Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway.

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H2O2-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H2O2-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.

Therapeutic potential of Coumarin-polyphenolic acid hybrids in PD: Inhibition of α-Syn aggregation and disaggregation of preformed fibrils, leading to reduced neuronal inclusion formation.

This study focuses on the discovery of new potential drugs for treating PD by targeting the aggregation of α-Syn. A series of hybrids combining Coumarin and phenolic acid were designed and synthesized. Four particularly promising compounds were identified, showing strong inhibitory effects with IC50 values ranging from low micromolar to submicromolar concentrations, as low as 0.63 µM. These compounds exhibited a higher binding affinity to α-Syn residues and effectively hindered the entire aggregation process, maintaining the proteostasis conformation of α-Syn and preventing the formation of ß-sheet aggregates. This approach holds significant promise for PD prevention. Additionally, these candidate compounds demonstrated the ability to break down preformed α-Syn oligomers and fibrils, resulting in the formation of smaller aggregates and monomers. Moreover, the candidate compounds showed impressive effectiveness in inhibiting α-Syn aggregation within nerve cells, thereby reducing the likelihood of α-Syn inclusion formation resembling Lewy bodies, which highlights their potential for treating PD.

Dual engineered bacteria improve inflammatory bowel disease in mice.

Currently, there are many different therapies available for inflammatory bowel disease (IBD), including engineered live bacterial therapeutics. However, most of these studies focus on producing a single therapeutic drug using individual bacteria, which may cause inefficacy. The use of dual drugs can enhance therapeutic effects. However, expressing multiple therapeutic drugs in one bacterial chassis increases the burden on the bacterium and hinders good secretion and expression. Therefore, a dual-bacterial, dual-drug expression system allows for the introduction of two probiotic chassis and enhances both therapeutic and probiotic effects. In this study, we constructed a dual bacterial system to simultaneously neutralize pro-inflammatory factors and enhance the anti-inflammatory pathway. These bacteria for therapy consist of Escherichia coli Nissle 1917 that expressed and secreted anti-TNF-α nanobody and IL-10, respectively. The oral administration of genetically engineered bacteria led to a decrease in inflammatory cell infiltration in colon and a reduction in the levels of pro-inflammatory cytokines. Additionally, the administration of engineered bacteria did not markedly aggravate gut fibrosis and had a moderating effect on intestinal microbes. This system proposes a dual-engineered bacterial drug combination treatment therapy for inflammatory bowel disease, which provides a new approach to intervene and treat IBD. KEY POINTS: • The paper discusses the effects of using dual engineered bacteria on IBD • Prospects of engineered bacteria in the clinical treatment of IBD.

Intrathecal morphine delivery at prepontine cistern to control refractory cancer-related pain: a case report of extensive metastatic and refractory cancer pain.

BACKGROUND: Extensive metastatic and refractory cancer pain is common, and exhibits a dissatisfactory response to the conventional intrathecal infusion of opioid analgesics. CASE PRESENTATION: The present study reports a case of an extensive metastatic esophageal cancer patient with severe intractable pain, who underwent translumbar subarachnoid puncture with intrathecal catheterization to the prepontine cistern. After continuous infusion of low-dose morphine, the pain was well-controlled with a decrease in the numeric rating scale (NRS) of pain score from 9 to 0, and the few adverse reactions to the treatment disappeared at a low dose of morphine. CONCLUSIONS: The patient achieved a good quality of life during the one-month follow-up period.

Smooth-Muscle-Cell-Specific Deletion of CD38 Protects Mice from AngII-Induced Abdominal Aortic Aneurysm through Inhibiting Vascular Remodeling.

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.

Biological Sentinel: An Efficient Engineered Bacterial System for Monitoring and Tracing Regulated Hazardous Chemicals.

Monitoring and tracing of regulated hazardous chemicals is a public security issue of global concern. However, accurately recording historical exposure remains challenging. Here, we designed a Biological Sentinel System (BOSS) for in situ and long-term monitoring of hazardous chemical exposure using a chemical-induced base-editing system that activates antibiotic resistance screening, producing an obvious colorimetric signal. Exposure events can be written into an inheritable genomic DNA sequence, which can be read using gene sequencing. As a proof of concept, we demonstrated the accurate detection of cocaine and 2,4-dinitrotoluene using BOSS under simulated application scenarios. In addition, we integrated alternative biosensors to illustrate the modularity and extensibility of this monitoring platform. This work provides a promising paradigm for developing engineered microorganisms as an alternative to electronic monitors for regulated hazardous chemicals.

