Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Trichoscopy for early diagnosis and follow-up of pet-related neonatal tinea capitis.

We report infant zigzag hairs as a distinct trichoscopic sign for follow up a case of pet-related newborn tinea capitis due to Microsporum canis. Formation of infant zigzag hairs due to ectothrix M. canis infection may be associated soft neonatal widespread thin hair, which is different from vellus hair and terminal hair. In addition, tinea capitis was further confirmed by transmission electric microscopy and fungal culture. The patient was successfully treated by weekly oral fluconazole (8 mg/kg). Therefore, the handheld dermoscopy is a simple, non-invasive and very inexpensive technique for the diagnosis and follow-up of tinea capitis, especially for infant.

Bedside Diagnosis for Disseminated Deep Dermatophytosis: a Case Series Study.

Deep cutaneous fungal infections including deep dermatophytosis are responsible for significant morbidity and mortality, especially in immunocompromised patients. Variable and longer turnaround time on tissue culture results delay diagnosis. We sought to seek the fast bedside diagnosis for disseminated deep dermatophytosis by direct microscopy using a blunt scalpel or needle aspiration before biopsy. This is a 6-year retrospective review of patients with a diagnosis of disseminated deep dermatophytosis seen at a single tertiary care institution. Trichophyton rubrum was isolated in four patients, and T. mentagrophyte complex in one patient. All the dermatophyte isolates can grow at 37 °C. Microscopy of purulence sampling from intact nodules demonstrated abundant septate hyphae, and also isolation from purulence was concordance with skin tissue culture. Ultrasound-guided sampling from non-eroded can yield purulence, and direct microscopy of purulence may facilitate rapid diagnosis of deep dermatophytosis and serve to prevent disease progression and dissemination.

Favus of Scrotum Due to Trichophyton rubrum in Immunocompetent Patients: A Clinical, Mycological and Ultrastructural Study.

PURPOSE: To characterize the clinical and mycological features of favus of scrotum due to Trichophyton rubrum. METHODS: A single-site prospective study was carried out in an outpatient dermatology clinic. Microscopic examination and fungal culture were done using skin scrapings. Scales on the scrotum were stained with PAS and visualized by microscopy, including in vivo reflectance confocal microscopy (RCM). Two strains were analyzed by RAPD typing. Scutular lesions were fixed for scanning electron microscopy (SEM) and transmission electron microscopy (TEM). RESULTS: Cultures of the scale from the scrotum and/or groin in all patients showed a growth of T. rubrum. T. rubrum strains from scrotum and groins in one patient were demonstrated as the same strain by RAPD typing. The average age of patients was 34.1 ± 12.78 years. The mean course was 8.2 ± 5.07 days. All the patients received only topical treatment for 2 weeks without recurrence. Direct smear, calcofluor-white staining and in vivo RCM study of the scrotal favus in patients showed a massive number of septate branching hyphae, while fewer septate hyphae in scales in the groin. Abundant hyphae were found only in the outer layer of the stratum corneum of the scrotum under SEM and TEM with intact bilateral cell walls, and normal nucleus, liposomes and reticulum. Few distorted hyphae structures, cell wall degeneration, degenerated cytoplasm and the autophagy phenomenon could be seen in scales from groin under TEM. CONCLUSIONS: Scrotal favus due to T. rubrum is still a true infection, which most often occurred in immunocompetent patients.

