Apoptosis of both brain neurons and peripheral blood leukocyte is believed to be an important biomarker for evaluating the functional status of Parkinson’s disease (PD). However, their correlation ...remains unknown. A better understanding of the pathophysiology of neurodegeneration is essential for the treatment and prevention of PD. The present study demonstrated that leukocyte apoptosis is significantly higher in PD patients and is associated with central dopamine neuron loss by using Tc 99 m -TRODAT-1 SPECT. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression.
HER2-ECD (human epidermal growth factor receptor 2 - extracellular domain) is a prominent therapeutic target validated for treating HER2-positive breast and gastric cancer, but HER2-specific ...therapeutic options for treating advanced gastric cancer remain limited. We have developed antibody-drug conjugates (ADCs), comprising IgG1 linked via valine-citrulline to monomethyl auristatin E, with potential to treat HER2-positive gastric cancer in humans. The antibodies optimally selected from the ADC discovery platform, which was developed to discover antibody candidates suitable for immunoconjugates from synthetic antibody libraries designed using antibody-antigen interaction principles, were demonstrated to be superior immunoconjugate targeting modules in terms of efficacy and off-target toxicity. In comparison with the two control humanized antibodies (trastuzumab and H32) derived from murine antibody repertoires, the antibodies derived from the synthetic antibody libraries had enhanced receptor-mediated internalization rate, which could result in ADCs with optimal efficacies. Along with the ADCs, two other forms of immunoconjugates (scFv-PE38KDEL and IgG1-AL1-PE38KDEL) were used to test the antibodies for delivering cytotoxic payloads to xenograft tumor models in vivo and to cultured cells in vitro. The in vivo experiments with the three forms of immunoconjugates revealed minimal off-target toxicities of the selected antibodies from the synthetic antibody libraries; the off-target toxicities of the control antibodies could have resulted from the antibodies' propensity to target the liver in the animal models. Our ADC discovery platform and the knowledge gained from our in vivo tests on xenograft models with the three forms of immunoconjugates could be useful to anyone developing optimal ADC cancer therapeutics.
We used the carbon tetrachloride (CCl
4
) induced liver cirrhosis model to test the molecular mechanism of action involved in cirrhosis-associated cardiac hypertrophy and the effectiveness of
Ocimum ...gratissimum
extract (OGE) and silymarin against cardiac hypertrophy. We treated male wistar rats with CCl
4
and either OGE (0.02 g/kg B.W. or 0.04 g/kg B.W.) or silymarin (0.2 g/kg B.W.). Cardiac eccentric hypertrophy was induced by CCl
4
along with cirrhosis and increased expression of cardiac hypertrophy related genes NFAT, TAGA4, and NBP, and the interleukin-6 (IL-6) signaling pathway related genes MEK5, ERK5, JAK, and STAT3. OGE or silymarin co-treatment attenuated CCl
4
-induced cardiac abnormalities, and lowered expression of genes which were elevated by this hepatotoxin. Our results suggest that the IL-6 signaling pathway may be related to CCl
4
-induced cardiac hypertrophy. OGE and silymarin were able to lower liver fibrosis, which reduces the chance of cardiac hypertrophy perhaps by lowering the expressions of IL-6 signaling pathway related genes. We conclude that treatment of cirrhosis using herbal supplements is a viable option for protecting cardiac tissues against cirrhosis-related cardiac hypertrophy.
Oral vaccination is the most desirable immunization method by which to prevent fish disease occurring at the early larval stage. We developed an
Escherichia coli-based oral nervous necrosis virus ...(NNV) subunit vaccine and demonstrated its effectiveness in orange spotted grouper (
Epinephelus coioides) fry. However, the incubation period was determined to be over 2
weeks. To enhance the efficacy and shorten the incubation period, a safe and digestible biological adjuvant should be found.
