[Enhancing survival outcomes in stage â ¢ gastric/esophagogastric junction cancer: a retrospective study of immune checkpoint inhibitors and adjuvant chemotherapy based on real-world data].

Objective: To explore the efficacy of immune checkpoint inhibitors combined with adjuvant chemotherapy in patients with phase III gastric cancer and esophagogastric junction cancer. Methods: This study used a retrospective cohort study method based on real-world data. Clinical data of 403 patients with stage III gastric/esophagogastric junction cancer who underwent gastrectomy followed by adjuvant therapy in the Department of Gastric Surgery at Sun Yat-sen University Cancer Center from January 2020 to December 2023 were retrospectively collected. The study cohort comprised 147 (36.5%) patients with stage IIIA, 130 (32.3%) with stage IIIB, and 126 (31.3%) with stage IIIC gastric/esophagogastric junction cancer. Of them, 15 (3.7%) were HER-2 positive, 25 (6.2%) dMMR, and 22 (5.5%) patients Epstein-Barr virus encoding RNA (EBER) positive. Based on treatment plans, the patients were divided into immune checkpoint inhibitor combined with chemotherapy group (immune therapy group, n=110, 71 males and 39 females, median age 59 years old) and chemotherapy alone group (chemotherapy group, n=293, 186 males and 107 females, median age 60 years old). All patients in the immunotherapy group received immune checkpoint inhibitors targeting the programmed cell death protein-1 (PD-1) and its ligand (PD-L1). Of them, 85 received pembrolizumab, 10 received sintilimab, 8 received tislelizumab, 4 received camrelizumab, 2 received toripalimab, and 1 received pabocizumab. The adjuvant chemotherapy regimens used among the chemotherapy alone group includes SOX regimen (132 cases), XELOX (102 cases), S-1 monotherapy (44 cases), and other regimens (15 cases). The 3-year DFS rate of the two groups was compared, and subgroup analysis was conducted based on different ages, molecular phenotypes, pTNM staging, extranodal infiltration, and tumor length. Results: The median follow-up was 20.5 months (range 3.1~46.3), with a 3-year overall DFS rate of 61.4% for the entire 403 patients. The 3-year DFS rate for the immunotherapy group was 82.7%, higher than the chemotherapy alone group (58.8%), with a statistically significant difference (P=0.021). Multivariate analysis showed that postoperative immunotherapy was a protective factor for DFS (HR=0.352, 95%CI: 0.180~0.685). Subgroup analysis showed that stage IIIC (HR=0.416, 95%CI: 0.184~0.940), aged ≥60 years (HR=0.336, 95%CI: 0.121~0.934) and extranodal invasion (HR=0.378, 95%CI: 0.170~0.839) were associated with benefit from the combined immune adjuvant chemotherapy, while no association was observed for MMR, HER-2 or EBER status. Conclusion: Stage III gastric/esophagogastric junction cancer patients may benefite from postoperative immune checkpoint inhibitor combined with adjuvant chemotherapy in real-world settings.

[Forecasting the burden of disease from diabetes under the scenarios of specific risk factors control in China in 2030].

Objective: To forecast mortality, age-standardized mortality, and probability of premature mortality from diabetes, and to simulate the impact of controlling risk factors by 2030 in China. Methods: We simulated the burden of disease from diabetes in six scenarios according to the development goals of risk factors control by the WHO and Chinese government. Based on the theory of comparative risk assessment and the estimates of the burden of disease for China from the Global Burden of Disease Study 2015, we used the proportional change model to project the number of deaths, age-standardized mortality, and probability of premature mortality from diabetes under different scenarios of risk factors control in 2030. Results: If the trends in exposures to risk factors from 1990 to 2015 continued. Mortality, age-standardized mortality, and probability of premature mortality from diabetes would increase to 32.57/100 000, 17.32/100 000, and 0.84% by 2030, respectively. During that time, mortality, age-standardized mortality and probability of premature mortality for males would all be higher than for females. If the goals of controlling risk factors were all achieved, the number of deaths from diabetes in 2030 would decrease by 62.10% compared to the predicted numbers based on the historical trends in exposure to risk factors, and the probability of premature mortality would drop to 0.29%. If only the exposure to a single risk factor were achieved by 2030, high fasting plasma glucose control would have the greatest impact on diabetes, resulting in a 56.00% reduction in deaths compared to the predicted numbers based on the historical trends, followed by high BMI (4.92%), smoking (0.65%), and low physical activity (0.53%). Conclusions: Risk factors control plays an important role in reducing the number of deaths, age-standardized mortality rate, and probability of premature mortality from diabetes. We suggest taking comprehensive measures to control relevant risk factors for certain populations and regions, to achieve the goal of reducing the burden of disease from diabetes as expected.

