Naringenin inhibits APAP-induced acute liver injury through activating PPARA-dependent signaling pathway.

Acute liver injury (ALI) refers to the damage to the liver cells of patients due to drugs, food, and diseases. In this work, we used a network pharmacology approach to analyze the relevant targets and pathways of the active ingredients in Citri Reticulatae Pericarpium (CRP) for the treatment of ALI and conducted systematic validation through in vivo and in vitro experiments. The network pharmacologic results predicted that naringenin (NIN) was the main active component of CRP in the treatment of ALI. GO functional annotation and KEGG pathway enrichment showed that its mechanism may be related to the regulation of PPARA signaling pathway, PPARG signaling pathway, AKT1 signaling pathway, MAPK3 signaling pathway and other signaling pathways. The results of in vivo experiments showed that (NIN) could reduce the liver lesions, liver adipose lesions, hepatocyte injury and apoptosis in mice with APAP-induced ALI, and reduce the oxidative stress damage of mouse liver cells and the inflammation-related factors to regulate ALI. In vitro experiments showed that NIN could inhibit the proliferation, oxidative stress and inflammation of APAP-induced LO2 cells, promote APAP-induced apoptosis of LO2 cells, and regulate the expression of apoptotic genes in acute liver injury. Further studies showed that NIN inhibited APAP-induced ALI mainly by regulating the PPARA-dependent signaling pathway. In conclusion, this study provides a preliminary theoretical basis for the screening of active compounds in CRP for the prevention and treatment of ALI.

Palliation of malignant esophageal stent esophagorespiratory fistula with rigid bronchoscope and Y silicone trachea stent: experience with seven patients.

Background: Malignant esophageal stent esophagorespiratory fistula (ERF) is an abnormal communication between esophagus and airway among advanced tumor patients with indwelling esophageal stent, which is devastating and life-threatening. This study aims to provide a new feasible treatment scheme for malignant esophageal stent ERF and report its potential advantage compared with double stenting, which was recommended by European Society of Gastrointestinal Endoscopy Guideline. Methods: We retrospectively analyzed the medical data of malignant esophageal stent ERF patients between January 2018 to May 2023 at the First Affiliated Hospital of Guangzhou Medical University and divided them into two groups. Group 1 consisted of patients treated with rigid bronchoscopy to remove the esophageal stent and implant Y silicone trachea stent, while group 2 consisted of patients treated with additional airway stenting without removing the esophageal stent. Demographic parameters, disease diagnoses and treatment, radiological findings before and after the intervention, and complications caused by the stents were obtained and analyzed with chi-squared, Mann-Whitney U, independent-samples t-tests, Kaplan-Meier methods, and log-rank test. Results: Ten patients (seven patients in group 1 and three in group 2) were included. No procedure complications occurred in both groups. The mean Karnofsky Performance Score after the procedure significantly improved compared to the pre-procedure (57.14 vs. 77.14, P=0.001) in group 1, while decreased in group 2 (50 vs. 40, P=0.026). The control of pneumonia in group 1 patients is better than that in group 2. There was significant improvement in the degree of dysphagia after the procedure (3.86 vs. 2.43, P=0.002) in group 1, while no improvement was found in group 2 (4.00 vs. 3.33, P=0.423). The mean survival of group 1 was significantly longer group 2 (381.00 vs. 80.33 days, P<0.001, log-rank test). No patient needed stent repositioning due to migration in both groups. Cause of death in the group 1 included disease progression, novel coronavirus pneumonia, massive hemoptysis, and respiratory insufficiency, while group 2 included severe pneumonia and disease progression. No death was directly attributed to the procedure in both groups. Conclusions: Removing the esophageal stent and implanting Y silicone trachea stent through a rigid bronchoscopy is a safe and feasible treatment for malignant esophageal stent ERF. This procedure can effectively seal the fistula, prevent from recurrent aspiration pneumonia, improve the quality of life, and prolong the survival time.

Regular use of aspirin and statins reduces the risk of cancer in individuals with systemic inflammatory diseases.

