Roux-en-Y Gastric Bypass Surgery for the Prevention of Long-term Renal Function Damage in Type 2 Diabetes: A Clinical Study.

Objective: Type 2 diabetes mellitus (T2DM) is strongly associated with obesity, a significant risk factor for the occurrence and progression of chronic kidney disease. In recent years, weight loss surgery has become an important treatment option for diabetes. This study examined whether Roux-en-Y gastric bypass surgery, a new metabolic bariatric surgery approach, can effectively reduce the risk of long-term renal impairment in individuals with type 2 diabetes. Methods: In a cohort study, 60 individuals suffering from both obesity and type 2 diabetes were stratified and randomly divided into 2 groups based on gender and weight. The control group (30 cases) received internal medicine treatment; the observation group (30 cases) received Roux-en-Y gastric bypass surgery. The study compared the changes in glycated hemoglobin, fasting blood glucose, fasting insulin, fasting C-peptide, postprandial 2-hour blood glucose, postprandial 2-hour insulin, postprandial 2-hour C-peptide, weight, waist circumference, and BMI before and at 6, 12, and 18 months after treatment. Kidney function-related indicators such as urinary protein excretion, microalbuminuria, and creatinine clearance were also compared. Results: There were no significant differences in the above indicators between the 2 groups before treatment (P > .05). After 6, 12, and 18 months of treatment, the levels of glycated hemoglobin, fasting blood glucose, fasting insulin, fasting C-peptide, postprandial 2-hour blood glucose, postprandial 2-hour insulin, postprandial 2-hour C-peptide, weight, waist circumference, and BMI were significantly decreased compared to before treatment (P < .05). Urinary protein excretion and microalbuminuria decreased, while creatinine clearance increased after 6, 12, and 18 months of surgery (P < .05). The differences in indicators between the 2 groups at each point after surgery were statistically significant (P < .05). Conclusion: Roux-en-Y gastric bypass surgery was more effective than medical treatment in treating type 2 diabetes and mitigating long-term kidney function damage. These findings confirm the clinical utility of Roux-en-Y gastric bypass surgery in these conditions, indicating its potential for generalization and reference.

Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11.

BACKGROUND: The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood. METHODS: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) expression in mTORC1-activated mouse embryonic fibroblasts, cancer cells, and laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF), and immunohistochemistry. Extensive in vitro and in vivo experiments were carried out to determine the role of ERO1α and its downstream target, member 11 of the solute carrier family 7 (SLC7A11), in mTORC1-mediated cell proliferation, angiogenesis, ferroptosis resistance, and tumor growth. The regulatory mechanism of ERO1α on SLC7A11 was investigated via RNA-sequencing, a cytokine array, an enzyme-linked immunosorbent assay, qRT-PCR, western blotting, IF, a luciferase reporter assay, and a chromatin immunoprecipitation assay. The combined therapeutic effect of ERO1α inhibition and the ferroptosis inducer imidazole ketone erastin (IKE) on mTORC1-activated cells was evaluated using cell line-derived xenografts, LSCC organoids, and LSCC patient-derived xenograft models. RESULTS: ERO1α is a functional downstream target of mTORC1. Elevated ERO1α induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1α stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1α inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors. CONCLUSIONS: The ERO1α/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1α inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.

ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer.

