Assessing the effectiveness and safety of surufatinib versus everolimus or sunitinib in advanced neuroendocrine neoplasms: insights from a real-world, retrospective cohort study using propensity score and inverse probability treatment weighting analysis.

Background: While surufatinib, sunitinib, and everolimus have shown efficacy for advanced neuroendocrine neoplasms (NENs) in randomized controlled trials (RCTs), direct comparisons in a real-world setting remain unexplored. This gap highlights the clinical need to understand their comparative effectiveness and safety within the diverse Chinese population. Addressing this, our study provides insights into the real-world performance of these therapies, aiming to inform treatment selection and improve patient outcomes. Methods: A retrospective, observational study was conducted at Fudan University Shanghai Cancer Center, including patients with advanced NENs treated with surufatinib, sunitinib, or everolimus between July 2020 and April 2023. Eligibility criteria focused on histologically confirmed, locally advanced, unresectable, or metastatic NENs, with patients having received at least one month of targeted therapy. We employed inverse probability weighting (IPW) with the propensity score (PS) matching to adjust for the bias of baseline characteristics. The assessment of covariates included age, sex, performance status, primary tumor site, functional status, genetic mutations, tumor differentiation, Ki67 index, tumor grade, metastasis site, and previous therapies. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: The study enrolled 123, 56, and 68 locally advanced or metastatic NEN patients treated with surufatinib, sunitinib, and everolimus, respectively. Before adjusting for confounding factors, surufatinib was used less frequently as a first-line treatment compared to sunitinib and everolimus in pancreatic NENs (pNENs) (11.1% vs. 22.1%, P=0.057). Significant differences were noted in prior treatments and tumor characteristics between surufatinib and everolimus groups in extrapancreatic NENs (epNENs) (P<0.05). Post-IPW, these disparities were resolved (P>0.05). Surufatinib demonstrated superior median PFS (mPFS) in both pancreatic [8.30 vs. 6.33 months, hazard ratio (HR) 0.592, P<0.001] and epNENs (8.73 vs. 3.70 months, HR 0.608, P<0.001) compared to everolimus or sunitinib. Notably, male gender (HR 1.75, P=0.001), functional status (HR 2.09, P=0.01), Ki67 index >20% (HR 12.7, P=0.004), previous somatostatin analogue (SSA) treatment (HR 1.73, P=0.001), germline mutation (HR 5.62, P<0.001), poor differentiation (HR 7.45, P<0.001), liver metastasis (HR 1.72, P=0.001) and multiple treatment lines (HR 1.62 for 2nd line, P=0.04; HR 1.88 for ≥3rd line, P=0.01) were identified as negative prognostic factors for PFS. Conversely, dose adjustment (HR 0.63, P=0.009) and treatment with surufatinib (HR 0.58 for pNEN, P<0.001; HR 0.62 for epNEN, P=0.002) were correlated with longer PFS. Conclusions: In a real-world Chinese cohort, surufatinib significantly outperformed sunitinib and everolimus in prolonging PFS among advanced NEN patients, with identifiable clinical features impacting survival, and conclusions regarding superiority should be interpreted with caution due to the retrospective design. Our findings underscore the need for prospective studies to further validate these results and explore additional predictive biomarkers for personalized treatment strategies.

Integration of single-nucleus and exosome RNA sequencing dissected inter-cellular communication and biomarkers in pancreatic ductal adenocarcinoma.

