[Clinical Efficacy and Safety of Flumatinib in the Treatment of Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase].

OBJECTIVE: To explore the clinical efficacy and safety of flumatinib mesylate produced in China in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). METHODS: 32 newly diagnosed CML-CP patients admitted to the Hematology Department of the Affiliated Hospital of Southwest Medical University from March 1, 2020 to March 31, 2022, who had never received any tyrosine kinase inhibitor (TKI) were included in the study. The patients were treated by flumatinib mesylate 600mg once daily. The hematologic, cytogenetic and molecular responses were assessed at 3-, 6- and 12-month, and adverse effects of the drug were evaluated. RESULTS: 31 patients were treated with flumatinib for≥3 months, of which 24 patients were treated for ≥6 months and 14 patients were treated for≥12 months. At 3rd month of treatment, 30 out of 31 patients achieved complete hematologic response (CHR); 24 patients underwent cytogenetic testing and 22 cases achieved major cytogenetic response(MCyR), of which 21 cases achieved complete cytogenetic response (CCyR); Among 25 patients who underwent molecular testing, 22 patients had BCR-ABLIS≤10%, including 10 patients with BCR-ABLIS≤0.1%, and 6 patients with BCR-ABLIS≤0.01%. At 6th month of treatment, 23 out of 24 patients achieved CHR; 17 patients underwent cytogenetic testing and all achieved CCyR; Among 23 patients who underwent molecular testing, 20 patients had BCR-ABLIS≤1%, including 16 patients with BCR-ABLIS≤0.1% and 12 patients with BCR-ABLIS≤0.01%. At 12nd month of treatment, all 14 patients achieved CHR and CCyR; Among them, 10 patients had BCR-ABLIS≤0.1%, including 9 patients with BCR-ABLIS≤0.01%. The grade Ⅲ/Ⅳ leukopenia, thrombocytopenia and anemia rates in the patients were 13.3%, 20.0% and 3.3%, respectively. One patient stopped flumatinib therapy due to severe and persistent hematologic toxicity. The major non-hematologic adverse events were abnormal liver function (20%), diarrhea (10%), bone/joint pain (10%), muscle spasm (10%), rash (6.7%), acute kidney injury (6.7%) and nausea(3.3%), most of which were grade I-II. No patient experienced grade Ⅳ non-hematologic adverse events. No drug toxicity-related death occurred. CONCLUSION: Flumatinib mesglate, as the first-line treatment for newly diagnosed CML-CP, can enable the patients to achieve early and deep molecular and cytogenetic responses, and shows good safety.

Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Colorectal cancer (CRC) belongs to the category of intestinal wind, anal ulcer, abdominal mass and other diseases in traditional Chinese medicine (TCM). Floris Sophorae Powder (F.S), is a classical prescription is recorded in Puji Benshi Fang for the treatment of intestinal carbuncle. It has been incorporated into the prescriptions for the treatment of intestinal diseases and achieved remarkable results in modern medicine. However, the mechanism of F.S in the treatment of colorectal cancer remains unclear and requires further study. AIM OF THE STUDY: To investigate F.S in treating CRC and clarify the underlying mechanism. MATERIALS AND METHODS: This study was based on Dextran Sulfate Sodium Salt (DSS) combined with Azoxymethane (AOM) induced CRC mouse model to clarify the pharmacological effects of F.S. The serum metabolomics was used to study the mechanism of action, and the chemical composition of F.S was found by UPLC-Q-TOF-MS. The rationality of serm metabolomics results was verified through the clinical target database of network pharmacology, and the upstream and downstream targets of related pathways were found. The mechanism pathway was verified by Western blot to clarify its mechanism of action. RESULTS: In vivo pharmacological experiments showed that F.S inhibited tumor growth and improved hematochezia. The vital signs of mice in the high-dose F.S group approached to those in the control group. A total of 43 differential metabolites were found to be significantly changed by serum metabolomics. F.S could modulate and recover most of the differential metabolites, which proved to be closely related to the KRAS/MEK-ERK signaling pathway. A total of 46 compounds in F.S were identified, and the rationality of serm metabolic pathway was verified by network pharmacology. Western blot results also verified that the expression of KRAS, E2F1, p-MEK and p-ERK were significantly decreased after F.S treatment. CONCLUSION: Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.

