Shenqi Fuzheng injection facilitates skeletal muscle mitophagy mediated by the ubiquitination of HIF-1α to ameliorate cancer-associated fatigue.

Cancer-related fatigue (CRF) significantly impacts the quality of life of cancer patients. This study investigates the therapeutic potential of Shenqi Fuzheng injection (SFI) in managing CRF, focusing on its mechanistic action in skeletal muscle. We utilized a CRF mouse model to examine the effects of SFI on physical endurance, monitoring activity levels, swimming times and rest periods. Proteomic analysis of the gastrocnemius muscle was performed using isobaric tags and liquid chromatography-tandem mass spectrometry to map the muscle proteome changes post-SFI treatment. Mitochondrial function in skeletal muscle was assessed via ATP bioluminescence assay. Furthermore, the regulatory role of the hypoxia inducible factor 1 subunit alpha (HIF-1α) signalling pathway in mediating SFI's effects was explored through western blotting. In CRF-induced C2C12 myoblasts, we evaluated cell viability (CCK-8 assay), apoptosis (flow cytometry) and mitophagy (electron microscopy). The study also employed pulldown, luciferase and chromatin immunoprecipitation assays to elucidate the molecular mechanisms underlying SFI's action, particularly focusing on the transcriptional regulation of PINK1 through HIF-1α binding at the PINK1 promoter region. Our findings reveal that SFI enhances physical mobility, reduces fatigue symptoms and exerts protective effects on skeletal muscles by mitigating mitochondrial damage and augmenting antioxidative responses. SFI promotes cell viability and induces mitophagy while decreasing apoptosis, primarily through the modulation of HIF-1α, PINK1 and p62 proteins. These results underscore SFI's efficacy in enhancing mitochondrial autophagy, thereby offering a promising approach for ameliorating CRF. The study not only provides insight into SFI's potential therapeutic mechanisms but also establishes a foundation for further exploration of SFI interventions in CRF management.

Lower extremity peripherally inserted central catheter placement ectopic to the ascending lumbar vein: A case report.

BACKGROUND: Peripherally inserted central catheters (PICCs) are an essential infusion route for oncology patients receiving intravenous treatments, but lower extremity venipuncture is the preferred technique for patients with superior vena cava syndrome (SVCS). We report the case of a patient with a lower extremity PICC ectopic to the ascending lumbar vein, to indicate and verify PICC catheterisation in the lower extremity is safe and feasible. And hope to provide different perspectives for clinical PICC venipuncture to get the attention of peers. CASE SUMMARY: On 24 August 2022, a 58-year-old male was admitted to our department due to an intermittent cough persisting for over a month, which worsened 10 d prior. Imaging and laboratory investigations suggested the patient with pulmonary malignancy and SVCS. Chemotherapy was not an absolute contraindication in this patient. Lower extremity venipuncture is the preferred technique because administering upper extremity venous transfusion to patients with SVCS can exacerbate oedema in the head, neck, and upper extremities. The patient and his family were informed about the procedure, and informed consent was obtained. After successful puncture and prompt treatment, the patient was discharged, experiencing some relief from symptoms. CONCLUSION: Inferior vena cava catheterisation is rare and important for cancer patients with SVCS, particularly in complex situations involving ectopic placement.

Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance.

Tumor drug resistance emerges from the interaction of two critical factors: tumor cellular heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute essential components of the TME. M2-like TAMs are essential in facilitating tumor metastasis as well as augmenting the drug resistance of tumors. This review encapsulates the mechanisms that M2-like TAMs use to promote tumor drug resistance. We also describe the emerging therapeutic strategies that are currently targeting M2-like TAMs in combination with other antitumor drugs, with some still undergoing clinical trial evaluation. Furthermore, we summarize and analyze various existing approaches for developing novel drugs that target M2-like TAMs to overcome tumor resistance, highlighting how targeting M2-like TAMs can effectively stop tumor growth, metastasis, and overcome tumor drug resistance.