Structural Regulation and Oxygen Reduction Reaction Activity of [Co(bpy)2BO2(OH)] and [Cu(bpy)(OH)]2- Complex Templated Borates.

Two templated borates, [Co(bpy)2BO2(OH)]·[B5O6(OH)4]·H3BO3·H3O·H2O (1) and [Cu(bpy)(OH)]2·[B5O6(OH)4]2·H2O (2), have been synthesized successfully and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, and Fourier transform infrared. The [Co(bpy)2BO2(OH)] complex in 1 shows a very rare coordination mode between Co2+ and BO2(OH)2-. The structures of 1 and 2 can be adjusted by changing the reagent. The oxygen reduction reaction activity of these Co- and Cu-based catalysts was studied. The E1/2 values of Co-C-750 and Cu-C-750 are 0.864 and 0.837 V, respectively.

Effect of intravenous vs. inhaled penehyclidine on respiratory mechanics in patients during one-lung ventilation for thoracoscopic surgery: a prospective, double-blind, randomised controlled trial.

BACKGROUND: Minimising postoperative pulmonary complications (PPCs) after thoracic surgery is of utmost importance. A major factor contributing to PPCs is the driving pressure, which is determined by the ratio of tidal volume to lung compliance. Inhalation and intravenous administration of penehyclidine can improve lung compliance during intraoperative mechanical ventilation. Therefore, our study aimed to compare the efficacy of inhaled vs. intravenous penehyclidine during one-lung ventilation (OLV) in mitigating driving pressure and mechanical power among patients undergoing thoracic surgery. METHODS: A double-blind, prospective, randomised study involving 176 patients scheduled for elective thoracic surgery was conducted. These patients were randomly divided into two groups, namely the penehyclidine inhalation group and the intravenous group before their surgery. Driving pressure was assessed at T1 (5 min after OLV), T2 (15 min after OLV), T3 (30 min after OLV), and T4 (45 min after OLV) in both groups. The primary outcome of this study was the composite measure of driving pressure during OLV. The area under the curve (AUC) of driving pressure from T1 to T4 was computed. Additionally, the secondary outcomes included mechanical power, lung compliance and the incidence of PPCs. RESULTS: All 167 participants, 83 from the intravenous group and 84 from the inhalation group, completed the trial. The AUC of driving pressure for the intravenous group was 39.50 ± 9.42, while the inhalation group showed a value of 41.50 ± 8.03 (P = 0.138). The incidence of PPCs within 7 days after surgery was 27.7% in the intravenous group and 23.8% in the inhalation group (P = 0.564). No significant differences were observed in any of the other secondary outcomes between the two groups (all P > 0.05). CONCLUSIONS: Our study found that among patients undergoing thoracoscopic surgery, no significant differences were observed in the driving pressure and mechanical power during OLV between those who received an intravenous injection of penehyclidine and those who inhaled it. Moreover, no significant difference was observed in the incidence of PPCs between the two groups.

Hybrids of polyphenolic acids and xanthone, the potential preventive and therapeutic effects on PD: Design, synthesis, in vitro anti-aggregation of α-synuclein, and disaggregation against the existed α-synuclein oligomer and fibril.

The misfolding and aggregation of α-Syn are the central mechanism linking and facilitating the other pathological mechanisms of PD. Maintaining α-Syn proteostasis by suitable inhibitors is an effective means to prevent PD. Disintegrating the neurotoxic oligomers and fibrils into the normal functional α-Syn by inhibitors is a more efficient way for PD treatment. This work synthesized two series hybrids of polyphenolic acids and xanthone. The hybrids possess a sheet-like conjugated skeleton and higher binding energies with α-Syn residues. Some compounds present well α-Syn aggregation inhibitory activities in vitro (IC50 down to 2.58 µM). The inhibitory action goes throughout the aggregation process from lag to the stationary phase by stabilizing α-Syn proteostasis conformation and preventing ß-sheets aggregation. The candidate compounds with appropriate LogP values (2.02-3.11) present good disintegration abilities against the existed α-Syn oligomers and fibrils. The preliminary mechanism studies suggest that the inhibitors could quickly and randomly bind to the specific site closed to the ß-sheet domain in the fibril, resulting in unstable and collapse of the protein fibril, yielding a complex system with aggregates of different sizes and monomers.

Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition.

Immune checkpoint blockade has shown significant clinical benefit in multiple cancer indications, but many patients are either refractory or become resistant to the treatment over time. HER2/neu oncogene overexpressed in invasive breast cancer patients associates with more aggressive diseases and poor prognosis. Anti-HER2 mAbs, such as trastuzumab, are currently the standard of care for HER2-overexpressing cancers, but the response rates are below 30% and patients generally suffer relapse within a year. In this study we developed a bispecific antibody (BsAb) simultaneously targeting both PD1 and HER2 in an attempt to combine HER2-targeted therapy with immune checkpoint blockade for treating HER2-positive solid tumors. The BsAb was constructed by fusing scFvs (anti-PD1) with the effector-functional Fc of an IgG (trastuzumab) via a flexible peptide linker. We showed that the BsAb bound to human HER2 and PD1 with high affinities (EC50 values were 0.2 and 0.14 nM, respectively), and exhibited potent antitumor activities in vitro and in vivo. Furthermore, we demonstrated that the BsAb exhibited both HER2 and PD1 blockade activities and was effective in killing HER2-positive tumor cells via antibody-dependent cellular cytotoxicity. In addition, the BsAb could crosslink HER2-positive tumor cells with T cells to form PD1 immunological synapses that directed tumor cell killing without the need of antigen presentation. Thus, the BsAb is a new promising approach for treating late-stage metastatic HER2-positive cancers.

MG53 represses high glucose-induced inflammation and angiogenesis in human retinal endothelial cells by repressing the EGR1/STAT3 axis.

BACKGROUND: Diabetic retinopathy (DR) is a vascular complication of diabetes mellitus that leads to visual injury and blindness. Both angiogenesis and inflammation play an important role in the pathogenesis of DR. Here we aimed to explore the mechanisms of mitsugumin 53 (MG53) in ameliorating the dysfunction induced by high glucose (HG) in humans retinal microvascular endothelial cells (HRECs). METHODS: HRECs were subjected to HG in the presence or absence of MG53 overexpression. The effect of MG53 on cell viability and inflammatory response in HG-treated HRECs was measured using the Cell Counting Kit-8 and ELISAs, respectively. Expression of MG53, EGR1, p-STAT3, FGF2, TGFB1, and Angiopoietin-1 in HG-treated HRECs was quantified by western blot or quantitative real-time polymerase chain reaction. RESULTS: HG significantly downregulated MG53 in HRECs, which reduced cell viability while inducing angiogenesis and inflammatory response. Upregulation of MG53 reversed these effects of HG. MG53 directly interacted with EGR1 and repressed its expression, which decreased phosphorylation of STAT3 and downregulated FGF2, TGFB1, and Angiopoietin-1. EGR1 up-regulation or STAT3 activation antagonized the protective effects of MG53. CONCLUSION: MG53 alleviates HG-induced dysfunction in HRECs by repressing EGR1/STAT3 signaling. Thereby MG53 may have therapeutic potential in DR.

Early chest CT features of patients with 2019 novel coronavirus (COVID-19) pneumonia: relationship to diagnosis and prognosis.

OBJECTIVE: To determine the consistency between CT findings and real-time reverse transcription-polymerase chain reaction (RT-PCR) and to investigate the relationship between CT features and clinical prognosis in COVID-19. METHODS: The clinical manifestations, laboratory parameters, and CT imaging findings were analyzed in 34 COVID-19 patients, confirmed by RT-PCR from January 20 to February 4 in Hainan Province. CT scores were compared between the discharged patients and the ICU patients. RESULTS: Fever (85%) and cough (79%) were most commonly seen. Ten (29%) patients demonstrated negative results on their first RT-PCR. Of the 34 (65%) patients, 22 showed pure ground-glass opacity. Of the 34 (50%) patients, 17 had five lobes of lung involvement, while the 23 (68%) patients had lower lobe involvement. The lesions of 24 (71%) patients were distributed mainly in the subpleural area. The initial CT lesions of ICU patients were distributed in both the subpleural area and centro-parenchyma (80%), and the lesions were scattered. Sixty percent of ICU patients had five lobes involved, while this was seen in only 25% of the discharged patients. The lesions of discharged patients were mainly in the subpleural area (75%). Of the discharged patients, 62.5% showed pure ground-glass opacities; 80% of the ICU patients were in the progressive stage, and 75% of the discharged patients were at an early stage. CT scores of the ICU patients were significantly higher than those of the discharged patients. CONCLUSION: Chest CT plays a crucial role in the early diagnosis of COVID-19, particularly for those patients with a negative RT-PCR. The initial features in CT may be associated with prognosis. KEY POINTS: • Chest CT is valuable for the early diagnosis of COVID-19, particularly for those patients with a negative RT-PCR. • The early CT findings of COVID-19 in ICU patients differed from those of discharged patients.

