The impact of SOX4-activated CTHRC1 transcriptional activity regulating DNA damage repair on cisplatin resistance in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the predominant subtype within the spectrum of lung malignancies. CTHRC1 has a pro-oncogenic role in various cancers. Here, we observed the upregulation of CTHRC1 in LUAD, but its role in cisplatin resistance in LUAD remains unclear. Bioinformatics analysis was employed to detect CTHRC1 and SRY-related HMG-box 4 (SOX4) expression in LUAD. Gene Set Enrichment Analysis predicted the enriched pathways related to CTHRC1. JASPAR and MotifMap databases predicted upstream transcription factors of CTHRC1. Pearson analysis was conducted to analyze the correlation between genes of interest. The interaction and binding relationship between CTHRC1 and SOX4 were validated through dual-luciferase and chromatin immunoprecipitation assays. Quantitative real-time polymerase chain reaction determined the expression of CTHRC1 and SOX4 genes. CCK-8 was performed to assess cell viability and calculate IC50 value. Flow cytometry examined the cell cycle. Comet assay and western blot assessed DNA damage. CTHRC1 and SOX4 were upregulated in LUAD. CTHRC1 exhibited higher expression in cisplatin-resistant A549 cells compared to cisplatin-sensitive A549 cells. Knockdown of CTHRC1 enhanced DNA damage during cisplatin treatment and increased the sensitivity of LUAD cells to cisplatin. Additionally, SOX4 modulated DNA damage repair (DDR) by activating CTHRC1 transcriptional activity, promoting cisplatin resistance in LUAD cells. SOX4 regulated DDR by activating CTHRC1, thereby enhancing cisplatin resistance in LUAD cells. The finding provides a novel approach to address clinical cisplatin resistance in LUAD, with CTHRC1 possibly serving as a candidate for targeted therapies in addressing cisplatin resistance within LUAD.

Methionine redox regulation of actin-interacting proteins primarily governs antioxidative signaling and response to the salvianolic acid B treatment in EA.hy926 cells.

Actin-interacting proteins are important molecules for filament assembly and cytoskeletal signaling within vascular endothelium. Disruption in their interactions causes endothelial pathogenesis through redox imbalance. Actin filament redox regulation remains largely unexplored, in the context of pharmacological treatment. This work focused on the peptidyl methionine (M) redox regulation of actin-interacting proteins, aiming at elucidating its role on governing antioxidative signaling and response. Endothelial EA.hy926 cells were subjected to treatment with salvianolic acid B (Sal B) and tert-butyl-hydroperoxide (tBHP) stimulation. Mass spectrometry was employed to characterize redox status of proteins, including actin, myosin-9, kelch-like erythroid-derived cap-n-collar homology-associated protein 1 (Keap1), plastin-3, prelamin-A/C and vimentin. The protein redox landscape revealed distinct stoichiometric ratios or reaction site transitions mediated by M sulfoxide reductase and reactive oxygen species. In comparison with effects of tBHP stimulation, Sal B treatment prevented oxidation at actin M325, myosin-9 M1489/1565, Keap1 M120, plastin-3 M592, prelamin-A/C M187/371/540 and vimentin M344. For Keap1, reaction site was transitioned within its scaffolding region to the actin ring. These protein M oxidation regulations contributed to the Sal B cytoprotective effects on actin filament. Additionally, regarding the Keap1 homo-dimerization region, Sal B preventive roles against M120 oxidation acted as a primary signal driver to activate nuclear factor erythroid 2-related factor 2 (Nrf2). Transcriptional splicing of non-POU domain-containing octamer-binding protein was validated during the Sal B-mediated overexpression of NAD(P)H dehydrogenase [quinone] 1. This molecular redox regulation of actin-interacting proteins provided valuable insights into the phenolic structures of Sal B analogs, showing potential antioxidative effects on vascular endothelium.

Bidirectional crosstalk of the cAMP/ROS-dependent signaling pathways in inflammatory macrophage: An activation of formononetin.

