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There is no standard therapy for nonsmall-cell lung cancer harboring rare coexistent EGFR mutations. Here, we report a female patient who was diagnosed as lung adenocarcinoma with three mutations of G724S, E709K, and V689I in exon 18. The patient responded to, but also showed rapid development of resistance to multiple therapies, including a second-generation EGFR-TKI of afatinib, a platinum-based doublet chemotherapy, and a multiple target TKI of anlotinib. As such, she ended up with a short overall survival time. Further research is required to understand the resistance mechanism(s) of these complex gene mutations. [ABSTRACT FROM AUTHOR]

[Display omitted] • Successful removal of nutrients and emerging contaminants in DWTR-based biofilter. • HLR influenced community compositions, assembly, and degradation functions of biofilm. • Higher HLR promoted denitrification and utilization of biodegradable contaminants. • Stronger removal of refractory contaminants achieved by co-metabolism under lower HLR. • Lower HLR maintained more intensive interactions of keystone degraders like Bacillus. Drinking water treatment residue (DWTR)-based biofilter is an environment-friendly and cost-effective technology for eliminating nutrients and emerging organic contaminants (EOCs) from natural water. This study explored the removal efficiencies of five trace-level EOCs and the associated microbial response of biofilm in two identical DWTR-based biofilters under varying hydraulic loading rate (HLR) conditions over six months of operation. The results showed that the most recalcitrant EOC (carbamazepine) was mainly removed by DWTR adsorption (7.8–11.0 ng g−1), while the response of the biofilm community to HLR significantly affected the degradation of 17α-ethinylestradiol, sulfamethoxazole, roxithromycin, and sulfathiazole (P < 0.001). A higher HLR significantly stimulated the production of extracellular polymeric substance and increased the stochasticity and diversity of community assembly, improving denitrification and the removal efficiency of DWTR-based biofilm for biodegradable roxithromycin (80 %) and sulfamethoxazole (76 %). In contrast, lower HLR led to carbon limitation and exerted substrate selection pressures, resulting in more deterministic and stable community assembly, with keystone species such as Bacillus enriched in EOC degradation-related functional genes. Moreover, co-occurrence network analysis revealed a simpler but more intensive interaction network among EOC degraders under the lower HLR condition. This interaction network facilitated the co-metabolism of influent organic carbon and the removal of more recalcitrant contaminants, 17α-ethinylestradiol (48 %) and sulfathiazole (37 %). This study offered a novel insight into biofilter management from a hybrid perspective of environmental microbiology and engineering science, highlighting the dynamic adaptation of microbes to specific EOC degradation under varying HLR conditions. [ABSTRACT FROM AUTHOR]

Nitrate and sulfate, as electron acceptors (EAs), influence microbial communities and the subsequent biodegradation of emerging contaminants, such as 17α-ethynylestradiol (EE2) in anaerobic sediments. Results of this study showed that nitrate amendment significantly raised nitrate reduction intensity within a short period (<5 days) and greatly influenced microbial community succession compared with sulfate amendment. Nitrate reduction induced deterministic selections that narrowed the niche widths of the microbial community, creating direct correlations between functional members, including denitrifiers and potential estrogen degraders like Pseudomonas. The facilitative coordination of microbes and increased denitrification resulted in greater EE2 biodegradation under nitrate-reducing (0.19 ± 0.02 μg g−1) and combined nitrate- and sulfate-reducing conditions (0.23 ± 0.01 μg g−1) after 120 days. Moreover, natural organic matter enhanced interspecies syntrophic cooperation (the number of direct connectors increased from 9 to 25 in the microbial network) in the microbial community and further improved EE2 biodegradation efficiency to 0.26 ± 0.03 μg g−1. Conversely, sulfate reduction required longer adaptation (>20 days) with a higher contribution of stochastic processes in community assembly, yielding fewer connections with estrogen degraders and weaker EE2 biodegradation (0.15 ± 0.03 μg g−1). These mechanistic understandings can guide EA selection in the bioremediation of emerging contaminants. [Display omitted] • Impacts of nitrate and sulfate as EAs on anaerobic degradation of EE2 were compared. • EE2 degradation follows the order of nitrate and sulfate > nitrate > sulfate reducing. • Direct collaborations of denitrifiers and estrogen degraders promote EE2 degradation. • Sulfate reduction needs longer adaptation and has fewer linkages with EE2 degradation. • Natural organic matter enhances syntrophic cooperation and improves EE2 degradation. [ABSTRACT FROM AUTHOR]