Background: Mounting evidence underscores the importance of cell communication within the tumor microenvironment, which is pivotal in tumor proliferation, invasion, and metastasis. Exosomes play a crucial role in cell-to-cell communication. Although single-cell RNA sequencing (scRNA-seq) provides insights into individual cell transcriptional characteristics, it falls short of comprehensively capturing exosome-mediated intercellular communication. Method: We analyzed Pancreatic Ductal Adenocarcinoma (PDAC) tissues, separating supernatant and precipitate for exosome purification and single-cell nucleus suspension. We then constructed Single-nucleus RNA sequencing (snRNA-seq) and small RNA-seq libraries from these components. Our bioinformatic analysis integrated these sequences with ligand-receptor analysis and public miRNA data to map the cell communication network. Results: We established intercellular communication networks using bioinformatic analysis to track exosome miRNA effects and ligand-receptor pairs. Significantly, hsa-miR-1293 emerged as a prognostic biomarker for pancreatic cancer, linked to immune evasion, increased myeloid-derived suppressor cells, and poorer prognosis. Targeting this miRNA may enhance anti-tumor immunity and improve outcomes. Conclusion: Our study offers a novel approach to constructing intercellular communication networks using snRNA-seq and exosome-small RNA sequencing. By integrating miRNA tracing with ligand-receptor analysis, we illuminate the complex interactions in the pancreatic cancer microenvironment, highlighting the pivotal role of miRNAs and identifying potential biomarkers and therapeutic targets.

Post-marketing safety surveillance of sacituzumab govitecan: an observational, pharmacovigilance study leveraging FAERS database.

Background and objective: Sacituzumab govitecan (SG), the first antibody-drug conjugate targeting human trophoblast cell-surface antigen 2 (Trop-2), has been approved by the Food and Drug Administration (FDA) for the treatment of advanced or metastatic breast cancer and urothelial cancer. However, there is currently a dearth of information regarding the safety profiles of SG in a large sample cohort. The objective of the present study is to investigate SG-related adverse events (AEs) in real-world settings leveraging the FDA Adverse Event Reporting System (FAERS) database to guide the safety management of clinical medication. Methods: The FAERS database was retrospectively queried to extract reports associated with SG from April 2020 to March 2023. To identify and evaluate potential AEs in patients receiving SG, various disproportionality analyses such as reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed. Results: Overall, 2069 reports of SG as the "primary suspect" were identified. Noteworthy, SG was significantly associated with an increased risk of blood lymphatic system disorders (ROR, 7.18; 95% CI, 6.58-7.84) and hepatobiliary disorders (ROR, 2.68; 95% CI, 2.17-3.30) at the System Organ Class (SOC) level. Meanwhile, 61 significant disproportionality preferred terms (PTs) simultaneously complied with all four algorithms were adopted. Therein, anemia, thrombocytopenia, neutropenia, leukopenia, diarrhea, asthenia, alopecia, and electrolyte imbalance were consistent with the common AEs described in the clinical trials and specification of SG. Furthermore, unexpected significant AEs include colitis (ROR, 12.09; 95% CI, 9.1-16.08), heart rate increased (ROR, 5.11; 95% CI, 3.84-6.79), sepsis (ROR, 4.77; 95% CI, 3.59-6.34), cholestasis (ROR, 6.28; 95% CI, 3.48-11.36), blood bilirubin increased (ROR, 4.65; 95% CI, 2.42-8.94) and meningitis (ROR, 7.23; 95% CI, 2.71-19.29) were also be detected. The median time to onset of SG-related AEs was 14 [interquartile range (IQR), 7-52] days, with the majority occurring within the initial month of SG treatment. Conclusion: Our study validates the commonly known AEs and also found some potentially emerging safety issues related to SG in real-world clinical practice, which could provide valuable vigilance evidence for clinicians and pharmacists to manage the safety issues of SG.

Targeting neoadjuvant chemotherapy-induced metabolic reprogramming in pancreatic cancer promotes anti-tumor immunity and chemo-response.

The molecular dynamics of pancreatic ductal adenocarcinoma (PDAC) under chemotherapy remain incompletely understood. The widespread use of neoadjuvant chemotherapy (NAC) provides a unique opportunity to investigate PDAC samples post-chemotherapy. Leveraging a cohort from Fudan University Shanghai Cancer Center, encompassing PDAC samples with and without exposure to neoadjuvant albumin-bound paclitaxel and gemcitabine (AG), we have compiled data from single-cell and spatial transcriptomes, proteomes, bulk transcriptomes, and metabolomes, deepening our comprehension of the molecular changes in PDACs in response to chemotherapy. Metabolic flux analysis reveals that NAC induces a reprogramming of PDAC metabolic patterns and enhances immunogenicity. Notably, NAC leads to the downregulation of glycolysis and the upregulation of CD36. Tissue microarray analysis demonstrates that high CD36 expression is linked to poorer survival in patients receiving postoperative AG. Targeting CD36 synergistically improves the PDAC response to AG both in vitro and in vivo, including patient-derived preclinical models.