[Prediction on the burden of disease of chronic obstructive pulmonary disease and simulation of the effectiveness of controlling risk factors in China by 2030].

Objective: To forecast the burden of chronic obstructive pulmonary disease (COPD) in China by 2030 and evaluate the effectiveness of controlling risk factors based on the predictive model. Methods: Based on the relationship between the death of COPD and exposure to risk factors and the theory of comparative risk assessment, we used the estimates of the Global Burden of Disease Study 2015 (GBD2015) for China, targets for controlling risk factors, and proportion change model to project the number of deaths, standardized mortality rate, and probability of premature mortality from chronic respiratory diseases by 2030 in different scenarios and to evaluate the impact of controlling the included risk factors to the disease burden of COPD in 2030. Results: If the trends in exposure to risk factors from 1990 to 2015 continued, the number of deaths and the mortality for COPD would be 1.06 million and 73.85 per 100 000 population in China by 2030, respectively, with an increase of 15.81% and 10.69% compared to those in 2015. Compared to 2015, the age-standardized mortality rate would decrease by 38.88%, and the premature mortality would reduce by 52.73% by 2030. If the smoking rate and fine particulate matter (PM2.5) concentration separately achieve their control targets by 2030, there would be 0.34 and 0.27 million deaths that could be avoided compared to the predicted numbers based on the natural trends in exposure to risk factors and the probability of premature death would reduce to 0.59% and 0.52%, respectively. If the control targets of all included risk factors were achieved by 2030, a total of 0.53 million deaths would be averted, and the probability of premature death would decrease to 0.44%. Conclusions: If the exposures to risk factors continued as showed from 1990 to 2015, the number of deaths and mortality for COPD would increase by 2030 compared to 2015, and the standardized mortality and the probability of premature death would decrease significantly, which would achieve the targets of preventing and controlling COPD. If the exposure to the included risk factors all achieved the targets by 2030, the burden of COPD would be reduced, suggesting that the control of tobacco use and air pollution should be enhanced to prevent and control COPD.

[Prediction of disease burden caused by malignant cancer in the context of risk factor control in China, 2030].

Objective: To predict the number of deaths, standardized mortality and probability of premature mortality caused by malignant cancer in the context of risk factor control at different levels in China in 2030, and assess the possibility of achieving the target of reducing the probability of premature mortality of malignant cancer. Methods: According to the risk factor control standard for malignant cancer used both at home and abroad, the results of China from Global Burden of Disease Study 2015 were used to calculate the population attributable fraction of the risk factors. Based on the comparative risk assessment theory, the deaths of malignant cancer were classified as attributable deaths and un-attributable deaths. Proportional change model was used to predict risk factor exposure and un-attributable deaths of malignant cancer in the future, then the number of deaths, standardized mortality rate and probability of premature mortality of malignant cancer in 2030 was estimated. Data analyses were performed by using software R 3.6.1. Results: If the risk factor exposure level during 1990-2015 remains, the number of deaths, standardized mortality rate, and probability of premature mortality of malignant cancer would increase to 3.62 million, 153.96/100 000 and 8.92% by 2030, respectively. If the risk factor exposure control level meets the requirement, the probability of premature mortality from cancer in people aged 30-70 years would drop to 7.57% by 2030. Conclusions: The control of risk factor exposure will play an important role in reducing deaths, standardized mortality rate and probability of premature mortality of malignant cancer. But more efforts are needed to achieve the goals of Health China Action.

Comparison of Both Sides for Retroperitoneal Laparoscopic Donor Nephrectomy: Experience From a Single Center in China.

