Tailoring Interlayer Chiral Exchange by Azimuthal Symmetry Engineering.

Recent theoretical and experimental studies of the interlayer Dzyaloshinskii-Moriya interaction (DMI) have sparked great interest in its implementation into practical magnetic random-access memory (MRAM) devices, due to its capability to mediate long-range chiral spin textures. So far, experimental reports focused on the observation of interlayer DMI, leaving the development of strategies to control interlayer DMI's magnitude unaddressed. Here, we introduce an azimuthal symmetry engineering protocol capable of additive/subtractive tuning of interlayer DMI through the control of wedge deposition of separate layers and demonstrate its capability to mediate field-free spin-orbit torque (SOT) magnetization switching in both orthogonally magnetized and synthetic antiferromagnetically coupled systems. Furthermore, we showcase that the spatial inhomogeneity brought about by wedge deposition can be suppressed by specific azimuthal engineering design, ideal for practical implementation. Our findings provide guidelines for effective manipulations of interlayer DMI strength, beneficial for the future design of SOT-MRAM or other spintronic devices utilizing interlayer DMI.

Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress.

BACKGROUND: Tumor cells display augmented capability to maintain endoplasmic reticulum (ER) homeostasis and hijack ER stress pathway for malignant phenotypes under microenvironmental stimuli. Metabolic reprogramming is a well-known hallmark for tumor cells to provide specific adaptive traits to the microenvironmental alterations. However, it's unknown how tumor cells orchestrate metabolic reprogramming and tumor progression in response to ER stress. Herein, we aimed to explore the pivotal roles of SEC63-mediated metabolic remodeling in hepatocellular carcinoma (HCC) cell metastasis after ER stress. METHODS: The expression levels of SEC63 in HCC tissues and adjacent non-cancerous tissues were determined by immunohistochemistry and western blot. The regulatory roles of SEC63 in HCC metastasis were investigated both in vitro and in vivo by RNA-sequencing, metabolites detection, immunofluorescence, and transwell migration/invasion analyses. GST pull-down, immunoprecipitation/mass spectrometry and in vivo ubiquitination/phosphorylation assay were conducted to elucidate the underlying molecular mechanisms. RESULTS: We identified SEC63 as a new regulator of HCC cell metabolism. Upon ER stress, the phosphorylation of SEC63 at T537 by IRE1α pathway contributed to SEC63 activation. Then, the stability of ACLY was upregulated by SEC63 to increase the supply of acetyl-CoA and lipid biosynthesis, which are beneficial for improving ER capacity. Meanwhile, SEC63 also entered into nucleus for increasing nuclear acetyl-CoA production to upregulate unfolded protein response targets to improve ER homeostasis. Importantly, SEC63 coordinated with ACLY to epigenetically modulate expression of Snail1 in the nucleus. Consequently, SEC63 promoted HCC cell metastasis and these effects were reversed by ACLY inhibition. Clinically, SEC63 expression was significantly upregulated in HCC tissue specimens and was positively correlated with ACLY expression. Importantly, high expression of SEC63 predicted unfavorable prognosis of HCC patients. CONCLUSIONS: Our findings revealed that SEC63-mediated metabolic reprogramming plays important roles in keeping ER homeostasis upon stimuli in HCC cells. Meanwhile, SEC63 coordinates with ACLY to upregulate the expression of Snail1, which further promotes HCC metastasis. Metastasis is crucial for helping cancer cells seek new settlements upon microenvironmental stimuli. Taken together, our findings highlight a cancer selective adaption to ER stress as well as reveal the potential roles of the IRE1α-SEC63-ACLY axis in HCC treatment.

