A High Threshold of Biotherapeutic Aggregate Numbers is Needed to Induce an Immunogenic Response In Vitro, In Vivo, and in the Clinic.

BACKGROUND AND PURPOSE: There is concern that subvisible aggregates in biotherapeutic drug products pose a risk to patient safety. We investigated the threshold of biotherapeutic aggregates needed to induce immunogenic responses. METHODS AND RESULTS: Highly aggregated samples were tested in cell-based assays and induced cellular responses in a manner that depended on the number of particles. The threshold of immune activation varied by disease state (cancer, rheumatoid arthritis, allergy), concomitant therapies, and particle number. Compared to healthy donors, disease state patients showed an equal or lower response at the late phase (7 days), suggesting they may not have a higher risk of responding to aggregates. Xeno-het mice were used to assess the threshold of immune activation in vivo. Although highly aggregated samples (~ 1,600,000 particles/mL) induced a weak and transient immunogenic response in mice, a 100-fold dilution of this sample (~ 16,000 particles/mL) did not induce immunogenicity. To confirm this result, subvisible particles (up to ~ 18,000 particles/mL, containing aggregates and silicone oil droplets) produced under representative administration practices (created upon infusion of a drug product through an IV catheter) did not induce a response in cell-based assays or appear to increase the rate of adverse events or immunogenicity during phase 3 clinical trials. CONCLUSION: The ability of biotherapeutic aggregates to elicit an immune response in vitro, in vivo, and in the clinic depends on high numbers of particles. This suggests that there is a high threshold for aggregates to induce an immunogenic response which is well beyond that seen in standard biotherapeutic drug products.

Cucurbitacin IIa: A review of phytochemistry and pharmacology.

Cucurbitacin IIa was first found in plants and it belongs to tetracyclo triterpenoids. It is one of the most important active components in cucurbitaceae plants. Studies have found that cucurbitacin IIa has a variety of pharmacological effects, such as antitumor, antiinflammatory, antibacterial, antihepatitis B virus, inhibition of human immunodeficiency virus replication, and antidepressant effect. However, the underlying mechanisms, intracellular targets, and structure-activity relationships of cucurbitacin IIa remain to be completely elucidated. This review summarizes the current advances concerning the phytochemistry and pharmacology of cucurbitacin IIa. Electronic databases such as PubMed, Web of Science, Google Scholar, Science Direct, and CNKI were used to find relevant information about cucurbitacin IIa using keywords such as "Cucurbitacin IIa," "Pharmacology," and "Phytochemistry." These pharmacological effects involve the actin cytoskeleton aggregation, the regulation of JAK2/STAT3, ERBB-MAPK, CaMKII α/CREB/BDNF signal pathways, as well as the regulation of survivin, caspases, and other cell cycles, apoptosis, autophagy-related cytokines, and kinases. It has high development and use value.

[Radiation Environment Study of Near Space in China Area].

Aerospace activity in near space (20-50 km) has become a research hotspot for aviation big countries worldwide. Solar radiation study, as the prerequisite to carry out aerospace activity, is facing the barrier of lacking of observation in near space layer. Ozone is the most important factor that affects radiation value in this layer. Based on ECMWF reanalysis data, this input key parameter and its horizontal, vertical and temporal characteristics are analyzedwith results showing obvious regional features in temporal-spatial distribution and varieties. With meteorological data and surface parameters, near space over China is divided into 5 parts. Key factors' value is confirmed over each division. With SBDART radiation transfer model, solar radiation and ultraviolet radiation simulation in near space are conducted separately. Results show that it is influenced by latitude, total ozone and its vertical distribution, radiation varies under complex rules. The average year and monthly solar radiation strengthens changes with latitude reduction, while annual range changes reversely. Air absorbing is related to latitude and land-sea contrast and shows different values and seasonal variations. The ultraviolet radiation over South China Sea reaches its maximum value and minimum annual range, as well as minimum monthly range with value strengthening in summer and weakening in winter. In other areas radiation increases in summer while weakens in winter, monthly range shows double peaks with higher value in spring and autumn, lower in summer and winter. Air absorption in ultraviolet radiation is influenced by multiple factors, vertical varieties over areas besides South China Sea enhance in summer time. The vertical changes of monthly ranges affected by air absorption show consistence in higher and lower layer in June and July, while in other months ranges are bigger in higher layer.