BACKGROUND: Laparoscopic donor nephrectomy (LDN) has gradually become the main approach to obtain live donor kidneys. However, the shorter right renal vein limits its wider application. The aim of this study was to compare the outcomes of left- and right-side retroperitoneal LDN. METHODS: We reviewed the perioperative data of 527 consecutive donors receiving retroperitoneal pure LDN with a new method at our center between April 2009 and April 2014. The patients were divided into group A (the first 100 patients) and group B (the remaining 427 patients). A total of 423 cases of left donor surgery and 104 cases of right donor surgery were compared. The comparison of the laterality of LDN was also performed between group A and group B. RESULTS: This is currently the largest case series of LDN in our country. Although right-side LDN patients had longer operation time and a slightly higher incidence of intraoperative complications compared with left-side LDN patients, the operation time was shorter in both the groups compared with previous reports. In group B, patients undergoing right-side LDN had longer operation time and more frequent complications. Once the learning curve of 100 cases was completed, the incidence of complications and operation time were greatly reduced in both sides for LDN. There was no significant difference in the serum creatinine levels in recipients at 6 months of follow-up. CONCLUSIONS: Despite a slightly higher incidence of complications and longer operation time, right-side LDN can achieve equally safe and effective transplantation outcomes. This expands the source of potential donor kidneys.

Exploring the osteoarthritis-related genes by gene expression analysis.

OBJECTIVE: Osteoarthritis (OA) is a most common chronic degenerative joint lesion, which affects both cartilage and bone. A better understanding of the gene expression profiling of OA may help understanding the pathogenesis of OA and finding the therapy targets for OA treatment. MATERIALS AND METHODS: GSE8077 was downloaded from Gene Expression Omnibus (GEO) including 5 OA rats induced by anterior cruciate ligament transection and partial medial meniscectomy and 5 rats that were performed sham surgery as control. Differentially expressed genes (DEGs) between OA group and control group were identified by t-test with p < 0.05 and the coding genes that transcription factors corresponded were screened by TRANSFAC. Then Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs and transcription factors were performed. The DEGs and transcription factors were integrated with information from STRING database to construct PPI network. RESULTS: A total of 119 up-regulated genes, 39 down-regulated genes and 9 transcription factors were identified in OA sample. The GO enrichment analysis showed that 119 up-regulated genes were significantly enriched in blood vessel development and KEGG pathway enrichment showed that genes were involved in circadian rhythm pathway. In the PPI network, Cd44, Mmp13, Timp1 and Igf1 showed higher degrees. CONCLUSIONS: The screened genes could provide a new and comprehensive view for treatment of OA.

Clinicopathological and prognostic significance of α5ß1-integrin and MMP-14 expressions in colorectal cancer.

The purpose of this study was to evaluate the association of expression level of α5ß1-integrin and MMP-14 with clinicopathologic features and prognosis in colorectal cancer (CRC). The expressions of α5ß1-integrin and MMP-14 in normal colorectal mucosa and CRC tissue were detected with immunohistochemistry. We estimated the five-year survival rate by the Kaplan-Meier method. The positive expressions rates of α5ß1-integrin and MMP-14 in CRC tissue were 60.6% and 63.3% respectively, and there were significant differences on their positive expression rates between in CRC tissue and in normal colorectal mucosa(P<0.05). The expression rates of α5ß1-integrin and MMP-14 in patients with poor histological differentiation, lymph node metastasis and high clinical staging were heightened. There was a significant difference (P<0.05) on the five-year survival rate for α5ß1-integrin expression, which was 44.6% in positive groups and 75.5% in negative groups. And there was a significant difference (P<0.05) on the five-year survival rate for MMP-14 expression, which was 48.2% in positive group and 73.1% in negative group. The expression of α5ß1-integrin and MMP-14 is correlated with the progression and metastasis of CRC, and α5ß1-integrin and MMP-14 may be used as prognostic markers in CRC.

Ubiquitin pathway and ovarian cancer.

The ubiquitin-proteasome pathway is a common cellular process in eukaryotic tissue. Ubiquitin binds to proteins and tags them for destruction; this tagging directs proteins to the proteosome in the cell that degrades and recycles unneeded proteins. The ubiquitin-proteasome pathway plays an important role in the regulation of cellular proteins with respect to cell cycle control, transcription, apoptosis, cell adhesion, angiogenesis, and tumour growth. This review article discusses the various ways that the ubiquitin pathway is involved in ovarian cancer, such as modulating the ovarian-cancer-related gene BRCA1 and tumour suppressor p53, and interfering with the erk pathway, the cyclin-dependent cell cycle regulation process, and ERBB2 gene expression.