Bacterial lipopolysaccharide (LPS) is a toxic stimulant to macrophage inflammation. Inflammation intersects cell metabolism and often directs host immunopathogenesis stress. We aim here at pharmacological discovering of formononetin (FMN) action, to which anti-inflammatory signaling spans across immune membrane receptors and second messenger metabolites. In ANA-1 macrophage stimulated by LPS, and simultaneous treatment with FMN, results show the Toll-like receptor 4 (TLR4) and estrogen receptor (ER) signals, in concert with reactive oxygen species (ROS) and cyclic adenosine monophosphate (cAMP), respectively. LPS stimulates inactivation of the ROS-dependent nuclear factor erythroid 2-related factor 2 (Nrf2) by upregulating TLR4, but it does not affect cAMP. However, FMN treatment not only activates Nrf2 signaling by TLR4 inhibition, but also it activates cAMP-dependent protein kinase activities by upregulating ER. The cAMP activity gives rise to phosphorylation (p-) of protein kinase A, liver kinase B1 and 5'-AMP activated protein kinase (AMPK). Moreover, bidirectional signal crosstalk is amplified between p-AMPK and ROS, as FMN combinational validation with AMPK activator/inhibitor/target small-interfering RNA or ROS scavenger. The signal crosstalk is well positioned serving as the 'plug-in' knot for rather long signaling axis, and the immune-to-metabolic circuit via ER/TLR4 signal transduction. Collectively, convergence of the FMN-activated signals drives significant reduction of cyclooxygenase-2, interleukin-6 and NLR family pyrin domain-containing protein 3, in LPS-stimulated cell. Although anti-inflammatory signaling is specifically related to the immune-type macrophage, the p-AMPK antagonizing effect arises from FMN combination with ROS scavenger H-bond donors. Information of our work assists in predictive traits against macrophage inflammatory challenges, using phytoestrogen discoveries.

Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mutations in mitochondrial DNA. However, there is no effective treatment for this disease. LHON-linked ND6 14484T > C (p.M64V) mutation caused complex I deficiency, diminished ATP production, increased production of reactive oxygen species (ROS), elevated apoptosis, and impaired mitophagy. Here, we investigated if the allotopic expression of human mitochondrial ND6 transgene corrected the mitochondrial dysfunctions due to LHON-associated m.14484T > C mutation. METHODS: Nucleus-versions of ND6 was generated by changing 6 non-universal codons with universal codons and added to mitochondrial targeting sequence of COX8. Stable transfectants were generated by transferring human ND6 cDNA expressed in a pCDH-puro vector into mutant cybrids carrying the m.14484T > C mutation and control cybrids. The effect of allotopic expression of ND6 on oxidative phosphorylation (OXPHOS) was evaluated using Blue Native gel electrophoresis and extracellular flux analyzer. Assessment of ROS production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Analyses for apoptosis and mitophagy were undertaken via flow cytometry, TUNEL and immunofluorescence assays. RESULTS: The transfer of human ND6 into the cybrids carrying the m.14484T > C mutation raised the levels of ND6, ND1 and ND4L but did not change the levels of other mitochondrial proteins. The overexpression of ND6 led to 20~23% increases in the assembly and activity of complex I, and ~ 53% and ~ 33% increases in the levels of mitochondrial ATP and ΔΨm in the mutant cybrids bearing m.14484T > C mutation. Furthermore, mutant cybrids with overexpression of ND6 exhibited marked reductions in the levels of mitochondrial ROS. Strikingly, ND6 overexpression markedly inhibited the apoptosis process and restored impaired mitophagy in the cells carrying m.14484T > C mutation. However, overexpression of ND6 did not affect the ND6 level and mitochondrial functions in the wild-type cybrids, indicating that this ND6 level appeared to be the maximum threshold level to maintain the normal cell function. CONCLUSION: We demonstrated that allotopic expression of nucleus-versions of ND6 restored complex I, apoptosis and mitophagy deficiencies caused by the m.14484T > C mutation. The restoration of m.14484T > C mutation-induced mitochondrial dysfunctions by overexpression of ND6 is a step toward therapeutic interventions for LHON and mitochondrial diseases.

Human health risks associated with metals in paddy plant (Oryza sativa) based on target hazard quotient and target cancer risk.