Exploring the Potential Role of Massa Medicata Fermentata in Alcoholic Liver Injury Disease Based on Network Pharmacology and Animal Experiments.

BACKGROUND: ALD is a chronic liver disease caused by chronic excessive alcohol consumption, for which there are no drugs with better efficacy. Ancient literature and modern studies have shown that Massa Medicata Fermentata (MMF) has a hangover effect and ameliorates hepatic inflammation, so we believe that MMF has a potential role in the treatment of alcoholic liver disease. METHODS: UPLC-Q-Orbitrap HRMS was used to characterize the chemical constituents in MMF. The database was utilized to collect targets for the components and diseases, and cross-targeting analysis of the targets was performed. PPI, KEGG, GO enrichment analysis and molecular docking were performed using the core cross-targeting information to preliminarily validate the mechanism of action of MMF on disease. Finally, animal validation was carried out using male KM mice of the alcoholic liver injury model. RESULTS: MMF could play a role in the therapeutic prevention of alcoholic liver disease through the core targets AKT1, TNF, TP53, IL6 and CASP3 to regulate cancer pathways, lipid, and atherosclerosis, targeting IL-17 signaling, TNF signaling pathway, and hepatitis C, which was confirmed by animal pharmacodynamic experiments. CONCLUSION: This study serves as a rationale to support MMF in the treatment of ALD and meets the urgent need for clinical treatment of ALD. At the same time, it broadens the scope of clinical application of MMF.

On the identification of internal solitary waves from moored observations in the northern South China Sea.

Based on the temperature data recorded by a mooring system deployed in the northern South China Sea (SCS), this study compares the traditional methods of identifying and extracting internal solitary waves (ISWs): the whole water column isotherm (WCI) method and the single isotherm (SI) method, and proposes a novel method: the temperature superposition (TS) method. Results indicate that the TS method identifies the most ISWs, followed by the WCI method, and the SI method identifies the fewest. When the ISW amplitudes are smaller than 60 m, the TS method can identify the most ISWs. When the ISW amplitudes are greater than 60 m, the number of ISWs identified by the three methods is the same. The TS method removes the internal tides, takes into account the temperature of all depth layers, and amplifies the signal of ISWs to a certain extent, so as to effectively identify ISWs.

Observation of near-inertial waves in the wake of four typhoons in the northern South China Sea.

Based on the velocity and temperature data recorded by two acoustic Doppler current profilers (ADCPs) at a mooring system deployed in the northern South China Sea (SCS), this study investigates the characteristics of near-inertial waves (NIWs) induced by typhoons Bebinca, Barijat, Mangkhut and Yutu in 2018. For the dynamical response, besides the motion of near inertial frequency induced by typhoons, the motion of 2 f ([1.80-2.20] f, f is the local inertial frequency) and f D1 (a harmonic wave with a frequency equal to the sum of frequencies of NIWs and diurnal tides) frequency will also increase. For near-inertial motions, the maximum near-inertial kinetic energy (NIKE) is confined to depths above 150 m. For stronger (weaker) wind forcing, the longer (shorter) the response time of the ocean to the atmospheric forcing is, and the shorter (longer) the response time is required in relaxation stage. There are upward and downward propagating energies after the passage of typhoons, and the upward propagating energy mainly occur in the stage of the geostrophic balance adjustment. The current structure suggests that the NIWs in the vertical direction are two antisymmetric rotary vortices in a near-inertial period, which is similar to the structure of the Langmuir circulation. Besides, the horizontal near-inertial currents (NICs) are much stronger than the vertical NICs, and the stronger the NIWs are, the stronger the horizontal NICs relative to the vertical NICs are. For the temperature response, the temperature variation reflects a clear stratified vertical structure. In the forcing stage, the upper layer becomes colder, the lower layer becomes warmer, and the thickness and intensity of the thermocline decrease. In the relaxation stage, the upper layer warms and the lower layer cools, and the thickness and intensity of thermocline increase.