Biological lability of dissolved organic matter (DOM) is a crucial indicator of carbon cycle and contaminant attenuation in freshwater lakes. In this study, we employed a multi-stage plug-flow bioreactor and spectrofluorometric indices to characterize the seasonal variations in DOM composition and lability across Poyang Lake (PY) and Lake Taihu (TH), two large freshwater lakes in China with distinct hydrological seasonality. Our findings showed that the export of floodplain-derived organics and river-lake interaction led to a remarkable increase in terrestrial aromatic and humic-like DOM with high molecular weights and long turnover times in PY. Consequently, the labile fraction was extremely low (average LDOC% of 3%) during the rising-to-flood season (spring and summer). Conversely, autochthonous production in TH considerably enriched semi-labile (average SDOC% of 26%) and biodegradable DOM (average BDOC% of 34%) during the phytoplankton bloom to post-bloom season (summer and autumn). This was reflected by the accumulation of low-light-absorbing and protein-like components with high biological and fluorescence indices. In the dry and non-bloom season (winter), the better preservation of humic substances maintained the high molecular weight and humic degree of DOM in PY, while the decay of aquatic plants strengthened autochthonous production, resulting in a similar BDOC% of PY samples (23%–34%) to TH samples (18%–33%). We further applied partial least squares regression using DOM optical indices as predictive proxies, which generated a greater prediction strength for BDOC% (R 2 = 0.80) compared to SDOC% (R 2 = 0.57) and LDOC% (R 2 = 0.28). The regression model identified aromaticity (SUVA 254) as the most effective and negative predictor and low molecular weight (A 250 / A 365) as the highly and positively influential factor. Our study provides new evidence that the seasonality of DOM lability profiles is regulated by the trade-off between flow-related variation and phytoplankton production, and presents an approach to describe and predict DOM lability across freshwater lakes. [Display omitted] • First study to directly compare DOM lability profiles in Poyang Lake and Lake Taihu. • Allochthonous aromatic organics input in flood season decreased BDOC% in Poyang Lake. • Autochthonous production increased BDOC% in bloom and post-bloom season of Lake Taihu. • Effective predictors of DOM lability included SUVA 254 , A 250 /A 365 , C/T, A/T, and HIX. • Higher predictive strength of DOM optical parameters for BDOC% than LDOC% and SDOC%. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC) develops resistance to tyrosine kinase inhibitors (TKIs). Here, we evaluated the efficacy of radiotherapy and continuation of TKIs in patients with advanced NSCLC with oligoprogression after EGFR‐TKIs. Methods: From January 2011 to January 2019, 33 patients with EGFR‐mutated NSCLC on TKIs were treated by radiotherapy and continuation of TKIs for oligoprogressive disease. The primary endpoints were median progression‐free survival 1 (mPFS1), mPFS2, and median overall survival (mOS). PFS1 was measured from the start of EGFR‐TKIs therapy to the oligoprogression of the disease. PFS2 was measured from the date of oligoprogression to the further progression of the disease, while OS was calculated from oligoprogression to death from any cause or was censored at the last follow‐up date. Result: The mPFS1, mPFS2, and mOS were 11.0 (95% CI, 4.4–17.6), 6.5 (95% CI, 1.4–11.6) and 21.8 (95% CI, 14.8–28.8) months, respectively. Univariate analysis showed that EGFR mutation type (p = 0.024), radiotherapy method (p = 0.001), and performance status (p = 0.017) were significantly correlated with PFS2. Univariate analysis showed that sex (p = 0.038), smoking history (p = 0.031), EGFR mutation type (p = 0.012), and radiotherapy method (p = 0.009) were significantly correlated with OS. Multivariate analysis suggested that radiotherapy method (p = 0.001) and performance status (p = 0.048) were prognostic factors for PFS2, and radiotherapy method (p = 0.040) was a prognostic factor for OS. Conclusion: Radiotherapy with continued TKIs is effective for EGFR‐mutated NSCLC with oligoprogression, and it should be conducted as soon as possible. T790M+ patients have higher sensitivity to radiotherapy, and patients with good performance status and stereotactic body radiation therapy have better PFS2 and OS. Almost all EGFR mutation‐positive advanced NSCLC patients treated with TKI will progress. The definition of oligometastasis disease included ≤5 metastases with ≤3 organs involved, and all metastatic sites could be amenable to local radical treatment. Radiotherapy with continued TKIs is effective for EGFR‐mutated NSCLC with oligoprogression. