There was no significant difference in the FEV1 and adverse effects and the rate of hospitalization. INTERPRETATION: Long-term use of carbocisteine (500 mg TID) may be associated with lower exacerbation rates, the smaller number of patients with at least one exacerbation and higher quality of life of patients with COPD.

Establishment and evaluation of an experimental rat model for high-altitude intestinal barrier injury.

In the present study an experimental high-altitude intestinal barrier injury rat model was established by simulating an acute hypoxia environment, to provide an experimental basis to assess the pathogenesis, prevention and treatment of altitude sickness. A total of 70 healthy male Sprague-Dawley rats were divided into two groups: Control group (group C) and a high-altitude hypoxia group (group H). Following 2 days adaptation, the rats in group H were exposed to a simulated 4,000-m, high-altitude hypoxia environment for 3 days to establish the experimental model. To evaluate the model, bacterial translocation, serum lipopolysaccharide level, pathomorphology, ultrastructure and protein expression in rats were assessed. The results indicate that, compared with group C, the rate of bacterial translocation and the apoptotic index of intestinal epithelial cells were significantly higher in group H (P<0.01). Using a light microscope it was determined that the intestinal mucosa was thinner in group H, there were fewer epithelial cells present and the morphology was irregular. Observations with an electron microscope indicated that the intestinal epithelial cells in group H were injured, the spaces among intestinal villi were wider, the tight junctions among cells were open and lanthanum nitrate granules (from the fixing solution) had diffused into the intestinal mesenchyme. The expression of the tight junction protein occludin was also decreased in group H. Therefore, the methods applied in the present study enabled the establishment of a stable, high-altitude intestinal barrier injury model in rats.

MtDNA haplogroups M7 and B in southwestern Han Chinese at risk for acute mountain sickness.

We conducted a case-control study to investigate the association of mitochondrial DNA (mtDNA) haplogroups with acute mountain sickness (AMS) in Han Chinese from southwestern (SW) China. Pearson's chi-square test or Fisher's exact test revealed significant reduction of mtDNA haplogroups D and M9, while a significant increase of haplogroup M7 in AMS subjects compared with non-AMS subjects. The multivariate logistic regression analysis after adjustment for body mass index (BMI), a risk factor of AMS in the present study, showed that both D and M9 were associated with significantly decreased risk of AMS, while M7 was associated with a significantly increased risk of AMS (OR=0.605, p=0.000; OR=0.037, p=0.001, and OR=2.419, p=0.001, respectively). In addition, further analysis stratified by the AMS severities indicated that haplogroup B was correlated with a 2.41-folds increased risk of developing severe AMS (95%C.I=1.288-4.514, p=0.006). Our findings provide evidence that, in SW Han Chinese, mtDNA haplogroups D and M9 are related to individual tolerance to AMS, while haplogroups M7 and B are risk factors for AMS.

[Experimental study on the expression and function of aquaporin-1 and aquaporin-5 in rats with acute lung injury induced by lipopolysaccharide].

OBJECTIVE: To investigate whether the expression and function of aquaporin-1 (AQP-1) is altered by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in primary rat lung microvessel endothelial cells (LMECs) after exposure to lipopolysaccharide (LPS), and to study the expressions of AQP-1 and AQP-5 in lung tissue of rats with acute lung injury (ALI) induced by LPS. The aim is to further clarify the pathogenesis of ALI/acute respiratory distress syndrome (ARDS). METHODS: (1) In vitro: The third passage LMECs were randomly divided into LPS group, TNF-alpha group, IL-1beta group and DMEM control group, and the experimental groups were exposed to LPS, TNF-alpha and IL-1beta respectively. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to quantify AQP-1 mRNA changes and an immunocytochemistry method was used for determining AQP-1 protein changes in cultured rat LMECs. Isotope tracer technique was applied for the assay of the intra-cellular tritium water ((3)H2O) signal intensity in rat LMECs. (2) In vivo: Forty male Wistar rats were randomly divided into five groups: LPS 2 h group, LPS 4 h group, LPS 6 h group, LPS 8 h group and a control group, eight rats per group; The LPS treated groups served as the ALI models. RT-PCR was used to observe the changes of AQP-1 and AQP-5 mRNA and the immunohistochemistry method was used for determining AQP-1 and AQP-5 protein changes in ALI rats. RESULTS: (1) In vitro: The expression of AQP-1 mRNA and protein in LMECs were decreased significantly in the LPS group (0.428 +/- 0.026, 0.366 +/- 0.009), the TNF-alpha group (0.446 +/- 0.029, 0.374 +/- 0.014) and IL-1beta group (0.454 +/- 0.023, 0.377 +/- 0.007) as compared to the DMEM control group (0.793 +/- 0.035, 0.660 +/- 0.013, respectively; all P < 0.01). The quantities of tritium water's permeability in the LPS group, the TNF-alpha group and the IL-1beta group [(726 +/- 58), (738 +/- 45), (774 +/- 44) counts per minute] were significantly less than that in the DMEM control group [(1 148 +/- 70) counts per minute, P < 0.01]. (2) In vivo: The expression levels of AQP-1 and AQP-5 mRNA in ALI rats (LPS 2 h group 0.409 +/- 0.018, 0.421 +/- 0.020; LPS 4 h group 0.421 +/- 0.023, 0.412 +/- 0.023; LPS 6 h group 0.435 +/- 0.020, 0.388 +/- 0.031; LPS 8 h group 0.438 +/- 0.016, 0.386 +/- 0.019, respectively) were significantly lower than that in the control group (0.794 +/- 0.015, 0.787 +/- 0.022; all P < 0.01). CONCLUSION: AQP-1 and AQP-5 may play a role in abnormal fluid transportation and probably involve in the formation of pulmonary edema in ALI/ARDS.