Paddy plants (Oryza sativa) contaminated with metals could be detrimental to human health if the concentrations of metals exceed the permissible limit. Thus, this study aims to assess the risk of the concentrations of As, Se, Cu, Cr, Co, and Ni and their distributions in various parts (roots, stems, leaves, and grains) of paddy plants collected from Sekinchan, Malaysia. Both soil and plant samples were digested according to the United States Environmental Protection Agency (USEPA) Method 3050B and the metal concentrations were determined by the Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). The highest mean translocation factor (TF) was from soil to roots (TF roots/soil ranged from 0.12 to 6.15) and the lowest was from leaves to grain (TF grain/leaves ranged from 0.06 to 0.87). Meanwhile, the bioaccumulation factor (BAF) for all metals was less than 1.0 indicating that paddy plants only absorb metals from the soil but do not accumulate in the grains. The average daily intake for As (1.15 ± 0.25 µg/kg/day) has exceeded the limit proposed by ATSDR and IRIS USEPA (0.30 µg/kg/day). Target cancer risk (TR) of 1.10 × 10-3 for As through rice consumption indicates that the potential cancer risk exists in one out of 1000 exposed individuals. The results from this study could serve as a reference for researchers and policymakers to monitor and formulate strategies in managing As and other metals in paddy plants, especially in Southeast Asian countries.

Deletion of Gtpbp3 in zebrafish revealed the hypertrophic cardiomyopathy manifested by aberrant mitochondrial tRNA metabolism.

GTPBP3 is a highly conserved tRNA modifying enzyme for the biosynthesis of τm5U at the wobble position of mitochondrial tRNAGlu, tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR). The previous investigations showed that GTPBP3 mutations were associated with hypertrophic cardiomyopathy (HCM). However, the pathophysiology of GTPBP3 deficiency remains elusively. Using the gtpbp3 knockout zebrafish generated by CRISPR/Cas9 system, we demonstrated the aberrant mitochondrial tRNA metabolism in gtpbp3 knock-out zebrafish. The deletion of gtpbp3 may alter functional folding of tRNA, indicated by conformation changes and sensitivity to S1-mediated digestion of tRNAGlu, tRNALys, tRNATrp and tRNALeu(UUR). Strikingly, gtpbp3 knock-out zebrafish displayed the global increases in the aminoacylated efficiencies of mitochondrial tRNAs. The aberrant mitochondrial tRNA metabolisms impaired mitochondrial translation, produced proteostasis stress and altered activities of respiratory chain complexes. These mitochondria dysfunctions caused the alterations in the embryonic heart development and reduced fractional shortening of ventricles in mutant zebrafish. Notably, the gtpbp3 knock-out zebrafish exhibited hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles. These cardiac defects in the gtpbp3 knock-out zebrafish recapitulated the clinical phenotypes in HCM patients carrying the GTPBP3 mutation(s). Our findings highlight the fundamental role of defective nucleotide modifications of tRNAs in mitochondrial biogenesis and their pathological consequences in hypertrophic cardiomyopathy.

A genome-wide survey of copy number variations reveals an asymmetric evolution of duplicated genes in rice.

BACKGROUND: Copy number variations (CNVs) are an important type of structural variations in the genome that usually affect gene expression levels by gene dosage effect. Understanding CNVs as part of genome evolution may provide insights into the genetic basis of important agricultural traits and contribute to the crop breeding in the future. While available methods to detect CNVs utilizing next-generation sequencing technology have helped shed light on prevalence and effects of CNVs, the complexity of crop genomes poses a major challenge and requires development of additional tools. RESULTS: Here, we generated genomic and transcriptomic data of 93 rice (Oryza sativa L.) accessions and developed a comprehensive pipeline to call CNVs in this large-scale dataset. We analyzed the correlation between CNVs and gene expression levels and found that approximately 13% of the identified genes showed a significant correlation between their expression levels and copy numbers. Further analysis showed that about 36% of duplicate pairs were involved in pseudogenetic events while only 5% of them showed functional differentiation. Moreover, the offspring copy mainly contributed to the expression levels and seemed more likely to become a pseudogene, whereas the parent copy tended to maintain the function of ancestral gene. CONCLUSION: We provide a high-accuracy CNV dataset that will contribute to functional genomics studies and molecular breeding in rice. We also showed that gene dosage effect of CNVs in rice is not exponential or linear. Our work demonstrates that the evolution of duplicated genes is asymmetric in both expression levels and gene fates, shedding a new insight into the evolution of duplicated genes.

