Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis.

Background: The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. Methods: A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. Results: A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. Conclusions: KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

MiR-210-5p promotes the differentiation of human induced pluripotent stem cells into dopaminergic neural precursors by targeting SMAD4 and SUFU and treats parkinsonian rats.

The differentiation of human induced pluripotent stem cells (hiPSCs) into functional dopaminergic neural precursors is the basis of cell therapy for Parkinson's disease (PD). However, the use of small molecule inhibitors/activators in the differentiation of hiPSCs in vitro leads to cell death and low differentiation efficiency. Moreover, the mechanism of differentiation remains unclear. MiR-210-5p was increased during hiPSCs differentiation. Whether it promotes hiPSCs differentiation and transplantation needs further study. Here, we overexpressed miR-210-5p in hiPSCs to study its roles and mechanisms. We found that miR-210-5p promoted the differentiation of hiPSCs into dopaminergic neural precursors and reduced the expression of SMAD4 and SUFU meanwhile. Luciferase assays showed that miR-210-5p binded to SMAD4 and SUFU, which are key molecules in the key signals (TGF-ß and SHH) of hiPSCs differentiation. Furthermore, in the effect evaluation of cell transplantation into parkinsonian rats, the degree of behavioral recovery and the growth of transplanted cells in the group overexpressed miR-210-5p were similar to those in the positive group with all small molecule inhibitors/activators. Therefore, we conclude that miR-210-5p promotes the differentiation of hiPSCs into dopaminergic neural precursors by targeting SMAD4 and SUFU. In the therapeutic evaluation of cell transplantation, miR-210-5p can replace the use of corresponding small molecule inhibitors/activators to reduce cell death. This study provides an experimental basis and a new target for the miRNA-modified differentiation of hiPSCs and cell transplantation in clinical treatment of PD in the future.

Highly Selective Cerebral ATP Assay Based on Micrometer Scale Ion Current Rectification at Polyimidazolium-Modified Micropipettes.

Development of new principles and methods for cerebral ATP assay is highly imperative not only for determining ATP dynamics in brain but also for understanding physiological and pathological processes related to ATP. Herein, we for the first time demonstrate that micrometer scale ion current rectification (MICR) at a polyimidazolium brush-modified micropipette can be used as the signal transduction output for the cerebral ATP assay with a high selectivity. The rationale for ATP assay is essentially based on the competitive binding ability between positively charged polyimidazolium and ATP toward negatively charged ATP aptamer. The method is well responsive to ATP with a good linearity within a concentration range from 5 nM to 100 nM, and high selectivity toward ATP. These properties essentially enable the method to determine the cerebral ATP by combining in vivo microdialysis. The basal dialysate level of ATP in rat brain cortex is determined to be 11.32 ± 2.36 nM (n = 3). This study demonstrates that the MICR-based sensors could be potentially used for monitoring neurochemicals in cerebral systems.

Tuning interionic interaction for highly selective in vivo analysis.

The development of highly selective methodologies to enable in vivo recording of chemical signals is of great importance for studying brain functions and brain activity mapping. However, the complexity of cerebral systems presents a great challenge in the development of chem/(bio)sensors that are capable of directly and selectively recording bioactive molecules involved in brain functions. As one of the most important and popular interactions in nature, interionic interaction constitutes the chemical essence of high specificity in natural systems, which inspires us to develop highly selective chem/(bio)sensors for in vivo analysis by precisely engineering interionic interaction in the in vivo sensing system. In this tutorial review, we focus on the recent progress in the tuning of interionic interaction to improve the selectivity of biosensors for in vivo analysis. The type and property of the interionic interaction is first introduced and several strategies to improve the selectivity of the biosensors, including enzyme-based electrochemical biosensors, aptamer-based electrochemical biosensors, and the strategies to recruit recognition molecules are reviewed. We also present an overview of the potential applications of the biosensors for in vivo analysis and thereby for physiological investigations. Finally, we present the major challenges and opportunities regarding the high selectivity of in vivo analysis based on tuning interionic interaction. We believe that this tutorial review provides critical insights for highly selective in vivo analysis and offers new concepts and strategies to understand brain chemistry.

Dual recognition unit strategy improves the specificity of the adenosine triphosphate (ATP) aptamer biosensor for cerebral ATP assay.