Aspirin has shown potential for cancer prevention, but a recent large randomized controlled trial found no evidence for a reduction in cancer risk. Given the anti-inflammatory effects of aspirin, systemic inflammatory diseases (SIDs), such as osteoporosis, cardiovascular diseases, and metabolic diseases, could potentially modify the aspirin-cancer link. To investigate the impact of aspirin in people with SIDs, we conducted an observational study on a prospective cohort of 478,615 UK Biobank participants. Individuals with at least one of the 41 SIDs displayed a higher cancer risk than those without SIDs. Regular aspirin use showed protective effects exclusively in patients with SID, contrasting an elevated risk among their non-SID counterparts. Nonetheless, aspirin use demonstrated preventative potential only for 9 of 21 SID-associated cancer subtypes. Cholesterol emerged as another key mediator linking SIDs to cancer risk. Notably, regular statin use displayed protective properties in patients with SID but not in their non-SID counterparts. Concurrent use of aspirin and statins exhibited a stronger protective association in patients with SID, covering 14 common cancer subtypes. In summary, patients with SIDs may represent a population particularly responsive to regular aspirin and statin use. Promoting either combined or individual use of these medications within the context of SIDs could offer a promising chemoprevention strategy.

Assessment for bone health in patients with differentiated thyroid carcinoma after postoperative thyroid-stimulating hormone suppression therapy: a new fracture risk assessment algorithm.

Purpose: The fracture risk assessment tool (FRAX) is used to assess the 10-year risk of major site and hip fractures; however, whether this tool can be applied to patients receiving levothyroxine-based thyroid-stimulating hormone (TSH) suppressive therapy for postoperative differentiated thyroid cancer (DTC) patients is yet to be clarified. Methods and design: A total of 64 patients with DTC following thyroidectomy and oral levothyroxine for TSH suppression therapy and 30 gender- and age-matched controls were collected. The fracture risk was compared between the affected groups with different TSH levels. FRAX was used to calculate the fracture risk with and without bone mineral density (BMD). The TSH level was converted to an age-weighted score to estimate the fracture risk of postoperatively differentiated thyroid cancer patients. The sensitivity, specificity, and area under the AUC curve of the traditional FRAX and the new algorithm for osteoporosis diagnosis were compared. The dual-energy X-ray bone mineral density measurement T score was used as the gold standard to diagnose osteoporosis. Results: There were 24 patients in the T ≥ -1-2.5 group, 23 in the -2.5 < T < -1 group, and 17 in the T ≤ -2.5 group. The T score of BMD in the disease group was significantly lower than that in the control group (p < 0.05). The risk of MOF and hip fracture without a T score were significantly different under various TSH levels (p < 0.05). The area under the curve (AUC) of FRAX without BMD for predicting major osteoporotic fractures (PMOF) and major hip fractures (PHF) was 0.694 and 0.683, respectively. The cutoff values were 2.15% and 0.25%, respectively. The AUC of FRAX with BMD for PMOF and PHF was 0.976 and 0.989, respectively, and the cutoff values were 4.15% and 1.1%, respectively. The AUC of FRAX without BMD for PMOF and PHF was 0.708 and 0.72, respectively, and the cutoff values were 5.5% and 1.55%, respectively. Conclusions: FRAX is suitable for postoperative DTC patients after TSH suppressive therapy. In the absence of BMD, TSH weighted by age can improve the specificity of FRAX in the diagnosis of osteoporosis in this population.