Evaluation of Electric Field Integral Voltage Measurement Method of Transmission Line Based on Error Transmission and Uncertainty Analysis.

Electric field numerical integration algorithms can realize the non-contact measurement of transmission line voltage effectively. Although there are many electric field numerical integration algorithms, lack of a comprehensive comparison of accuracy and stability among various algorithms results in difficulties in evaluating the measurement results of various algorithms. Therefore, this paper presents the G-L (Gauss-Legendre) algorithm, the I-G-L (improved Gauss-Legendre) algorithm, and the I-G-C (improved Gauss-Chebyshev) algorithm and proposes a unified error propagation model of the derived algorithms to assess the accuracy of each integration method by considering multiple error sources. Moreover, evaluation criteria for the uncertainty of transmission line voltage measurement are proposed to analyze the stability and reliability of these algorithms. A simulation model and experiment platform were then constructed to conduct error propagation and uncertainty analyses. The results show that the G-L algorithm had the highest accuracy and stability in the scheme with five integral nodes, for which the simulation error was 0.603% and the relative uncertainty was 2.130%. The I-G-L algorithm was more applicable due to the smaller number of integral nodes required, yet the algorithm was less stable in achieving the same accuracy as the G-L algorithm. In addition, the I-G-C algorithm was relatively less accurate and stable in voltage measurement.

Screening weight related genes of velvet antlers by whole genome re-sequencing.

The velvet antler is a special organ that has important biological significance for deer, and its growth is a complicated biological metabolism process. Growing evidence suggests that genetics factors play essential roles in the weight of velvet antlers. In this study, we investigated five sika deer (Cervus nippon) populations under the same feeding condition, and screened genetic variations in the 100 samples (including 50 heavy and 50 light velvet antler weight samples) by whole genome re-sequencing. The results showed that 94 genetic variations were related to the velvet antler weight, among which two single nucleotide polymorphism (SNP) sites were located on the exon regions of OAS2 and ALYREF/THOC4, respectively. Furthermore, ALYREF/THOC4 is highly expressed in the velvet antler. The biological functions of these genetic variations were highly related to the growth and development of deer velvet antlers. Collectively, we screened genes related to the velvet antler weight in sika deer populations by whole genome re-sequencing and identified 94 sites as candidate genetic variations related to the velvet antler weight. We hope that it will contribute to further mechanistic studies of velvet antler development and weight variations.

MicroRNA-495 mimics delivery inhibits lung tumor progression.

MicroRNAs (miRNAs) can function as tumor suppressors and might provide an efficient strategy for annihilating cancer. Specific miRNAs can be reintroduced into tumor cells to elicit the tumor suppressor activities. We show that systemically delivered, synthetic miRNA mimics in complex with a novel neutral lipid emulsion are preferentially targeted to lung tumors and show therapeutic benefit in mouse models of lung cancer. The delivery was demonstrated using mimics of the tumor suppressor microRNA-495 which is found downregulated in most lung cancer. Systemic treatment of a Kras-activated autochthonous mouse model of non-small cell lung cancer (NSCLC) led to a significant decrease in tumor burden. Specifically, mice treated with microRNA-495 displayed a large reduction in tumor area compared to mice treated with a miRNA control. These findings provide direct evidence that systematically delivered synthetic miRNA mimics to the mammalian lung can inhibit tumor proliferation and support the promise of miRNAs as a targeted therapy for lung cancer in future.

[Project to Reduce the Incidence Rate of Nasogastric Tube Slippage in the Rehabilitation Ward].