Identification of key genes in chronic intermittent hypoxia-induced lung cancer progression based on transcriptome sequencing.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk of lung cancer mortality. Nevertheless, little is known about the underlying molecular mechanisms. This research aimed to investigate differentially expressed genes (DEGs) and explore their function in Lewis lung carcinoma (LLC)-bearing mice exposed to chronic intermittent hypoxia (CIH) by transcriptome sequencing. METHODS: Lung cancer tissues in LLC-bearing mice exposed to CIH or normoxia were subjected for transcriptome sequencing to examine DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to explore the function of DEGs. To evaluate the prognostic value of DEGs, the Kaplan-Meier survival analysis in combination with Cox proportional hazard model were applied based on The Cancer Genome Atlas. RESULTS: A total of 388 genes with 207 up-regulated and 181 down-regulated genes were differentially expressed between the CIH and normoxia control groups. Bioinformatics analysis revealed that the DEGs were related to various signaling pathways such as chemokine signaling pathway, IL-17 signaling pathway, TGF-ß signaling pathway, transcriptional misregulation in cancer, natural killer cell mediated cytotoxicity, PPAR signaling pathway. In addition, the DEGs including APOL1, ETFB, KLK8, PPP1R3G, PRL, SPTA1, PLA2G3, PCP4L1, NINJ2, MIR186, and KLRG1 were proven to be significantly correlated with poorer overall survival in lung adenocarcinoma. CONCLUSIONS: CIH caused a significant change of gene expression profiling in LLC-bearing mice. The DEGs were found to be involved in various physiological and pathological processes and correlated with poorer prognosis in lung cancer.

Hyperfractionated Accelerated Radiotherapy Versus Stereotactic Body Radiotherapy in the Treatment of Limited-Stage Small Cell Lung Cancer: A Matched-Pair Analysis.

BACKGROUND: Concurrent chemoradiotherapy based on hyperfractionated accelerated radiotherapy (HART) is the first-line recommended regimen for the treatment of small-cell lung cancer (SCLC). However, Stereotactic Body Radiotherapy (SBRT) is also regarded as an effective treatment for limited-stage (LS) SCLC, and the efficacy and safety of HART versus SBRT stay controversial. METHODS: In this study, 188 LS-SCLC patients were retrospectively divided into two groups receiving chemotherapy combined with either HART or SBRT. In HART group, patients received 4500 cGy in 30 fractions, administered twice daily for 3 weeks. Whereas in the SBRT group, a total radiation dose of 4000-4500 cGy was delivered in 10 fractions over 2 weeks. Thirty-three pairs of patients were finally included for next analysis. RESULTS: The estimated objective response rates were 63.6 % (21/33) and 78.8 % (26/33) in HART group and SBRT group, respectively (P = 0.269). Furthermore, there was no significant difference between HART and SBRT groups in overall survival (26 months vs. 29 months, P = 0.362) and progression free survival (11 months vs. 15 months, P = 0.223). As for the adverse events, toxicity of both groups is similar and slight that no grade 4 event was observed. Grade 3 pneumonitis cases were all occurred in the HART group (9.1%, 3/33, P = 0.238), and grade 3 esophagitis cases were all occurred in the SBRT group (6.1%, 2/33, P = 0.492). CONCLUSION: Compared with HART, SBRT could be another effective treatment with satisfactory safety for the concurrent chemoradiotherapy in patients with LS-SCLC.

The relationship between cadmium exposure and preeclampsia: a systematic review and meta-analysis.

Background: Cadmium (Cd) is a heavy metal associated with several human disorders. Preeclampsia is a major cause of maternal mortality worldwide. The association between maternal Cd exposure and preeclampsia remains elusive. Methods: To better understand this relationship, we conducted a systematic review and meta-analysis of eligible studies from five databases (PubMed, Embase, Web of Science, Scopus, and CNKI) from their inception to September 10, 2022. The quality of these studies was evaluated using the Newcastle-Ottawa quality assessment scale (NOS). We use random-effects models to calculate overall standardized mean differences (SMDs) and 95% confidence intervals (CIs). Sensitivity analyses were performed to assess the robustness of our results. We also evaluated publication bias using Egger's and Begg's tests. Additionally, we conducted meta-regression and sub-group analyses to identify potential sources of heterogeneity between studies. Results: Our analysis included a total of 17 studies with 10,373 participants. We found a significant association between maternal cadmium exposure and the risk of preeclampsia (SMD 0.27, 95% CI 0.09-0.44, p < 0.01). No significant publication bias was detected in Begg's or Egger's tests. Meta-regression suggested that geographical location, year of publication, cadmium samples, sample size, and measurement methods did not contribute to heterogeneity between studies. Conclusion: Our findings suggest that maternal blood cadmium levels are associated with an increased risk of preeclampsia. In contrast, the pregnant women's urine or placental levels of cadmium may not suggest preeclamptic risk during pregnancy. Further high-quality clinical studies and animal experiments are needed to understand this association better. Systematic review registration: PROSPERO, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=361291, identifier: CRD42022361291.