Anticoccidial activity of herbal complex in broiler chickens challenged with Eimeria tenella.

The objective of the present study was to evaluate the anticoccidial effect of different concentrations of the herbal complex of 4 plants (leaves of Azadirachta indica and Nicotiana tabacum, flowers of Calotropis procera and seeds of Trachyspermum ammi) in broiler chickens in comparison with amprolium anticoccidial. Three concentrations (2 g, 4 g and 6 g) of herbal complex were given to the experimental groups once a day and amprolium (at the dose rate of 125 ppm) was given orally in drinking water from the 14th to the 21st days of age. One group was kept as infected, non-medicated control and one as non-infected, non-medicated control. All groups were inoculated orally with 75,000 sporulated oocysts on the 14th day of age except the non-infected, non-medicated control. Among herbal complex medicated groups, the maximum anticoccidial effect was seen in the group medicated with 6 g herbal complex followed by 4 g and 2 g herbal complex medicated groups. Treatment with 6 g of the herbal complex significantly reduced the negative performance and pathogenic effects associated with Eimeria tenella challenge at a level that was comparable with amprolium when using a largely susceptible recent field isolate. In summary, concentration-dependent anticoccidial activity of the studied herbal complex suggests its use as an alternative anticoccidial agent to chemotherapeutic drugs for Eimeria tenella control.

Anticoccidial activity of hydrochloric acid (HCl) against Eimeria tenella in broiler chickens

The present study was planned to evaluate the anticoccidial activity of the different concentrations of the HCl against Eimeria tenella infection in broiler chickens in comparison with the amprolium anticoccidial. For this purpose, a total of 198 chicks were placed 11 per pen with three pens per treatment. The different concentrations of HCl (1000ppm, 2000ppm and 3000ppm) and amproilum (at the dose rate of 125ppm) were given to the experimental groups in drinking water from 10 to 19th days of age. One group was kept as infected non medicated control and one as non infected non medicated control. At the 12th day of age, all the groups were inoculated orally with 75,000 sporulated oocysts except non infected non medicated control. Anticoccidial activity was evaluated on the basis of performance (weight gain, feed conversion ratio) and pathogenic (oocyst score, lesion score and mortality percentage) parameters. Among HCl medicated groups, the maximum anticoccidial effect was seen in the group medicated with 1000ppm HCl followed by 2000ppm and 3000ppm HCl medicated groups. Amprolium and 1000ppm HCl were almost equivalent in suppressing the negative performance and pathogenic effects associated with coccidiosis (Eimeria tenella) challenge. In summary, the lower doses of HCl have the potential to be used as alternative to chemotherapeutic drugs for Eimeria tenella control. It is therefore suggested that further studies should be carried out to determine the possible minimum safe levels of HCl with least toxic effects to be used as anticoccidial.

Anticoccidial effects of acetic acid on performance and pathogenic parameters in broiler chickens challenged with Eimeria tenella

The objective of the present study was to evaluate the anticoccidial effect of the different concentrations of the acetic acid in the broiler chickens in comparison with the amprolium anticoccidial. A total of 198 chicks were placed 11 per pen with three pens per treatment. The different concentrations (1 percent, 2 percent and 3 percent) of acetic acid and amproilum (at the dose rate of 125ppm) were given to the experimental groups in drinking water from 10-19th days of age. One group was kept as infected non medicated control and one as non infected non medicated control. All the groups were inoculated orally with 75,000 sporulated oocysts at the 12th day of age except non infected non medicated control. Anticoccidial effect was evaluated on the basis of performance (weight gain, feed conversion ratio) and pathogenic (oocyst score, lesion score and mortality percentage) parameters. Among acetic acid medicated groups, the maximum anticoccidial effect was seen in the group medicated with 3 percent acetic acid followed by 2 percent and 1 percent acetic acid medicated groups. Amprolium and 3 percent acetic acid were almost equivalent in suppressing the negative performance and pathogenic effects associated with coccidiosis (Eimeria tenella) challenge. In summary, acetic acid has the potential to be used as alternative to chemotherapeutic drugs for Eimeria tenella control. Concentration-dependent anticoccidial effect of acetic acid suggests that further studies should be carried out to determine the possible maximum safe levels of acetic acid with least toxic effects to be used as anticoccidial.