Colonization characteristics of fungi in Polygonum hydropipe L. and Polygonum lapathifolium L. and its effect on the content of active ingredients.

Polygonum hydropiper, is a plant of the Persicaria genus, which is commonly used to treat various diseases, including gastrointestinal disorders, neurological disorders, inflammation, and diarrhea. However, because of different local standards of P. hydropiper, people often confuse it with Polygonum lapathifolium L. and other closely related plants. This poses a serious threat to the safety and efficacy of the clinical use of P. hydropiper. This study aims to determine the six active ingredients of P. hydropiper and P. lapathifolium. Then the endophytic fungi and rhizosphere soil of the two species were sequenced by Illumina Miseq PE300. The results show significant differences between the community composition of the leaves, stems, and roots of the P. hydropiper and the P. lapathifolium in the same soil environment. Of the six secondary metabolites detected, five had significant differences between P. hydropiper and P. lapathifolium. Then, we evaluated the composition of the significantly different communities between P. hydropiper and P. lapathifolium. In the P. hydropiper, the relative abundance of differential communities in the leaves was highest, of which Cercospora dominated the differential communities in the leaves and stem; in the P. lapathifolium, the relative abundance of differential community in the stem was highest, and Cladosporium dominated the differential communities in the three compartments. By constructing the interaction network of P. hydropiper and P. lapathifolium and analyzing the network nodes, we found that the core community in P. hydropiper accounted for 87.59% of the total community, dominated by Cercospora; the core community of P. lapathifolium accounted for 19.81% of the total community, dominated by Sarocladium. Of these core communities, 23 were significantly associated with active ingredient content. Therefore, we believe that the community from Cercospora significantly interferes with recruiting fungal communities in P. hydropiper and affects the accumulation of secondary metabolites in the host plant. These results provide an essential foundation for the large-scale production of P. hydropiper. They indicate that by colonizing specific fungal communities, secondary metabolic characteristics of host plants can be helped to be shaped, which is an essential means for developing new medicinal plants.

Nomogram for predicting post-traumatic hydrocephalus after decompressive craniectomy for traumatic brain injury.

OBJECTIVE: This study aimed to develop and validate a practical nomogram to predict the occurrence of post-traumatic hydrocephalus in patients who have undergone decompressive craniectomy for traumatic brain injury. METHODS: A total of 516 cases were enrolled and divided into the training (n=364) and validation (n=152) cohorts. Optimal predictors were selected through least absolute shrinkage and selection operator regression analysis of the training cohort then used to develop a nomogram. Receiver operating characteristic, calibration plot, and decision curve analysis, respectively, were used to evaluate the discrimination, fitting performance, and clinical utility of the resulting nomogram in the validation cohort. RESULTS: Preoperative subarachnoid hemorrhage Fisher grade, type of decompressive craniectomy, transcalvarial herniation volume, subdural hygroma, and functional outcome were all identified as predictors and included in the predicting model. The nomogram exhibited good discrimination in the validation cohort and had an area under the receiver operating characteristic curve of 0.80 (95%CI 0.72-0.88). The calibration plot demonstrated goodness-of-fit between the nomogram's prediction and actual observation in the validation cohort. Finally, decision curve analysis indicated significant clinical adaptability. CONCLUSION: The present study developed and validated a model to predict post-traumatic hydrocephalus. The nomogram that had good discrimination, calibration, and clinical practicality can be useful for screening patients at a high risk of post-traumatic hydrocephalus. The nomogram can also be used in clinical practice to develop better therapeutic strategies.