Ocular adverse events associated with BRAF and MEK inhibitor combination therapy: a pharmacovigilance disproportionality analysis of the FDA adverse event reporting system.

BACKGROUND: BRAF and MEK inhibitor combination therapy have significantly improved the outcome of several BRAF-mutation tumors, but it also confers the risk of drug-induced ocular adverse events (oAEs). However, very few studies focused on this risk. METHODS: The United States Food and Drug Administration Adverse Event Reporting System (FAERS) data from Quarter 1-2011 to Quarter 2-2022 were searched to detect signs of oAEs of three marketed BRAF and MEK inhibitor combination therapies: vemurafenib plus cobimetinib (V + C), dabrafenib plus trametinib (D + T), and encorafenib plus binimetinib (E + B). Disproportionality analyses were performed by calculating the proportional reporting ratio (PRR), χ2 (chi-square), and reporting odds ratios (RORs) with a 95% confidence interval (CI). RESULTS: A series of oAEs were identified, including 42 preferred terms, which could be classified into 8 aspects. In addition to previously reported oAEs, several unexpected oAE signals were detected. Moreover, differences in oAE profiles were found among three combination therapies (V + C, D + T, and E + B). CONCLUSIONS: Our findings support an association between several oAEs and BRAF and MEK inhibitor combination therapies, including several new oAEs. In addition, oAEs profiles may vary across the treatment regimens. Further studies are needed to better quantify these oAEs.

Safety of trastuzumab deruxtecan: A meta-analysis and pharmacovigilance study.

WHAT IS KNOWN AND OBJECTIVE: This study aimed to explore the safety profile of trastuzumab deruxtecan (T-DXd, formerly DS-8201a) using multi-source medical data. METHODS: We explored trastuzumab deruxtecan related adverse events (AEs) in clinical trials available in ClinicalTrials.gov and electronic databases (MEDLINE, EMBASE and PubMed) up to July 16, 2022. Meta-analysis was performed by using incidence rate with 95%CIs. In the pharmacovigilance study of FDA Adverse Event Reporting System (FAERS), the reporting odds ratio (ROR) and the medicines and healthcare products regulatory agency (MHRA) methods were used to analyse the real-world AEs (up to June 28, 2022). RESULTS AND DISCUSSION: A 8 clinical trials enrolled 1457 patients were included. The most common AEs of any grade were gastrointestinal disorders and blood and lymphatic system disorders. The most common AE of grade 3 or higher was neutropenia (21.4%, 95%CI: 14.7%-28.1%, I2  = 91%). The incidence of interstitial lung disease (ILD) and decreased left ventricular ejection fraction were 10.9% (95%CI: 7.2%-14.5%, I2  = 82%) and 1.2% (95%CI: 0.7%-2.2%, I2  = 98%), respectively. A total of 1244 AE reports were identified in the pharmacovigilance study. Gastrointestinal toxicity (ROR = 21.65), myelosuppression (ROR = 36.88), interstitial lung disease (ROR = 50.30), pneumonitis (ROR = 36.59), decreased ejection fraction (ROR = 16.08), and taste disorder (ROR = 14.06) mentioned in the instructions showed strong signals. Also, ascites (ROR = 14.90), lung opacity (ROR = 78.80), pulmonary fibrosis (ROR = 5.59), and increased KL-6 (ROR = 1761.97), which were not mentioned in the instructions, showed strong signals. WHAT IS NEW AND CONCLUSION: Trastuzumab deruxtecan was well tolerated, and more attention should be paid on ILD as well as decreased ejection fraction.

Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

Neuromuscular junction dysfunctions due to immune checkpoint inhibitors therapy: An analysis of FAERS data in the past 15 years.

