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Background: Intermediate cells are present in the early stages of human prostate development and adenocarcinoma. While primary cells isolated from benign human prostate tissues or tumors exhibit an intermediate phenotype in vitro, they cannot form tumors in vivo unless genetically modified. It is unclear about the stem cell properties and tumorigenicity of intermediate cells. Methods: We developed a customized medium to culture primary human intermediate prostate cells, which were transplanted into male immunodeficient NCG mice to examine tumorigenicity in vivo. We treated the cells with different concentrations of dihydrotestosterone (DHT) and enzalutamide in vitro and surgically castrated the mice after cell transplantation in vivo. Immunostaining, qRT-PCR, RNA sequencing, and western blotting were performed to characterize the cells in tissues and 2D and 3D cultures. Results: We found intermediate cells expressing AR+PSA+CK8+CK5+ in the luminal compartment of human prostate adenocarcinoma by immunostaining. We cultured the primary intermediate cells in vitro, which expressed luminal (AR+PSA+CK8+CK18+), basal (CK5+P63+), intermediate (IVL+), and stem cell (CK4+CK13+PSCA+SOX2+) markers. These cells resisted castration in vitro by upregulating the expression of AR, PSA, and proliferation markers KI67 and PCNA. The intermediate cells had high tumorigenicity in vivo, forming tumors in immunodeficient NCG mice in a month without any genetic modification or co-transplantation with embryonic urogenital sinus mesenchyme (UGSM) cells. We named these cells human castration-resistant intermediate prostate cancer stem cells or CriPCSCs and defined the xenograft model as patient primary cell-derived xenograft (PrDX). Human CriPCSCs resisted castration in vitro and in vivo by upregulating AR expression. Furthermore, human CriPCSCs differentiated into amplifying adenocarcinoma cells of luminal phenotype in PrDX tumors in vivo, which can dedifferentiate into CriPCSCs in vitro. Conclusions: Our study identified and established methods for culturing human CriPCSCs, which had high tumorigenicity in vivo without any genetic modification or UGSM co-transplantation. Human CriPCSCs differentiated into amplifying adenocarcinoma cells of luminal phenotype in the fast-growing tumors in vivo, which hold the potential to dedifferentiate into intermediate stem cells. These cells resisted castration by upregulating AR expression. The human CriPCSC and PrDX methods hold significant potential for advancing prostate cancer research and precision medicine. [ABSTRACT FROM AUTHOR]

Introduction: Fibrosing mediastinitis (FM) is a rare disease characterized by excessive proliferation of fibrous tissue in the mediastinum and can cause bronchial stenosis, superior vena cava obstruction, pulmonary artery and vein stenosis, etc. Case presentation: An aging patient with intermittent chest tightness and shortness of breath was diagnosed with FM associated pulmonary hypertension (FM-PH) by echocardiography and enhanced CT of the chest, and CT pulmonary artery (PA)/ pulmonary vein (PV) imaging revealed PA and PV stenosis. Selective angiography revealed complete occlusion of the right upper PV, and we performed endovascular intervention of the total occluded PV. After failure of the antegrade approach, the angiogram revealed well-developed collaterals of the occluded RSPV-V2b, so we chose to proceed via the retrograde approach. We successfully opened the occluded right upper PV and implanted a stent. Conclusions: This report may provide new management ideas for the interventional treatment of PV occlusion. [ABSTRACT FROM AUTHOR]

Purpose: Rectal tumor segmentation on post neoadjuvant chemoradiotherapy (nCRT) magnetic resonance imaging (MRI) has great significance for tumor measurement, radiomics analysis, treatment planning, and operative strategy. In this study, we developed and evaluated segmentation potential exclusively on post-chemoradiation T2-weighted MRI using convolutional neural networks, with the aim of reducing the detection workload for radiologists and clinicians. Methods: A total of 372 consecutive patients with LARC were retrospectively enrolled from October 2015 to December 2017. The standard-of-care neoadjuvant process included 22-fraction intensity-modulated radiation therapy and oral capecitabine. Further, 243 patients (3061 slices) were grouped into training and validation datasets with a random 80:20 split, and 41 patients (408 slices) were used as the test dataset. A symmetric eight-layer deep network was developed using the nnU-Net Framework, which outputs the segmentation result with the same size. The trained deep learning (DL) network was examined using fivefold cross-validation and tumor lesions with different TRGs. Results: At the stage of testing, the Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95), and mean surface distance (MSD) were applied to quantitatively evaluate the performance of generalization. Considering the test dataset (41 patients, 408 slices), the average DSC, HD95, and MSD were 0.700 (95% CI: 0.680–0.720), 17.73 mm (95% CI: 16.08–19.39), and 3.11 mm (95% CI: 2.67–3.56), respectively. Eighty-two percent of the MSD values were less than 5 mm, and fifty-five percent were less than 2 mm (median 1.62 mm, minimum 0.07 mm). Conclusions: The experimental results indicated that the constructed pipeline could achieve relatively high accuracy. Future work will focus on assessing the performances with multicentre external validation. [ABSTRACT FROM AUTHOR]