Comprehensive assessment of base excision repair (BER)-related lncRNAs as prognostic and functional biomarkers in lung adenocarcinoma: implications for personalized therapeutics and immunomodulation.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, and comprehending its molecular mechanisms is pivotal for advancing treatment efficacy. This study aims to explore the prognostic and functional significance of base excision repair (BER)-related long non-coding RNAs (BERLncs) in LUAD. METHODS: A risk score model for BERLncs was developed using the least absolute shrinkage and selection operator regression and Cox regression analysis. Model validation and prognostic evaluation were performed using Kaplan-Meier and receiver-operating characteristic curve analyses. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to elucidate the potential biological functions of BERLncs. Comparative analyses were carried out to investigate disparities in tumor mutation burden (TMB), immune infiltration, tumor immune dysfunction and exclusion (TIDE) score, chemosensitivity, and immune checkpoint gene expression between the two risk groups. RESULTS: A predictive risk score model comprising 19 BERLncs was successfully developed. Patients were divided into high-risk and low-risk groups according to the median risk score. The high-risk subgroup exhibited significantly inferior overall survival. Functional enrichment analysis revealed pathways associated with lung cancer development, notably the neuroactive ligand-receptor interaction pathway. High-risk patients demonstrated elevated TMB, diminished TIDE scores, and an immunosuppressive tumor microenvironment, while low-risk patients displayed potential benefits from immunotherapy. Additionally, the risk model identified potential anticancer agents. CONCLUSION: The risk score model based on BERLncs shows promise as a prognostic biomarker for LUAD patients, providing valuable insights for clinical decision-making, therapeutic strategies, and understanding of underlying biological mechanisms.

Progress of research on the role of active ingredients of Citri Reticulatae Pericarpium in liver injury.

BACKGROUND: Liver is a vital organ responsible for metabolizing and detoxifying both endogenous and exogenous substances in the body. However, it is susceptible to damage from chemical and natural toxins. The high incidence and mortality rates of liver disease and its associated complications impose a significant economic burden and survival pressure on patients and their families. Various liver diseases exist, including cholestasis, viral and non-viral hepatitis, fatty liver disease, drug-induced liver injury, alcoholic liver injury, and severe end-stage liver diseases such as cirrhosis, hepatocellular carcinoma (HCC), and cholangiocellular carcinoma (CCA). Recent research has shown that flavonoids found in Citri Reticulatae Pericarpium (CRP) have the potential to normalize blood glucose, cholesterol levels, and liver lipid levels. Additionally, these flavonoids exhibit anti-inflammatory properties, prevent oxidation and lipid peroxidation, and reduce liver toxicity, thereby preventing liver injury. Given these promising findings, it is essential to explore the potential of active components in CRP for developing new drugs to treat liver diseases. OBJECTIVE: Recent studies have revealed that flavonoids, including hesperidin (HD), hesperetin (HT), naringenin (NIN), nobiletin (NOB), naringin (NRG), tangerine (TN), and erodcyol (ED), are the primary bioactive components in CRP. These flavonoids exhibit various therapeutic effects on liver injury, including anti-oxidative stress, anti-cytotoxicity, anti-inflammatory, anti-fibrosis, and anti-tumor mechanisms. In this review, we have summarized the research progress on the hepatoprotective effects of HD, HT, NIN, NOB, NRG, TN, ED and limonene (LIM), highlighting their underlying molecular mechanisms. Despite their promising effects, the current clinical application of these active ingredients in CRP has some limitations. Therefore, further studies are needed to explore the full potential of these flavonoids and develop new therapeutic strategies for liver diseases. METHODS: For this review, we conducted a systematic search of three databases (ScienceNet, PubMed, and Science Direct) up to July 2022, using the search terms "CRP active ingredient," "liver injury," and "flavonoids." The search data followed the PRISMA standard. RESULTS: Our findings indicate that flavonoids found in CRP can effectively reduce drug-induced liver injury, alcoholic liver injury, and non-alcoholic liver injury. These therapeutic effects are mainly attributed to the ability of flavonoids to improve liver resistance to oxidative stress and inflammation while normalizing cholesterol and liver lipid levels by exhibiting anti-free radical and anti-lipid peroxidation properties. CONCLUSION: Our review provides new insights into the potential of active components in CRP for preventing and treating liver injury by regulating various molecular targets within different cell signaling pathways. This information can aid in the development of novel therapeutic strategies for liver disease.

Tumour-pleura relationship on CT is a risk factor for occult lymph node metastasis in peripheral clinical stage IA solid adenocarcinoma.