Vibrio anguillarum, a common marine bacterium with immune-stimulatory capability was selected as an expression host. An expression vector containing its heat shock protein 60 gene (
groE) as an inducible promoter was constructed to express recombinant NNV coat protein as an antigen. The recombinant
V. anguillarum was inactivated and encapsulated in
Artemia nauplii to formulate a
V. anguillarum-based oral vaccine. Compared to the
E. coli-based oral vaccine, this novel oral vaccine not only elicited a higher expression of
Mx (encoding for an anti-viral protein) in the brain and viscera but also a higher specific antibody titer against NNV in the first week after inoculation. Meanwhile, a higher survival rate compared to an equal dosage of an
E. coli-based oral vaccine was also noticed in two individual challenge trials, indicating that an antigen expressed in an
V. anguillarum-based oral vaccine could enhance efficacy in a shorter incubation period and could reduce the risk of NNV infection.
► We development an oral nervous necrosis virus vaccine using
V. anguillarum as an expression host. ► The expression vector containing its heat shock protein 60 gene (
groE) as an inducible promoter. ► This novel oral vaccine elicited a higher expression of
Mx in the brain and viscera. ► It also a higher specific antibody titer against NNV in the first week after inoculation. ► The vaccine would shorter incubation period and reduce the risk of NNV infection.
Previously we found carbon tetrachloride (CCl₄) induced cirrhosis associated cardiac hypertrophy and apoptosis. The purpose of this study is to determine whether further CCl₄ treatment would induce ...cardiac cell fibrosis. The cardiac tissues were analyzed by H&E. histological staining, Trichrome Masson staining and Western blotting. The results showed that the CCl₄-treated-only group exhibits more trichrome staining, meaning that more fibrosis is present. Moreover, CCl₄ could further induce cardiac-fibrosis via TGF-β-p-Smad2/3-CTGF pathway. However, our data showed that the CCl₄- indcued cardiac abnormalities were attenuated by Ocimum gratissimum extract (OGE) and silymarin co- treatments. In conclusion, our results indicated that the OGE and silymarin may be a potential traditional herb for the protection of cardiac tissues from the CCl4 induced cirrhosis associated cardiac fibrosis through modulating the TGF-β signaling pathway.
Epidemiological investigations suggest that increased age is associated with susceptibility to infection. Pseudomonas aeruginosa (P. aeruginosa) infection and associated exotoxin A (PEA) toxicity ...have been reported in hospitalized elderly patients and young children with cystic fibrosis. The present study investigated age-related differences in PEA-induced hepatotoxicity in post weaning (PW, 3 weeks), young adult (YA, 12 weeks), and mature adult (MA, 60-64 weeks) rats. PEA (20 microg/kg) was injected intraveneously and mortality, clinical chemistry, hepatic histopathology, TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) and PCNA (proliferating cell nuclear antigen) staining, and serum cytokine levels were assessed at specific time points, up to 72 hr post-exposure (HPE). Mortality in MA rats was 100% at less than 48 HPE. Serum ALT levels in MA rats were approximately 5-fold greater than levels in PW and YA rats at 36 HPE. MA rat liver histological sections showed diffuse hepatocellular necrosis. In contrast, hepatocellular apoptosis, demonstrable by the TUNEL method, was noted simply in the periportal and midzonal regions from 36 to 48 HPE. Increased morphological mitoses and PCNA-positive hepatocytes were seen in PW and YA rats at 72 HPE. These parameters were correlated with age-dependent significant increases in TNF-alpha, IL-2, IL-6, and IL-18 levels. These data suggest that inflammatory cytokines play an important role in age-related differences in PEA-induced hepatotoxicity. Moreover, these cytokines might correlate with different patterns histopathologic features at various ages.
Timely trauma care is crucial, especially for severely injured patients. We developed a set of criteria based on physiological changes, anatomic regions injured, and trauma mechanisms in our hospital ...to identify these patients. This study was performed to examine whether or not our revised activation protocol was strictly followed, and to identify areas of deficiency for ongoing quality improvement. The impact of the activation protocol on clinical outcome was also examined.