Purpose: Lung cancer is a major cause of morbidity and mortality globally, necessitating the identification of predictive markers for effective immunotherapy. Mutations in SWI/SNF chromatin remodeling complex genes were reported sensitized human tumors to immune checkpoint inhibitors (ICIs), but the underlying mechanisms are unclear. This study aims to investigate the association between SWI/SNF gene ARID1B mutation and ICI response in non-small cell lung cancer (NSCLC) patients, to explore the functional consequences of ARID1B mutation on DNA damage response, immune microenvironment, and cGAS-STING pathway activation. Methods: TCGA LUAD, LUSC, and AACR GENIE data are analyzed to assess ARID1B mutation status in NSCLC patients. Prognostic analysis evaluates the effect of ARID1B mutation on patient outcomes. In vitro experiments carried to investigate the consequences of ARID1B knockdown on DNA damage response and repair. The immune microenvironment is assessed based on ARID1B expression, and the relationship between ARID1B and the cGAS-STING pathway is explored. Results: ARID1B mutation frequency is 5.7% in TCGA databases and 4.4% in the AACR GENIE project. NSCLC patients with ARID1B mutation showed improved overall and progression-free survival following ICIs treatment. ARID1B knockdown in lung cancer cell lines enhances DNA damage, impairs DNA repair, alters chromatin accessibility, and activates the cGAS-STING pathway. ARID1B deficiency is associated with immune suppression, indicated by reduced immune scores, decreased immune cell infiltration, and negative correlations with immune-related cell types and functions. Conclusion: ARID1B mutation may predict improved response to ICIs in NSCLC patients. ARID1B mutation leads to impaired DNA damage response and repair, altered chromatin accessibility, and cGAS-STING pathway activation. These findings provide insights into ARID1B's biology and therapeutic implications in lung cancer, highlighting its potential as a target for precision medicine and immunotherapy. Further validation and clinical studies are warranted.

Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in PKD1 mutant mouse and human ADPKD kidneys. Genetic knockout of SMYD3 in a PKD1 knockout mouse model delayed cyst growth and improved kidney function compared with PKD1 single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in PKD1 mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in PKD1 mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD.

Compounding engineered mesenchymal stem cell-derived exosomes: A potential rescue strategy for retinal degeneration.

The prevalence of retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, has been increasing globally and is linked to the aging population and improved life expectancy. These diseases are characterized by chronic, progressive neuronal damage or depletion of the photoreceptor cells in the retina, and limited effective treatment options are currently available. Mesenchymal stem cell-derived exosomes (MSC-EXOs) containing cytokines, growth factors, lipids, mRNA, and miRNA, which act as mediators of intercellular communication transferring bioactive molecules to recipient cells, offer an appealing, non-cellular nanotherapeutic approach for retinal degenerative diseases. However, treatment specificity is compromised due to their high heterogeneity in size, content, functional effects, and parental cellular source. To improve this, engineered MSC-EXOs with increased drug-loading capacity, targeting ability, and resistance to bodily degradation and elimination have been developed. This review summarizes the recent advances in miRNAs of MSC-EXOs as a treatment for retinal degeneration, discussing the strategies and methods for engineering therapeutic MSC-EXOs. Notably, to address the single functional role of engineered MSC-EXOs, we propose a novel concept called "Compound Engineered MSC-EXOs (Co-E-MSC-EXOs)" along with its derived potential therapeutic approaches. The advantages and challenges of employing Co-E-MSC-EXOs for retinal degeneration in clinical applications, as well as the strategies and issues related to them, are also highlighted.

PTEN deficiency potentiates HBV-associated liver cancer development through augmented GP73/GOLM1.

BACKGROUND: Although hepatitis B virus (HBV) infection is a major risk factor for hepatic cancer, the majority of HBV carriers do not develop this lethal disease. Additional molecular alterations are thus implicated in the process of liver tumorigenesis. Since phosphatase and tensin homolog (PTEN) is decreased in approximately half of liver cancers, we investigated the significance of PTEN deficiency in HBV-related hepatocarcinogenesis. METHODS: HBV-positive human liver cancer tissues were checked for PTEN expression. Transgenic HBV, Alb-Cre and Ptenfl/fl mice were inter-crossed to generate WT, HBV, Pten-/- and HBV; Pten-/- mice. Immunoblotting, histological analysis and qRT-PCR were used to study these livers. Gp73-/- mice were then mated with HBV; Pten-/- mice to illustrate the role of hepatic tumor biomarker golgi membrane protein 73 (GP73)/ golgi membrane protein 1 (GOLM1) in hepatic oncogenesis. RESULTS: Pten deletion and HBV transgene synergistically aggravated liver injury, inflammation, fibrosis and development of mixed hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). GP73 was augmented in HBV; Pten-/- livers. Knockout of GP73 blunted the synergistic effect of deficient Pten and transgenic HBV on liver injury, inflammation, fibrosis and cancer development. CONCLUSIONS: This mixed HCC-ICC mouse model mimics liver cancer patients harboring HBV infection and PTEN/AKT signaling pathway alteration. Targeting GP73 is a promising therapeutic strategy for cancer patients with HBV infection and PTEN alteration.

KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis.

Aberrant lysine lactylation (Kla) is associated with various diseases which are caused by excessive glycolysis metabolism. However, the regulatory molecules and downstream protein targets of Kla remain largely unclear. Here, we observed a global Kla abundance profile in colorectal cancer (CRC) that negatively correlates with prognosis. Among lactylated proteins detected in CRC, lactylation of eEF1A2K408 resulted in boosted translation elongation and enhanced protein synthesis which contributed to tumorigenesis. By screening eEF1A2 interacting proteins, we identified that KAT8, a lysine acetyltransferase that acted as a pan-Kla writer, was responsible for installing Kla on many protein substrates involving in diverse biological processes. Deletion of KAT8 inhibited CRC tumor growth, especially in a high-lactic tumor microenvironment. Therefore, the KAT8-eEF1A2 Kla axis is utilized to meet increased translational requirements for oncogenic adaptation. As a lactyltransferase, KAT8 may represent a potential therapeutic target for CRC.

Active AKT2 stimulation of SREBP1/SCD1-mediated lipid metabolism boosts hepatosteatosis and cancer.

Due to soared obesity population worldwide, hepatosteatosis is becoming a major risk factor for hepatocellular carcinoma (HCC). Undertaken molecular events during the progression of steatosis to liver cancer are thus under intensive investigation. In this study, we demonstrated that high-fat diet potentiated mouse liver AKT2. Hepatic AKT2 hyperactivation through gain-of-function mutation of Akt2 (Akt2E17K) caused spontaneous hepatosteatosis, injury, inflammation, fibrosis, and eventually HCC in mice. AKT2 activation also exacerbated lipopolysaccharide and D-galactosamine hydrochloride-induced injury/inflammation and N-Nitrosodiethylamine (DEN)-induced HCC. A positive correlation between AKT2 activity and SCD1 expression was observed in human HCC samples. Activated AKT2 enhanced the production of monounsaturated fatty acid which was dependent on SREBP1 upregulation of SCD1. Blockage of active SREBP1 and ablation of SCD1 reduced steatosis, inflammation, and tumor burden in DEN-treated Akt2E17K mice. Therefore, AKT2 activation is crucial for the development of steatosis-associated HCC which can be treated with blockage of AKT2-SREBP1-SCD1 signaling cascade.

Oncogenic ß-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis.

BACKGROUND: Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for ß-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1 ), the most frequently altered proto-oncogene in hepatic neoplasms. METHODS: Constitutive ß-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( ß-catenin Δ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited ß-catenin Δ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on ß-catenin-activated human liver cancer cells were determined in vitro . Immuno-deficient nude mice subcutaneously inoculated with ß-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV ); ß-catenin lox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of ß-catenin mutant liver cancer. RESULTS: MTX was identified and validated as a preferential agent against the proliferation and tumor formation of ß-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in ß-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV ; ß-catenin lox(ex3)/+ mice, which stimulated concurrent Ctnnb1- activated mutation and HBV infection in liver cancer. CONCLUSION: MTX is a promising chemotherapeutic agent for ß-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of ß-catenin mutant liver cancer.

Electrical Properties of Human Lung Nodules In Vitro From 100 Hz to 100 MHz.