Establishing biosynthetic pathway for the production of p-hydroxyacetophenone and its glucoside in Escherichia coli.

p-Hydroxyacetophenone (p-HAP) and its glucoside picein are plant-derived natural products that have been extensively used in chemical, pharmaceutical and cosmetic industries owing to their antioxidant, antibacterial and antiseptic activities. However, the natural biosynthetic pathways for p-HAP and picein have yet been resolved so far, limiting their biosynthesis in microorganisms. In this study, we design and construct a biosynthetic pathway for de novo production of p-HAP and picein from glucose in E. coli. First, screening and characterizing pathway enzymes enable us to successfully establish functional biosynthetic pathway for p-HAP production. Then, the rate-limiting step in the pathway caused by a reversible alcohol dehydrogenase is completely eliminated by modulating intracellular redox cofactors. Subsequent host strain engineering via systematic increase of precursor supplies enables production enhancement of p-HAP with a titer of 1445.3 mg/L under fed-batch conditions. Finally, a novel p-HAP glucosyltransferase capable of generating picein from p-HAP is identified and characterized from a series of glycosyltransferases. On this basis, de novo biosynthesis of picein from glucose is achieved with a titer of 210.7 mg/L under fed-batch conditions. This work not only demonstrates a microbial platform for p-HAP and picein synthesis, but also represents a generalizable pathway design strategy to produce value-added compounds.

Improving the Mechanical Properties of Damaged Hair Using Low-Molecular Weight Hyaluronate.

Chemical treatments of hair such as dyeing, perming and bleaching could cause mechanical damage to the hair, which weakens the hair fibers and makes the hair break more easily. In this work, hyaluronate (HA) with different molecular weight (MW) was investigated for its effects on restoring the mechanical properties of damaged hair. It was found that low-MW HA (average MW~42 k) could significantly improve the mechanical properties, specifically the elastic modulus, of overbleached hair. The fluorescent-labeling experiments verified that the low-MW HA was able to penetrate into the cortex of the hair fiber, while high-MW HA was hindered. Fourier transform infrared spectrometry (FT-IR) results implied the formation of additional intermolecular hydrogen bonds in the HA-treated hair. Thermos gravimetric analysis (TGA) indicated that the HA-treated hair exhibited decreased content of loosely bonded water, and differential scanning calorimetry (DSC) characterizations suggested stronger water bonding inside the HA-treated hair, which could alleviate the weakening effect of loosely bonded water on the hydrogen bond networks within keratin. Therefore, the improved elastic modulus and mechanical strength of the HA-treated hair could be attributed to the enhanced formation of hydrogen bond networks within keratin. This study illustrates the capability of low-MW HA in hair damage repair, implying an enormous potential for other moisturizers to be used in hair care products.

The Systematic Analyses of RING Finger Gene Signature for Predicting the Prognosis of Patients with Hepatocellular Carcinoma.

RING finger (RNF) proteins are frequently dysregulated in human malignancies and are tightly associated with tumorigenesis. However, the expression profiles of RNF genes in hepatocellular carcinoma (HCC) and their relations with prognosis remain undetermined. Here, we aimed at constructing a prognostic model according to RNF genes for forecasting the outcomes of HCC patients using the data from The Cancer Genome Atlas (TCGA) program. We collected HCC datasets to validate the values of our model in predicting prognosis of HCC patients from International Cancer Genome Consortium (ICGC) platform. Then, functional experiments were carried out to explore the roles of the representative RNF in HCC progression. A total of 107 differentially expressed RNFs were obtained between TCGA-HCC tumor and normal tissues. After comprehensive evaluation, a prognostic signature composed of 11 RNFs (RNF220, RNF25, TRIM25, BMI1, RNF216P1, RNF115, RNF2, TRAIP, RNF157, RNF145, and RNF19B) was constructed based on TCGA cohort. Then, the Kaplan-Meier (KM) curves and the receiver operating characteristic curve (ROC) were employed to evaluate predictive power of the prognostic model in testing cohort (TCGA) and validation cohort (ICGC). The KM and ROC curves illustrated the good predictive power in testing and validation cohort. The areas under the ROC curve are 0.77 and 0.76 in these two cohorts, respectively. Among the prognostic signature genes, BMI1 was selected as a representative for functional study. We found that BMI1 protein level was significantly upregulated in HCC tissues. Moreover, the inhibitor of BMI1, PTC-209, displayed an excellent anti-HCC effect in vitro. Enrichment analysis of BMI1 downstream targets showed that BMI1 might be involved in tumor immunotherapy. Together, our overall analyses revealed that the 11-RNFs prognostic signature might provide us latent chances for evaluating HCC prognosis and developing novel HCC therapy.