Effect of Ulinastatin Combined with Xingnaojing Injection on Severe Traumatic Craniocerebral Injury and Its Influence on Oxidative Stress Response and Inflammatory Response.

OBJECTIVE: This study is aimed at exploring the effect of ulinastatin combined with Xingnaojing injection on severe traumatic craniocerebral injury and its influence on oxidative stress response and inflammatory response in patients. METHODS: A total of 100 patients with severe traumatic craniocerebral injury admitted to our hospital from January 2018 to January 2020 were selected and equally assigned into a study group (50 cases) and a control group (50 cases) according to a random sampling method. Patients in study group received treatment of ulinastatin combined with Xingnaojing injection, while those in control group were treated with ulinastatin only. The study compared the two groups on the oxidative stress response, inflammatory response, the therapeutic effect, and the incidence rate of adverse reactions. RESULTS: It is observed that patients in study group obtained lower levels of free cortisol (FC) and norepinephrine (NE) in the serum and higher level of total thyroxine (TT4) after treatment compared with those in control group with significant difference (P < 0.05); in the meantime, they were examined to have significantly fewer oxidative stress response products, lower serum inflammatory factor level, and serum indicator levels of craniocerebral injury as opposed to those in control group, suggesting significant differences (P < 0.05); study group demonstrated higher treatment response rate and lower incidence rate of adverse reactions compared with control group with a significant difference (P < 0.05). CONCLUSION: The study found that ulinastatin combined with Xingnaojing infection has a significant effect in the treatment of severe traumatic craniocerebral injury, which can reduce the degree of craniocerebral injury and the level of inflammatory factors in the serum of patients. It is worthy of being promoted and applied clinically.

Effect of Massa Medicata Fermentata on the Gut Microbiota of Dyspepsia Mice Based on 16S rRNA Technique.

Massa Medicata Fermentata (MMF) is a traditional Chinese medicine (TCM) for treating indigestion and its related disorders. This study analyzes the effect of MMF on intestinal microorganisms in dyspepsia mice based on 16S rRNA technology. We take a dyspepsia model caused by a high-protein, high-calorie, high-fat diet. The 60 specific-pathogen free Kunming (SPF KM) mice were randomly divided into a model group (n=12), an MMF group (LSQ group, n=12), a Jianweixiaoshi group (JWXS group, n=12), a domperidone group (DP group, n=12), and a blank group (n=12). On the seventh day of administration, mice were fasted and deprived of water. After 24 h, take the second feces of stress defecation in mice under strict aseptic conditions and quickly transfer them to a sterile cryotube. This study comprehensively evaluates the α-diversity, ß-diversity, flora abundance and composition of each group of mice's intestinal microorganisms, and their correlation with functional dyspepsia based on the 16S rRNA gene sequencing technology. After modeling, some dyspepsia reactions, proximal gastric relaxation reduction, and intestinal microflora changes were noted. Dyspepsia mice showed dyspepsia reactions and proximal gastric relaxation reduction, characterized by a significant decrease of contents of gastrin (P < 0.01) and cholinesterase (P < 0.01). MMF can improve dyspepsia symptoms and promote proximal gastric relaxation. Significant intestinal flora disorders were found in dyspepsia mice, including downregulation of Bacteroidetes, Lactobacillus, and Prevotellaceae and upregulation of Proteobacteria, Verrucomicrobia, Epsilonbacteraeota, Firmicutes, Lachnospiraceae NK4A136 group, and Lachnospiraceae. MMF could alleviate intestinal microflora disturbance, and the regulation effect of MMF on Bacteroidetes, Verrucomicrobia, and Epsilonbacteraeota was more reliable than that of Jianweixiaoshi tables and domperidone. The intestinal microflora may be correlated with the promoted digestion of MMF.