Plants have evolved a multilayered and sophisticated immune system to establish effective resistance to a variety of pathogens. Phytophthora species are among the most notorious plant pathogens, causing destructive diseases on a variety of agricultural crops. Understanding the plant immune system is crucial for protecting crops from Phytophthora diseases. Here, we summarize the recent work on genes involved in plant resistance against Phytophthora pathogens, including cell surface pattern recognition receptors, cytoplasmic nucleotide-binding leucine-rich repeat receptors, regulator genes, and non-host resistance genes, small RNA, and long non-coding RNA are also discussed in this review. Although the molecular mechanisms of only a small proportion of them have been clarified, emergence of new mechanisms of plant defense will offer exciting opportunities for utilization of these genes in disease resistance breeding as well as generation of disease-resistant crop germplasms. [ABSTRACT FROM AUTHOR]

Background: Balanced translocations may cause the loss of genetic material at the breakpoints and may result in failure of spermatogenesis. However, carriers of reciprocal translocation may naturally conceive. Genetic counseling of male carriers of translocations remains challenging. This study explores the clinical features of carriers of chromosome 5 translocations, enabling informed genetic counseling of these patients. Results: Of 82 translocation carriers, 9 (11%) were carriers of a chromosome 5 translocation. One case had azoospermia, while three cases had experienced recurrent spontaneous abortions, two cases had each experienced stillbirth, and three cases produced a phenotypically normal child confirmed by amniocentesis. A literature review identified 106 patients who carried chromosome 5 translocations. The most common chromosome 5 translocation was t(4,5), observed in 13 patients. Breakpoint at 5p15 was observed in 11 patients. All breakpoints at chromosome 5 were associated with gestational infertility. Conclusion: In genetic counseling, physicians should consider chromosome 5 and its breakpoints. Carriers of chromosome 5 translocations may continue with natural conception or use assisted reproductive technologies, such as preimplantation genetic diagnosis. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide. Patients with chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), are exposed to a higher risk of developing lung cancer. Chronic inflammation may play an important role in the lung carcinogenesis among those patients. The present study aimed at identifying candidate biomarker predicting lung cancer risk among patients with chronic respiratory diseases.Methods: We applied clinical bioinformatics tools to analyze different gene profile datasets with a special focus on screening the potential biomarker during chronic inflammation-lung cancer transition. Then we adopted an in vitro model based on LPS-challenged A549 cells to validate the biomarker through RNA-sequencing, quantitative real time polymerase chain reaction, and western blot analysis.Results: Bioinformatics analyses of the 16 enrolled GSE datasets from Gene Expression Omnibus online database showed myocyte enhancer factor 2D (MEF2D) level significantly increased in COPD patients coexisting non-small-cell lung carcinoma (NSCLC). Inflammation challenge increased MEF2D expression in NSCLC cell line A549, associated with the severity of inflammation. Extracellular signal-regulated protein kinase inhibition could reverse the up-regulation of MEF2D in inflammation-activated A549. MEF2D played a critical role in NSCLC cell bio-behaviors, including proliferation, differentiation, and movement.Conclusions: Inflammatory conditions led to increased MEF2D expression, which might further contribute to the development of lung cancer through influencing cancer microenvironment and cell bio-behaviors. MEF2D might be a potential biomarker during chronic inflammation-lung cancer transition, predicting the risk of lung cancer among patients with chronic respiratory diseases. [ABSTRACT FROM AUTHOR]