Introduction: The adverse effects of neuromuscular junction dysfunctions caused by immune checkpoint inhibitor (ICI) drugs have not been thoroughly assessed in the clinics. Objective: To assess the neuromuscular junction dysfunctions in cancer patients with adverse events caused by ICI therapy by searching the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: The FAERS data from January 2004 to December 2020 were collected to analyze the association between neuromuscular connection dysfunction and ICI use. Disproportionate analysis and Bayesian analysis were used to quantify the association between the neuromuscular junction dysfunctions and ICIs. The onset time and outcome of neuromuscular junction dysfunctions in different ICI regimens were also compared. Results: Out of 88,617 adverse event reports, 557 neuromuscular junction dysfunction reports (0.63%) were analyzed. Marketed ICI drugs, including ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab, avelumab, as well as their combinations, showed positive associations with four detection methods. Most of the adverse event reports were associated with the use of nivolumab (53.32%) and pembrolizumab (31.96%). However, nivolumab-related neuromuscular junction dysfunctions were similar with pembrolizumab (33.33% vs 33.14%, p > 0.05). The onset time of neuromuscular junction dysfunctions showed no significant difference among different ICIs (p > 0.05). Conclusions: Analysis of FAERS data identified that over 30% (32.85%) of reports of neuromuscular junction dysfunctions resulted in death. Ongoing monitoring, risk evaluations, and further comparative studies of ICIs should be considered.

Pharmacoeconomic evaluations of CDK4/6 inhibitors plus endocrine therapy for advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer: a systematic review.

Background: Hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer is the most common molecular subtype of breast cancer in many countries, and endocrine therapy remains a mainstay in its treatment. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of targeted agents administered orally that are recommended being used in combination with endocrine therapy as first and second line treatments for advanced HR+/HER2- breast cancer. However, their high prices largely hinder using these drugs in real world settings. To offer a new basis for future research, we investigated the cost-effectiveness of combinations of CDK4/6 inhibitors with endocrine therapy in the treatment of advanced HR+/HER2- breast cancer. Methods: We systematically searched several frequently used databases and identified economic evaluations published from February 2015 to April 2021. The systematic review was performed after retrieving the literatures and extracting data based on inclusion and exclusion criteria. The quality of each selected economic evaluation was assessed by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). Results: The literature search yielded 161 articles, among which fourteen studies (15 articles) with CHEER scores ranging from 58.33% to 87.50% entered the final analysis. Markov models were used in most studies. Based on the currently available data, CDK4/6 inhibitors plus endocrine therapy were less cost-effective in first- or second-line treatment of patients with HR+/HER2- advanced breast cancer. However, ribociclib plus letrozole was more cost-effective than palbociclib plus letrozole in the first-line treatment of postmenopausal women. The economic impacts of CDK4/6 inhibitors plus endocrine therapy in non-postmenopausal patients or second-line therapy cannot be fully evaluated due to the limited number of studies. The three most common factors affecting economic outcomes were the prices of CDK4/6 inhibitors, hazard ratios for progression-free survival and overall survival, and health status utility values. Discussion: CDK4/6 inhibitors plus endocrine therapy have shown significantly improved efficacy outcomes in HR+/HER2- metastatic breast cancer (mBC)/advancer breast cancer (ABC) first-line and second-line treatment for endocrine-sensitive and endocrine-resistant populations, while more potential fields including neoadjuvant and adjuvant settings are being identified to benefit a wider range of breast cancer patients. Meanwhile, risk of severe adverse events that more likely to happen in patients treated with CDK4/6 inhibitors can lead to reduced life quality and higher medical costs patients need to afford. The adverse drug reaction related cost in several economic burden studies were explored to be primarily driven by hospitalizations and outpatient, and assessment of cost associated with CDK4/6 inhibitors adverse events is worth further developing. Drug wastage costs were found higher in palbociclib regimen than ribociclib regimen due to different dosing patterns. Moreover, current economic evaluations showed that ribociclib plus letrozole had better economic benefits than palbociclib plus letrozole for first-line treatment of postmenopausal women with HR+/HER2- ABC.