OBJECTIVES: To investigate whether the tumour-pleura relationship on computed tomography (CT) is a risk factor for occult lymph node metastasis (OLNM) in peripheral clinical stage IA solid adenocarcinoma. METHODS: A total of 232 patients were included in the study. The tumour-pleura relationship was divided into four types: type 1, the tumour was unrelated to the pleura; type 2, the tumour was not in contact with the pleura, and one or more linear or striated pleural tags were visible; type 3, the tumour was not in contact with the pleura, and one or more linear or striated pleural tags with soft tissue component at the pleural end were visible; and type 4, the tumour was in contact with the pleura. Univariate and multivariate logistic regression analyses were used to identify the predictive factors, including the tumour-pleura relationship, clinical factors, conventional CT findings, and pathology-reported visceral pleural invasion, for OLNM. RESULTS: Type 3 and 4 tumour-pleura relationships were more likely to have visceral pleural invasion than type 1 and 2 tumour-pleura relationships (p < 0.001). Univariate and multivariate logistic regression analyses revealed that the type 3 or 4 tumour-pleura relationship (OR: 3.261, p = 0.026), carcinoembryonic antigen level (OR: 3.361, p = 0.006), cytokeratin 19 fragments level (OR: 2.539, p = 0.025), and mediastinal window tumour size (OR: 1.078, p = 0.020) were predictive factors for OLNM. CONCLUSIONS: The type 3 or 4 tumour-pleura relationship is correlated with a greater risk of OLNM in peripheral clinical stage IA solid adenocarcinoma. KEY POINTS: • The tumour-pleura relationship on CT is a risk factor for occult lymph node metastasis in peripheral clinical stage IA solid adenocarcinoma. • Other risk factors for OLNM include CEA level, CYFRA level, and mediastinal window tumour size. • Pathology-reported visceral pleural invasion is not a risk factor for OLNM.

Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. METHODS: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. RESULTS: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference. CONCLUSIONS: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.

PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer.

Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. SIGNIFICANCE: Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.

CT-based radiomics nomogram for predicting visceral pleural invasion in peripheral T1-sized solid lung adenocarcinoma.

The preoperative assessment of visceral pleural invasion (VPI) in patients with early lung adenocarcinoma is vital for surgical treatment. This study aims to develop and validate a CT-based radiomics nomogram to predict VPI in peripheral T1-sized solid lung adenocarcinoma. A total of 203 patients were selected as subjects, and were divided into a training cohort (n=141; scanned with Brilliance iCT256, Brilliance 64, Somatom Force, and Optima CT660) and a test cohort (n=62; scanned with Somatom Definition AS+). Radiomics characteristics were extracted from CT images. Variance thresholding, SelectKBest, and least absolute shrinkage and selection operator (LASSO) method were applied to determine optimum characteristics to construct the radiomic signature (radscore). After multivariate logistic regression analysis, a nomogram was structured regarding clinical factors, conventional CT features, and radscore. The nomogram property was tested based on its area under the curve (AUC). The nomogram based on the radscore and two conventional CT features (tumor pleura relationship and lymph node enlargement) showed high discrimination with an AUC of 0.877 (95% CI: 0.820-0.935) and 0.837 (95% CI: 0.737-0.937) in the training and test cohorts, respectively. The calibration curve and decision curve analysis showed good consistency and high clinical value of the nomogram. In conclusion, The CT-based radiomics nomogram was helpful in predicting VPI in peripheral T1-sized solid lung adenocarcinoma.

Sirtuins: Research advances on the therapeutic role in acute kidney injury.