Background: The aim of the current research was to investigate the unplanned readmission rates and identify the risk factors of unplanned readmissions in pediatric general surgical specialties.Methods: A retrospective review of unplanned readmissions following initial surgery from July 1, 2010, to June 30, 2017, in the general surgical specialties at an academic tertiary care hospital was performed. The main outcome of interest was unplanned readmission rates, the common causes for readmission. The risk factors involved in the unplanned readmissions were further investigated using univariate and multivariate analyses.Results: Of the 3263 patients who underwent surgery and discharge, 176 (9%) were unplanned readmissions. The most frequent surgical operation related to readmission was appendectomy, and the common readmission causes were associated with treatment of gastrointestinal complaints/complications. Multivariable analysis demonstrated that emergency surgery (p = 0.016, odds ratio [OR] = 2.73; 95% CI = 1.35-6.19), major complications (p = 0.042, OR = 2.43; 95% CI = 1.12-4.71) and the initial hospital length of stay (p = 0.036, OR = 3.46; 95% CI = 1.67-7.53) were independent risk factors for readmission.Conclusions: This study identified potential risks for readmission, which should be targeted for interventions to improve quality and resource allocation. [ABSTRACT FROM AUTHOR]

Background: Negative pressure pulmonary edema (NPPE) is a rare complication that is more prevalent in young patients. NPPE usually results from acute upper airway obstruction, which is most commonly caused by laryngospasm during extubation. NPPE is characterized by the sudden onset of coughing, hemoptysis, tachycardia, tachypnea, and hypoxia, and is dramatically improved with supportive care, which prevents severe sequelae. To our knowledge, there is no report of a patient developing NPPE after percutaneous endoscopic interlaminar lumbar discectomy.Case Presentation: Herein, we report the case of a 22-year-old amateur basketball player with L5/S1 disc herniation who developed NPPE during extubation after general anesthesia for a minimally invasive spinal surgery (percutaneous endoscopic interlaminar lumbar discectomy). The NPPE was treated by maintaining the airway patency, applying positive-pressure ventilation, administering dexamethasone and antibiotics, and limiting the volume of fluid infused. The patient had an uneventful postoperative course, and was discharged to his home on postoperative day 3.Conclusions: Although NPPE is an infrequent complication, especially in patients undergoing percutaneous endoscopic interlaminar lumbar discectomy, this case report highlights the importance of early diagnosis and prompt treatment of NPPE to prevent the development of potentially fatal complications. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of thiscascade. In the current study, we tested the hypothesis that curcumin, a phytochemical compound with potent anti-inflammatory properties that is extracted from the rhizome Curcuma longa, alleviates acute inflammatory injury mediated by TLR4 following TBI.Methods: Neurological function, brain water content and cytokine levels were tested in TLR4⁻/⁻ mice subjected to weight-drop contusion injury. Wild-type (WT) mice were injected intraperitoneally with different concentrations of curcumin or vehicle 15 minutes after TBI. At 24 hours post-injury, the activation of microglia/macrophages and TLR4 was detected by immunohistochemistry; neuronal apoptosis was measured by FJB and TUNEL staining; cytokines were assayed by ELISA; and TLR4, MyD88 and NF-κB levels were measured by Western blotting. In vitro, a co-culture system comprised of microglia and neurons was treated with curcumin following lipopolysaccharide (LPS) stimulation. TLR4 expression and morphological activation in microglia and morphological damage to neurons were detected by immunohistochemistry 24 hours post-stimulation.Results: The protein expression of TLR4 in pericontusional tissue reached a maximum at 24 hours post-TBI. Compared with WT mice, TLR4⁻/⁻ mice showed attenuated functional impairment, brain edema and cytokine release post-TBI. In addition to improvement in the above aspects, 100 mg/kg curcumin treatment post-TBI significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release and neuronal apoptosis in WT mice. Furthermore, Western blot analysis indicated that the levels of TLR4 and its known downstream effectors (MyD88, and NF-κB) were also decreased after curcumin treatment. Similar outcomes were observed in the microglia and neuron co-culture following treatment with curcumin after LPS stimulation. LPS increased TLR4 immunoreactivity and morphological activation in microglia and increased neuronal apoptosis, whereas curcumin normalized this upregulation. The increased protein levels of TLR4, MyD88 and NF-κB in microglia were attenuated by curcumin treatment.Conclusions: Our results suggest that post-injury, curcumin administration may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis through a mechanism involving the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages in TBI. [ABSTRACT FROM AUTHOR]