[Mechanism of famous classical formula Huaihua Powder in treatment of ulcerative colitis based on metabonomics].

Ultra-high performance liquid chromatography-quadrupole-time of flight tandem mass spectrometry(UHPLC-Q-TOF-MS) was employed in this study to observe the effect of Huaihua Powder on the serum metabolites of mice with ulcerative colitis and reveal the mechanism of Huaihua Powder in the treatment of ulcerative colitis. The mouse model of ulcerative colitis was established by dextran sodium sulfate salt(DSS). The therapeutic effect of Huaihua Powder on ulcerative colitis was preliminarily evaluated based on the disease activity index(DAI), colon appearance, colon tissue morphology, and the content of inflammatory cytokines such as tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1ß(IL-1ß). UHPLC-Q-TOF-MS was employed to profile the endogenous metabolites of serum samples in blank control group, model group, and low-, medium-, and high-dose Huaihua Powder groups. Multivariate analyses such as principal component analysis(PCA), partial least squares discriminant analysis(PLS-DA), and orthogonal partial least squares discriminant analysis(OPLS-DA) were performed for pattern recognition. Potential biomarkers were screened by Mass Profiler Professional(MPP) B.14.00 with the thresholds of fold change≥2 and P<0.05. The metabolic pathways were enriched by MetaboAnalyst 5.0. The results showed that Huaihua Powder significantly improved the general state and colon tissue morphology of mice with ulcerative colitis, reduced DAI, and lowered the levels of TNF-α, IL-6, and IL-1ß in serum. A total of 38 potential biomarkers were predicted to be related to the regulatory effect of Huaihua Powder, which were mainly involved in glycerophospholipid metabolism, glycine, serine, and threonine metabolism, mutual transformation of glucuronic acid, and glutathione metabolism. This study employed metabolomics to analyze the mechanism of Huaihua Powder in the treatment of ulcerative colitis, laying a foundation for the further research.

[Effect of Recombinant Human Thrombopoietin (rhTPO) on Hematopoietic Reconstitution in Allogeneic Hematopoietic Stem Cell Transplantation Model].

OBJECTIVE: To explore the effect of recombinant human thrombopoietin (rhTPO) on hematopoietic reconstruction in allogeneic hematopoietic stem cell transplantation (allo-HSCT) model. METHODS: The C57BL/6 mice were employed as the donors, and BALB/c mice as recipients. The bone marrow mononuclear cells of the donor mice were extracted and pretreated, which then were injected with 5×106 per mouse through the tail vein of the recipient to establish an allo-HSCT model. The implantation of hematopoietic stem cells in the recipient mice was detected by flow cytometry on the 28th day after transplantation. Next, the successfully modeled recipient mice were randomly divided into experimental group and control group. The rhTPO was injected into mice in the experimental group on the first day after transplantation, while the saline was injected into mice in the control group. Both groups were injected for 14 consecutive days. The peripheral blood and bone marrow hematopoiesis of the two groups were observed on day 1, 3, 7, 14, and 21 after transplantation. RESULTS: The expression rate of H-2Kb in the bone marrow of recipient mice was 43.85% (>20%) on the 28th day after transplantation, which indicated that the recipient mice were successfully chimerized. Meanwhile, counts of PLTs on the day 3, 7, 14, and 21 after transplantation in the experimental group were higher than those in the control group with statistical significances (P<0.05). In addition, hematopoietic function of bone marrow was suppressed in both groups on day 1, 3 and 7 after transplantation, but hematopoietic bone marrow hyperplasia was better in the experimental group than in the control group. On day 14 and 21 after transplantation, the hematopoietic function of bone marrow in the two groups was recovered, and the experimental group showed more obvious than the control group. CONCLUSION: rhTPO can effectively stimulate the production of PLTs and facilitate the recovery of white blood cells and hemoglobin after allo-HSCT, and promote hematopoietic recovery and reconstitution of bone marrow.

