Wernekinck Commissure Syndrome with Holmes Tremor: A Report of Two Cases and Review of Literature.

Wernekinck commissure syndrome is a rare midbrain infarction, it consists of several symptoms including bilateral cerebellar ataxia, ophthalmoplegia, and palatal tremor. Holmes tremor is a rare clinical syndrome characterized by a combination of resting, postural, and action tremors. We describe two cases of Wernekinck commissure syndrome with Holmes tremor. To the best of our knowledge, it has been rarely reported in the literature to date. Both of the cases were presented with acute onset of bilateral cerebellar ataxia, dysarthria, and Holmes tremor. In the treatment, one patient was given "clonazepam and benheisol," the other was received acupuncture therapy, both of them showed a marked improvement in ataxia and tremor.

Conjugating MMAE to a novel anti-HER2 antibody for selective targeted delivery.

OBJECTIVE: To investigate the target delivery properties of RC48-ADC, a novel antibody drug conjugate (ADC) comprising cytotoxic monomethyl auristatin E (MMAE) and an anti-human epidermal growth factor receptor 2 (HER2) antibody tethered via valine-citrulline linker, in vitro and in vivo. MATERIALS AND METHODS: Dissociation rate of MMAE from RC48-ADC was used as an estimate of its stability in serum. Cytotoxicity of the antibody and RC48-ADC towards multiple cell lines was measured. Subcellular distribution of the drug was determined by fluorescence imaging. The mechanism of lysosome targeting was verified. Endocytic pathways of RC48-ADC were assessed by the cellular fluorescence intensity of fluorescently-labelled drugs. Intracellular and extracellular distribution of MMAE was analysed after RC48-ADC or MMAE administration to characterize MMAE release. The serum and tumour concentration of MMAE was compared after tail-vein injection of RC48-ADC into tumour-bearing mice. RESULTS: RC48-ADC was highly stable in human serum. HER2-overexpressed cell line SK-BR-3 proliferation was stronger when suppressed by RC48-ADC than by the naked antibody. Both RC48-ADC and naked antibody were internalized via caveolae-mediated and clathrin-mediated endocytosis and concentrated in lysosomes. Higher HER2 expression was associated with enhanced uptake and intracellular release of conjugated MMAE; free MMAE could kill tumour cells via the bystander effect. Although serum RC48-ADC concentration was higher than that in tumours, exposure of MMAE in tumours was ~200 times higher than in serum, which rationalized the reduced toxicity of RC48-ADC. CONCLUSIONS: In vitro and in vivo experiments confirmed the targeted transport and release of RC48-ADC; it could selectively deliver MMAE to the targeted HER2-positive cell or tumour tissue, which could reduce off-target toxicity and enhance anti-tumour potency in humans.

[Synchronous lymphoma and carcinoma-clinical analyses of 17 patients].

Objective: To explore the clinical features of patients with synchronous lymphoma and carcinoma. Methods: The clinical data of 17 patients with Synchronous lymphoma and carcinoma from February 2012 to October 2017 were analyzed retrospectively. Results: Among 17 patients of lymphoma, 1 case HL, 2 cases B-NHL, 6 cases MZBL, 3 cases DLBCL, 1 case mantle cell lymphoma (MCL) , 3 cases NK/T- cell lymphoma, 1 case anaplastic large cell lymphoma(ALCL). In terms of 17 patients with carcinoma, 3 cases esophageal carcinoma, 3 cases gastric carcinoma, 2 cases colorectal carcinoma, 7 cases thyroid carcinoma, 1 case hepatocellular carcinoma and lung cancer. Up to 15 patients received operation, and some of them combined with chemotherapy, radiotherapy and autologous transplant. Follow-up analysis showed that 3 cases was undergoing treatment, 2 cases lost follow-up, 4 cases died, 3 cases achieved CR, 3 cases remained to be at SD, and 2 cases assessed for progression or recurrence. Conclusion: The relationship between lymphoma and carcinoma was under discussion, patients with synchronous lymphoma and carcinoma were not unusual. We herein should raise awareness to avoid misdiagnosis.

[Clinical features of 11 cases of primary bone lymphoma].