Effects of PKM2 on global metabolic changes and prognosis in hepatocellular carcinoma: from gene expression to drug discovery.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor that threatens global human health. High PKM2 expression is widely reported in multiple cancers, especially in HCC. This study aimed to explore the effects of PKM2 on global gene expression, metabolic damages, patient prognosis, and multiple transcriptional regulation relationships, as well as to identify several key metabolic genes and screen some small-molecule drugs. METHODS: Transcriptome and clinical HCC data were downloaded from the NIH-GDC repository. Information regarding the metabolic genes and subsystems was collected from the Recon 2 human metabolic model. Drug-protein interaction data were obtained from the DrugBank and UniProt databases. We defined patients with PKM2 expression levels ≥11.25 as the high-PKM2 group, and those with low PKM2 expression (< 11.25) were defined as the low-PKM2 group. RESULTS: The results showed that the global metabolic gene expression levels were obviously divided into the high- or low-PKM2 groups. In addition, a greater number of affected metabolic subsystems were observed in the high-PKM2 group. Furthermore, we identified 98 PKM2-correlated deregulated metabolic genes that were associated with poor overall patient survival. Together, these findings suggest more comprehensive influences of PKM2 on HCC. In addition, we screened several small-molecule drugs that target these metabolic enzymes, some of which have been used in antitumor clinical studies. CONCLUSIONS: HCC patients with high PKM2 expression showed more severe metabolic damage, transcriptional regulation imbalance and poor prognosis than low-PKM2 individuals. We believe that our study provides valuable information for pathology research and drug development for HCC.

Folate Deficiency and Gene Polymorphisms of MTHFR, MTR and MTRR Elevate the Hyperhomocysteinemia Risk.

BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVDs). We aimed to investigate the joint effect of homocysteine metabolism gene polymorphisms, as well as the folate deficiency on the risk of HHcy in a Chinese hypertensive population. METHODS: This study enrolled 480 hypertensive patients aged 28 - 75 from six hospitals in different Chinese regions from 9/2005 - 12/2005. Known genotypes of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G were detected by PCRRFLP methods. Serum Hcy was measured by high-performance liquid chromatography and serum folate was measured by chemiluminescent immunoassay. RESULTS: MTHFR C677T and MTR A2756G can independently elevate the risk of HHcy (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA, p = 0.026, respectively), whereas MTHFR A1298C decreased HHcy risk (AC + CC vs. AA, p < 0.001) and showed a protective effect against HHcy risk. Importantly, the joint effect of these risk genotypes showed significantly higher odds of HHcy than non-risk genotypes, especially the patients with four risk genotypes. It is noteworthy that this deleterious effect was aggravated by folate deficiency. These findings were verified by generalized multifactor dimensionality reduction model (p = 0.001) and a cumulative effects model (p < 0.001). CONCLUSIONS: We have first demonstrated that the joint effect of homocysteine metabolism gene polymorphisms and folate deficiency lead to dramatic elevations in the HHcy risk.

Joint associations of folate, homocysteine and MTHFR, MTR and MTRR gene polymorphisms with dyslipidemia in a Chinese hypertensive population: a cross-sectional study.

BACKGROUND: Dyslipidemia is a well-established risk factor for cardiovascular disease. Serum lipids were affected by several gene polymorphisms, folate, homocysteine and other metabolite levels. We aim to investigate the effects of homocysteine metabolism enzyme polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) and their interactions with folate, homocysteine on serum lipid levels in Chinese patients with hypertension. METHODS: Participants were 480 hypertensive adults that enrolled in September to December 2005 from six different Chinese hospitals (Harbin, Shanghai, Shenyang, Beijing, Xi'an, and Nanjing). Known MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genotypes were determined by PCR-RFLP methods. Serum folate was measured by chemiluminescent immunoassay, homocysteine was measured by high-performance liquid chromatography, serum lipids parameters were determined by an automatic biochemistry analyzer, low-density lipoprotein was calculated by Friedewald's equation. Unitary linear regression model was used to assess the associations of gene polymorphisms, folate and homocysteine on serum lipid profiles. Unconditional logistic regression model was applied to test the interactions of folate, homocysteine and gene polymorphisms on dyslipidemia. RESULTS: No correlations between gene polymorphisms and homocysteine on serum lipid profiles. Compared with normal folate patients, patients with low folate showed higher odds of hypertriglyceridemia (OR = 2.02, 95 % CI: 1.25-3.25, P = 0.004) and low levels of high-density lipoprotein cholesterol (OR = 1.88, 95 % CI: 1.07-3.28, P = 0.027). Each of four gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) combined with low folate showed higher odds of hypertriglyceridemia (P for trend: 0.049, 0.004, 0.007 and 0.005, respectively). MTHFR C677T and A1298C with low folate showed higher odds of low levels of high-density lipoprotein cholesterol (P for trend: 0.008 and 0.031). CONCLUSIONS: Low folate status and homocysteine metabolism gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) may have a synergistic effect increased the incidence of dyslipidemia in Chinese hypertensive population.