Triorthocresyl phosphate-induced neuronal losses in lumbar spinal cord of hens--an immunohistochemistry and ultrastructure study.

To investigate the neuronal losses of hens' spinal cords in the model of organophosphate-induced delayed neuropathy (OPIDN) and to analyze the impact of apoptosis on the pathogenesis of OPIDN. Adult hens were challenged with triorthocresyl phosphate (TOCP) at a single dose (750 mg/kg). Neuronal losses in the 3rd lumbar spinal cord (L3) were assessed by light-microscopy and electron-microscopy methods at different days post exposure, respectively. The typical OPIDN signs were seen in the TOCP-exposed hens at about 9th day. The number of large nerve cells declined gradually. And these cells were verified as neurons by immunostained with neuronal marker NeuN. The expression of FasL reached proximal at about 9th day, decreased from 14th day. Neurons in TOCP exposed groups displayed degenerative morphologies in electronic microscopy. Some neurons showed apoptotic-like ultrastructure profiles at 5th day. The nuclear membrane was complete with chromatin condensed to the margins of nuclear membrane like a crescent-shaped body. Mitochondria morphologic changes appeared early (5 d) following exposure to TOCP, and developed in a time-dependent fashion. Apoptosis might be involved in the development of OPIDN, and play a role in the pathogenesis of OPIDN.

Differential expression of NMDA and AMPA receptor subunits in DARPP-32-containing neurons of the cerebral cortex, hippocampus and neostriatum of rats.

Dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa (DARPP-32) is a key element of dopamine/D1/DARPP-32/protein phosphatase-1 (PP-1) signaling cascades of mammalian brain. We are interested in the expression patterns of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in DARPP-32-containing neurons, which may constitute morphological basis for interaction between dopamine and ionotropic glutamate receptors in dopaminoceptive cells. Double immunofluorescence was performed to visualize neurons showing coexpression of DARPP-32 with NMDA or AMPA receptor subunits (i.e., NR1, NR2a/b, glutamate receptor subunit 1 [GluR1], GluR2/3, and GluR4) in the forebrains of rats. Distribution of DARPP-32-positive neurons completely or partially overlapped with that of NMDA receptor- or AMPA receptor-immunoreactive ones in the frontal and parietal cortex, hippocampus and neostriatum, and neurons double-labeled with DARPP-32/NR1, DARPP-32/NR2a/b, DARPP-32/GluR1, DARPP-32/GluR2/3, or DARPP-32/GluR4 immunoreactivity were numerously observed. Semiquantification analysis indicated that most of DARPP-32-containing neurons (86-98%) expressed NR1, NR2a/b and GluR2/3, while less of them (14-90%) expressed GluR1 and GluR4. Although high rates (90-98%) of DARPP-32-positive cells expressed NMDA receptors in all regions above, variant percentages of them expressing AMPA receptor subunits were observed among the cortex (54-90%), hippocampus (59-97%) and neostriatum (14-97%). The study presents differential expression patterns of NMDA and AMPA receptors in DARPP-32-postive neurons in these forebrain regions. Taken together with previous reports, the present data suggest that interaction between dopamine and glutamate receptors may occur in the dopaminoceptive neurons with distinct receptor compositions and may be involved in modulating neuronal properties and excitotoxicity in mammalian forebrain.

Crystallization and preliminary x-ray crystallographic studies of trichosanthin delta C7.

Trichosanthin (TCS) is a type I ribosome-inactivating protein (RIP) which possesses rRNA N-glycosidase activity. TCS has various pharmacological properties. It is possible to reduce the antigenicity of TCS by deleting up to seven C-terminal residues of TCS (TCS-C7) with minimal effect on its activity. TCS-C7 has been crystallized and the crystal diffracted to 1.8 A. It belongs to space group P2(1), with unit-cell parameters a=71.6A, b=74.4A, c=87.6A, beta=97.0 degrees. It is given that there are four molecules per asymmetric unit.

Crystallization and preliminary X-ray crystallographic studies of a macromolecular antitumour antibiotic, C1027.