Inner ear function in patients with obstructive sleep apnea.

OBJECTIVE: Because of their high metabolic activity and low-resting oxygen tension, the organs of the inner ear are vulnerable to hypoxia, a condition that occurs repetitively in obstructive sleep apnea-hypopnea syndrome (OSAHS). The present study aimed to investigate the inner ear function of patients with OSAHS. METHODS: A total of 58 patients with OSAHS (116 ears) and 20 adults without OSAHS were enrolled in the present study. The clinical features, such as air-conduction thresholds, auditory brainstem response (ABR, 11 times/s and 51 times/s stimulation rates), and distorted products otoacoustic emission (DPOAE), were evaluated and compared between these two groups. RESULTS: Air-conduction thresholds at 4 kHz and 8 kHz were higher in patients with OSAHS compared with controls (P < 0.001). At the rate of 11 times per second, biauricular wave I latencies and wave V latencies in the OSAHS group were longer than those in the control group (1.51 ± 0.13 vs. 1.33 ± 0.07 ms, P < 0.001; 5.65 ± 0.23 vs. 5.53 ± 0.23 ms, P = 0.0016). At the rate of 51 times per second, biauricular wave I latencies and wave V latencies in the OSAHS group were longer than those in the control group (1.64 ± 0.12 vs. 1.44 ± 0.06 ms, P = 0.0001; 5.92 ± 0.26 vs. 5.80 ± 0.18 ms, P = 0.0077). However, there was no significant difference in the wave I and wave V interval between these two groups (P = 0.10). DPOAE amplitude was significantly reduced in OSAHS patients, although no hearing loss was observed. CONCLUSION: High-frequency hearing loss was detected in adults with severe OSAHS, and wave I latencies and wave V latencies of ABR were prolonged.

Proximal femoral nail anti-rotation versus cementless bipolar hemiarthroplasty for unstable femoral intertrochanteric fracture in the elderly: a retrospective study.

BACKGROUND: The treatment for unstable intertrochanteric fractures in the elderly has always been a controversial issue. The aim in this study was to compare the curative effects of proximal femoral nail anti-rotation (PFNA) and cementless bipolar hemiarthroplasty (CPH) on femoral intertrochanteric fracture in the elderly. METHODS: From March 2008 to December 2012, 108 elderly patients with femoral intertrochanteric fractures were treated by PFNA or CPH. There were 63 males and 45 females, aged 75.3-99.1 years [(83.7 ± 5.6) years]. The patients' bone mineral density was routinely measured, and the fractures were classified according to Evans-Jensen. The patients were divided into CPH group and PFNA group. The differences in operation time, intraoperative bleeding, immobilization duration, hospitalization time, Harris scores and postoperative complications including deep venous thrombosis, lung and urinary infection were analyzed. RESULTS: All patients were followed for 12.5-36.2 months [(28.0 ± 6.3) months)]. The operation time was (53.7 ± 15.2) min and (77.5 ± 16.8) min in PFNA group and CPH group, respectively (P < 0.05); intraoperative bleeding was (132.5 ± 33.2) mL and (286.3 ± 43.2) mL, respectively (P < 0.05); immobilization duration was (28.2 ± 3.7) days and (3.1 ± 1.2) days, respectively (P < 0.05); hospitalization time was (7.6 ± 1.8) days and (6.9 ± 2.2) days, respectively (P > 0.05); and the Harris scores after 1 year were (87.7 ± 7.9) points and (88.3 ± 9.2) points, respectively (P > 0.05). There was no significant difference in postoperative complications between the two groups (P > 0.05). CONCLUSION: Both PFNA and CPH are safe and effective treatments for femoral intertrochanteric fracture in elderly patients. Nonetheless, CPH allows faster mobilization and recovery. TRIAL REGISTRATION: Registration Number: ChiCTR1900022846 . Reg Date:2019-04-26 00:27:33 Retrospective registration.