Introduction: The renal clearance of infused crystalloid fluid is very low during anaesthesia and surgery, but experiments in conscious sheep indicate that the renal fluid clearance might approach a normal rate when the adrenergic balance is modified.Methods: Sixty females (mean age, 32 years) undergoing laparoscopic gynecological surgery were randomized to control group and received only the conventional anesthetic drugs and 20 ml/kg of lactated Ringer's over 30 mins. The others were also given an infusion of 50 μg/kg/min of esmolol (beta1-receptor blocker) or 0.01 μg/kg/min of phenylephrine (alpha1-adrenergic agonist) over 3 hours. The distribution and elimination of infused fluid were studied by volume kinetic analysis based on urinary excretion and blood hemoglobin level.Results: Both drugs significantly increased urinary excretion while heart rate and arterial pressure remained largely unaffected. The urine flows during non-surgery were 43, 147, and 176 ml in the control, esmolol, and phenylephrine groups, respectively (medians, P<0.03). When surgery had started the corresponding values were 34, 65 and 61 ml (P<0.04). At 3 hours, averages of 9%, 20%, and 25% of the infused volume had been excreted in the three groups (P<0.01). The kinetic analyses indicated that both treatments slowed down the distribution of fluid from the plasma to the interstitial fluid space, thereby preventing hypovolemia.Conclusions: Esmolol doubled and phenylephrine almost tripled urinary excretion during anesthesia-induced depression of renal fluid clearance. [ABSTRACT FROM AUTHOR]

Background: Several inflammatory indicators have been reported to have predictive value in many types of malignant cancer. This research was aimed to explore the ability of the monocyte-to-lymphocyte ratio (MLR) to predict prognosis in patients with intrahepatic cholangiocarcinoma (ICC) who subjected to curative hepatectomy., Methods: This retrospective analysis included 196 patients with ICC who underwent curative hepatectomy between May 2018 and April 2023. The predictive abilities of the preoperative MLR in assessing overall survival (OS) and disease-free survival (DFS) in those patients were compared with other inflammation-based scores, including monocyte-to-white ratio, neutrophil-to-lymphocyte ratio, neutrophil-to-white ratio, platelet-to-lymphocyte ratio, platelet-to-white ratio, and systemic immune-inflammation index, as well as tumor markers, like carcinoembryonic antigen (CEA) and carbohydrate antigen 19 - 9 (CA19-9)., Results: The area under the time-dependent receiver operating characteristic curve indicated that the preoperative MLR had higher predictive efficiency in contrast with other inflammation-based scores and tumor markers in assessing OS and DFS. Stratifying patients according to the optimal cut-off value for the preoperative MLR, the data showed that both OS and DFS in the high MLR group were significantly worse than those in the low MLR group (p < 0.05 for all). Univariable and multivariable Cox analyses revealed that the preoperative MLR was an independent risk factor for OS and DFS in patients with ICC. In addition to predicting OS in patients with high CEA levels and predicting DFS in patients with high CA19-9 levels, patients with different CEA and CA19-9 levels were divided into completely different OS and DFS subgroups based on the risk stratification of the preoperative MLR., Conclusions: Our results demonstrated that the preoperative MLR was a good prognosis indicator to predict DFS and OS following curative hepatectomy in patients with ICC., (© 2024. The Author(s).)

Background: Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide. Patients with chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), are exposed to a higher risk of developing lung cancer. Chronic inflammation may play an important role in the lung carcinogenesis among those patients. The present study aimed at identifying candidate biomarker predicting lung cancer risk among patients with chronic respiratory diseases., Methods: We applied clinical bioinformatics tools to analyze different gene profile datasets with a special focus on screening the potential biomarker during chronic inflammation-lung cancer transition. Then we adopted an in vitro model based on LPS-challenged A549 cells to validate the biomarker through RNA-sequencing, quantitative real time polymerase chain reaction, and western blot analysis., Results: Bioinformatics analyses of the 16 enrolled GSE datasets from Gene Expression Omnibus online database showed myocyte enhancer factor 2D (MEF2D) level significantly increased in COPD patients coexisting non-small-cell lung carcinoma (NSCLC). Inflammation challenge increased MEF2D expression in NSCLC cell line A549, associated with the severity of inflammation. Extracellular signal-regulated protein kinase inhibition could reverse the up-regulation of MEF2D in inflammation-activated A549. MEF2D played a critical role in NSCLC cell bio-behaviors, including proliferation, differentiation, and movement., Conclusions: Inflammatory conditions led to increased MEF2D expression, which might further contribute to the development of lung cancer through influencing cancer microenvironment and cell bio-behaviors. MEF2D might be a potential biomarker during chronic inflammation-lung cancer transition, predicting the risk of lung cancer among patients with chronic respiratory diseases.