The Integrative Analysis of Thrombospondin Family Genes in Pan-Cancer Reveals that THBS2 Facilitates Gastrointestinal Cancer Metastasis.

Recent cancer studies have found that the thrombospondin (THBS) family, including THBS1, THBS2, THBS3, THBS4, and THBS5, play vital roles in the development and progression of human cancers. However, their relationships with tumor stage, prognosis, and tumor immunity in pan-cancer have not been systematically reported. In the present study, we employed versatile public databases to assess the expression and mutations of different THBSs in pan-cancer and performed functional experiments to analyze the roles of THBS2 in gastrointestinal cancer metastasis. Our findings indicate that THBS genes are frequently mutated in various cancers and the dysregulation of THBS family members is associated with the progression of some cancers such as gastric cancer, colon cancer, and lung cancer. Further analyses indicate that THBS genes are associated with cancer hallmarks such as cell cycle and epithelial-mesenchymal transition (EMT). Importantly, thrombospondins, especially THBS1 and THBS2, are correlated with the immune cell infiltration level in gastrointestinal cancers. Our experiments further verified that THBS2 participates in tumor metastasis by enhancing EMT. Therefore, the overall analyses reveal that THBSs might offer us potential chances for tumor diagnosis and therapy.

Spectral polarization camera based on ghost imaging via sparsity constraints.

A spectral polarization camera based on ghost imaging via sparsity constraints (GISC) is presented. The proposed imager modulates three-dimensional spatial and spectral information of the target into two-dimensional speckle patterns using a spatial random phase modulator and then acquires the speckle patterns at four linear polarization channels through a polarized CCD. The experimental results verify the feasibility of the system structure and reconstruction algorithm. The GISC spectral polarization camera, which has a simple structure and achieves compressive sampling during the imaging acquisition process, provides a simple scheme for obtaining multi-dimensional information of the light field.

Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/ß-catenin pathway.

BACKGROUND: Cancer stem cell (CSC)-related chemoresistance leads to poor outcome of the patients with colorectal cancer (CRC). In this study, we identified the chemoresistance-relevant molecules and decipher the involved mechanisms to provide potential therapeutic target for CRC. We focused on Sec62, a novel target with significantly increased expression in chemoresistant CRC tissues, and further investigated its role in the progression of CRC. METHODS: Through analyzing the differentially-expressed genes between chemoresistant and chemosensitive CRCs, we selected Sec62 as a novel chemoresistance-related target in CRC. The expression and clinical significance of Sec62 were determined by immunoblotting and immunohistochemistry in tissues and cell lines of CRC. The roles of Sec62 in drug resistance, stemness and tumorigenesis were evaluated in vitro and in vivo using functional experiments. GST pull-down, western blot, coimmunoprecipitation and Me-RIP assays were performed to further explore the downstream molecular mechanisms. RESULTS: Sec62 upregulation was associated with the chemoresistance of CRC and poor outcome of CRC patients. Depletion of Sec62 sensitized CRC cells to chemotherapeutic drugs. Sec62 promoted the stemness of CRC cells through activating Wnt/ß-catenin signaling. Mechanistically, Sec62 bound to ß-catenin and inhibited the degradation of ß-catenin. Sec62 competitively disrupted the interaction between ß-catenin and APC to inhibit the ß-catenin destruction complex assembly. Moreover, Sec62 expression was upregulated by the m6A-mediated stabilization of Sec62 mRNA. CONCLUSIONS: Sec62 upregulated by the METTL3-mediated m6A modification promotes the stemness and chemoresistance of CRC by binding to ß-catenin and enhancing Wnt signalling. Thus, m6A modification-Sec62-ß-catenin molecular axis might act as therapeutic targets in improving treatment of CRC.