Core-Shell Au@Pd Bimetallic Nanozyme Mediated Mild Photothermal Therapy through Reactive Oxygen Species-Regulating Tumor Thermoresistance.

Mild photothermal therapy (mPTT), which circumvents the limitations of conventional photothermal therapy, is emerging and exhibits remarkable potential in clinical applications. Nevertheless, mPTT is not able to efficiently eradicate tumors because its therapeutic efficacy is dramatically diminished by stress-induced heat shock proteins (HSP). Herein, a core-shell structured Au@Pd (AP) bimetallic nanozyme was fabricated for reactive oxygen species (ROS) augmentation-induced mPTT. The nanocatalytic AP nanozymes with photothermal conversion performance harbor multienzymatic (catalase, oxidase, and peroxidase) activities to induce ROS storm formation. The generated ROS could suppress the heat-defense response of tumor cells by cleaving HSP. Overall, our work highlights a ROS-regulating strategy to counteract hyperthermia-associated resistance in mPTT.

Analysis of Long Time Series of Summer Surface Urban Heat Island under the Missing-Filled Satellite Data Scenario.

Surface urban heat islands (SUHIs) are mostly an urban ecological issue. There is a growing demand for the quantification of the SUHI effect, and for its optimization to mitigate the increasing possible hazards caused by SUHI. Satellite-derived land surface temperature (LST) is an important indicator for quantifying SUHIs with frequent coverage. Current LST data with high spatiotemporal resolution is still lacking due to no single satellite sensor that can resolve the trade-off between spatial and temporal resolutions and this greatly limits its applications. To address this issue, we propose a multiscale geographically weighted regression (MGWR) coupling the comprehensive, flexible, spatiotemporal data fusion (CFSDAF) method to generate a high-spatiotemporal-resolution LST dataset. We then analyzed the SUHI intensity (SUHII) in Chengdu City, a typical cloudy and rainy city in China, from 2002 to 2022. Finally, we selected thirteen potential driving factors of SUHIs and analyzed the relation between these thirteen influential drivers and SUHIIs. Results show that: (1) an MGWR outperforms classic methods for downscaling LST, namely geographically weighted regression (GWR) and thermal image sharpening (TsHARP); (2) compared to classic spatiotemporal fusion methods, our method produces more accurate predicted LST images (R2, RMSE, AAD values were in the range of 0.8103 to 0.9476, 1.0601 to 1.4974, 0.8455 to 1.3380); (3) the average summer daytime SUHII increased form 2.08 °C (suburban area as 50% of the urban area) and 2.32 °C (suburban area as 100% of the urban area) in 2002 to 4.93 °C and 5.07 °C, respectively, in 2022 over Chengdu City; and (4) the anthropogenic activity drivers have a higher relative influence on SUHII than other drivers. Therefore, anthropogenic activity driving factors should be considered with CO2 emissions and land use changes for urban planning to mitigate the SUHI effect.

Increased expression of Nav1.6 of reactive astrocytes in the globus pallidus is closely associated with motor deficits in a model of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease in elderly people, which is characterized by motor disabilities in PD patients. Nav1.6 is the most abundant subtype of voltage-gated sodium channels (VGSCs) in the brain of adult mammals and rodents. Here we investigated the role of Nav1.6 in the external globus pallidus (GP) involved in the pathogenesis of motor deficits in unilateral 6-OHDA(6-hydroxydopamine)lesioned rats. The results show that Nav1.6 is dramatically increased in reactive astrocytes of the ipsilateral GP in the middle stage, but not different from the control rats in the later stage of the pathological process in 6-OHDA lesioned rats. Furthermore, the down-regulation of Nav1.6 expression in the ipsilateral GP can significantly improve motor deficits in 6-OHDA lesioned rats in the middle stage of the pathological process. The electrophysiological experiments show that the down-regulation of Nav1.6 expression in the ipsilateral GP significantly decreases the abnormal high synchronization between the ipsilateral M1 (the primary motor cortex) and GP in 6-OHDA lesioned rats. Ca2+ imaging reveals that the down-regulation of Nav1.6 expression reduces the intracellular concentration of Ca2+ ([Ca2+ ]i) in primary cultured astrocytes. These findings suggest that the increased Nav1.6 expression of reactive astrocytes in the GP play an important role in the pathogenesis of motor dysfunction in the middle stage in 6-OHDA lesioned rats, which may participate in astrocyte-neuron communication by regulating [Ca2+ ]i of astrocytes, thereby contributing to the formation of abnormal electrical signals of the basal ganglia (BG) in 6-OHDA lesioned rats.