BACKGROUND: Nasogastric (NG) tubes are used for providing nutrition to patients who have difficulties swallowing. However, the difficult process of repeatedly inserting NG tubes may lead to gastric erosions. PURPOSE: The rehabilitation ward in this study had an NG tube slippage rate of 2.26% in 2012, significantly higher than the same rate in 2011. A proposal was developed to design better techniques for nurses to perform NG tube insertions in order to decrease the rate of NG tube slippage. RESOLUTION: The following were identified as the major causes of NG tube slippage: (1) caretaker is unfamiliar with NG tube care instructions, (2) caretaker disengages NG tube constraints, and (3) improper rotation of patients or carelessness when turning patients. Therefore, the following solutions were proposed: (1) establish an NG tube safety standard operating procedure, (2) publish bilingual (English and Bahasa Indonesia) pamphlets providing instructions on the correct method of securing and placing the NG tubes, (3) make bilingual (English and Bahasa Indonesia) instructional videos showing the correct method for securing and placing the NG tubes, (4) fabricate a novel tube constraint tool (the constraint ball) that is easy to use, (5) install creative bedside NG tube warning signs, and (6) reinforce the importance of NG tube constraint and placement among caretakers. RESULTS: The NG tube slippage rate was reduced from 2.26% to 0.77%, and was maintained at 0.75% during the follow-up period. The caretaker assessment further showed 100% understanding of the implemented NG tube safety procedures. CONCLUSION: This proposal was established using literature research, problem identification, and creative problem solving to achieve an effective reduction in NG tube slippage as well as to enhance nursing quality.

Socioeconomic and gender group differences in early literacy skills: a multiple-group confirmatory factor analysis approach.

Socioeconomic status and gender are important demographic variables that strongly relate to academic achievement. This study examined the early literacy skills differences between 4 sociodemographic groups, namely, boys ineligible for free or reduced-price lunch (FRL), girls ineligible for FRL, boys eligible for FRL, and girls eligible for FRL. Data on kindergarteners (N = 462) were analysed using multiple-group confirmatory factory analysis. Early literacy skill differences between boys and girls are more nuanced than previously reported; subsidy status and gender interact. Both boys and girls from high-poverty households performed significantly lower than the girls from low-poverty households in alphabet knowledge, phonological awareness, and spelling. There were gender gaps, with a female advantage, among children from high-poverty households in alphabet knowledge and spelling and among children from low-poverty households in alphabet knowledge. These results highlight the importance of employing methodologically sound techniques to ascertain group differences in componential early literacy skills.

Electrochemical detection of leukemia oncogenes using enzyme-loaded carbon nanotube labels.

We describe an ultrasensitive electrochemical nucleic acid assay amplified by carbon nanotubes (CNTs)-based labels for the detection of human acute lymphocytic leukemia (ALL)-related p185 BCR-ABL fusion transcript. The carboxylated CNTs were functionalized with horseradish peroxidase (HRP) molecules and target-specific detection probes (DP) via diimide-activated amidation and used to label and amplify the target hybridization signal. The activity of captured HRP was monitored by square-wave voltammetry measuring the electroactive enzymatic product in the presence of 2-aminophenol and hydrogen peroxide substrate solution. The signal-amplified assay achieved a detection limit of 83 fM (5 × 10(-18) mol in 60 µL) targets oligonucleotides and has a 4-order-wide dynamic range of target concentration. The resulting assay allowed robust discrimination between the perfect match and a three-base mismatch sequence. When exposed to the full-length (491 bp) DNA oncogene, the approach demonstrated a detection limit of 1 × 10(-16) mol in 60 µL, corresponding to approximately 33 pg of the target gene. The high sensitivity and specificity of the assay enabled a PCR-free detection of target transcripts in as little as 65 ng of mRNA extracted from positive ALL cell lines SUP-B15 in comparison to those obtained from negative cell line HL-60. The approach enables a simple, low-cost and ultrasensitive electrochemical nucleic acid detection in portable devices, point-of-care and early disease diagnostic applications.

[A project to reduce the incidence of intubation care errors among foreign health aides].