Objective: To analyze the clinical features, treatment and outcomes of primary lymphoma of bone (PLB) . Methods: The clinical data of 11 PLB patients were retrospectively analyzed. Results: 11 patients were enrolled in our study including 7 females and 4 males. The median age of the patients was 45 years old. The main histologic type was diffuse large B cell lymphoma and anaplastic large cell lymphoma. Of the 11 PLB cases, 3 cases were at stage ⅠE, 2 at stage ⅡE, 6 at stage ⅣE respectively. 6 cases were treated with chemotherapy and radiotherapy, 2 cases with total joint arthroplasty and chemotherapy, and 3 cases chemotherapy alone respectively. 5 cases got complete remission, 4 cases partial remission and 2 cases stable disease respectively. The median progression free survival was 17 (5-58) months after a median follow up of 21 (6-58) months. Conclusions: Most of PLB patients were clinically in late stage lacking of clinical and imagine features. The optimal treatment for PLB was radiotherapy combined with chemotherapy, and its prognosis was relatively good.

The potential of mesenchymal stem cells in the management of radiation enteropathy.

Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies.

Harnessing the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated Cas9 system to disrupt the hepatitis B virus.

The current therapies to treat hepatitis B virus (HBV) infection are limited. Recently, clustered regularly interspaced short palindromic repeat (CRISPR) systems, originally identified in bacteria and archaea, have been found to consist of an RNA-based adaptive immune system that degrades complimentary sequences of invading plasmids and viruses. Here, we studied the effects of the CRISPR/CRISPR-associated Cas9 system that was targeted to the surface antigen (HBsAg)-encoding region of HBV, both in a cell culture system and in vivo. The HBsAg levels in the media of the cells and in the sera of mice were analyzed by a quantitative enzyme-linked immunosorbent assay. The HBV DNA levels were assessed by quantitative PCR and HBsAg expression in mouse livers was assessed by an immunohistochemical assay. The amount of HBsAg secreted in the cell culture and mouse serum was reduced by CRISPR/Cas9 treatment. Immunohistochemistry analyses showed almost no HBsAg-positive cells in the liver tissue of CRISPR/Cas9-S1+X3-treated mice. The CRISPR/Cas9 system efficiently produced mutations in HBV DNA. Thus, CRISPR/Cas9 inhibits HBV replication and expression in vitro and in vivo and may constitute a new therapeutic strategy for HBV infection.

Radiosensitization of breast cancer cells by TRAIL-endostatin-targeting gene therapy.

One of the key issues in cancer radiotherapy research is to sensitize tumor cells to the cell killing effects of ionizing radiation while leaving normal tissues intact. One potential approach to achieve this is gene-radiotherapy, i.e. a combination of radiation therapy and gene therapy. It is to choose certain exogenous radiation-inducible regulatory genes, for example, early growth response-1 (Egr-1), and transcript its downstream tumor-therapeutic genes under ionizing radiation so as to kill the tumor cells synergistically by the expressed gene products together after transfection and irradiation exposure. In this study, we engineered a plasmid encoding both TRAIL and endostatin under the control of the radiation-inducible Egr-1 promoter, and evaluated its anti-tumor efficacy in combination with radiotherapy. Our plasmid showed significant efficacy in up-regulating the levels of TRAIL and endostatin proteins after transfected into breast cancer cells and exposed to X-ray irradiation. The detected cellular effects in vitro manifested that TRAIL-endostatin-based gene therapy could enhance radiosensitizing effects in breast cancer cells in terms of tumor cell growth inhibition, promoting apoptosis and the induction of cell cycle arrest. In summary, our results suggest that TRAIL-endostain-targeting approach might be a promising method to sensitize solid tumors to radiation therapy.

Microstructure, mechanical property and corrosion behavior of interpenetrating (HA+ß-TCP)/MgCa composite fabricated by suction casting.