Impact of Red Yeast Rice on Metabolic Diseases: A Review of Possible Mechanisms of Action.

Metabolic diseases constitute a major public health burden and are linked with high morbidity and mortality. They comprise atherosclerosis dyslipidemia, diabetes, hypertension, and obesity. However, there is no single drug that can simultaneously treat multiple diseases with complex underlying mechanisms. Therefore, it is necessary to identify a class of adjuvant drugs that block the development of metabolic diseases from a preventive perspective. Red yeast rice is a food fermentation product widely used to promote blood circulation and remove blood stasis. Modern pharmacology has shown that red yeast rice exerts potential protective effects on the liver, pancreas, blood vessels, and intestines. Therefore, this study was carried out to analyze and summarize the effect of red yeast rice on several metabolic diseases and the mechanisms of action involved. It was found that red yeast rice may be beneficial in the prevention and treatment of metabolic diseases.

Hesperidin: A Therapeutic Agent For Obesity.

Obesity is a chronic metabolic disease caused by multiple factors and is considered to be a risk factor for type 2 diabetes, cardiovascular disease, hypertension, stroke and various cancers. Hesperidin, a flavanone glycoside, is a natural phenolic compound with a wide range of biological effects. Mounting evidence has demonstrated that hesperidin possesses inhibitory effect against obesity diseases. Our review discusses mechanisms of hesperidin in the treatment of obesity. Hesperidin regulates lipid metabolism and glucose metabolism by mediating AMPK and PPAR signaling pathways, directly regulates antioxidant index and anti-apoptosis, and indirectly mediates NF-κB signaling pathway to regulate inflammation to play a role in the treatment of obesity. In addition, hesperidin-enriched dietary supplements can significantly improve symptoms such as postprandial hyperglycemia and hyperlipidemia. Further clinical trials are also required for confirming lipid-lowering efficacy of this natural flavonoid and evaluating its safety profile.

Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors.

c-Met is a well-characterized receptor tyrosine kinase for hepatocyte growth factor (HGF). Compelling evidence from studies in human tumors and both cellular and animal tumor models indicates that signaling through the HGF/c-Met pathway mediates a plethora of normal cellular activities, including proliferation, survival, migration, and invasion, that are at the root of cancer cell dysregulation, tumorigenesis, and tumor metastasis. Inhibiting HGF-mediated signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of human tumors. Toward this goal, we generated and characterized five different fully human monoclonal antibodies that bound to and neutralized human HGF. Antibodies with subnanomolar affinities for HGF blocked binding of human HGF to c-Met and inhibited HGF-mediated c-Met phosphorylation, cell proliferation, survival, and invasion. Using a series of human-mouse chimeric HGF proteins, we showed that the neutralizing antibodies bind to a unique epitope in the beta-chain of human HGF. Importantly, these antibodies inhibited HGF-dependent autocrine-driven tumor growth and caused significant regression of established U-87 MG tumor xenografts. Treatment with anti-HGF antibody rapidly inhibited tumor cell proliferation and significantly increased the proportion of apoptotic U-87 MG tumor cells in vivo. These results suggest that an antibody to an epitope in the beta-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors.

Nomogram for predicting post-traumatic hydrocephalus after decompressive craniectomy for traumatic brain injury