C1027 is a macromolecular antitumour antibiotic produced by Streptomyces globispourus C1027 and consists of an apoprotein and a non-protein labile chromophore. Little is known about how the thermally unstable chromophore is stabilized by the apoprotein. The purified C1027 was monodisperse according to dynamic light-scattering measurements and crystallized in two different crystal forms from two different starting conditions using the vapour-diffusion method. Condition I yielded hexagonal prism crystals having space group P3(1)/P3(2) and unit-cell parameters a = b = 66.8, c = 55.4 A. Diffraction data were collected to 2.1 A resolution using an in-house Rigaku rotating Cu anode X-ray generator. Another condition produced rod-like crystals with space group P3(1)21/P3(2)21 and unit-cell parameters a = b = 55.15, c = 55.87 A. A data set to 1.8 A resolution was collected from a rod-like crystal using a MAR CCD detector at the SRS synchrotron source.

Evidence for involvement of the neural pathway containing the peripheral vagus nerve, medullary visceral zone and central amygdaloid nucleus in neuroimmunomodulation.

It is now evident that a bidirectional communication network exists between the central nervous system (CNS) and immune system (IS). However, the way in which the IS passes inform to the brain is not quite clear.In the present study, one of the neural pathways involved in the cytokine-to-brain communication was investigated in the rat. This pathway starts at the vagal nerve projecting to the medullary visceral zone (MVZ), an arc-shape band from the dorsomedial to ventrolateral area in the middle-caudal segment of the medulla oblongata, and terminates at the central amygdaloid nucleus (Ce) which receives projections from large catecholaminergic neurons in the MVZ. Animals were randomly divided into two experimental groups. Triple-labeling was used in Group I animals to combine wheat germ aggulutinin-conjugated horseradish peroxidase (WGA-HRP) retrograde tracing with anti-Fos and anti-tyrosine hydroxylase (TH) immunostaining. WGA-RP was stereotaxically injected into the unilateral Ce of the animals and, after a survival period of 48 h, intraperitoneal (IP) injection of lipopolysaccharide (LPS) was performed. Seven kinds of labeled neurons were observed in the MVZ, namely, HRP-, Fos- or TH-singly-labeled neurons; Fos/HRP-, Fos/TH- or HRP/TH-doubly-labeled neurons; and Fos/HRP/TH-triply-labeled neurons. As for Group II animals, bilateral subdiaphragmatic vagotomy (SDV) or sham operation was performed, followed 4 weeks later by IP injection of LPS. The number of Fos-positive neurons within the Ce and MVZ was significantly lower (P<0.01) in rats having SDV when compared with those receiving sham operation. Our results suggest that part of the peripheral immune information can be conveyed through the vagus to the catecholaminergic neurons in the MVZ, where it is transported to the Ce. The MVZ is a neural relay station in the immune-to-brain communication and might play a significant role in neuroimmuno-modulation via the vagus-MVZ-Ce pathway.

Evidence for the medullary visceral zone as a neural station of neuroimmunomodulation.

The aim of the present study was to test the possibility that the catecholaminergic projectional pathway from the vagus nerve to the medullary visceral zone (MVZ) thence to the paraventricular nucleus of hypothalamus (PVN) was involved in the cytokine-to-brain communication. A triple labeling method in which WGA-HRP retrograde tracing was combined with anti-Fos and -TH immunohistochemical staining was used. WGA-HRP was stereotaxically injected into unilateral PVN in the rat, after a survival of 48 h, animals received intraperitoneal injection of lipopolysaccharide (LPS). The distribution of the HRP retrogradely labeled neurons, Fos protein positive and catecholaminergic neurons (tyrosine hydroxylase as marker) in the MVZ was observed. Subdiaphragmatic vagotomy (SDV) and sham surgery were also used to observe the different Fos expression in the MVZ after intraperitoneal administration of lipopolysaccharide (LPS) or pyrogen-free saline (NS). Under light microscope, seven types of positively stained neurons could be distinguished within the MVZ, namely neurons single-labeled with Fos, HRP or TH, respectively; neurons double-labeled with Fos/TH, Fos/HRP or HRP/TH separately; and neurons triple-labeled with Fos, HRP and TH staining. Intraperitoneal LPS caused lots of robust Fos expression within the MVZ in the sham surgery groups and this response in the MVZ was markedly inhibited in the vagotomized rats. The results suggested that some catecholaminergic neurons in the MVZ could send projections to the PVN and this pathway might be involved in the relay of peripheral immune information via vagus nerve. MVZ was a neural relay station in the immune-to-brain communication and might play a significant role in the neuroimmunomodulation via vagus-MVZ-PVN pathway.