Conventional MRI Features of Central Nervous System Embryonal Tumor, Not Otherwise Specified in Adults: Comparison with Glioblastoma.

RATIONALE AND OBJECTIVES: The purpose of this study was to explore conventional MRI features that can accurately differentiate central nervous system embryonal tumor, not otherwise specified (CNS ETNOS) from glioblastoma (GBM) in adults. MATERIALS AND METHODS: Preoperative conventional MRI images of 30 CNS ETNOS and 98 GBMs were analyzed by neuroradiologists retrospectively to identify valuable MRI features. Five blinded neuroradiologists independently reviewed all these MRI images, and scored MRI features on a five-point scale. Kendall's coefficient of concordance was used to measure inter-rater agreement. Diagnostic value was assessed by the area under the curve (AUC) of receiver operating curve, and sensitivity and specificity were also calculated. RESULTS: Seven MRI features, including isointensity on T1WI, T2WI, and FLAIR, ill-defined margin, severe peritumoral edema, ring enhancement, and broad-based attachment sign, were helpful for the differential diagnosis of these two entities. Among these features, ring enhancement showed the highest inter-rater concordance (0.80). Ring enhancement showed the highest AUC value (0.79), followed by severe peritumoral edema (0.67). The combination of seven features showed the highest AUC value (0.86), followed by that of three features (ill-defined margin, severe peritumoral edema, and ring enhancement) (0.83). CONCLUSION: Enhancement pattern, peritumoral edema, and margin are valuable for the discrimination between CNS ETNOS and GBM in adults.

Long noncoding RNA PCA3 contributes to the progression of choriocarcinoma by acting as a ceRNA against miR-106b.

BACKGROUND: Choriocarcinoma is the most aggressive gestational trophoblastic disease, with massive local trophoblast invasion and vascular percolation, resulting in multiple organ metastases. Recent evidence has shown that long noncoding RNAs (lncRNAs) play an important role in tumor progression. This study aimed to investigate the expression and role of lncRNA PCA3 in the progression of choriocarcinoma. METHODS: First, the expression of lncRNA PCA3 in choriocarcinoma cells was detected using quantitative real-time PCR (qRT-PCR). Then functional assays such as cell proliferation assay, wound healing assay, and invasion assay were conducted to determine the role of PCA3. In addition, the specific molecular mechanism was studied using western blot, luciferase assay, and rescue experiment. RESULTS: We demonstrated that the expression of PCA3 is significantly higher in choriocarcinoma cells in contrast to normal human chorionic trophoblast cells. Furthermore, PCA3 could promote cell proliferation, migration and invasion in gestational choriocarcinoma cells and facilitated epithelial to mesenchymal transition (EMT) in vitro. In addition, PAC3 could directly bind to miR-106b and effectively liberate the expression of its endogenous target matrix metallopeptidase 2 (MMP2). CONCLUSION: Our results suggest that PCA3 contributes to the progression of choriocarcinoma by acting as a ceRNA against miR-106b.

The Study of Nrf2 Signaling Pathway in Ovarian Cancer.

Ovarian cancer is one of the most malignant gynecological tumors in the world, with a high fatality rate and resistance to chemotherapy. Much basic research has revealed that oxidative stress is involved in tumor occurrence and development processes and is associated with tumor progression as well as metastasis. In recent years, oxidative stress has been proven to have a close connection with malignant biological behavior in ovarian cancer, and this topic has garnered increasing attention. This article reviews the research aimed toward elucidating the relationship between oxidative stress and ovarian cancer.

SP-D, KL-6, and HTI-56 levels in children with mycoplasma pneumoniae pneumonia.