Pharmacist-Led Management Improves Treatment Adherence and Quality of Life in Opioid-Tolerant Patients With Cancer Pain: A Randomized Controlled Trial.

INTRODUCTION: Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life. METHODS: Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035). RESULTS: In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522). CONCLUSIONS: Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03455023.

Efficient Removal of Ciprofloxacin from Contaminated Water via Polystyrene Anion Exchange Resin with Nanoconfined Zero-Valent Iron.

Ciprofloxacin (CIP), an important emerging contaminant, has been frequently detected in water, and its efficient removal has become an issue of great concern. In this study, a nanocomposite material nZVI/PA was synthesized by impregnating nanoscale zero-valent iron (nZVI) inside a millimeter-sized porous host (polystyrene-based anion exchange resin (PA)) for CIP removal. The nZVI/PA composite was characterized by field emission scanning electron microscopy coupled with energy-dispersive X-ray, transmission electron microscopy, X-ray diffraction, as well as X-ray photoelectron spectroscopy, and it was confirmed that nZVI was uniformly dispersed in PA with a small particle size. Furthermore, several key factors were investigated including initial solution pH, initial CIP concentration, co-existing ions, organic ligands, and dissolved oxygen. The experimental results indicated that the nZVI/PA composites exhibited a high removal efficiency for CIP under the conditions of initial pH 5.0, and initial CIP concentration 50 mg L-1 at 25 °C, with the maximum removal rate of CIP reaching 98.5%. Moreover, the nZVI/PA composites exhibited high efficiency even after five cycles. Furthermore, quenching tests and electron spin resonance (ESR) confirmed that CIP degradation was attributed to hydroxyl (·OH) and superoxide radicals (⋅O2-). Finally, the main degradation products of CIP were analyzed, and degradation pathways including the hydroxylation of the quinolone ring, the cleavage of the piperazine ring, and defluorination were proposed. These results are valuable for evaluating the practical application of nZVI/PA composites for the removal of CIP and other fluoroquinolone antibiotics.

Meta-analysis of risk factors associated with oxaliplatin hypersensitivity reactions in cancer patients.

This study aimed to investigate risk factors associated with oxaliplatin hypersensitivity reactions in cancer patients through a meta-analysis. A comprehensive retrieve of Chinese databases China National Knowledge Infrastructure, Wanfang Data, VIP Database and English databases PubMed, ScienceDirect, Embase and Cochrane library was conducted. The studies that meet the requirements for meta-analysis according to inclusion and exclusion criteria were screened and assessed for eligibility. Odds ratio (OR) / Weighted mean difference (WMD) and 95% confidence intervals (95% CIs) or calculable dichotomous and continuous raw data were extracted to perform meta-analysis using random effect model or fixed effect model on the basis of heterogeneity between studies through Review Manager 5.4 software. A total of 14 cross-sectional studies and 3367 cancer patients were included. Meta-analysis results showed that platinum exposure history (OR value 3.13, 95% CI 2.19-4.48, heterogeneity P = 0.26), allergy history (OR value 1.76, 95% CI 1.09-2.85, heterogeneity P = 0.61), platinum free interval (OR value 3.75, 95% CI 2.00-7.06, heterogeneity P = 0.83), dexamethasone premedication dose (OR value 0.28, 95% CI 0.13-0.58, heterogeneity P = 0.21) were significantly correlated to oxaliplatin hypersensitivity reactions. Gender, age, metastasis, combination with bevacizumab, XELOX regimen and cancer types were detected to have no statistically significant effect on oxaliplatin hypersensitivity reactions. Platinum exposure history, allergy history and long platinum-free interval are risk factors of oxaliplatin hypersensitivity reactions. High dexamethasone premedication dose is a protective factor of oxaliplatin hypersensitivity reactions.

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer.