Depletion of histone deacetylase 3 antagonizes PI3K-mediated overgrowth of Drosophila organs through the acetylation of histone H4 at lysine 16.

Core histone modifications play an important role in chromatin remodeling and transcriptional regulation. Histone acetylation is one of the best-studied gene modifications and has been shown to be involved in numerous important biological processes. Herein, we demonstrated that the depletion of histone deacetylase 3 (Hdac3) in Drosophila melanogaster resulted in a reduction in body size. Further genetic studies showed that Hdac3 counteracted the organ overgrowth induced by overexpression of insulin receptor (InR), phosphoinositide 3-kinase (PI3K) or S6 kinase (S6K), and the growth regulation by Hdac3 was mediated through the deacetylation of histone H4 at lysine 16 (H4K16). Consistently, the alterations of H4K16 acetylation (H4K16ac) induced by the overexpression or depletion of males-absent-on-the-first (MOF), a histone acetyltransferase that specifically targets H4K16, resulted in changes in body size. Furthermore, we found that H4K16ac was modulated by PI3K signaling cascades. The activation of the PI3K pathway caused a reduction in H4K16ac, whereas the inactivation of the PI3K pathway resulted in an increase in H4K16ac. The increase in H4K16ac by the depletion of Hdac3 counteracted the PI3K-induced tissue overgrowth and PI3K-mediated alterations in the transcription profile. Overall, our studies indicated that Hdac3 served as an important regulator of the PI3K pathway and revealed a novel link between histone acetylation and growth control.

Isoindolone derivative QSN-10c induces leukemic cell apoptosis and suppresses angiogenesis via PI3K/AKT signaling pathway inhibition.

AIM: 2-(4,6-Dimethoxy-1,3-dioxoisoindolin-2-yl) ethyl 2-chloroacetate (QSN-10c) is one of isoindolone derivatives with antiproliferative activity against human umbilical vein endothelial cells (HUVECs). The aim of this study was to investigate its antitumor activity in vitro and anti-angiogenic effects in vitro and in vivo. METHODS: K562 leukemic cells and HUVECs were used for in vitro studies. Cell viability was examined using MTT assay. Cell apoptosis and mitochondrial transmembrane potential (Δψm) were detected with flow cytometry. Tube formation and migration of HUVECs were studied using two-dimensional Matrigel assay and wound-healing migration assay, respectively. VEGF levels were analyzed with RT-PCR and Western blotting. A zebrafish embryo model was used for in vivo anti-angiogenic studies. The molecular mechanisms for apoptosis in K562 cells and antiangiogenesis were measured with Western blotting. RESULTS: In antitumor activity studies, QSN-10c suppressed the viability of K562 cells and induced apoptosis in dose- and time-dependent manners. Furthermore, QSN-10c dose-dependently decreased the Δψm in K562 cells, increased the release of cytochrome c and the level of Bax, and decreased the level of Bcl-2, suggesting that QSN-10c-induced apoptosis of K562 cells was mediated via the mitochondrial apoptotic pathway. In anti-angiogenic activity studies, QSN-10c suppressed the viability of HUVECs and induced apoptosis in dose dependent manners. QSN-10c treatment did not alter the Δψm in HUVECs, but dose-dependently inhibited the expression of VEGF, inhibited the tube formation and cell migration in vitro, and significantly suppressed the number of ISVs in zebrafish embryos in vivo. Furthermore, QSN-10c dose-dependently suppressed the phosphorylation of AKT and GSK3ß in both HUVECs and K562 cells. CONCLUSION: QSN-10c is a novel antitumor compound that exerts both antitumor and anti-angiogenic effects via inhibiting the PI3K/AKT/GSK3ß signaling pathway.