N-Heterocyclic carbene-catalyzed enantioselective annulation of 2-amino-1H-indoles and bromoenals for the synthesis of chiral 2-aryl-2,3-dihydropyrimido[1,2-a]indol-4 (1H)-ones.

An efficient N-heterocyclic carbene (NHC)-catalyzed enantioselective [3 + 3] annulation of 2-bromoenals with 2-amino-1H-indoles has been developed. A series of functionalized 2-aryl-2,3-dihydropyrimido[1,2-a]indol-4(1H)-ones were synthesized using NHCs as the catalyst in good yields with high to excellent enantioselectivities.

Circulating tumor DNA analysis detects micrometastatic disease and predicts recurrence in a patient with colon cancer: A case report.

RATIONALE: Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide, and approximately 50% of patients with early-stage disease develop metastases. A critical limitation for successful management of CRC is early disease detection and identification of progression. Next-generation sequencing-based circulating tumor DNA (ctDNA) profiling has emerged as a promising biomarker for the assessment of minimal or molecular residual disease in CRC. PATIENT CONCERNS: The patient was initially diagnosed with resectable CRC with uncertain small lung nodules. DIAGNOSES: The patient was diagnosed with sigmoid colon adenocarcinoma placed at 15 to 20 cm above the anal verge (ypT4N1R0). Lung nodules were found in the apical part of the upper lobe of the right lung and the dorsal segment of the lower lobe of the left lung. INTERVENTIONS: The patient received systemic therapy and local treatment and plasma ctDNA-MRD detection was performed for monitoring the molecular disease status after surgery. OUTCOMES: The patient achieved a complete response after treatment. However, he presented with disease recurrence in liver lesions. The postoperative ctDNA detection suggested the possibility of micrometastatic pulmonary disease, and that was confirmed by follow-up examination. Serial ctDNA detection revealed disease relapse ahead of radiologic imaging by a lead time of 9 months. This case demonstrated the potential of ctDNA analysis to be a sensitive and specific tool for the detection of micrometastatic disease and prediction of recurrence.

Reduction in gefitinib resistance mediated by Yi-Fei San-Jie pill in non-small cell lung cancer through regulation of tyrosine metabolism, cell cycle, and the MET/EGFR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal prescription Yi-Fei San-Jie pill (YFSJ) has been used for adjuvant treatment in patients with lung cancer for a long time. AIM OF THE STUDY: Reports have indicated that the combination of gefitinib (Gef) with YFSJ inhibits the proliferation of EGFR-TKI-resistant cell lines by enhancing cellular apoptosis and autophagy in non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying the effect of YFSJ on EGFR-TKI resistance and related metabolic pathways remain to be explored. MATERIALS AND METHODS: In our report, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), metabolomics, network pharmacology, bioinformatics, and biological analysis methods were used to investigate the mechanism. RESULTS: The UPLC-MS/MS data identified 42 active compounds of YFSJ extracts. YFSJ extracts can enhance the antitumor efficacy of Gef without hepatic and renal toxicity in vivo. The analysis of the metabolomics pathway enrichment revealed that YFSJ mainly affected the tyrosine metabolism pathway in rat models. Moreover, YFSJ has been shown to reverse Gef resistance and improve the effects of Gef on the cellular viability, migration capacity, and cell cycle arrest of NSCLC cell lines with EGFR mutations. The results of network pharmacology and molecular docking analyses revealed that tyrosine metabolism-related active compounds of YFSJ affect EGFR-TKIs resistance in NSCLC by targeting cell cycle and the MET/EGFR signaling pathway; these findings were validated by western blotting and immunohistochemistry. CONCLUSIONS: YFSJ inhibits NSCLC by inducing cell cycle arrest in the G1/S phase to suppress tumor growth, cell viability, and cell migration through synergistic effects with Gef via the tyrosine metabolic pathway and the EGFR/MET signaling pathway. To summarize, the findings of the current study indicate that YFSJ is a prospective complementary treatment for Gef-resistant NSCLC.