Borane-Catalyzed Chemoselective and Enantioselective Reduction of 2-Vinyl-Substituted Pyridines.

Herein, we report that highly chemoselective and enantioselective reduction of 2-vinyl-substituted pyridines has been achieved for the first time. The reaction, which uses chiral spiro-bicyclic bisboranes as catalysts and HBpin and an acidic amide as reducing reagents, proceeds through a cascade process involving 1,4-hydroboration followed by transfer hydrogenation of a dihydropyridine intermediate. The retained double bond in the reduction products permits their conversion to natural products and other useful heterocyclic compounds by simple transformations.

RON and MET Co-overexpression Are Significant Pathological Characteristics of Poor Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is highly malignant and has poor prognosis and a high mortality rate. The lack of effective therapy has spurred our investigation of new targets for treating this malignant cancer. Here, we identified RON (macrophage-stimulating 1 receptor) and MET (MET proto-oncogene, receptor tyrosine kinase) as a prognostic biomarker and therapeutic targets for potential TNBC treatment. MATERIALS AND METHODS: We analyzed RON and MET expression in 187 primary TNBC clinical samples with immunohistochemistry. We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. The preclinical therapeutic efficacy of the TKIs was mainly estimated using a TNBC xenograft model. RESULTS: Patients with TNBC had widespread, abnormal expression of RON and MET. There was RON overexpression, MET overexpression, and RON and MET co-overexpression in 63 (33.7%), 63 (33.7%), and 43 cases (23.0%), respectively, which had poor prognosis and short survival. In vivo, the TKI targeting RON ant MET inhibited the activation of the downstream signaling molecules, inhibited TNBC cell migration and proliferation, and increased TNBC cell apoptosis; in the xenograft model, they significantly inhibited tumor growth and shrank tumor volumes. The TKI targeting RON and Met, such as BMS-777607 and tivantinib, yielded stronger anti-tumor effects than INCB28060. CONCLUSION: RON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.

Pulmonary intimal sarcoma involving the pulmonary valve and right ventricular outflow tract: A case report and literature review.

INTRODUCTION: Pulmonary artery intimal sarcoma (PAIS) is a rare and highly aggressive tumor, and approximately 80% of pulmonary cases occur in the pulmonary trunk. We report herein a case of retrograde extension of the sarcoma to the pulmonary valve and right ventricle, which is an uncommon manifestation of this lethal tumor. PATIENT CONCERNS: A 41-year-old woman was initially diagnosed with pulmonary thromboembolism (PTE) and transferred to our hospital. DIAGNOSIS: Computed tomographic pulmonary angiography (CTPA) showed that there are low-density filling defects in both pulmonary arteries, and the patient was diagnosed with PTE. However, the ultrasonographers considered that the lesion is a space-occupying type that involves the right ventricular outflow tract and pulmonary valve instead of PTE. Postoperative pathology confirmed the diagnosis of PAIS. INTERVENTIONS: The patient underwent resection of pulmonary artery sarcoma and endarterectomy. OUTCOMES: During the follow-up via telephone 1 month after discharge, the patient reported to have been feeling well. CONCLUSION: Owing to the rarity of the disease and its non-specific clinical manifestations, approximately half of the PAIS cases are misdiagnosed or have a delayed diagnosis. Thus, improving our understanding of the disease and facilitating its early diagnosis are essential.

Aberrant RON and MET Co-overexpression as Novel Prognostic Biomarkers of Shortened Patient Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Pancreatic Cancer.