Four new koumine metabolites in rat liver microsomes.

Four new metabolites M-1 [1,2,18,19-tetradehydro-4-demethyl-3,17-epoxy-7,20(2H,19H)-cyclovobasan], M-2 [1,2,4,21,18,19-hexadehydro-4-demethyl-3,17-epoxy-7,20(2H,19H)-cyclovobasan], M-3 [1,2,18,19-tetradehydro-4-demethyl-4-formaldehyde-3,17-epoxy-7,20(2H,19H)-cyclovobasan], and M-4 [1,2,4,21,18,19-hexadehydro-4-demethyl-4-oxy-3,17-epoxy-7,20(2H,19H)-cyclovobasan] were isolated from the chloroform extract of koumine incubated with phenobarbital-treated rat liver microsomes. The structures of M-1, M-2, M-3, and M-4 were elucidated by spectroscopic methods including ESI-TOF-MS, 1D, and 2D NMR experiments. The metabolic pathway of koumine was proposed. The cytotoxic activities between koumine and its metabolites were also compared in the A549 cell line.

Assessing the association between the circulating levels of inflammatory cytokines and the risk of tuberculosis: A bidirectional two-sample mendelian randomization study.

BACKGROUND: Numerous observational studies have previously reported an association between inflammatory cytokines and tuberculosis (TB). However, the causal relationship between these factors remains unclear. Consequently, we conducted two-sample Mendelian randomization (MR) analyses to ascertain the causal link between levels of inflammatory cytokines and the risk of TB. METHODS: Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene. SNP was obtained from genome-wide association studies (GWAS) of 8293 individuals of Finnish. TB data was obtained from the UK Biobank, which included 46,293 individuals of European ancestry (comprising 2277 TB cases and 46,056 controls). Two-sample, bi-directional MR analyses using inverse-variance weighted (IVW) method as the primary analysis. Followed by comprehensive sensitivity analyses to validate the robustness of results. RESULT: The study showed that the causal relationship between circulating levels of interleukin (IL)-7 and risk of TB (odds ratio [OR] = 1.001, 95% confidence intervals [CIs]: 1.000, 1.003. p = 0.047). No causal associations were observed between other influencing factors and the occurrence of TB. Furthermore, the analysis revealed that TB infection exhibited negative causal associations with macrophage inflammatory protein 1 alpha ([MIP-1α], OR = 0.007, 95% CI: 0.000, 0.192. p = 0.004), IL-2 (OR = 0.014, 95% CI: 0.010, 0.427. p = 0.014), interleukin-2 receptor alpha chain([IL-2rα], OR = 0.019, 95% CI: 0.001, 0.525. p = 0.019) and basic fibroblast growth factor ([bFGF], OR = 0.066, 95% CI: 0.006, 0.700. p = 0.024). CONCLUSION: The study has illuminated the causal link between inflammatory cytokines and TB, thereby enhancing our comprehension of the potential mechanisms underlying TB pathogenesis. This discovery offers promising avenues for the identification of novel therapeutic targets in TB treatment. These insights may ultimately pave the way for more effective treatment approaches, thereby improving patient outcomes.

Impact factors of Blastocystis hominis infection in persons living with human immunodeficiency virus: a large-scale, multi-center observational study from China.