UNLABELLED: The study was aimed to evaluate the potential biomarkers from pulmonary surfactant protein D (SP-D), Krebs von den Lungen-6 (KL-6), and 56-kD a human type I protein (HTI-56) in serum and bronchoalveolar lavage fluid samples of children with Mycoplasma pneumoniae pneumonia. This retrospective study, self-controlled study enrolled 34 Chinese children with M. pneumoniae pneumonia. The levels of SP-D, KL-6, and HTI-56 in bronchoalveolar lavage fluid samples were assessed and compared between patients with unilateral lung infection and contralateral lungs without any abnormal findings. Significant differences in the levels of SP-D, KL-6, and HTI-56 were observed in infected bronchoalveolar lavage fluid samples compared with uninfected samples (all P<0.05); however, there was no correlation between the serum level of SP-D, KL-6, and HTI-56 and their levels in infected and uninfected bronchoalveolar lavage fluid samples (P>0.05). CONCLUSION: The high levels of SP-D, KL-6, and HTI-56 in infected bronchoalveolar lavage fluid samples may reflect the injury of alveolar epithelium caused by M. pneumoniae. Instead of SP-D in uninfected bronchoalveolar lavage fluid samples obtained by invasive bronchoscopy, serum SP-D may serve as a convenient medium to distinguish lung infection caused by M. pneumoniae.

Pituitary tumor-transforming gene 1 enhances metastases of cervical cancer cells through miR-3666-regulated ZEB1.

Early cancer metastases often occur in cervical cancer (CC) patients, resulting in poor prognosis and poor therapeutic outcome after resection of primary cancer. Hence, there is a compelling requirement for elucidating the molecular mechanisms underlying the CC cell invasiveness. Recently, the role of microRNAs (miRNAs) and pituitary tumor-transforming gene 1 (Pttg1) in the carcinogenesis of CC has been reported. Nevertheless, the relationship between miRNAs and Pttg1 remains ill-defined. Here, we showed that the levels of miR-3666 were significantly decreased and the levels of zinc finger E-box binding homeobox 1 (ZEB1) and Pttg1 were significantly increased in the CC specimens from patients, compared to the paired non-tumor tissue. Moreover, the levels of miR-3666 and ZEB1 inversely correlated. Bioinformatics analyses showed that miR-3666 targeted the 3'-untranslated region (3'-UTR) of ZEB1 messenger RNA (mRNA) to inhibit its translation, which was confirmed by luciferase reporter assay. Moreover, Pttg1 overexpression inhibited miR-3666 and subsequently increased ZEB1 and cell invasion, while Pttg1 depletion increased miR-3666 and subsequently decreased ZEB1 and cell invasion. Together, our data suggest that Pttg1 may increase CC cell metastasis, possibly through miR-3666-regulated ZEB1 levels.

The Inhibition of Oxidised Low-Density Lipoprotein-Induced Apoptosis of Macrophages by Recombinant Human Brain Natriuretic Peptide and the Underlying Mechanism.