Tumor-Secreted Exosomal miR-222 Promotes Tumor Progression via Regulating P27 Expression and Re-Localization in Pancreatic Cancer.

BACKGROUND/AIMS: MicroRNAs (miRNAs) or exosomes have recently been shown to play vital regulatory or communication roles in cancer biology. However, the roles and mechanisms of exosomal miRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unknown. We aimed to investigate the detailed roles and mechanisms of tumor-generated exosomal miRNAs in progression of PDAC. METHODS: miR-222 was identified by miRNA microarray studies in exosomes of PDAC cells, and further analyzed in plasma exosomes of PDAC patients. The regulatory mechanisms of miR-222 were explored by qRT-PCR, WB, dual-luciferase assays and immunofluorescence or confocal analysis. Other biological assays include transwell, xenograft models and so on. RESULTS: miR-222 is significantly high in tumor exosomes or highly invasive PDAC cells. miR-222 could directly regulate p27 to promote cell invasion and proliferation. miR-222 could also activate AKT by inhibiting PPP2R2A expression, thus inducing p27 phosphorylation and cytoplasmic p27 expression to promote cell survival, invasion and metastasis. Expressions of miR-222 and p27 were significantly inversely correlated, and cytoplasmic p27, instead of nuclear p27, was associated with tumor malignancy. miR-222 could be transmitted between PDAC cells via exosome communication, and the exosomal miR-222 communication is functional. Plasma exosomal miR-222 in PDAC patients was high and significantly correlated to tumor size and TNM stage, and was an independent risk factor for PDAC patient survival. CONCLUSION: Tumor-generated exosomes could promote invasion and proliferation of neighboring tumor cells via miR-222 transmission, the plasma exosomal miR-222 plays important roles and may be a useful prognostic maker in PDAC.

Low expression level of HMBOX1 in high-grade serous ovarian cancer accelerates cell proliferation by inhibiting cell apoptosis.

Homeobox-containing 1 (HMBOX1) has been described as a transcription factor involved in the occurrence of some tumors, but its roles in ovarian cancer have never been reported. Here we aimed to investigate the roles of HMBOX1 on high-grade serous ovarian carcinoma (HGSOC). In this present study, HMBOX1 expression was decreased in HGSOC tissues and ovarian cancer cell lines (HO8910 and A2780) compared with ovarian surface epithelial tissues or normal human ovarian surface epithelial cell line (HOSEpiC). The cell proliferation of HOSEpiC was weaker than ovarian cancer cell lines. By altering the expression of HMBOX1 in A2780 and HOSEpiC, we demonstrated that HMBOX1 inhibited the cell proliferation and promoted the cell apoptosis. Furthermore, our study revealed that HMBOX1 downregulated the expression of anti-apoptotic proteins (Bcl-2, Bcl-xL), raised the expression of pro-apoptotic-regulated proteins (Bad, Bax), apoptotic executionior (Caspase3), and P53. In conclusion, HMBOX1 played important roles in occurrence of HGSOC through regulation of proliferation and apoptosis, which implied that HMBOX1 might serve as a new therapeutic target for HGSOC.

[Choice of total knee arthroplasty: posterior cruciate ligament preserved or not].

Total knee arthroplasty is an effective method for the treatment of end-stage knee osteoarthrosis, which can effectively relieve joint pain and reconstruct the integrity of the joint. Whether the posterior cruciate ligament should be preserved during surgery or not, which is still in dispute. In recent years, posterior cruciate-retaining and substituting total knee prostheses are both applied in clinical practice. Both domestic and international studies have shown that there are no significant difference in patient satisfaction, knee flexion, survival rate of the prosthesis and the main clinical manifestations between two prostheses. However, posterior cruciate-retaining total knee prosthesis is more consistent with the normal physiology and biomechanics of the human body. The gait is more balanced and proprioceptive when walking up and down the stairs, but when the joints are buckling, the femur is abnormal to move back to the tibia, resulting in abnormal motion. While posterior cruciate-substituting total knee prosthesis can correct severe deformity of the knee, and keep better balance between flexion and extension of the knee joint, but there is a potential complication of patellar clunk syndrome. Therefore, under the same conditions, the younger patients may prefer to chose posterior cruciate-retaining total knee prosthesis, while elder patients may prefer to chose posterior cruciate-substituting total knee prosthesis. This paper reviews the function of posterior cruciate ligament, as well as the advantages and disadvantages of two prostheses, so as to provide some references for clinic.