BACKGROUND: Blastocystis hominis (Bh) is zoonotic parasitic pathogen with a high prevalent globally, causing opportunistic infections and diarrhea disease. Human immunodeficiency virus (HIV) infection disrupts the immune system by depleting CD4+ T lymphocyte (CD4+ T) cell counts, thereby increasing Bh infection risk among persons living with HIV (PLWH). However, the precise association between Bh infection risk and HIV-related biological markers and treatment processes remains poorly understood. Hence, the purpose of the study was to explore the association between Bh infection risk and CD4+ T cell counts, HIV viral load (VL), and duration of interruption in antiviral therapy among PLWH. METHODS: A large-scale multi-center cross-sectional study was conducted in China from June 2020 to December 2022. The genetic presence of Bh in fecal samples was detected by real-time fluorescence quantitative polymerase chain reaction, the CD4+ T cell counts in venous blood was measured using flowcytometry, and the HIV VL in serum was quantified using fluorescence-based instruments. Restricted cubic spline (RCS) was applied to assess the non-linear association between Bh infection risk and CD4+ T cell counts, HIV VL, and duration of interruption in highly active antiretroviral therapy (HARRT). RESULTS: A total of 1245 PLWH were enrolled in the study, the average age of PLWH was 43 years [interquartile range (IQR): 33, 52], with 452 (36.3%) being female, 50.4% (n = 628) had no immunosuppression (CD4+ T cell counts > 500 cells/µl), and 78.1% (n = 972) achieved full virological suppression (HIV VL < 50 copies/ml). Approximately 10.5% (n = 131) of PLWH had interruption. The prevalence of Bh was found to be 4.9% [95% confidence interval (CI): 3.8-6.4%] among PLWH. Significant nonlinear associations were observed between the Bh infection risk and CD4+ T cell counts (Pfor nonlinearity < 0.001, L-shaped), HIV VL (Pfor nonlinearity < 0.001, inverted U-shaped), and duration of interruption in HARRT (Pfor nonlinearity < 0.001, inverted U-shaped). CONCLUSIONS: The study revealed that VL was a better predictor of Bh infection than CD4+ T cell counts. It is crucial to consider the simultaneous surveillance of HIV VL and CD4+ T cell counts in PLWH in the regions with high level of socioeconomic development. The integrated approach can offer more comprehensive and accurate understanding in the aspects of Bh infection and other opportunistic infections, the efficacy of therapeutic drugs, and the assessment of preventive and control strategies.

E2 ligase dRad6 regulates DMP53 turnover in Drosophila.

The turnover of tumor suppressor p53 is critical for its role in various cellular events. However, the pathway that regulates the turnover of the Drosophila melanogaster DMP53 is largely unknown. Here, we provide evidence for the first time that the E2 ligase, Drosophila homolog of Rad6 (dRad6/Dhr6), plays an important role in the regulation of DMP53 turnover. Depletion of dRad6 results in DMP53 accumulation, whereas overexpression of dRad6 causes enhanced DMP53 degradation. We show that dRad6 specifically interacts with DMP53 at the transcriptional activation domain and regulates DMP53 ubiquitination. Loss of dRad6 function in transgenic flies leads to lethalities and altered morphogenesis. The dRad6-induced defects in cell proliferation and apoptosis are found to be DMP53-dependent. The loss of dRad6 induces an accumulation of DMP53 that enhances the activation of apoptotic genes and leads to apoptosis in the presence of stress stimuli. In contrast to that, the E3 ligase is the primary factor that regulates p53 turnover in mammals, and this work demonstrates that the E2 ligase dRad6 is critical for the control of DMP53 degradation in Drosophila.

Antibacterial, antifungal and cytotoxic isoquinoline alkaloids from Litsea cubeba.