BACKGROUND & PROBLEMS: Foreign health aides are the main providers of care for the elderly and the physically disabled in Taiwan. Correct care skills improve patient safety. In 2010, the incidence of mistakes among foreign health aides in our hospital unit was 58% for nasogastric tube care and 57% for tracheostomy tube care. A survey of foreign health aides and nurses in the unit identified the main causes of these mistakes as: communication difficulties, inaccurate instructions given to patients, and a lack of standard operating procedures given to the foreign health aides. PURPOSE: This project was designed to reduce the rates of improper nasogastric tube care and improper tracheostomy tube care to 20%, respectively. METHODS: This project implemented several appropriate measures. We produced patient instruction hand-outs in Bahasa Indonesia, established a dedicated file holder for Bahasa Indonesian tube care reference information, produced Bahasa Indonesian tube-care-related posters, produced a short film about tube care in Bahasa Indonesian, and established a standardized operating procedure for tube care in our unit. RESULTS: Between December 15th and 31st, 2011, we audited the performance of a total of 32 foreign health aides for proper execution of nasogastric tube care (21 aides) and of proper execution of tracheostomy tube care (11 aides). Patients with concurrent nasogastric and tracheostomy tubes were inspected separately for each care group. The incidence of improper care decreased from 58% to 18% nasogastric intubation and 57% to 18% for tracheostomy intubation. CONCLUSIONS: This project decreased significantly the incidence of improper tube care by the foreign health aides in our unit. Furthermore, the foreign health aides improved their tube nursing care skills. Therefore, this project improved the quality of patient care.

Primary pulmonary adenoid cystic carcinoma: A clinicopathological study of 64 patients.

BACKGROUND: This study aimed to investigate the clinicopathological features and prognostic indicators of primary pulmonary adenoid cystic carcinoma (PACC). METHODS: Clinical data were collected from 64 primary PACC patients and analyzed retrospectively at the Tianjin Medical University General Hospital, the West China Hospital of Sichuan University, the First Affiliated Hospital of Guangxi Medical University, and the Bishan Hospital of Chongqing Medical University from January 2003 to August 2023. The 64 patients (28 males and 36 females) were aged from 20 to 73 years, with a median age of 49 years and an average age of 49.3 years. RESULTS: Immunohistochemical staining showed that the tumors expressed CK7, S-100 protein, CK5/6, CD117, and p63. Seven patients underwent fluorescence in situ hybridization (FISH) testing and three were found to have myeloblastosis (MYB) gene translocation. In total, 53 patients underwent surgery, among whom 31 received only surgery and 22 received both surgery and postoperative chemoradiotherapy. In addition, 10 patients received chemoradiotherapy only, while one patient underwent treatment with traditional Chinese medicine. The overall survival rates in the first, third, and fifth years were 98.4%, 95.3%, and 87.5%, respectively. CONCLUSION: Prognostic analysis revealed that age, tumor size, lymph node metastasis status, margin status, and choice of treatment modality significantly influenced the patients' prognosis.

Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction.

BACKGROUND: Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2. AIM: To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism. METHODS: In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured. RESULTS: LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage. CONCLUSION: Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.

Low­dose venetoclax combined with azacitidine in older and frail patients with newly diagnosed acute myeloid leukaemia.

In the present study, the aim was to evaluate the clinical efficacy and safety of low-dose venetoclax combined with azacitidine for the treatment of older and frail patients with newly diagnosed acute myeloid leukaemia (AML). Data of 26 older patients with newly diagnosed AML admitted to Yuyao People's Hospital (Yuyao, China) between January 2021 and May 2023 were retrospectively analysed. The treatment regimens were as follows: Subcutaneous injection of 100 mg azacitidine on days 1-5 and 100 mg oral venetoclax on days 3-16 or 200 mg oral venetoclax on days 3-30. The median age of the 26 patients was 73 years. After the first course of treatment, the complete remission (CR) and CR with incomplete haematological recovery rate was 84.6%, and the objective response rate was 96.2%. The most common adverse events noted during treatment were haematological adverse events including grade 3/4 granulocytosis (57.7%), febrile neutropenia (30.8%), pulmonary infection (32.0%), thrombocytopenia (42.3%) and anaemia (42.3%). A total of 13 (50.0%) patients did not require platelet (PLT) infusion during treatment. The main non-haematological adverse reactions included gastrointestinal reactions such as nausea, vomiting and diarrhoea. Patients were followed up until December 2023, with a median follow-up time of 9.5 months (range, 1.9-26.0 months). Of the 26 patients, nine (34.6%) patients experienced relapse, with a mean recurrence time of 5.9 months. In conclusion, preliminary results indicated that low-dose venetoclax combined with azacitidine is effective and safe for the treatment of older and frail patients with newly diagnosed AML, providing a new treatment option for these patients.