Background: Previous studies have reported that eEF-2 kinase is associated with tumour cell sensitivity to certain therapies. In the present study, we investigated the relationship between eEF-2 kinase and lapatinib, a dual inhibitor of EGFR and HER-2, in nasopharyngeal carcinoma (NPC) cells., Methods: The effect of treatment on the growth and proliferation of NPC cells was measured by three methods: cell counting, crystal violet staining and colony counting. Apoptosis was evaluated by flow cytometry to determine Annexin V-APC/7-AAD and cleaved PARP levels, and the results were further confirmed by Western blot analysis. The expression of eEF-2 kinase and the impacts of different treatments on different signalling pathways were analysed by Western blot analysis., Results: The expression of eEF-2 kinase was significantly associated with NPC cell sensitivity to lapatinib. Therefore, suppression of this kinase could increase the cytocidal effect of lapatinib, as well as reduce cell viability and colony formation. Furthermore, inhibition of eEF-2 kinase, by either RNA interference (eEF-2 kinase siRNA or shRNA) or pharmacological inhibition (NH125), enhanced lapatinib-induced apoptosis of NPC cells. The results also showed that lapatinib combined with NH125 had a synergistic effect in NPC cells. In addition, mechanistic analyses revealed that downregulation of the ERK1/2 and Src pathways, but not the AKT pathway, was involved in this sensitizing effect., Conclusions: The results of this study suggest that targeting eEF-2 kinase may improve the efficacy of therapeutic interventions such as lapatinib in NPC cells.

Background: Prognostic indicators for gastrointestinal stromal tumors (GISTs) are under investigation. The latest risk classification criteria may still have room for improvement. This study aims to investigate prognostic factors for primary GISTs from three aspects, including clinicopathological parameters, immunohistochemical (IHC) expression of PTEN, and Ki-67 labeling index (LI), and attempts to find valuable predictors for the malignancy potential of primary GISTs., Methods: Tumor samples and clinicopathological data from 84 patients with primary GISTs after R0 resection were obtained. Immunohistochemical analysis was performed based on tissue microarray (TMA) to estimate expression of PTEN and Ki-67 in tumor cells., Results: The cut-off point of Ki-67 LI was determined as 1%, using a receiver operator characteristic test with a sensitivity of 71.7% and a specificity of 64.5%. Univariate analysis demonstrated the following factors as poor prognostic indicators for relapse-free survival (RFS) against a median follow-up of 40.25 months: gastrointestinal (GI) bleeding (P = 0.009), non-gastric tumor location (P = 0.001), large tumor size (P = 0.022), high mitotic index (P < 0.001), high cellularity (P = 0.012), tumor rupture (P = 0.013), absent or low expression of PTEN (P = 0.036), and Ki-67 LI >1% (P = 0.043). Gastrointestinal bleeding (hazard ratio, 3.85; 95% confidence interval, 1.63 to 9.10; P = 0.002) was a negative independent risk predictor in multivariate analysis, in addition to tumor size (P = 0.023), and mitotic index (P = 0.002). In addition, GI bleeding showed a good ability to predict recurrence potential, when included in our re-modified risk stratification criteria., Conclusions: This study suggests that GI bleeding is an independent predictor of poor prognosis for RFS in primary GISTs. Expression of PTEN and Ki-67 are correlated with high risk potential and may predict early recurrence in univariate analysis.

Background: Endoplasmic reticulum (ER) stress is considered one of the mechanisms contributing to reactive oxygen species (ROS)-mediated cell apoptosis. In diabetic cardiomyopathy (DCM), cell apoptosis is generally accepted as the etiological factor and closely related to cardiac ROS generation. ER stress is proposed the link between ROS and cell apoptosis; however, the signaling pathways and their roles in participating ER stress-induced apoptosis in DCM are still unclear., Methods: In this study, we investigated the signaling transductions in ROS-dependent ER stress-induced cardiomocyte apoptosis in animal model of DCM. Moreover, in order to clarify the roles of IRE1 (inositol-requiring enzyme-1), PERK (protein kinase RNA (PKR)-like ER kinase) and ATF6 (activating transcription factor-6) in conducting apoptotic signal in ROS- dependent ER stress-induced cardiomocyte apoptosis, we further investigated apoptosis in high-glucose incubated cardiomyocytes with IRE1, ATF6 and PERK-knocked down respectively., Results: we demonstrated that the ER stress sensors, referred as PERK, IRE1 and ATF6, were activated in ROS-mediated ER stress-induced cell apoptosis in rat model of DCM which was characterized by cardiac pump and electrical dysfunctions. The deletion of PERK in myocytes exhibited stronger protective effect against apoptosis induced by high-glucose incubation than deletion of ATF6 or IRE in the same myocytes. By subcellular fractionation, rather than ATF6 and IRE1, in primary cardiomyocytes, PERK was found a component of MAMs (mitochondria-associated endoplasmic reticulum membranes) which was the functional and physical contact site between ER and mitochondria., Conclusions: ROS-stimulated activation of PERK signaling pathway takes the major responsibility rather than IRE1 or ATF6 signaling pathways in ROS-medicated ER stress-induced myocyte apoptosis in DCM.