Five novel isoquinoline alkaloids (+)-N-(methoxylcarbonyl)-N-nordicentrin (1), (+)-N-(methoxylcarbonyl)-N-norpredicentrine (2), (+)-N-(methoxylcarbonyl)-N-norbulbodione (3), and (+)-N-(methoxylcarbonyl)-N-norisocorydione (4), and (+)-8-methoxyisolaurenine-N- oxide (5) were isolated, together with one known compound, (+)-N-(methoxylcarbonyl)- N-norglaucine (6), from a 70% EtOH extract of the barks of Litsea cubeba. Structural elucidation of all the compounds were performed by spectral methods such as 1D- and 2D-NMR, IR, UV, and HRESIMS. Alkaloids 1, 2 and 6 showed antimicrobial activity against the bacterium S. aureus and two fungi (A. alternata and C. nicotianae). Compounds 3,4 exhibited significant cytotoxicity against all of six tested tumor cell lines.

Violet colonies of Talaromyces marneffei produce on CHROMagar candida medium.

In the present report, we describe an unusual case of mixed infection of Candida albicans and Talaromyces marneffei in the oral cavity and oropharynx with cutaneous involvement. On the CHROMagar Candida plate, green colonies (identified as C. albicans) and tiny violet colonies (identified as T. marneffei) grew from the throat swab after incubation for 96 hours. 10 clinical isolates of T. marneffei were used to verify their color production on CHROMagar Candida. All colonies were violet on the fourth, seventh and ninth day incubated at 37 °C. T. marneffei appears violet on the CHROMagar Candida plate, but it may be easily ignored because of its slow growth and small colony size, especially after incubation for 48 hours. Therefore, when using CHROMagar Candida plate to detect specimens in AIDS patients, special attention must be paid to detect non-yeasts such as T. marneffei for up to 96 hours.

Neuroprotective Effects of Lindleyin on Hydrogen Peroxide-Induced Cell Injury and MPTP-Induced Parkinson's Disease in C57BL/6 Mice.

Oxidative stress (OS) is a crucial factor influencing the development of Parkinson's disease (PD). Here we first reported that Lindleyin (Lin), one of the major components of rhubarb, possessed neuroprotective effects against H2O2-induced SH-SY5Y cell injury and MPTP-induced PD of C57BL/6 mice. The results showed that Lin can decrease cell death and apoptotic rate induced by H2O2 through inhibiting mitochondrial apoptotic pathway and increasing the activities of SOD, GSH-Px, and CAT as well as decreasing the level of MDA. In addition, in vivo studies showed that oral administration of Lin (5 or 20 mg/kg) showed significant change in motor function deficits, antioxidant enzyme activities, apoptotic pathway, and tyrosine hydroxylase expression. Our results reveal that Lin might be a promising anti-PD agent by reducing OS and apoptosis.

Safety of combining vascular endothelial growth factor receptor tyrosine-kinase inhibitors with chemotherapy in patients with advanced non-small-cell lung cancer: A PRISMA-compliant meta-analysis.

BACKGROUND: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) have been developed for targeted therapies in non-small-cell lung cancer (NSCLC); moreover, some drug-related toxic reactions among cancer patients have been reported. A meta-analysis of randomized controlled trials (RCTs) to definite the incidence and the risk of grade ≥3 adverse events (AEs), serious and fatal AEs (SAEs and FAEs), with VEGFR-TKIs in advanced/metastatic NSCLC patients was performed. METHODS: A comprehensive literature search was conducted for the clinical trials published up to December 2017. Qualified studies allotted patients with advanced/metastatic NSCLC to receive either chemotherapy alone or in combination with VEGFR-TKIs. Data were extracted by 2 authors. RESULTS: Eighteen RCTs of VEGFR-TKIs plus chemotherapy, involving 8461 advanced NSCLC patients were included. The proportion of patients with grade ≥3 AEs was increased with the addition of VEGFR-TKIs (relative risk, 1.35; 95% confidence interval [CI] 1.19-1.52; incidence, 68.1% vs 50.1%; P < .001). The most common grade ≥3 AEs was neutropenia (24.9% vs 15.4%, P < .001). Addition of VEGFR-TKIs was also related to the increased risk of SAEs (relative risk, 1.34; 95% CI 1.14-1.56; incidence, 37.8% vs 27.9%; P < .001) and FAEs (relative risk, 2.16, 95% CI 1.47-3.19; incidence, 3.4% vs 1.8%). Subgroup analysis suggested there was no difference in the rates of SAEs and FAEs in the second-line settings. No evidence of bias was found between the literatures. The study was registered with PROSPERO (CRD42018099654). CONCLUSIONS: In comparison with chemotherapy alone, the addition of VEGFR-TKIs in advanced NSCLC patients was related to the increased risk of grades ≥3 AEs, SAEs, and FAEs, especially in the first-line settings. Physicians should be aware of some specific grade ≥3 adverse effect, especially haematologic adverse events, and it is also necessary to monitor cancer patients receiving VEGFR-TKIs.