Resistance is the major cause of treatment failure and disease progression in non-small cell lung cancer (NSCLC). There is evidence that hypoxia is a key microenvironmental stress associated with resistance to cisplatin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and immunotherapy in solid NSCLCs. Numerous studies have contributed to delineating the mechanisms underlying drug resistance in NSCLC; nevertheless, the mechanisms involved in the resistance associated with hypoxia-induced molecular metabolic adaptations in the microenvironment of NSCLC remain unclear. Studies have highlighted the importance of posttranslational regulation of molecular mediators in the control of mitochondrial function in response to hypoxia-induced metabolic adaptations. Hypoxia can upregulate the expression of sirtuin 1 (SIRT1) in a hypoxia-inducible factor (HIF)-dependent manner. SIRT1 is a stress-dependent metabolic sensor that can deacetylate some key transcriptional factors in both metabolism dependent and independent metabolic pathways such as HIF-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-gamma coactivator 1-alpha (PGC-1α) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1α can regulate both innate and adaptive immune responses through metabolism-dependent and -independent ways. The objective of this review is to delineate a possible SIRT1/PGC-1α/PPAR-γ signaling-related molecular metabolic mechanism underlying hypoxia-induced chemotherapy resistance in the NSCLC microenvironment. Targeting hypoxia-related metabolic adaptation may be an attractive therapeutic strategy for overcoming chemoresistance in NSCLC.

ZnO Nanoneedle-Modified PEEK Fiber Felt for Improving Anti-fouling Performance of Oil/Water Separation.

Membrane separation has been considered to be the most effective decontamination method for oily waste water. The most significant point of membrane separation is the resistance against membrane fouling. Fabricating hierarchical architectures on the membrane surface is an available approach to improving its anti-fouling property. In this study, ZnO nanoneedles were successfully anchored onto surface-sulfonated poly(ether-ether-ketone) (PEEK) felt via UV/ozone cleaning and hydrothermal synthesis. The modified felt (PEEK-f-Z) showed much better anti-fouling properties and far higher rejection height (33 cm) than the unmodified felt (17 cm) with a separation efficiency up to 99.99%. The enhanced separation properties could be attributed to the stronger water locking capability of the hierarchical architectures on the surface. Furthermore, benefiting from the great chemical stability of PEEK substrates and ZnO nanoneedles, the as-prepared membrane exhibited admirable solvent resistance, mechanical strength, and thermal stability. As a result, PEEK-f-Z could even separate immiscible organic liquids with different polarities and collect hot water from the oil/water mixture, promising to be used under severe conditions.

Effect of 3 mg versus 6 mg pegfilgrastim on the prevention of febrile neutropenia in breast cancer patients receiving docetaxel and cyclophosphamide: a retrospective study.

BACKGROUND: An ECCOPG (Eastern China Cooperative Oncology Pharmacy Group) funded study was designed to compare the effect of 3 versus 6 mg pegfilgrastim for primary prevention of febrile neutropenia (FN) in Chinese breast cancer patients retrospectively. METHODS: Patients undergoing a docetaxel and cyclophosphamide chemotherapy regimen, followed by pegfilgrastim, for primary prevention during 2018 and 2020 were retrospectively enrolled in the present study. The patients were divided into 2 groups according to the dose of pegfilgrastim. The incidence of severe neutropenia (absolute neutrophil count <0.5×109/L), incidence of FN, and recovery time were calculated to compare the efficacy of different groups. P<0.05 was considered statistically significant. RESULTS: A total of 295 patients were enrolled, 150 in the 3 mg pegfilgrastim group and 145 in the 6 mg pegfilgrastim group. No significant differences were found in the incidence of severe neutropenia (3 vs. 6 mg, 39.3% vs. 34.5%, P=0.401) and the incidence of FN (3 vs. 6 mg, 7.3% vs. 8.3%, P=0.830). Median recovery time was 2 days for both groups (P=0.485). CONCLUSIONS: 3 mg pegfilgrastim may be effective and safe for Chinese breast cancer patients as the primary prevention for FN. Prospective studies are needed to further confirm the prophylactic effect of 3 mg pegfilgrastim.

Exosomal miR-30a and miR-222 derived from colon cancer mesenchymal stem cells promote the tumorigenicity of colon cancer through targeting MIA3.