BACKGROUND: Acute kidney injury (AKI), a common multidisciplinary diagnostic clinical critical illness, eventually causes end-stage renal disease (ESRD). Although many clinical measures have been taken to prevent or treat AKI, high morbidity and death rates were recorded. Therefore, in-depth pathogenesis study and search for new therapeutic targets are in demand. Interestingly, the suirtuins family showed a significant protective effect in AKI. Sirtuins (SIRT1-7) is a family of seven proteins with NAD+-dependent type III histone deacetylase activity. Sirtuins family members were involved by AKI, and regulation of sirtuins activities significantly improved AKI-induced renal injury. Therefore, the therapeutic role and molecular mechanisms of the sirtuins family in AKI has important research implications for clinical applications or basic research. PURPOSE: This review summarizes recent advances in the roles and functions of the sirtuins family, discusses their therapeutic effects on AKI and related molecular mechanisms, and the mechanisms of action of small molecule specific activators or inhibitors sirtuins in the prevention and treatment of AKI were discussed. METHODS: The data in this review were retrieved from various scientific databases (PubMed, Google scholar, Science Direct, and Web of Science), till December 2021. The keywords were used as follows: "Sirtuins", "Acute kidney injury", "AKI", "Sirtuins modulators" and "Histone deacetylation". The retrieved data followed PRISMA criteria (preferred reporting items for systematic review). RESULTS: Growing evidence indicates that members of the sirtuins family regulate the development and progression of different renal diseases, including AKI, through anti-inflammation, antioxidation, anti-apoptotic, and maintenance of mitochondrial homeostasis. The molecular mechanism of Sirtuins family on AKI mainly regulated NF-κB, JNK/ERK, and AMPK/mTOR signaling pathways, upregulated the expression of PGC-1α, HO-1, NRF2, Bcl-2, OPA1, and AMPK, and downregulated the expression of NRLP3, IL-1ß, TNF-α, IL-6, ROS, MFF, Drp1, Bax, ERK, and mTOR. In addition, the active ingredients of herbs (resveratrol, thujaplicins, huperzine, and curcumin) could activate the activity of SIRT1 or SIRT3, thereby improving AKI. Meanwhile, the synthetic Sirtuins inhibitor (AK-1) inhibited SIRT2 activity, thus alleviating AKI. In the future, more specific modulators will remain needed to enhance the clinical therapeutic role of the Sirtuins family in AKI. CONCLUSION: The sirtuins family is a promising type III histone deacetylase for AKI treatment. This review will provide insight into sirtuins family's therapeutic role in AKI and promote the clinical use of sirtuins modulators in AKI.

Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice.

BACKGROUND: Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). METHODS: A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. RESULTS: Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045). CONCLUSIONS: Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.

Assessment of anti-PD-(L)1 for patients with coexisting malignant tumor and tuberculosis classified by active, latent, and obsolete stage.

BACKGROUND: It is not a rare clinical scenario to have patients presenting with coexisting malignant tumor and tuberculosis. Whether it is feasible to conduct programmed death-(ligand) 1 [PD-(L)1] inhibitors to these patients, especially those with active tuberculosis treated with concurrent anti-tuberculosis, is still unknown. METHODS: This study enrolled patients with coexisting malignancy and tuberculosis and treated with anti-PD-(L)1 from Jan 2018 to July 2021 in 2 institutions. The progression-free survival (PFS), objective response rate (ORR), and safety of anti-PD-(L)1 therapy, as well as response to anti-tuberculosis treatment, were evaluated. RESULTS: A total of 98 patients were screened from this cohort study, with 45 (45.9%), 21 (21.4%), and 32 (32.7%) patients diagnosed with active, latent, and obsolete tuberculosis, respectively. The overall ORR was 36.0% for anti-PD-(L)1 therapy, with 34.2%, 35.5%, and 41.2% for each subgroup. Median PFS was 8.0 vs 6.0 vs 6.0 months (P=0.685) for each subgroup at the time of this analysis. For patients with active tuberculosis treated with concurrent anti-tuberculosis, median duration of anti-tuberculosis therapy was 10.0 (95% CI, 8.01-11.99) months. There were 83.3% (20/24) and 93.3% (42/45) patients showing sputum conversion and radiographic response, respectively, after anti-tuberculosis therapy, and two patients experienced tuberculosis relapse. Notably, none of the patients in latent and only one patient in obsolete subgroups showed tuberculosis induction or relapse after anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 33 patients (73.3%) when treated with concurrent anti-PD-(L)1 and anti-tuberculosis. Grade 3 or higher TRAEs were hematotoxicity (n = 5, 11.1%), and one patient suffered grade 3 pneumonitis leading to the discontinuation of immunotherapy. CONCLUSIONS: This study demonstrated that patients with coexisting malignant tumor and tuberculosis benefited equally from anti-PD-(L)1 therapy, and anti-tuberculosis response was unimpaired for those with active tuberculosis. Notably, the combination of anti-PD-(L)1 and anti-tuberculosis therapy was well-tolerated without significant unexpected toxic effects.