The novel interpenetrating (HA+ß-TCP)/MgCa composites were fabricated by infiltrating MgCa alloy into porous HA+ß-TCP using suction casting technique. The microstructure, mechanical properties and corrosion behaviors of the composites have been evaluated by means of scanning electron microscopy (SEM), X-ray diffraction (XRD), mechanical testing, electrochemical and immersion tests. It was shown that the composites had compact structure and the interfacial bonding between MgCa alloy and HA+ß-TCP scaffolds was very well. The ultimate compressive strength of the composites was about 500-1000 fold higher than that of the original porous scaffolds, and it still retained quarter-half of the strength of the bulk MgCa alloy. The electrochemical and immersion tests indicated that the corrosion resistance of the composites was better than that of the MgCa matrix alloy, and the corrosion products of the composite surface were mainly Mg(OH)2, HA and Ca3(PO4)2. Meanwhile, the mechanical and corrosive properties of the (HA+ß-TCP)/MgCa composites were adjustable by the choice of HA content.

Microstructure, mechanical property and corrosion behaviors of interpenetrating C/Mg-Zn-Mn composite fabricated by suction casting.

A novel interpenetrating C/Mg-Zn-Mn composite was fabricated by infiltrating Mg-Zn-Mn alloy into porous carbon using suction casting technique. The microstructure, mechanical properties and corrosion behaviors of the composite have been evaluated by means of SEM, XRD, mechanical testing and immersion test. It was shown that the composite had a compact structure and the interfacial bonding between Mg-Zn-Mn alloy and carbon scaffold was very well. The composite had an ultimate compressive strength of (195 ± 15) MPa, which is near with the natural bone (2-180 MPa) and about 150-fold higher than that of the original porous carbon scaffold, and it still retained half of the strength of the bulk Mg-Zn-Mn alloy. The corrosion test indicated that the mass loss percentage of the composite was 52.9% after 30 days' immersion in simulated body fluid (SBF) at 37 ± 0.5 °C, and the corrosion rates were 0.043 mg/cm(2)h and 0.028 mg/cm(2)h after 3 and 7 days' immersion, respectively. The corrosion products on the composite surface were mainly Mg(OH)2 and hydroxyapatite (HA).

Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy.

Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients.

Receptor-based QSAR study for a series of 3,3-disubstituted-5-aryl oxindoles and 6-aryl benzimidazol-2-ones derivatives as progesterone receptor inhibitors.

Receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 54 progesterone receptor (PR) inhibitors. The established CoMFA model from the training set gives statistically significant results with the cross-validated q (2) of 0.534 and non-cross-validated [Formula: see text] of 0.947. The best CoMSIA model was derived by the combination of steric field and hydrophobic field with a q (2) of 0.615 and [Formula: see text] of 0.954. A test set of 18 compounds was used to validate the predictive ability of the two models. The predicted correlation coefficients [Formula: see text] are 0.681 and 0.677 for CoMFA and CoMSIA models, respectively. Based on the CoMFA maps, the key structural characters of progesterone receptor inhibitors are identified. Moreover, the binding modes of oxindoles and benzimidazol-2-ones are also given by the quantum mechanical/molecular mechanical (QM/MM) calculations. This may provide useful information for drug design.

Sources and properties of natural organic matter (NOM) in water along the Dongjiang River (the Source of Hong Kong's drinking water) and toxicological assay of its chlorination by-products.

The Dongjiang River is the major source of the drinking water supply for Hong Kong and also other parts of the Pearl River Delta in China, and the deterioration in the water quality of this river and the excessive levels of trihalomethanes (THMs) in the tap water of some districts in Hong Kong have become a matter of public concern. The main objective of the present study is to investigate the distribution patterns of natural organic matter (NOM) and their association with THM production in the Dongjiang River. We examined the physicochemical and biological properties of the river water and the corresponding sediment elutriate collected from four sampling sites along the Dongjiang River from upstream to downstream and chlorination experiments were conducted. Algal bioassays were performed in order to test the chlorination effects. The results showed that: (1) upstream NOM was derived from terrestrial input, while that at mid- and downstream was most likely derived from phytoplankton; (2) phytoplankton is a major contributor to NOM in the sediments, whereas sediments seem to be the site for major microbial degradation of NOM, biogeochemical recycling of nutrients and a potential NOM pool for the overlaying water during sediment resuspension; (3) dissolved organic carbon (DOC) in surface water is a good indicator for THM production, whereas ultraviolet (UV) absorbance at 254 nm (UV(254)) is a better predictor for THM formation in the elutriates; (4) the bioassay results showed that toxic compounds other than THMs in the chlorinated water are the major factors causing algal growth inhibition.