BACKGROUND: Multipotent mesenchymal stem cells (MSCs) derived from virus tumors have been reported to contribute to malignant cell growth, invasion, and metastasis. However, the mechanism of communication between MSCs and colon cancer cells is poorly understood. Recent studies have suggested that exosomes are an important player in crosstalk between cells and could significantly suppress the invasion ability of human cancer cells (hCCs) when transfected with a microRNA inhibitor. However, to date, no study has illuminated the miRNA changes in exosomes derived from hCC-MSCs. METHODS: Colon cancer stem cells were cultured in medium and passaged to develop fibroblast-like morphology. Exosomes were collected using ExoQuick precipitation and exosome morphology was visualized by transmission electron microscopy. Small RNA sequencing was analyzed using an Illumina HiSeq4000 analyzer, and the expression of MIA3 was assessed by real-time PCR and Western blot. The functional roles of miR-30a and miR-222 in colon cancer cells were evaluated through cell and animal experiments. RESULTS: Our results showed that the characteristics of MSC-like cells (hCC-MSCs) derived from human colon cancer stem cells were comparable to those of bone marrow-derived MSCs, including surface antigens and the ability to multi-differentiate to osteocytes and adipocytes. Furthermore, we screened the microRNA (miRNA) profiles of exosomes derived from hCC-MSCs and the corresponding parent hCC-MSCs. We found a significant enrichment in the miR-30a and miR-222 level in hCC-MSC-derived exosomes. Furthermore, in vitro and in vivo experiments demonstrated that miR-30a and miR-222 bound to their shared downstream target, MIA3, to promote the ability of colon cells to proliferate, migrate, and metastasize, thus evidencing their functional roles as oncogenic miRNAs. CONCLUSIONS: These data suggest that hCC-MSC-secreted exosomes promote colon cancer cell proliferation and metastasis through delivering miR-30a and miR-222. Subsequently, exosomal miR-30a and miR-222 simultaneously target MIA3, suppress its expression, and promote colon cell proliferation, migration, and metastasis.

Efficacy and safety of domestic and imported gefitinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It was approved by the U.S. Food and Drug Administration (FDA) for clinical use in 2003. However, gefitinib has only come to China in recent years. Previous studies have not compared the efficacy and safety of domestic and imported gefitinib. Therefore, we conducted this study. METHODS: This study included 227 patients with advanced non-small cell lung cancer (NSCLC) who received gefitinib treatment in four medical institutions: The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Fudan University Shanghai Cancer Center, Shandong Provincial Institute of Cancer Prevention and Jiangsu Cancer Hospital, from January 2017 to July 2018. The patients were divided into a Yiruike group (55 patients treated with domestic gefitinib, Yiruike) and an Iressa group (172 patients treated with imported gefitinib, Iressa). Because gefitinib resistance usually occurs within 8-10 months of gefitinib administration, the patients were followed up for one year to observe their conditions and compare the occurrence of adverse reactions between the two groups. RESULTS: The two groups had no significant difference in baseline data. The median progression-free survival (PFS) of Yiruike group and that of Iressa group were 10.270±2.036 and 12.970±1.634 months, respectively. The mean PFS of Yiruike group and that of Iressa group were 12.598±1.083 and 15.958±0.987 months, respectively. The one-year disease control rate (DCR) of Yiruike group and that of Iressa group were 61.8% and 59.3%, respectively. The differences were all insignificant (P>0.05). The incidence of adverse reactions in these two groups were not significantly different. CONCLUSIONS: Yiruike was slightly superior to Iressa in terms of DCR. However, comparisons of bioequivalence and DCR were not sufficient for evaluating a drug. Other comparisons require long-term follow-up studies with a large sample size.

Efficient removal of sulfamethoxazole by resin-supported zero-valent iron composites with tunable structure: Performance, mechanisms, and degradation pathways.