Expression and changes of HSP70 in the rat forebrain subjected to gamma knife (100Gy) irradiation targeted on the caudate putamen and survived for different times.

Forebrain heat shock protein 70 (HSP70) immunohistochemical reactivity was investigated in rats subjected to gamma knife irradiation focusing on the right caudate putamen nucleus. The forebrain sections of all experimental animals were processed with anti-HSP70 antiserum and then by avidin-biotin peroxidase complex immunohistochemistry after gamma ray irradiation with a dose of 100Gy and they each survived for different times (from 30 min to 30 days). Some neurons, glial cells, and endothelial cells were HSP70-like immunoreactivity (HSP70-LI) positive. HSP70-LI was mainly distributed in the target area of irradiation, as well as in non-target regions, e.g. the cortex, hippocampus, and hypothalamus, etc. The expression and change of HSP70-LI from 3 h to 30 days after irradiation followed the following rules: (1) Within 3 to 24 h, the dilated vessels with HSP70-LI endothelial cells were found at first, and a few lightly stained HSP70-LI neurons and glias were observed in the target and non-target regions; (2) In 3-7 days, darkly stained HSP70-LI neurons and glias were apparently increased and formed an expression peak. From 14 to 30 days, HSP70-LI cells were distinctly decreased and became weakly stained or negative. These results suggested that although the irradiation target of the gamma knife was localized, the response to irradiation occurred extensively.

Time-dependent astroglial changes after gamma knife radiosurgery in the rat forebrain.

OBJECTIVE: Using an experimental rat model and a clinically relevant treatment dose, we performed gamma knife radiosurgery to define the hyperacute radiation effects in normal rat forebrain, the time dependence of the astrocytic reaction, and the participation of astrocytes in the healing process after single-dose gamma radiation injuries. METHODS: Seventy-one rats underwent radiosurgical treatment (4-mm collimator) of the caudate-putamen nucleus (single-fraction maximal dose of 100 Gy) and were killed at times ranging from 3 hours to 90 days. Serial cryostat brain sections were processed with the immunohistochemical avidin-biotin complex technique, using anti-glial fibrillary acidic protein as the primary antibody (to identify astrocytes). RESULTS: Vascular changes, including endothelial hyperplasia and vessel wall thickening, were identified as the earliest postradiation manifestations and continued throughout the observation period. Astrocytes reacted to the radiation injury with hyperplasia and hypertrophy. At earlier time points (3-24 h), proliferation was the predominant reaction. The expression of glial fibrillary acidic protein in the proliferating and hypertrophic astrocytes formed an initial peak in the adjacent corpus callosum 3 days after radiosurgery and peaked within the target site between 14 and 30 days. Astrocytic proliferation and hypertrophy were also observed in distant cortices (frontal, parietal, insular, and piriform cortices) and in the hippocampus. No necrosis was observed less than 30 days after irradiation. By Day 90, necrotic lesions with a mean diameter of 4 mm were identified, with glial scar at their peripheries. Astrocytic morphological features varied according to the distance from the necrosis. The irradiated side contained more glial fibrillary acidic protein-containing cells than did the nonirradiated contralateral side. CONCLUSION: During the early phase after radiation, vasculopathy was the first morphological change and may serve as the initiating factor for subsequent changes. Reactive astrocytes appeared not only at the target site but also in the surrounding regions; the severity of injury was determined by the distance from the target.

Design and synthesis of new steroidal inhibitors of estrogen synthase (aromatase).

The estrogen synthase (aromatase) enzyme system is responsible for the biosynthesis of estrogen hormones in human females. Estrogens are vital for normal growth and development, but will promote the growth of certain breast cancers. Approximately 30-50% of breast cancers are considered to be hormone-dependent. Consequently regulation of estrogen biosynthesis has advanced as a potential therapeutic strategy. This has led to the development of active-site inhibitors, which may have potential for the control of breast cancer. We have recently prepared a number of new steroidal inhibitors that have been evaluated as aromatase inhibitors. These include steroidal A/B-ring isoxazoles and a series of A/B-ring pyrazoles with alkyl- and aryl-substituted nitrogen. In addition, we have developed new chemical procedures for the synthesis of 6beta-hydroxy steroids, which could be key intermediates in the preparation of C-19 inhibitors of aromatase activity.