RON (recepteur d'origine nantais) and MET (hepatocyte growth factor receptor) are tyrosine kinase receptors. Various cancers have aberrant RON and MET expression and activation, which contribute to cancer cell proliferation, invasiveness, and metastasis. Here, we explored RON and MET expression in pancreatic cancer and their relationship with overall survival (OS) time, and evaluated their significance as therapeutic targets of tyrosine kinase inhibitors in pancreatic cancer. We enrolled 227 patients with pancreatic cancer in the study. RON and MET expression was analyzed by immunohistochemical staining. Four human pancreatic cancer cell lines expressing variable levels of RON or MET and four MET superfamily inhibitors (BMS777607, PHA665752, INCB28060, Tivantinib) were used. The effect of the four tyrosine kinase inhibitors on cell viability, migration, and apoptosis were determined using cell viability, scratch wound healing, and Caspase-Glo 3/7 assays. Cellular signaling was analyzed by immunoprecipitation and western blotting. The therapeutic efficacy of the tyrosine kinase inhibitors was determined with mouse xenograft pancreatic cancer models in vivo. There was wide aberrant RON and MET expression in the cancer tissues. In 227 pancreatic cancer samples, 33% had RON overexpression, 41% had MET overexpression, and 15.4% had RON and MET co-overexpression. RON and MET expression were highly correlated. RON and MET expression levels were significantly related to OS. Patients with RON and MET co-overexpression had poorer OS. BMS777607 and PHA665752 inhibited pancreatic cancer cell viability and migration, and promoted apoptosis by inhibiting RON and MET phosphorylation and further inhibiting the downstream signaling pathways in vitro. They also inhibited tumor growth and further inhibited phosphorylated (phosphor)-RON and phospho-MET expression in the mouse xenograft models in vivo effectively. INCB28060, which inhibits the MET signaling pathway alone, was not effective. RON and MET can be important indicators of prognosis in pancreatic cancer. Tyrosine kinase inhibitors targeting RON and MET in pancreatic cancer are a novel and potential approach for pancreatic cancer therapy.

Optimization of light fields in ghost imaging using dictionary learning.

Ghost imaging (GI) is a novel imaging technique based on the second-order correlation of light fields. Due to limited number of samplings in practice, traditional GI methods often reconstruct objects with unsatisfactory quality. To improve the imaging results, many reconstruction methods have been developed, yet the reconstruction quality is still fundamentally restricted by the modulated light fields. In this paper, we propose to improve the imaging quality of GI by optimizing the light fields, which is realized via matrix optimization for a learned dictionary incorporating the sparsity prior of objects. A closed-form solution of the sampling matrix, which enables successive sampling, is derived. Through simulation and experimental results, it is shown that the proposed scheme leads to better imaging quality compared to the state-of-the-art optimization methods for light fields, especially at a low sampling rate.

Immunological microenvironment alterations in follicles of women with proven severe endometriosis undergoing in vitro fertilization.

The purpose of this study was to test the hypothesis that different cytokine profiles may exist in the follicular fluid of endometriosis (EM) patients undergoing in vitro fertilization (IVF), as these differences may provide insights into the pathogenesis of the disease. This was a cross-sectional study conducted at the reproductive center of a medical university hospital. The study included 49 patients receiving IVF. 20 infertile women with proven EM and 29 women without diagnosed EM (control group) were evaluated. Follicular fluid (FF) and serum were collected at the time of follicle aspiration and the concentrations of 38 cytokines were determined by multiplexed immunoassay. The results indicated that the levels of IL-4, IL-13, IL-3 and IL-1α were significantly increased in the FF of women with EM, while levels of IFN-γ, IL-17A, MDC and MIP-1α were decreased compared with in the control subjects. In conclusions, the immune microenvironment of the FF in patients with EM is altered. This may contribute to the pathologic mechanism responsible for the poor outcome of IVF in patients with EM.

Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy.