Nanoscale zero-valent iron loaded polymer-based composites (D201-nZVI) are effective materials for the removal of inorganic contaminants from water. However, the removal efficiency of organic contaminants and the role of the distribution of nZVI in the performance of the composites still remains unclear. Herein, four resin-supported nZVI composites with different nZVI distributions (D1, D2, D3, and D4) were prepared and used for sulfamethoxazole (SMX) degradation. The four composites, D1-D4, demonstrated a high efficiency of SMX removal (99.02%, 94.61%, 89.00%, and 86.28%, respectively, at pH 5.0). In addition, the performance of D201-nZVI only dropped by approximately 10% after five cycles, indicating its strong potential for practical application. On the basis of kinetic and electron spin resonance (ESR) spectral analyses, this study showed that the formation of hydroxyl radicals (⋅OH) and superoxide radicals (⋅O2-) is the main mechanism of SMX degradation. Finally, based on six major degradation intermediates of SMX, five possible degradation pathways were proposed, including the coupling of N-centered radicals, demethylation, the isomerization of isoxazole rings, the oxidation of amino groups, and the S-N bond cleavage in the D201-nZVI system. These results are not only important for better understanding the role of Fe distribution in the removal of SMX but are also crucial for the potential application of D201-nZVI composites with a different Fe distribution in many other scenarios.

Polarizability and aromaticity index govern AhR-mediated potencies of PAHs: A QSAR with consideration of freely dissolved concentrations.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants associated with adverse human effects including cancer, and the aryl hydrocarbon receptor (AhR) is a key ligand-activated transcription factor mediating their toxicity. However, there is presently a lack of data on AhR potencies of PAHs. Simple, transparent, interpretable and predictive quantitative structure-activity relationship (QSAR) models are helpful, especially with the consideration of freely dissolved concentrations linked to bioavailability. Here, QSAR models on AhR-mediated luciferase activity of PAHs were developed with nominal median effect concentrations (EC50, nom) and freely dissolved concentration (EC50, free) as endpoints, and quantum chemical and Dragon descriptors as predictor variables. Results indicated that only the EC50, free model met the acceptable criteria of QSAR model (determination coefficient (R2) > 0.600, leave-one-out cross validation (QLOO2) > 0.500, and external validation coefficient (QEXT2) > 0.500), implying that it has good goodness-of-fit, robustness and external predictive power. Molecular polarizability and aromaticity index reflecting the partition behavior and intermolecular interactions can effectively predict AhR-mediated potencies of PAHs. The results highlight the necessity of adoption of the freely dissolved concentration in the QSAR modeling and more in silico models need to be further developed for different animal models (in vivo or in vitro).

Chemotherapy-Induced Reduction of Neutrophil-to-Lymphocyte Ratio Is Associated With Better Survival in Pancreatic Adenocarcinoma: A Meta-Analysis.

OBJECTIVES: Numerous studies have suggested that an increase in neutrophil-to-lymphocyte ratio (NLR) before treatment is associated with worse survival in pancreatic adenocarcinoma (PAC). The aim of this study was to investigate the prognostic value of treatment-induced NLR change among PAC patients so as to better identify the characteristics of those who can benefit more from treatment. METHODS: This meta-analysis was undertaken using the PRISMA statement. Previously published studies between the correlation of NLR change and patients' survival were searched in Pubmed, Embase, and Web of Science databases. RevMan 5.3 was used to conduct statistical analysis. RESULTS: A total of 1213 patients with PAC from 6 retrospective studies were included in this meta-analysis. Four studies investigated the HR of pre-treatment NLR, demonstrating its prognostic impact on overall survival (OS) (HR = 2.21, 95%CI: 1.45-3.36). One study reported that an elevated post-treatment NLR was associated with poorer OS (HR = 1.28, 95%CI = 1.08-1.52). Pooled analysis indicated that NLR reduction might predict favorable survival in both the overall population (HR = 1.52, 95% CI: 1.34-1.73) and the subgroup treated with chemotherapy (HR = 1.50, 95% CI: 1.32-1.70). CONCLUSION: Treatment-induced NLR change can act as an early predictor for PAC. Patients with reduced NLR after chemotherapy are expected to have better survival.