OBJECTIVE: The incidence of pulmonary nodules has been increasing over the past 30 years. Different types of nodules are associated with varying degrees of malignancy, and they engender inconsistent treatment approaches. Therefore, correct distinction is essential for the optimal treatment and recovery of the patients. The commonly-used medical imaging methods have limitations in distinguishing lung nodules to date. A new approach to this problem may be provided by electrical properties of lung nodules. Nevertheless, difference identification is the basis of correct distinction. So, this paper aims to investigate the differences in electrical properties between various lung nodules. METHODS: At variance with existing studies, benign samples were included for analysis. A total of 252 specimens were collected, including 126 normal tissues, 15 benign nodules, 76 adenocarcinomas, and 35 squamous cell carcinomas. The dispersion properties of each tissue were measured over a frequency range of 100 Hz to 100 MHz. And the relaxation mechanism was analyzed by fitting the Cole-Cole plot. The corresponding equivalent circuit was estimated accordingly. RESULTS: Results validated the significant differences between malignant and normal tissue. Significant differences between benign and malignant lesions were observed in conductivity and relative permittivity. Adenocarcinomas and squamous cell carcinomas are significantly different in conductivity, first-order, second-order differences of conductivity, α-band Cole-Cole plot parameters and capacitance of equivalent circuit. The combination of the different features increased the tissue groups' differences measured by Euclidean distance up to 94.7%. CONCLUSION AND SIGNIFICANCE: In conclusion, the four tissue groups reveal dissimilarity in electrical properties. This characteristic potentially lends itself to future diagnosis of non-invasive lung cancer.

GOLM1 Promotes Pulmonary Fibrosis through Upregulation of NEAT1.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.

Application of Hospital-Community-Family "Trinity" Remote Rehabilitation Guidance Based on Internet + WeChat Platform in Patients with Stroke After Discharge.

Objective: To investigate the impact of an Internet + WeChat platform-based "trinity" remote rehabilitation model involving the hospital, community, and family on stroke patient rehabilitation nursing. Methods: 159 patients with stroke who were discharged from Beijing Luhe Hospital of Capital Medical University from January 1, 2018, to December 31, 2019, were selected and divided into a control group (79 cases) and an experimental group (80 cases) by the random drawing method. The control group was given routine nursing, and the experimental group was given remote rehabilitation nursing intervention by using the WeChat network platform based on the control group. Limb function [Fugl-Meyer Assessment Scale (FMA)] and activities of daily living [Modified Barthel Index (MBI)] were evaluated at enrollment and at the end of 3 months, 6 months and 12 months in both groups. The compliance and satisfaction surveys in the two groups were evaluated after 6 months and 12 months of intervention. Results: (1) Before the intervention, there was no statistical significance in FMA score between the two groups (t = 0.798, P > .05). After 3 months, 6 months and 12 months of intervention, the FMA score in the two groups was increased compared with that before intervention (t = 2.463, P < .05), and the FMA scores in the experimental group at the above time points were higher than those in the control group (ts = 7.057, 14.285, Ps < .05). (2) There was no statistical difference in MBI scores between the two groups before intervention (t = 0.798, P > .05). After 3 months, 6 months, and 12 months of intervention, the MBI score in the two groups was increased compared with that before intervention (t = 0.232, P < .05), and MBI scores in the experimental group at the above time points were higher compared to the control group (ts = 4.959, 8.842, 8.131, Ps < .05). (3) The compliance scores in the experimental group were higher than those in the control group after 6 months and 12 months of intervention (ts = 4.959, 8.842, 8.131, Ps < .05). (4) The satisfaction survey scores in the experimental group after 6 months and 12 months of intervention were higher than those in the control group (ts = 2.120 ~ 14.554, Ps < .05). Conclusion: The Hospital-community-family "trinity" stroke rehabilitation model on the WeChat network platform holds significant importance. Enhancing limb function and daily living for stroke patients improves their quality of life and lessens reliance on caregivers. This positively impacts both survivors' well-being and healthcare resources. Increased patient satisfaction and compliance suggest a potential revolution in post-stroke care, favoring a more patient-centered approach. Overall, this model has transformative potential for stroke treatment, offering holistic and patient-focused strategies. Its success promises better rehabilitation outcomes, patient satisfaction, and cost reduction, while paving the way for innovative research in stroke treatment and rehabilitation.

Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1G93A mice and ALS patients. SOD1G93A mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).

Phosphorylation of MIF by PIP4K2a is necessary for cilia biogenesis.

Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Macrophage migration inhibitory factor (MIF) has long been recognized as a secreted cytokine in the pathogenesis of various human diseases, including cancer and autosomal dominant polycystic kidney disease (ADPKD). Unlike other cytokines, unique functional characteristics of intracellular MIF have emerged. In this study, we show that MIF is localized and formed a ring like structure at the proximal end of centrioles, where it regulates cilia biogenesis through affecting 1) the recruitment of TTBK2 to basal body and the removal of CP110 from mother centriole, 2) the accumulation of CEP290 at centriolar satellites, and 3) the trafficking of intraflagellar transport (IFT) related proteins. We also show that MIF functions as a novel transcriptional factor to regulate the expression of genes related to ciliogenesis via binding on the promotors of those genes. MIF also binds chromatin and regulates transcription of genes involved in diverse homeostatic signaling pathways. We identify phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2a) as an upstream regulator of MIF, which interacts with and phosphorylates MIF at S91 to increase its interaction with 14-3-3ζ, resulting in its nuclear translocation and transcription regulation. This study suggests that MIF is a key player in cilia biogenesis and a novel transcriptional regulator in homeostasis, which forward our understanding of how MIF is able to carry out several nonoverlapping functions.

Apatinib added when NSCLC patients get slow progression with EGFR-TKI: A prospective, single-arm study.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) acquired resistance was an inevitably events in NSCLC treatment. AIMS: Intending to overcome the acquired resistance of EGFR-TKI. MATERIALS & METHODS: A clinical trial was, we enrolled 12 patients who were slowly progressing on first-generation EGFR-TKI, and added apatinib when the patients got slow progression. RESULTS: Seven patients were included in the efficacy analysis. The median PFS2 of apatinib combined with EGFR-TKI was 8.2 months (95% CI, 7.3 m-NA), and the total PFS reached 20.9 months (95% CI, 17.3 m-NA) when plus PFS1. All the adverse events were manageable. The median PFS was significantly longer for circulating tumor DNA (ctDNA)-cleared patients (8.4 months; 95% CI, 8.2-NA) than for those ctDNA not cleared (7.1 months; 95% CI, 6.9-NA) (p = 0.0082). DISCUSSION: The addition of apatinib did improve the duration of first-generation EGFR-TKI use, and the duration was better than the first-line use of third-generation EGFR-TKI. CONCLUSION: The addition of apatinib when the patients got slow progression after initial EGFR-TKI therapy may be a good treatment option and the side effects are controllable. It is possible to monitor treatment efficacy using ctDNA.

Establishment of a prognostic signature for patients with advanced lung squamous cell carcinoma based on tumor-infiltrating immune cells.

Background: With the advancements in the fields of science, technology, and medical therapy, there is an increasing awareness among the general public regarding tumor-infiltrating immune cells. These immune cells have a close association with the prognosis of clinical patients with lung cancer. Methods: The research used a comprehensive analysis and assessed tumor-infiltrating immune cells in advanced lung squamous cell carcinoma (LUSC) using The Cancer Genome Atlas (TCGA) database and the CIBERSORT algorithm. The research examined 22 types of tumor-infiltrating immune cells and observed notable differences in the infiltration patterns of immune cells between normal tissue and advanced LUSC. Results: Univariate Cox regression analyses revealed a positive correlation between macrophages M2 and patient prognoses, as well as potential influences on patient prognosis by natural killer (NK) cells resting, monocytes, and activated mast cells. Multivariate Cox regression models were developed, incorporating three types of immune cells. The efficacy of the model was evaluated using a receiver operating characteristic (ROC) curve. Furthermore, the research constructed a nomogram model to individually predict the mortality risk in patients with advanced LUSC. This prediction model serves as a valuable tool for clinicians, enabling them to provide effective guidance based on tumor-infiltrating immune cells for advanced LUSC patients. Conclusions: The research comprehensively analyzed and evaluated 22 types of tumor-infiltrating immune cells from advanced LUSC, revealing the correlation between immune cell infiltration and overall survival (OS) in clinical patients. Based on the nomogram of NK cells resting, monocytes, and macrophages M2, it can make specific prognostic predictions for advanced LUSC patients.