SUMMARY OBJECTIVE: This study aimed to develop and validate a practical nomogram to predict the occurrence of post-traumatic hydrocephalus in patients who have undergone decompressive craniectomy for traumatic brain injury. METHODS: A total of 516 cases were enrolled and divided into the training (n=364) and validation (n=152) cohorts. Optimal predictors were selected through least absolute shrinkage and selection operator regression analysis of the training cohort then used to develop a nomogram. Receiver operating characteristic, calibration plot, and decision curve analysis, respectively, were used to evaluate the discrimination, fitting performance, and clinical utility of the resulting nomogram in the validation cohort. RESULTS: Preoperative subarachnoid hemorrhage Fisher grade, type of decompressive craniectomy, transcalvarial herniation volume, subdural hygroma, and functional outcome were all identified as predictors and included in the predicting model. The nomogram exhibited good discrimination in the validation cohort and had an area under the receiver operating characteristic curve of 0.80 (95%CI 0.72-0.88). The calibration plot demonstrated goodness-of-fit between the nomogram's prediction and actual observation in the validation cohort. Finally, decision curve analysis indicated significant clinical adaptability. CONCLUSION: The present study developed and validated a model to predict post-traumatic hydrocephalus. The nomogram that had good discrimination, calibration, and clinical practicality can be useful for screening patients at a high risk of post-traumatic hydrocephalus. The nomogram can also be used in clinical practice to develop better therapeutic strategies.

Epratuzumab, a humanized monoclonal antibody targeting CD22: characterization of in vitro properties.

PURPOSE: Epratuzumab is a novel humanized antihuman CD22 IgG1 antibody that has recently shown promising clinical activity, both as a single agent and in combination with rituximab, in patients with non-Hodgkin's lymphomas (NHL). In an attempt to better understand the mode of action of epratuzumab, the antibody was tested in vitro in a variety of cell-based assays similar to those used to evaluate the biological activity of other therapeutic monoclonal antibodies, including rituximab. In this report, we present epratuzumab activities as they relate to binding, signaling, and internalization of the receptor CD22. METHODS: Chinese hamster ovary-expressed CD22 extracellular domain was used to measure epratuzumab affinity on Biacore. CD22 receptor density and internalization rate were measured indirectly using a monovalently labeled, noncompeting (with epratuzumab) anti-CD22 antibody on Burkitt lymphoma cell lines, primary B cells derived from fresh tonsils, and B cells separated from peripheral blood samples obtained from patients with chronic lymphocytic leukemia or healthy volunteers. Epratuzumab-induced CD22 phosphorylation was measured by immunoprecipitation/Western blot and compared with that induced by anti-IgM stimulation. RESULTS: Epratuzumab binds to CD22-extracellular domain, with an affinity of K(D) = 0.7 nM. Binding of epratuzumab to B cell lines, or primary B cells from healthy individuals and patients with NHL, results in rapid internalization of the CD22/antibody complex. Internalization appears to be faster at early time points in cell lines than in primary B cells and NHL patient-derived B cells, but the maximum internalization reached is comparable for all B cell populations after several hours of treatment and appears to reach saturation at antibody concentrations of 1-5 micro g/ml. Finally, epratuzumab binding results in modest but significant CD22 phosphorylation. CONCLUSIONS: Epratuzumab represents an excellent anti-CD22 ligating agent, highly efficacious in inducing CD22 internalization, and can induce phosphorylation. Although we cannot unequivocally demonstrate here that epratuzumab-induced internalization and signaling of CD22 directly contribute to its therapeutic efficacy, these properties are the fundamental characteristics of the target CD22 and its interaction with epratuzumab. Similar results were observed when epratuzumab was tested in vitro on Burkitt B cell lines as well as on primary normal B cells and neoplastic B cells separated from fresh peripheral blood samples from patients with chronic lymphocytic leukemia.

Application of MSI in MRI-negative focal cortical dysplasia patients with epilepsy.

BACKGROUND: Focal cortical dysplasia (FCD) is the most common cause of intractable epilepsy in children and adolescent. PURPOSE: To evaluate the application value of magnetic source imaging (MSI) in treatment of magnetic resonance imaging (MRI)-negative FCD patients with epilepsy. METHODS: MSI characteristics of 17 cases of MRI-negative focal cortical dysplasia patients with epilepsy were retrospectively analyzed. All patients were treated by surgery. RESULTS: In 17 patients, there were 3 cases of FCD Ia, 7 cases of FCDIb, 3 cases of FCDIIa and 4 cases of FCDIIb. FCD was located at temporal lobe in 8 cases, occipital lobe in 3 cases, frontal lobe in 2 cases and two lobes in 4 cases. In follow-up, 14 patients obtained satisfied curative effect. 1 patient was improved significantly and 2 patients were fine. The concordance between MSI and electrocorticogram in localizing epileptogenic foci was 65%. CONCLUSION: MSI is a new prospective noninvasive functional neuroimaging technique for identifying and delineating epileptogenic foci in MRI-negative FCD patients.