Isolation of a peptide from Ph.D.-C7C phage display library for detection of Cry1Ab.

Traditional ELISA methods of using animal immunity yield antibodies for detection Cry toxin. Not only is this incredibly harmful to the animals, but is also time-intensive. Here we developed a simple method to yield the recognition element. Using a critical selection strategy and immunoassay we confirmed a clone from the Ph.D-C7C phage library, which has displayed the most interesting Cry1Ab-binding characteristics examined in this study (Fig. 1). The current study indicates that isolating peptide is an alternative method for the preparation of a recognition element, and that the developed assay is a potentially useful tool for detecting Cry1Ab.

Low CREBBP expression is associated with adverse long-term outcomes in paediatric acute lymphoblastic leukaemia.

OBJECTIVES: CREBBP alterations are associated with many diseases including leukaemia. However, CREBBP expression and its clinical relevance in paediatric acute lymphoblastic leukaemia have not been elucidated. METHODS: We studied CREBBP mRNA expression in 349 patients treated with either the BCH-2003 or CCLG-2008 protocol. Using a receiver operating characteristic curve, patients were divided into low- or high-CREBBP. The association among clinicobiological characteristics, outcomes and CREBBP level was analysed. RESULTS: Low expression of CREBBP (<1.0) at diagnosis was found in 97.7% of patients and increased significantly after complete remission. Low-CREBBP patients were associated with unfavourable clinical presentations, poor prednisone response and high minimal residual disease (>10-2 ) after induction. We found significantly poorer event-free survival (EFS) and overall survival (OS) in low-CREBBP group whether administered BCH-2003 or CCLG-2008. Low-CREBBP was an inferior independent prognostic factor in BCH-2003; patients with low-CREBBP had better outcomes on an intermediate-risk regimen than a standard-risk regimen involving the CCLG-2008 protocol. Patients stratified to high-risk with low-CREBBP had the worst EFS and OS. CONCLUSIONS: These findings indicate that low-CREBBP is predictive of unfavourable outcomes; thus, a more intensive treatment protocol is necessitated for standard-risk patients with insufficient CREBBP and that a specific target therapy is necessitated for high-risk patients.

Wenshen Zhuanggu formula effectively suppresses breast cancer bone metastases in a mouse Xenograft model.

Wenshen Zhuanggu formula (WSZG) is a traditional Chinese medicine used as an adjuvant for the prevention of bone metastases in breast cancer patients. In this study we investigated the efficacy of WSZG in preventing bone metastases and the potential mechanisms in a mouse xenograft model of breast cancer bone metastases. This model was established by injection of human MDA-MB-231BO-Luc breast cancer cells alone or a mixture of the cancer cells with bone marrow-derived mesenchymal stem cells (BMSCs) into left ventricle of the heart in female nude mice. Then the mice were treated with WSZG (3.25, 6.5 or 13.0 mg·kg-1·d-1, ig) for four weeks, whereas zoledronic acid (100 µg/kg per week, ig) was used as a positive control. The occurrence and development of bone metastases were monitored via bioluminescent imaging, and bone lesions were assessed using micro-CT. Intracardiac injection of the mixture of MDA-MB-231BO-Luc breast cancer cells with BMSCs significantly facilitated the bone metastatic capacity of the breast cancer cells, and aggravated bone lesions in the mouse xenograft model of breast cancer bone metastases. Administration of WSZG dose-dependently inhibited the incidence and intensity of bone metastases and protected against bone lesions by suppressing osteoclast formation and tumor cell infiltration. Furthermore, administration of WSZG caused a marked reduction in the expression of CCL5/CCR5 and IL-17B/IL-17BR in bone metastatic tissues. The results demonstrate that WSZG exerts potential therapeutic effects in a mouse xenograft model of breast cancer bone metastases, which are partially mediated by weakening the interaction between BMSCs and breast cancer cells in the tumor microenvironment.