High PKM2 expression is independently correlated with decreased overall survival in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal and malignant types of cancer that affects global human health. The present study aimed to investigate the effect of pyruvate kinase muscle isozyme M2 (PKM2) expression on the clinical features and prognosis of HCC. The present study employed univariate logistic regression to investigate the correlation between PKM2 expression and clinical features. Univariate and multivariate Cox regression analyses were performed to estimate the independent effect of PKM2 expression on survival status. The results revealed that patients in the high PKM2 group (≥11.25) exhibited significantly lower creatinine levels (P=0.043), higher fetoprotein levels (P<0.001), advanced stage (P<0.001) and higher grade (P=0.004) compared with patients with low PKM2 expression levels (<11.25). In addition, patients with high PKM2 expression exhibited poor prognosis compared with patients with low PKM2 expression. After correcting the covariates, PKM2 expression remains significantly associated with reduced overall survival (P<0.05). These findings suggested that PKM2 is an independent risk factor for HCC and provides valuable information for future studies on the pathogenesis of HCC and drug discovery.

Comprehensive integrated analysis of gene expression datasets identifies key anti-cancer targets in different stages of breast cancer.

Breast cancer is one of the primary threats to women's health worldwide. However, the molecular mechanisms underlying the development of breast cancer remain to be fully elucidated. The present study aimed to investigate specific target gene expression profiles in breast cancer tissues in general and in different breast cancer stages, as well as to explore their functions in tumor development. For integrated analysis, a total of 5 gene expression profiling datasets for 3 different stages of breast cancer (stages I-III) were downloaded from the Gene Expression Omnibus of the National Center for Biotechnology Information. Pre-processing of these datasets was performed using the Robust Multi-array Average algorithm and global renormalization was performed for all studies. Differentially expressed genes between breast cancer patients and controls were estimated using the empirical Bayes algorithm. The Database for Annotation, Visualization and Integrated Discovery web server was used for analyzing the enrichment of the differentially expressed genes in Gene Ontology terms of the category biological process and in Kyoto Encyclopedia of Genes and Genomes pathways. Furthermore, breast cancer target genes were downloaded from the Thomson Reuters Integrity Database. We merged these target genes with the genes in breast cancer datasets. Analysis of anti-breast cancer gene networks was performed using the Genome-scale Integrated Analysis of Gene Networks in Tissues web server. The results demonstrated that the normal functions of the cell cycle, cell migration and cell adhesion were altered in all stages of breast cancer. Furthermore, 12 anti-breast cancer genes were identified to be dysregulated in at least one of the three stages. Among all of these genes, ribonucleotide reductase regulatory subunit M2 (RRM2) exhibited the highest degree of interaction with other interacting genes. Analysis of the network interactions revealed that the transcription factor of RRM2 is crucial for cancer development. Other genes, including mucin 1, progesterone receptor and cyclin-dependent kinase 5 regulatory subunit associated protein 3, also exhibited a high degree of interaction with the associated genes. In conclusion, several key anti-breast cancer genes identified in the present study are mainly associated with the regulation of the cell cycle, cell migration, cell adhesion and other cancer-associated cell functions, particularly RRM2.