OBJECTIVE: Macrophage apoptosis plays a key role in atherosclerotic plaque rupture. This study investigated the effects of recombinant human brain natriuretic peptide (BNP) on oxidised low-density lipoprotein (ox-LDL)-induced macrophage apoptosis and explored the underlying mechanism. METHODS: A model of ox-LDL-induced macrophage injury was established to evaluate the role of BNP. Flow cytometry was employed to detect apoptosis and changes in mitochondrial membrane potential (x0394;x03A8;m), and confocal microscopy was used to determine cellular reactive oxygen species (ROS) levels. Additionally, reverse transcription-polymerase chain reaction and colourimetry were used to detect the mRNA expression and activity, respectively, of superoxide dismutase (SOD) and malondialdehyde (MDA). RESULTS: Ox-LDL induced macrophage apoptosis in a concentration-dependent manner, and maximum apoptosis occurred at 100 µg/ml ox-LDL (45.62 ± 2.76 vs. 6.84 ± 1.94%; p < 0.05). Conversely, BNP suppressed macrophage apoptosis, with a maximal effect at 10-9 mol/l (18.56 ± 1.79%; p < 0.05). Compared with the control group, intracellular ROS levels increased, x0394;x03A8;m decreased, SOD mRNA expression and activity decreased and MDA mRNA expression and content increased in the 100-µg/ml ox-LDL group (527.30 ± 36.20 vs. 100.00 ± 0.00%, 3.01 ± 0.52 vs. 9.67 ± 0.51%, 0.53 ± 0.18 vs. 1.00 ± 0.00, 256.6 ± 8.20 vs. 355.8 ± 9.58 U/ml, 1.59 ± 0.23 vs. 1.00 ± 0.00 and 29.4 ± 1.68 vs. 5.94 ± 0.51 nmol/ml; p < 0.05); these effects were significantly counteracted by 10-9 mol/l BNP (237.30 ± 30.62%, 6.55 ± 1.57%, 0.90 ± 0.07, 310.4 ± 2.97 U/ml, 1.14 ± 0.10, 20.54 ± 1.55 nmol/ml; p < 0.05). CONCLUSION: BNP attenuates ox-LDL-induced macrophage apoptosis by suppressing oxidative stress and preventing x0394;x03A8;m loss.

Low expression of phosphatase and tensin homolog in clear­cell renal cell carcinoma contributes to chemoresistance through activating the Akt/HDM2 signaling pathway.

Clear-cell renal cell carcinoma (CCRCC) is the most frequent primary malignancy in the adult kidney. Most patients with advanced CCRCC have poor prognosis as CCRCC remains resistant to chemotherapy. The present study explored the possible mechanism underlying CCRCC resistance to chemotherapy and found that loss of PTEN in CCRCC may be involved. Knockdown of PTEN in the CCRCC cell line ACHN blocked etoposide-induced apoptosis and etoposide-impaired cell proliferation was also inhibited. It has been demonstrated that most chemotherapy drugs exert their anti-cancer effects via p53-mediated apoptosis, and in accordance, with this, the present study showed that treatment with etoposide significantly increased p53 levels. Silencing of PTEN in ACHN inhibited the Akt/HDM2 signaling cascade and depressed p53 expression, and the interaction between HDM2 and p53 was also enhanced. This was further verified in CCRCC tissue specimens from patients The results of the present study suggested that loss of PTEN, which deactivated Akt/HDM2 signaling followed by degradation of p53, may contribute to the development of etoposide resistance in CCRCC.

Crystal structure of bis-{µ-4,4'-[1,3-phenyl-enebis(-oxy)]dibenzoato-κ(4) O,O':O'',O'''}bis[(1,10-phenanthroline-κ(2) N,N')zinc(II)] dihydrate.

Two 4,4'-[1,3-phenyl-enebis(-oxy)]dibenzoate anions bridge two 1,10-phenanthroline-chelated Zn(II) cations about a center of inversion to generate the dinuclear title compound, [Zn2(C20H12O6)2(C12H8N2)2]·2H2O. The geometry about the Zn(II) atom is a distorted octa-hedron. In the crystal, the mol-ecules are connected by classical O-H⋯O hydrogen bonds, weak C-H⋯O hydrogen bonds and C-H⋯π inter-actions, forming a three dimensional network. π-π stacking is also observed between aromatic rings of adjacent mol-ecules, centroid-centroid distances are 3.753 (2), 3.5429 (16) and 3.5695 (17) Å.

Crystal structure of bis-{2-[bis-(2-hy-droxy-eth-yl)amino]-ethanol-κ(4) O,N,O',O''}cadmium terephthalate.

In the title salt, [Cd(C6H15NO3)2](C8H4O4), the Cd(2+) cation is coordinated by six O atoms and two N atoms from two tetra-dentate 2-[bis-(2-hy-droxy-eth-yl)amino]-ethanol ligands, displaying a distorted square-anti-prismatic coordination. The terephthalate dianion does not coordinate to the cation but is connected through O⋯H-O hydrogen bonds of medium strength to the complex cations, leading to a layered structure extending parallel to (100).

Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer's disease and tauopathies.

Neuronal insulin signaling abnormalities have been associated with Alzheimer's disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS(616), IRS1-pS(312) and downstream target Akt-pS(473) measures were most elevated in AD but were also significantly increased in the tauopathies: Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS(616) with pathologic tau in neurons and dystrophic neurites. To further investigate an association between tau and abnormal serine phosphorylation of IRS1, we examined the presence of abnormal IRS1-pS(616) expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS(616) frequently co-localizes in tangle-bearing neurons. Conversely, we observed increased levels of hyperphosphorylated tau in the high-fat diet-fed mouse, a model of insulin resistance. These results provide confirmation and specificity that abnormal phosphorylation of IRS1 is a pathological feature of AD and other tauopathies, and provide support for an association between insulin resistance and abnormal tau as well as amyloid-ß.

[Etiological study of pelvic organ prolapse and stress urinary incontinence with collagen status and metabolism].

OBJECTIVE: To explore the alteration of collagen ultrastructure and content in uterine ligaments and paraurethral tissue and explore whether the alteration may contribute to stress urinary incontinence (SUI) and pelvic organ prolapse (POP). METHODS: The cardinal ligament, uterosacral ligament and paraurethral tissue samples were obtained from 90 subjects undergoing hysterectomy. Collagen ultrastructure was examined with transmission electron microscopy. And collagen content and expression of vasoactive intestinal peptide (VIP) were examined with immunohistochemistry. RESULTS: The smooth muscle fascicles were thinner in the patients of SUI and POP. Arrangement of smooth muscle fascicles was disorderly. Fibroblast was metabolically active. The mean collagen fibril diameters in the SUI and POP groups were larger than that in the control group (P < 0.01). The mean contents of collagen I and III in the SUI and POP groups were lower than that in the control group (P < 0.01). The expression of VIP was lower (P < 0.05). CONCLUSION: Predominance of collagen degradation during tissue repair may contribute to and promote POP and SUI. The decrease of VIP might be related with nerve damage or degeneration to cause or accelerate the progress of pelvic organ prolapse.

Expression of MiR200a, miR93, metastasis-related gene RECK and MMP2/MMP9 in human cervical carcinoma--relationship with prognosis.

AIM AND BACKGROUND: Cervical cancer remains the third most common cancer in women globally after breast and colorectal cancer. Well-characterized biomarkers are necessary for early diagnosis and to predict metastatic progression and effective therapy. MiRNAs can regulate gene expression, cell growth, differentiation and apoptosis by targeting mRNAs for translational repression or degradation in tumor cells. The present study was conducted to assess expression of miR93, miR200a, RECK, MMP2, MMP9 in invasive cervical carcinoma, and analyze their clinical significance. METHOD: A total of 116 patients with invasive cervical carcinoma and 100 patients undergoing hysterectomy for benign lesions were retrospectively examined. Quantitative real-time PCR was performed to determine expression of miR93 and miR200a while RECK, MMP2, MMP9 and MVD were assessed by immunohistochemical staining. RESULTS: Cervical carcinoma patients demonstrated up-regulation of miR-93, miR-200a, MMP2 and MMP9, with down-regulation of RECK as compared to benign lesion tissues. RECK was significantly inversely related to invasion and lymphatic metastasis. The 5-year survival rate for patients with strong RECK expression was significantly higher than that with weakly expressing tumors. CONCLUSION: MiR-93 and miR-200a are associated with metastasis and invasion of cervical carcinoma. Thus together with RECK they are potential prognostic markers for cervical carcinoma. RECK cooperating with MMP2, MMP9 expression is a significant prognostic factor correlated with long-term survival for patients with invasive cervical carcinoma.

Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer's disease.