We reviewed demographic data, mechanisms of injury, trauma scores, and outcome for all trauma patients admitted to a Level I trauma center in southern Taiwan between October 2010 and October 2011. All trauma protocol activation (TPA) decisions were subjected to careful scrutiny. Clinical outcomes for TPA patients and for non-TPA patients who fulfilled the activation criteria were compared. We also analyzed data for patients who did not meet our activation criteria but were found on subsequent work-up to have an Injury Severity Score (ISS) ≥16.
During Phase I of the study there were 2988 trauma admissions. The overall accuracy for TPA was 95.9%. Among 281 TPA patients, only 181 (64.4%) fulfilled the activation criteria. Among 204 patients who met the activation criteria, the protocol was not activated for 23 (11.3%). After we redesigned the computer program to prompt triage nurses and re-educated healthcare personnel, the false TPA and non-TPA rates improved to 14.6% and 2.8%, respectively, during Phase II of the study. There were 187 patients who did not meet our activation criteria and had ISS ≥ 16. TPA patients had a significantly lower Glasgow Coma Scale (GCS) score and were more likely to be admitted to the intensive care unit than non-TPA patients. However, there were no significant differences in ISS, mortality, or admission days. Some 120 patients had a significant brain injury (Abbreviated Injury Scale–Head ≥2) and only 76% of them presented with signs or symptoms suggesting head trauma. These patients were older and had a lower ISS compared to brain-injured TPA patients.
The study shows that our TPA criteria are easy to follow and have a high accuracy rate. For patients with ISS ≥16 who did not meet our TPA criteria, escape was mainly due to head trauma. Additional factors besides GCS scores should be incorporated in the protocol to identify patients with significant head trauma.
Severe acute respiratory syndrome (SARS), a new disease with symptoms similar to those of atypical pneumonia, raised a global alert in March 2003. Because of its relatively high transmissibility and ...mortality upon infection, probable SARS patients were quarantined and treated with special and intensive care. Therefore, instant and accurate laboratory confirmation of SARS-associated coronavirus (SARS-CoV) infection has become a worldwide interest. For this need, we purified recombinant proteins including the nucleocapsid (N), envelope (E), membrane (M), and truncated forms of the spike protein (S1–S7) of SARS-CoV in Escherichia coli. The six proteins N, E, M, S2, S5, and S6 were used for Western blotting (WB) to detect various immunoglobulin classes in 90 serum samples from 54 probable SARS patients. The results indicated that N was recognized in most of the sera. In some cases, S6 could be recognized as early as 2 or 3 days after illness onset, while S5 was recognized at a later stage. Furthermore, the result of recombinant-protein-based WB showed a 90% agreement with that of the whole-virus-based immunofluorescence assay. Combining WB with existing RT-PCR, the laboratory confirmation for SARS-CoV infection was greatly enhanced by 24.1%, from 48.1% (RT-PCR alone) to 72.2%. Finally, our results show that IgA antibodies against SARS-CoV can be detected within 1 week after illness onset in a few SARS patients.
We used the carbon tetrachloride (CCl4) induced liver cirrhosis model to test the molecular mechanism of action involved in cirrhosis-associated cardiac hypertrophy and the effectiveness of Ocimum ...gratissimum extract (OGE) and silymarin against cardiac hypertrophy. We treated male wistar rats with CCl4 and either OGE (0.02 g/kg B.W. or 0.04 g/kg B.W.) or silymarin (0.2 g/kg B.W.). Cardiac eccentric hypertrophy was induced by CCl4 along with cirrhosis and increased expression of cardiac hypertrophy related genes NFAT, TAGA4, and NBP, and the interleukin-6 (IL-6) signaling pathway related genes MEK5, ERK5, JAK, and STAT3. OGE or silymarin co-treatment attenuated CCl4-induced cardiac abnormalities, and lowered expression of genes which were elevated by this hepatotoxin. Our results suggest that the IL-6 signaling pathway may be related to CCl4-induced cardiac hypertrophy. OGE and silymarin were able to lower liver fibrosis, which reduces the chance of cardiac hypertrophy perhaps by lowering the expressions of IL-6 signaling pathway related genes. We conclude that treatment of cirrhosis using herbal supplements is a viable option for protecting cardiac tissues against cirrhosis-related cardiac hypertrophy.
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