Localization of the human language cortex by magnetic source imaging.

OBJECTIVE: To localize the language cortex associated with Chinese word processing by magnetic source imaging (MSI). METHODS: Eight right-handed and one left-handed healthy native Chinese subjects were examined by magnetoencephalography (MEG) and a 1.5T magnetic resonance imaging (MRI) unit. All subjects were given pure tone stimuli 50 times, 150 pairs of Chinese words (meaning related or unrelated) auditory stimuli, and pure tone stimuli subsequently 50 times. Evoked response fields time locked to the pure tone and Chinese words were recorded using a whole-head neuromagnetometer in real-time. The acquired data were averaged by the acquisition computer according to the response to the pure tone, related pairs of words and unrelated pairs of words. The data obtained by MEG were superimposed on MRI, using a GE Signa 1.5T system. RESULTS: MEG, showed there were two obviously higher magnetic waves named M50 and M100, which were localized in the bilateral transverse temporal gyri in all subjects. The responses to the pairs of Chinese words (meaning related or unrelated) were similar in the same hemisphere of the same subjects. There was a higher peak during 300 - 600 ms in the right hemisphere of one left handed subject, but no peak in the left hemisphere, indicating that the language dominant hemisphere was localized in the right hemisphere. Superimposing the MEG data on MRI, the language area was localized in the Wernicke's areas. A 300 - 600 ms response peak was obsarved in each hemisphere (the amplitude of the 300 - 600 ms response peak in each hemisphere was almost the same) in two right-handed subjects, showing that the language area was localized in the 2 hemispheres in the two subjects. There was one peak in each hemisphere (300 - 600 ms response) in 6 subjects, but the amplitude of the wave in the left hemisphere in the 6 subjects was much higher than that in the right hemisphere. By choosing randomly from the later component (300 - 600 ms response) several time points and superimposing them on MRI, all time points were localized in the posterior part of the superior temporal gyri, which is the Wernicke's areas. CONCLUSIONS: Comparing with the later component of the bilateral hemispheres, the wave amplitude in the language dominant hemisphere was much higher than that in the non-language dominant hemisphere. The language areas could be identified by judging whether meanings of pairs of Chinese words were related or not.

[The clinical study of somatosensory evoked magnetic fields in patients with acute cerebral infarction by magnetoencephalography].

OBJECTIVE: To investigate the characteristics of somatosensory evoked magnetic fields (SEF) in patients with acute cerebral infarction by magnetoencephalgraphy (MEG). METHODS: SEFs were recorded from 17 patients with acute cerebral infarction and 18 healthy volunteers using 306-channel whole-head MEG. The electric stimuli were presented with interstimulus intervals of 0.5 s. The peaks of SEF were estimated by equivalent current dipole (ECD), which were superimposed on MRI. RESULTS: M20 was the most elemental components of SEF in all subjects, originating from the area close to the "hand area" of the primary somatosensory cortex. There appeared several abnormal SEF parameters in the patient group: (1) the value of interhemispheric difference of the M20 positions was (8 +/- 4) mm in the normal group and (11 +/- 3) mm in the patient group (P < 0.01); (2) the peak latency of M20 responses in the healthy group was (20.7 +/- 1.1) ms, significantly shorter than those in both the unaffected hemisphere and affected hemisphere in the patient group, (21.8 +/- 1.2) ms and (23.6 +/- 1.9) ms, (both P < 0.01); (3) the strength of ECD in the affected hemisphere was (17 +/- 10) nAm, significantly smaller than that in the unaffected hemisphere, (26 +/- 10) nAm (P < 0.01). CONCLUSION: Latent cortical impairment may be evaluated by MEG with higher spatial and temporal resolution. MEG provides objective and sensitive indexes to evaluate the function of somatosensory cortex in patients with acute cerebral infarction.