BACKGROUND: Antibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer therapy. Here we describe a humanized antibody recognizing the RON plexin-semaphorin-integrin (PSI) domain with increased drug delivery capability for potential clinical application. METHOD: Monoclonal antibody PCM5B14 specific to the human and monkey RON PSI domain was generated and characterized by various immunological methods. Humanized antibody H5B14 was created by grafting PCM5B14 complementarity-determining regions into human IgG1/κ acceptor frameworks and conjugated with monomethyl auristatin E and duocarmycin to form two H5B14-based ADCs. Stability of H5B14-based ADCs in human plasma was measured using hydrophobic interaction chromatography. Various biochemical and biological assays were used to determine ADC- regulated RON internalization, cell viability, spheroid formation, and death of cancer stem-like cells. Efficacies of H5B14-based ADCs in vivo were validated using tumor xenograft models. Maximal tolerated doses of H5B14-based ADCs were established in mice. RESULTS: H5B14 was highly specific to the human RON PSI domain and superior over other anti-RON ADCs in induction of RON internalization in various cancer cell lines tested. H5B14-based ADCS had a drug to antibody ratio of ~ 3.70:1 and were stable in human plasma with a minimal dissociation within a 10-day period. Functionally, H5B14-mediated drug delivery decreased cell viability at early stages with an average IC50 at ~ 20 nM in multiple cancer cell lines examined. H5B14-based ADCs also inhibited spheroid formation and caused death of cancer stem-like cells with RON+/CD44+/ESA+ phenotypes. In vivo, H5B14-based ADCs in a single injection inhibited tumor xenograft growth mediated by multiple cancer cell lines. Tumoristatic concentrations calculated from xenograft tumor models were in the range of 0.63 to 2.0 mg/kg bodyweight. Significantly, H5B14-based ADCs were capable of eradicating tumors at variable levels across multiple xenograft models regardless their malignant statuses. Toxicologically, H5B14-based ADCs were well tolerated in mice up to 60 mg/kg. CONCLUSION: H5B14-based ADCs targeting the RON PSI domain are superior in inducing RON internalization, leading to robust drug delivery and overall inhibition and eradication of tumors in multiple xenograft models. These findings warrant H5B14-based ADCs for clinical trials in the future.

Ghost imaging LiDAR via sparsity constraints using push-broom scanning.

Ghost imaging LiDAR via sparsity constraints using push-broom scanning is proposed. It can image the stationary target scene continuously along the scanning direction by taking advantage of the relative movement between the platform and the target scene. Compared to conventional ghost imaging LiDAR that requires multiple speckle patterns staring the target, ghost imaging LiDAR via sparsity constraints using push-broom scanning not only simplifies the imaging system, but also reduces the sampling number. Numerical simulations and experiments have demonstrated its efficiency.

Correction to: Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy.

Following publication of the original article [1], the author reported two errors in the authors affiliations.

Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy.

BACKGROUND: Aberrant expression of the RON receptor tyrosine kinase is a pathogenic feature and a validated drug target in various types of cancers. Currently, therapeutic antibodies targeting RON for cancer therapy are under intensive evaluation. Here we report the development and validation of a novel humanized anti-RON antibody-drug conjugate for cancer therapy. METHODS: Antibody humanization was achieved by grafting sequences of complementarity-determining regions from mouse monoclonal antibody Zt/g4 into human IgG1/κ acceptor frameworks. The selected humanized Zt/g4 subclone H1L3 was conjugated with monomethyl auristatin E using a dipeptide linker to form H-Zt/g4-MMAE. Pharmacokinetic analysis of H-Zt/g4-MMAE was determined using hydrophobic interaction chromatography and a MMAE ADC ELISA kit. Biochemical and biological assays were used for measuring RON expression, internalization, cell viability and death. Therapeutic efficacies of H-Zt/g4-MMAE were validated in vivo using three pancreatic cancer xenograft models. Toxicological activities of H-Zt/g4-MMAE were determined in mouse and cynomolgus monkey. RESULTS: H-Zt/g4-MMAE had a drug to antibody ratio of 3.77:1 and was highly stable in human plasma with a dissociation rate less than 5% within a 20 day period. H-Zt/g4-MMAE displayed a favorable pharmacokinetic profile in both mouse and cynomolgus monkey. In vitro, H-Zt/g4-MMAE induced RON internalization, which results in killing of pancreatic cancer cells with IC50 values at 10-20 nM. In vivo, H-Zt/g4-MMAE inhibited pancreatic cancer xenograft growth with tumoristatic concentrations at 1~3 mg/kg bodyweight. Significantly, H-Zt/g4-MMAE eradicated tumors across multiple xenograft models regardless their chemoresistant and metastatic statuses. Moreover, H-Zt/g4-MMAE inhibited and eradicated xenografts mediated by pancreatic cancer stem-like cells and by primary cells from patient-derived tumors. Toxicologically, H-Zt/g4-MMAE is well tolerated in mice up to 60 mg/kg. In cynomolgus monkey, H-Zt/g4-MMAE up to 30 mg/kg had a manageable and reversible toxicity profile. CONCLUSIONS: H-Zt/g4-MMAE is superior in eradication of pancreatic cancer xenografts with favorable pharmacokinetic profiles and manageable toxicological activities. These findings warrant the transition of H-Zt/g4-MMAE into clinical trials in the future.