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that psychological resilience is a key factor in drug rehabilitation. To explore the feasibility of developing psychological resilience as an addiction treatment intervention, it is essential to explore the role that it plays in drug addiction. Objectives: This study aimed to investigate the relationship between psychological resilience and drug addiction, as well as to examine the underlying mediational roles of maladjustment and impulsiveness in this association. Methods: We used a cross-sectional design that included a sample of 140 male drug addicts in compulsory isolation centers and used questionnaires and scales to ascertain their level of drug addiction, psychological resilience, maladjustment, impulsiveness, social support, and loneliness. Correlation and mediation effect analyses were performed to determine the roles of impulsiveness and maladjustment in the association of psychological resilience with drug addiction. Results: Psychological resilience was an inverse predictor of drug addiction. The results of the mediation effect analysis showed that maladjustment acted as a mediator between resilience and drug addiction and between impulsiveness and drug addiction. Furthermore, impulsiveness and maladjustment jointly mediated the relationship between psychological resilience and drug addiction. Conclusion: These findings highlight the importance of psychological resilience in maladjustment and impulsiveness for drug addicts and suggest that the role of psychological resilience in drug addiction needs to be further explored. [ABSTRACT FROM AUTHOR]

Pembrolizumab, an immune checkpoint inhibitor against the programmed death-1 pathway, has been used in combination with acitinib for the first-line treatment of advanced renal cell carcinoma. Neurotoxicity is a rare immune-related adverse event (irAE). The present study reports a case of Guillain-Barre syndrome (GBS) induced by pembrolizumab and sunitinib, and reviews other previous studies to elucidate the clinical characteristics and suitable management of this rare irAE. An advanced renal cell carcinoma patient who received several cycles of pembrolizumab combined with sunitinib developed limb weakness and numbness of the extremities, and was diagnosed with GBS by electrodiagnostic and cerebrospinal fluid examination. The patient improved after treatment with intravenous immunoglobulin along with prednisone. To the best of our knowledge, this is the first case of GBS during treatment with pembrolizumab in combination with sunitinib in advanced renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Background: Chronic lymphocytic leukemia (CLL) remains incurable with standard therapy, and is characterized by excessive expansion of monoclonal abnormal mature B cells and more regulatory immune properties of T cell compartment. Thus, developing novel strategies to enhance immune function merits further investigation as a possible therapy for CLL.Methods: We generated a fusion cytokine (fusokine) arising from the combination of human GM-CSF and IL-4 (named GIFT4). Primary CLL cells were treated with GIFT4 or GM-CSG and IL-4 in vitro. GIFT4-triggered STAT5 signaling in CLL cells was examined by Western blot. The phenotype and secretome of GIFT4-treated CLL cells (GIFT4-CLL cells), and the immune stimulatory function of GIFT4-CLL cells on autologous T cells were analyzed by flow cytometry and luminex assay.Results: GIFT4-CLL up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86 and adhesion molecule CD54. GIFT4-CLL cells secreted IL-1β, IL-6, ICAM-1 and substantial IL-2 relative to unstimulated CLL cells. GIFT4 treatment led to JAK1, JAK2 and JAK3-mediated hyper-phosphorylation of STAT5 in primary CLL cells, which is essential for GIFT4-triggered conversion of CLL cells. GIFT4-CLL cells directly propelled the expansion of autologous IFN-γ-producing CD314(+) cytotoxic T cells in vitro, and that these could lyse autologous CLL cells. Furthermore, administration of GIFT4 protein promoted the expansion of human T cells in NOD-scid IL2Rγ(null) immune deficient mice adoptively pre-transferred with peripheral blood mononuclear cells from subjects with CLL.Conclusion: GIFT4 has potent capability to converts primary CLL cells into APC-like immune helper cells that initiate a T cell driven anti-CLL immune response. [ABSTRACT FROM AUTHOR]