Although neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect, as some people exhibit normal cognition despite high levels of Alzheimer's disease (AD) pathology. We compared the cellular, synaptic, and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: (1) pathological AD with normal cognition ("AD-Resilient"), (2) pathological AD with AD-typical dementia ("AD-Dementia"), and (3) pathologically normal with normal cognition ("Normal Comparison"). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared with the AD-Dementia group, and increased densities of glial fibrillary acidic protein astrocytes compared with both the AD-Dementia and Normal Comparison groups. Further, in a discovery-type antibody microarray protein analysis, we identified a number of candidate protein abnormalities that were associated with a particular diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.

Transduction of mesenchymal stem cells with multidrug resistance gene provides protection for bone marrow toxicity after being transplanted into a nude mice model.

BACKGROUND: Myelosuppression is the main dose-related toxicity of many chemotherapeutic drugs. The human multidrug resistance (mdr1) gene is well-known for its ability to confering drug resistance. In this study, we meant to transplant the placenta mesenchymal stem cells (P-MSCs) moderated by mdr1 gene into a nude mice model radiated by γ-Co(60) and to explore the chemoprotection for bone marrow (BM) toxicity. METHODS: Human P-MSCs were isolated from trypsin-digested term placentas and then transduced by with reconstructed retroviral vector containing mdr1 gene and green fluorescent protein (GFP) reporter gene. The integration and expression of mdr1 gene was observed indirectedly by the expression of GFP. A nude mice model was constructed after irradiation with a sublethal dosage of γ-Co(60). These irradiated mice were transplanted with mdr1-MSCs through the caudal vein and then received paclitaxel (PAC) intraperitoneal chemotherapy. The Peripheral peripheral blood (PB) of the nude mice was collected, and the PB cells counts and values were determined using an automatic analyzer. RESULTS: After PAC treatment, mdr1-MSCs transplanted mice showed markedly improved survival upon compared to MSCs transplanted mice (85.7% vs. 57.1%). White blood cell (WBC) and red blood cell (RBC) counts as well as the hemoglobin (Hb) values were significantly increased in PAC treated mdr1-MSCs mice compared to PAC treated control mice when PAC chemotherapy had been finished (all P < 0.05), but the difference was not found in the plateltes (PLT) count (P > 0.05). CONCLUSION: Human P-MSCs moderated by mdr1 gene when transplanted into nude mice may provide chemoprotection for hematopoietic toxicity.

Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS6¹6) and IRS-1 pS6³6/6³9. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS6¹6 and IRS-1 pS6³6/6³9 and their activated kinases correlated positively with those of oligomeric Aß plaques and were negatively associated with episodic and working memory, even after adjusting for Aß plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aß oligomers and yet promoting cognitive decline independent of classic AD pathology.

[Transfer and identification of multidrug resistance gene in mesenchymal stem cells derived from human placenta].

OBJECTIVE: To explore the feasibility and safety of mdr1 gene transferred into placenta derived mesenchymal stem cells (P-MSCs) by reconstructed retroviral vector. METHODS: Human P-MSCs were isolated and expanded by Percoll density gradient and then transduced repeatedly by reconstructed retroviral vector containing mdr1 gene. The transfection and expression of mdr1 gene was detected by reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence-activated cell sorting (FACS). Meanwhile, the biological features of mdr1-MSCs were identified and analyzed. RESULTS: The expression of mdr1mRNA was found in transfected cells. The expression of P-glycoprotein (P-gp) encoded by mdr1 gene was (27.6 ± 5.1)% in the transfected P-MSCs cells versus (0.4 ± 0.1)% in the non-transfected P-MSCs cells (t = 14.291, P < 0.01). The percent of P-MSCs at quiescent phase (G0/G1 phase) was around 95.40% and it was in accord with the characterization of stem cells. The mdr1-MSCs exhibited typical ultrastructures of low-differentiated stem cells. Moreover, they still retained the potency of adipogenic and osteogenic differentiation in the presence of appropriate conditioned media. CONCLUSION: A stable expression of P-gp may be obtained by reconstructed retroviral-mediated transfection in vitro. And transfected MSCs retain the characteristics of stem cells.