Background: p53 is the most frequently mutated tumor-suppressor gene in human cancers. It has been reported that mutations in p53 result not only in the loss of its ability as a tumor suppressor, but also in the gain of novel cancer-related functions that contribute to oncogenesis. The present study evaluated the potential of silencing of mutant p53 by small interfering RNA in the treatment of bladder cancer cells in vitro., Methods: We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability and flow cytometry to detect cell cycle alterations and apoptosis. The related molecular mechanisms were assessed by western blotting. We also used the MTT assay and flow cytometry to investigate if silencing of mutant p53 by knockdown with small interfering (si)RNA would change the sensitivity to cisplatin treatment., Results: Using 5637 and T24 human bladder cancer cell lines characterized by mutations in p53, we found that silencing of the mutant p53 by RNA interference induced evident inhibition of cell proliferation and viability, which was related to the induction of G2 phase cell cycle arrest and apoptosis. Moreover, our study also showed that the p53-targeting siRNA cooperated with cisplatin in the inhibition of bladder cancer cells., Conclusions: These findings suggest that RNA interference targeting mutant p53 may be a promising therapeutic strategy for the treatment of bladder cancer.

Background: Multiple myeloma (MM) is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common flavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined., Results: In this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells but not against normal peripheral blood mononuclear cells. Together, kinase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the Hsp90/Cdc37/client complex and induced the degradation of multiple kinase clients, including RIP1, Src, Raf-1, Cdk4 and AKT. By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-κB. The treatment also downregulated the expression of the antiapoptotic proteins Mcl-1, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells. In addition, apigenin had a greater effects in depleting Hsp90 clients when used in combination with the Hsp90 inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat., Conclusions: Our results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2-Cdc37-Hsp90, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.

Background: Feature gene extraction is a fundamental issue in microarray-based biomarker discovery. It is normally treated as an optimization problem of finding the best predictive feature genes that can effectively and stably discriminate distinct types of disease conditions, e.g. tumors and normals. Since gene microarray data normally involves thousands of genes at, tens or hundreds of samples, the gene extraction process may fall into local optimums if the gene set is optimized according to the maximization of classification accuracy of the classifier built from it., Results: In this paper, we propose a novel gene extraction method of error margin analysis to optimize the feature genes. The proposed algorithm has been tested upon one synthetic dataset and two real microarray datasets. Meanwhile, it has been compared with five existing gene extraction algorithms on each dataset. On the synthetic dataset, the results show that the feature set extracted by our algorithm is the closest to the actual gene set. For the two real datasets, our algorithm is superior in terms of balancing the size and the validation accuracy of the resultant gene set when comparing to other algorithms., Conclusion: Because of its distinct features, error margin analysis method can stably extract the relevant feature genes from microarray data for high-performance classification.

Background: Due to the high morbidity and mortality of fulminant hepatitis, early diagnosis followed by early effective treatment is the key for prognosis improvement. So far, little is known about the gene expression changes in the early stage of this serious illness. Identification of the genes related to the very early stage of fulminant hepatitis development may provide precise clues for early diagnosis., Results: Balb/C mice were used for ConA injection to induce fulminant hepatitis that was confirmed by pathological and biochemical examination. After a gene chip-based screening, the data of gene expression in the liver, was further dissected by ANOVA analysis, gene expression profiles, gene network construction and real-time RT-PCR. At the very early stage of ConA-triggered fulminant hepatitis, totally 1,473 genes with different expression variations were identified. Among these, 26 genes were finally selected for further investigation. The data from gene network analysis demonstrate that two genes, MPDZ and Acsl1, localized in the core of the network., Conclusions: At the early stages of fulminant hepatitis, expression of twenty-six genes involved in protein transport, transcription regulation and cell metabolism altered significantly. These genes form a network and have shown strong correlation with fulminant hepatitis development. Our study provides several potential targets for the early diagnosis of fulminant hepatitis.