Solitary extramedullary plasmacytoma of the left main bronchus: A case report and literature review.

Tracheal tumors are rare, accounting for 0.1% of all malignancies. Squamous cell carcinoma and adenoid cystic carcinoma are the two most prevalent tracheal cancers. Less than 20 cases of extramedullary plasmacytoma in the trachea and main bronchus have ever been documented in the literature, making it extremely uncommon. Although the origin of these lesions is unclear, viral pathogenesis and persistent inflammation are thought to be the main causes. Clinically, these individuals exhibit vague symptoms such as stridor, a persistent cough, dyspnea, or wheezing, making a correct diagnosis difficult.

Prognostic characteristics of T-cell mediated cell killing-related genes in lung adenocarcinoma.

Constituted by various heterogeneous cells, the tumor microenvironment (TME) is capable of promoting tumor proliferation, invasion, and metastasis through extensive crosstalk. The pivotal factor influencing the survival time of patients and their response to immunotherapy lies in the intratumoral immune environment. We obtained 112 differential genes related to T cell-mediated tumor killing in LUAD by employing bioinformatics analysis on the basis of the TCGA and TISIDB databases. Then the 6-gene prognostic risk score model (CA9, OIP5, TIMP1, SEC11C, FURIN, and TLR10) was constructed by conducting univariate LASSO as well as multivariate Cox regression analyses. The median risk score was taken as the threshold to classify the samples into two groups. Survival analysis revealed that the low-risk group exhibited a more favorable prognosis. Subsequently, the Cox regression analysis combined with clinical information (age, gender, and pathological stage) and the risk score of LUAD patients demonstrated the potential of this model as an independent prognostic factor. The nomogram established based on clinical information and a risk score in combination with the calibration curve indicated that this model had good predictive ability. Notable enrichment of the differential genes from the high- and low-risk groups was discovered in immune-associated processes or pathways, as shown by the GO and KEGG enrichment analyses. The combined use of single-sample gene enrichment analysis (ssGSEA) and immunophenoscore (IPS) demonstrated heightened immune infiltration and IPS scores in the low-risk group, indicating that immunotherapy was likely to show good efficacy in patients from this group. To sum up, the prognostic model of LUAD constructed based on T-cell-mediated cell killing-related genes was not only capable of screening the prognosis of LUAD patients but was also used for screening those LUAD patients with high sensitivity to immunotherapy. Our study offered novel insights into the clinical treatment and prognostic prediction of LUAD patients.

PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis: A druggable pathway of calycosin against triptolide cardiotoxicity.

Mitochondrion-related cardiotoxicity due to cardiotoxin stimuli is closely linked to abnormal activities of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), followed by co-inactivation of nuclear respiratory factor-1(NRF1). Pharmacological interventions targeting mitochondria may be effective for developing agents against cardiotoxicity. Herein, in triptolide-treated H9C2 cardiomyocytes, we observed defective mitochondrial biogenesis and respiration, characterized by depletion of mitochondrial mass and mitochondrial DNA copy number, downregulation of mitochondrial respiratory chain complexes subunits, and disorders of mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Dysregulation of mitochondria led to cardiac pathological features, such as myocardial fiber fracture, intercellular space enlargement, and elevation of serum aspartate aminotransferase, creatine kinase isoenzyme, lactate dehydrogenase, and cardiac troponin I. However, following calycosin treatment, an active compound from Astragali Radix, the mitochondrion-related disorders at both cell and tissue levels were significantly ameliorated, which was facilitated by the activation of PGC-1α via deacetylation, followed by NRF1 co-activation. Calycosin-enhanced PGC-1α deacetylation is impelled by increasing sirtuin-1 expression and NAD+/NADH ratio. PGC-1α/NRF1 signaling in calycosin-mediated mitochondrial biogenesis protection was further confirmed by NRF1 knockdown and PGC-1α inhibition with SR18292. We conclude that calycosin ameliorated triptolide-induced cardiotoxicity by protecting PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis and respiration, which is the druggable pathway for cardiotoxicity mitigation.