Epitope-specific mechanisms of IGF1R inhibition by ganitumab.

BACKGROUND: Therapeutic antibodies targeting the IGF1R have shown diverse efficacy and safety signals in oncology clinical trials. The success of these agents as future human therapeutics depends on understanding the specific mechanisms by which these antibodies target IGF1R signaling. METHODOLOGY/PRINCIPAL FINDINGS: A panel of well-characterized assays was used to investigate the mechanisms by which ganitumab, a fully human anti-IGF1R antibody undergoing clinical testing, inhibits IGF1R activity. Epitope mapping using IGF1R subdomains localized the ganitumab binding site to the L2 domain. Binding of ganitumab inhibited the high-affinity interaction of IGF-1 and IGF-2 required to activate IGF1R in cells engineered for IGF1R hypersensitivity and in human cancer cell lines, resulting in complete blockade of ligand-induced cellular proliferation. Inhibition of IGF1R activity by ganitumab did not depend on endosomal sequestration, since efficient ligand blockade was obtained without evidence of receptor internalization and degradation. Clinically relevant concentrations of ganitumab also inhibited the activation of hybrid receptors by IGF-1 and IGF-2. Ganitumab was not an agonist of homodimeric IGF1R or hybrid receptors in MCF-7 and COLO 205 cells, but low-level IGF1R activation was detected in cells engineered for IGF1R hypersensitivity. This activation seems biologically irrelevant since ganitumab completely inhibited ligand-driven proliferation. The in vivo efficacy profile of ganitumab was equivalent or better than CR and FnIII-1 domain-specific antibodies, alone or in combination with irinotecan. CR domain-specific antibodies only blocked IGF-1 binding to IGF1R but were more potent than ganitumab at inducing homodimer and hybrid receptor downregulation in vitro, however this difference was less obvious in vivo. No inhibition of hybrid receptors was observed with the FnIII-1 domain antibodies, which were relatively strong homodimer and hybrid agonists. CONCLUSIONS/SIGNIFICANCE: The safety and efficacy profile of ganitumab and other anti-IGF1R antibodies may be explained by the distinct molecular mechanisms by which they inhibit receptor signaling.

Magnetoencephalography assessment of evoked magnetic fields and cognitive function in subcortical ischemic vascular dementia patients.

OBJECTIVE: To investigate the relationship between cognitive impairment and somatosensory evoked magnetic field and auditory evoked magnetic field changes in elderly male patients with subcortical ischemic vascular dementia (SIVD). METHODS: Magnetoencephalography (MEG) was used to record evoked magnetic field changes from 4 SIVD patients (76-88 years), 3 patients with vascular cognitive impairment with no dementia (VCI-ND; 74-87 years), and 6 healthy volunteers (72-85 years). Latency peaks, equivalent current dipole (ECD) strength, and bilateral ECD position were recorded. The MEG data were superimposed on magnetic resonance imaging to produce magnetic source imaging. RESULTS: Compared to controls, SIVD patients showed increased M20 latency and ECD strength. There were no significant differences in M20 inter-hemispheric positions across diagnostic categories. At M100, SIVD patients showed delayed auditory evoked magnetic field latency compared to controls. However, ECD strength and 3-dimensional inter-hemispheric differences were similar across the groups at the M100 measurement. CONCLUSIONS: Changes in somatosensory and auditory evoked magnetic field changes correlated with cognitive impairment in SIVD patients. Magnetic field latency measures may provide an objective and sensitive index for early dementia detection and monitoring of cognitive function.