Adenosine triphosphate (ATP) aptamer has been widely used as a recognition unit for biosensor development; however, its relatively poor specificity toward ATP against adenosine-5'-diphosphate (ADP) and adenosine-5'-monophosphate (AMP) essentially limits the application of the biosensors in real systems, especially in the complex cerebral system. In this study, for the first time, we demonstrate a dual recognition unit strategy (DRUS) to construct a highly selective and sensitive ATP biosensor by combining the recognition ability of aptamer toward A nucleobase and of polyimidazolium toward phosphate. The biosensors are constructed by first confining the polyimidazolium onto a gold surface by surface-initiated atom transfer radical polymerization (SI-ATRP), and then the aptamer onto electrode surface by electrostatic self-assembly to form dual-recognition-unit-functionalized electrodes. The constructed biosensor based on DRUS not only shows an ultrahigh sensitivity toward ATP with a detection limit down to the subattomole level but also an ultrahigh selectivity toward ATP without interference from ADP and AMP. The constructed biosensor is used for selective and sensitive sensing of the extracellular ATP in the cerebral system by combining in vivo microdialysis and can be used as a promising neurotechnology to probing cerebral ATP concentration.

A sensitive amperometric immunosensor for carcinoembryonic antigen detection with porous nanogold film and nano-Au/chitosan composite as immobilization matrix.

A sensitive amperometric immunosensor for carcinoembryonic antigen (CEA) was prepared. Firstly, a porous nano-structure gold (NG) film was formed on glassy carbon electrode (GCE) by electrochemical reduction of HAuCl4 solution, then nano-Au/Chit composite was immobilized onto the electrode because of its excellent membrane-forming ability, and finally the anti-CEA was adsorbed onto the surface of the bilayer gold nanoparticles to construct an anti-CEA/nano-Au/Chit/NG/GCE immunosensor. The characteristics of the modified electrode at different stages of modification were studied by cyclic voltammetry (CV). The gold colloid, chitosan and nano-Au/Chit were characterized by transmission electron microscopy and UV-vis spectroscopy. In addition, the performances of the immunosensor were studied in detail. The resulting immunosensor offers a high-sensitivity (1310 nA/ng/ml) for the detection of CEA and has good correlation for detection of CEA in the range of 0.2 to 120.0 ng/ml with a detection limit of 0.06 ng/ml estimated at a signal-to-noise ratio of 3. The proposed method can detect the CEA through one-step immunoassay and would be valuable for clinical immunoassay.

A novel amperometric immunosensor based on layer-by-layer assembly of gold nanoparticles-multi-walled carbon nanotubes-thionine multilayer films on polyelectrolyte surface.

A highly sensitive and label-free amperometric immunosensor has been developed for the detection of carcinoembryonic antigen (CEA) based on layer-by-layer (LBL) assembly of gold nanoparticles (GNPs), multi-walled carbon nanotubes-thionine (MWNTs-THI) and chitosan (CHIT) on 3-mercaptopropanesulfonic, sodium salt (MPS)-modified gold electrode surface by electrostatic adsorption. The stepwise LBL assembly process of electroactive species on electrode surface was characterized by means of cyclic voltammetry (CV) in PBS. The factors influencing the performance of the resulting immunosensor were studied in detail. The morphologies of MWNTs, MWNTs-THI and GNPs-MWNTs-THI-CHIT were further characterized by transmission electron microscopy (TEM). The immunosensor was highly sensitive to CEA with a detection limit of 0.01 ng mL(-1) (signal/noise ratio of 3) and the linear range with two concentration intermittences was from 0.5 to 15.0 ng mL(-1) and from 15.0 to 200.0 ng mL(-1), respectively. In addition, the prepared immunosensor could be regenerated 10 times with 5 M urea solution. When the immunosensor was stored at 4 degrees C and measured intermittently (every 4-6 days), no apparent change was found over 3 months. The immunosensor system showed an excellent reproducibility and stability.

[Risk factors of traditional Chinese medical syndromes in moderate and advanced lung cancer patients with concurrent fungal pneumonia].

OBJECTIVE: To analyze the relationship between traditional Chinese medical syndromes and fungal pneumonia for moderate and advanced lung cancer patients. METHODS: We retrospected 115 moderate and advanced lung cancer patients with different syndromes in traditional Chinese medicine (qi deficiency, yin deficiency, blood deficiency, yang deficiency, blood stasis, phlegm dampness, phlegm heat, damp heat, cold dampness, qi stagnation, heat toxin), who had the concurrent fungal pneumonia, and used regression analysis method to analyze the data. RESULTS: When the patients had the phlegm heat syndrome, they got a significantly higher risk of having fungal pneumonia (P < 0.01); and when they had the heat toxin syndrome, they also had a high risk of having fungal pneumonia (P < 0.05). CONCLUSION: The phlegm heat and heat toxin syndromes are the risk factors for moderate and advanced lung cancer patients having concurrent fungal pneumonia.