Polo-like kinase 1 promotes sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) is the main cause of mortality in sepsis. In this study, we identified Polo-like kinase 1 (Plk-1) is a promoter of SIMD. Plk-1 expression was increased in lipopolysaccharide (LPS)-treated mouse hearts and neonatal rat cardiomyocytes (NRCMs). Inhibition of Plk-1 either by heterozygous deletion of Plk-1 or Plk-1 inhibitor BI 6727 alleviated LPS-induced myocardial injury, inflammation, cardiac dysfunction, and thereby improved the survival of LPS-treated mice. Plk-1 was identified as a kinase of inhibitor of kappa B kinase alpha (IKKα). Plk-1 inhibition impeded NF-κB signal pathway activation in LPS-treated mouse hearts and NRCMs. Augmented Plk-1 is thus essential for the development of SIMD and is a druggable target for SIMD.

Case Report: ALK rearranged locally advanced lung adenocarcinoma showing inconsistent radiographic findings and pathological responses during neoadjuvant alectinib therapy.

Alectinib has been approved as first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small cell lung carcinoma. Oncologists are also exploring the possibility of applying alectinib in the perioperative period. Here, we present a patient with locally advanced lung adenocarcinoma associated with EML4-ALK fusion mutation, who received neoadjuvant chemotherapy and alectinib treatment, and then underwent thoracoscopic left lower lung lobectomy. The patient initially received eight chemotherapy cycles and achieved partial remission. After eight cycles of chemotherapy, the lymph nodes in the hilar region again enlarged. The patient was then switched to 4 months of alectinib therapy, but no significant lesion changes were detected on imaging during this period. This raised the question of whether the patient developed alectinib resistance. The pathological findings of the postoperative lung lobe specimens indicated extensive necrosis in the tumor area with no residual tumor cells and massive chronic inflammatory cell infiltration around the tumor area, confirming inconsistency between the imaging findings and pathological results. Multi-point tumor specimen sampling was postoperatively performed. Tumor immune-related gene expression was detected in the sample with the help of the PanCancer IO360™ panel based on the nCounter platform. This is a rare case of a patient who was treated with neoadjuvant alectinib and had paradoxical radiographic findings and pathological responses. The possibility that intratumoral immune heterogeneity was responsible for this phenomenon has been discussed. Based on the findings, it is argued that the pathological response should be an important basis for assessing the effectiveness of neoadjuvant alectinib therapy.

Polo-like kinase 1 promotes pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a lethal vascular disease with limited therapeutic options. The mechanistic connections between alveolar hypoxia and PH are not well understood. The aim of this study was to investigate the role of mitotic regulator Polo-like kinase 1 (PLK1) in PH development. METHODS: Mouse lungs along with human pulmonary arterial smooth muscle cells and endothelial cells were used to investigate the effects of hypoxia on PLK1. Hypoxia- or Sugen5416/hypoxia was applied to induce PH in mice. Plk1 heterozygous knockout mice and PLK1 inhibitors (BI 2536 and BI 6727)-treated mice were checked for the significance of PLK1 in the development of PH. RESULTS: Hypoxia stimulated PLK1 expression through induction of HIF1α and RELA. Mice with heterozygous deletion of Plk1 were partially resistant to hypoxia-induced PH. PLK1 inhibitors ameliorated PH in mice. CONCLUSIONS: Augmented PLK1 is essential for the development of PH and is a druggable target for PH.