Identification of the active compounds in the Yi-Fei-San-Jie formula using a comprehensive strategy based on cell extraction/UPLC-MS/MS, network pharmacology, and molecular biology techniques.

BACKGROUND: Chinese herbal formulae has multiple active constituents and targets, and the good clinical response is encouraging more scientists to explore the bio-active ingredients in such complex systems. Yi-Fei-San-Jie formula (YFSJF) is commonly used to treat patients with lung cancer in South China; however, its bio-active ingredients remain unknown. PURPOSE: We investigated the bio-active ingredients of the YFSJF using a novel comprehensive strategy. METHODS: A549 cell extraction coupled with ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) was used for the screening of potential bio-active ingredients. Network pharmacology approach and molecular dynamics simulation were performed for the screening of targets. Surface plasmon resonance (SPR) assay and molecular biology techniques were used to verify the targets. RESULTS: Nine A549 cell membrane-binding compounds were identified through cell extraction/UPLC-MS/MS. Five compounds, namely ginsenoside Ro, ginsenoside Rb1, ginsenoside Rc, peimisine, and peimine were cytotoxic to A549 cells, and they were considered the bio-active ingredients of the YFSJF in vitro. Network pharmacology analysis revealed that TGFBR2 is the key target and the TGFß pathway is the key pathway targeted by YFSJF in non-small cell lung cancer. Peimisine showed an affinity to TGFBR2 using molecular docking and dynamic stimulation, which was confirmed using surface plasmon resonance spectroscopy. The molecular biology-based analysis further confirmed that peimisine targets TGFBR2 and can reverse A549 epithelial-mesenchymal transition by inhibiting the TGFß pathway. CONCLUSION: Taken together, cell extraction/UPLC-MS/MS, network pharmacology, and molecular biology-based analysis comprise a feasible strategy to explore active ingredients in YFSJF.

Distinct circulating cytokine/chemokine profiles correlate with clinical benefit of immune checkpoint inhibitor monotherapy and combination therapy in advanced non-small cell lung cancer.

BACKGROUND: An ever-increasing number of efforts are focused on identifying effective biomarkers for immune checkpoint inhibitors (ICIs). Cytokines and chemokines are critical to tumor growth, metastasis, tumor angiogenesis, and the immune response against tumor cells. In the study here, we determined the correlation between circulating cytokines/chemokines and the clinical benefit of ICIs for non-small cell lung cancer (NSCLC) patients. METHODS: Peripheral blood samples were collected before and during treatment (at 12th week). Plasma levels of cytokines/chemokines and specific stress response markers were measured using the Bio-Plex Pro Human Cytokines Grp I Panel (27-plex), an APEX1 detection kit, and a human LAP(TGF-ß1) immunoassay kit. A Mann-Whitney U-test or Wilcoxon signed-rank test and a Cox proportional hazards model were employed for statistical analysis. RESULTS: In the ICI monotherapy cohort, a high level of IL-6 at pretreatment or an elevation of IL-6, IL-8, FGF2, CXCL10, CCR1, PDFGB, TNF, and APEX1 posttreatment was associated with poor progress-free survival (PFS). A posttreatment elevation (defined herein as change rate) of CXCL10 was also associated with poor overall survival (OS). In the combinational therapy group, a high level of IL-12, IL-17A, FGF2, VEGF, and APEX1 at pretreatment and an elevation of CCL2 posttreatment were associated with poor PFS. A high level of IL-9, FGF2, PDFGB, CCL4, TFGB, and APEX1 at pretreatment and an elevation of IL-13, CSF2, and CCL2 at posttreatment were associated with poor OS of patients receiving combination therapy. CONCLUSIONS: The study here suggests that circulating cytokines/chemokines are feasible, noninvasive biomarkers for predicting clinical benefit of ICI treatment for NSCLC. Distinct circulating factor profiles were observed in individuals receiving ICI monotherapy or combination therapy.

Programmable A-to-Y base editing by fusing an adenine base editor with an N-methylpurine DNA glycosylase.

Here we developed an adenine transversion base editor, AYBE, for A-to-C and A-to-T transversion editing in mammalian cells by fusing an adenine base editor (ABE) with hypoxanthine excision protein N-methylpurine DNA glycosylase (MPG). We also engineered AYBE variants enabling targeted editing at genomic loci with higher transversion editing activity (up to 72% for A-to-C or A-to-T editing).