Finding diseases associated with amyotrophic lateral sclerosis: a total population-based case-control study.

OBJECTIVE: To investigate diseases associated with amyotrophic lateral sclerosis (ALS) by using a total population-based medical database. METHODS: This study included 705 ALS patients aged older than 15 years diagnosed from January 1, 2007, to December 31, 2013, along with 14,100 controls matching in sex, age, residence, and insurance premium. Data from the National Health Insurance Research Database (NHIRD) and Serious Disabling Diseases (SDD) database in Taiwan were used to conduct a total population-based case-control study. Prior diseases were categorized as being diagnosed 1, 3, 5, 7, or 9 years before first ALS diagnosis. Chi-square or t test was used to examine differences in demographic characteristics between the new patients with ALS and controls. Previous diseases were screened using a conditional logistic regression model. Multivariate analysis was performed using stepwise selection to evaluate the association between these diseases and the risk of ALS. The path analysis was conducted to analyze the pathway between prior diseases and ALS. RESULTS: In total, 28 diseases were associated with ALS, including 17 positive associations and 11 negative associations. The path analysis revealed that the 11 negatively associated diseases could be attributed to diabetes mellitus and its comorbidities. The 17 positively associated diseases could be categorized as metabolic syndrome, neuroinflammation, head trauma, sports injuries, infections, and their comorbidities. CONCLUSIONS: Our results support the hypothesis that diseases developing prior to ALS diagnoses are hypermetabolic disorders. Hypometabolic disorders may have a beneficial effect on ALS incidence. Defective energy metabolism may play a role in ALS pathogenesis.

Molecular Characteristics, Functions, and Related Pathogenicity of MERS-CoV Proteins.

Middle East respiratory syndrome (MERS) is a viral respiratory disease caused by a de novo coronavirus-MERS-CoV-that is associated with high mortality. However, the mechanism by which MERS-CoV infects humans remains unclear. To date, there is no effective vaccine or antibody for human immunity and treatment, other than the safety and tolerability of the fully human polyclonal Immunoglobulin G (IgG) antibody (SAB-301) as a putative therapeutic agent specific for MERS. Although rapid diagnostic and public health measures are currently being implemented, new cases of MERS-CoV infection are still being reported. Therefore, various effective measures should be taken to prevent the serious impact of similar epidemics in the future. Further investigation of the epidemiology and pathogenesis of the virus, as well as the development of effective therapeutic and prophylactic anti-MERS-CoV infections, is necessary. For this purpose, detailed information on MERS-CoV proteins is needed. In this review, we describe the major structural and nonstructural proteins of MERS-CoV and summarize different potential strategies for limiting the outbreak of MERS-CoV. The combination of computational biology and virology can accelerate the advanced design and development of effective peptide therapeutics against MERS-CoV. In summary, this review provides important information about the progress of the elimination of MERS, from prevention to treatment.