Synthesis of 4-styrylcoumarins via FeCl3-promoted cascade reactions of propargylamines with ß-keto esters.

A versatile and highly regioselective FeCl3-promoted tandem cyclization reaction of in situ generated alkynyl o-quinone methides (o-AQMs) with ß-keto esters has been developed on the basis of the mode involving an intermolecular 1,4-conjugate addition/alkyne-allene isomerization/intramolecular transesterification/isomerization cascade. Using this method, a variety of diversely substituted 4-styryl-2H-chromen-2-ones were prepared with good efficiency and exclusive site-selectivity.

FeCl3-promoted tandem 1,4-conjugate addition/6-endo-dig cyclization/oxidation of propargylamines and benzoylacetonitriles/malononitriles: direct access to functionalized 2-aryl-4H-chromenes.

An efficient and concise procedure has been developed for the synthesis of functionalized 2-aryl-4H-chromenes based on a tandem reaction of propargylamines and benzoylacetonitriles/malononitriles in the presence of FeCl3 as an environmentally friendly promoter. This reaction involves a highly efficient tandem sequence consisting of 1,4-conjugate addition, 6-endo-dig cyclization, and oxidation. This protocol tolerates a variety of functional groups, thereby providing a practical and efficient method for the fabrication of 2-aryl-4H-chromene skeletons.

Effects of preventive therapy for latent tuberculosis infection and factors associated with treatment abandonment: a cross-sectional study.

BACKGROUND: Routine data on the use of preventive therapy (PT) for latent tuberculosis infection (LTBI) in students are scarce in high tuberculosis (TB) burden countries. This study aimed to investigate the effects of PT and identify factors related to PT abandonment during the school TB epidemic in Guangzhou, southern China. METHODS: Purified protein derivative (PPD) skin testing was performed on all staff and students in a vocational school in Guangzhou, southern China during December 2014. Subjects (n=362) with a reactive PPD induration ≥15 mm, or with papules, blisters, and a normal chest X-ray image were recommended for PT. The subjects were assigned to a PT group (n=156) and control group (n=206), respectively, on a voluntary basis. Subjects in the PT group received isoniazid (INH) combined with rifampicin (RFP) for 3 consecutive months; after which, the incidence of TB and protective rate of PT for reducing TB were observed during a 2-year follow up period. An improved questionnaire was used to identify factors that influenced treatment abandonment. All data were subjected to univariate and multivariate logistic regression analyses. RESULTS: Two cases in the PT group and 20 cases in the control group developed TB. The protective rate of PT for reducing TB was 86.8%. In the PT group, 69 cases finished PT, with a completion rate of 44.2%, and the incidence rates of adverse events and hepatotoxicity were 12.2% and 1.9%, respectively. Among 362 LTBI cases, a total of 293 cases abandoned PT. Discrimination (OR =7.173, 95% CI, 3.361-15.307), worry about adverse drug reactions (OR =2.752, 95% CI, 1.459-5.192), a low parental education level (OR =2.605, 95% CI, 1.420-4.777), and accepting the opinion of a non-TB specialist (OR =6.017, 95% CI, 3.077-11.765) were identified as high-risk factors for abandoning PT. CONCLUSIONS: A PT regimen consisting of INH combined with RFP for 3 consecutive months is reasonable for use in schools. Discrimination, worry about adverse drug reactions, a low parental education level, and accepting the opinion of a non-TB specialist are all factors that may increase the risk for treatment abandonment among LTBI cases. To overcome psychological obstacles is critical for improving treatment adherence.