[Treatment of orbital vascular malformations with intralesional bleomycin injection and N-butyl-2-cyanoacrylate glue embolization].

Objective: To evaluate the clinical efficacy of bleomycin lavage combined with N-butyl-2-cyanoacrylate glue embolization and resection in the treatment of orbital vascular malformations. Methods: It was a retrospective case series study. Patients with orbital vascular malformations diagnosed at the Ophthalmology Division of Chinese PLA General Hospital from January 2018 to October 2021 were included and divided into exophthalmos group and non-exophthalmos group based on whether the patients had postural exophthalmos. Intralesional bleomycin injection and N-butyl-2-cyanoacrylate glue embolization were performed. The preoperative and postoperative visual acuity, the dosages of bleomycin and isobutyl cyanoacrylate glue, pathological results, imaging findings and remission rate were recorded and analyzed. The Chi-square test, Wilcoxon signed rank analysis and Mann-Whitney U test were used for statistical analysis. Results: A total of 58 patients (58 eyes)were included, and there were 22 males (37.9%)　and 36 females (62.1%). Nineteen (32.8%) patients had postural exophthalmos, and 39 (67.2%) patients did not suffer postural exophthalmos. The patient's age of the two groups was 39.0 (28.0, 54.5) years vs. 14.0 (5.7, 26.5) years, with a statistically significant difference (Z=-3.96, P<0.001). There was no significant difference in gender, eye laterality, follow-up time and the disease course between the two groups (all P>0.05). During the operation, the dosage of bleomycin was 15 000 (13 500, 15 000) U in the exophthalmos group, and 15 000 (9 000, 16 500) U in the non-exophthalmos group (Z=-0.70, P=0.944). The dosages of N-butyl-2-cyanoacrylate glue were 2.8 (1.0, 3.0) ml and 1.7 (1.0, 2.2) ml, respectively, in the two groups, with no significant difference (Z=-1.11, P=0.268). There was no visual impairment in both groups, while the visual acuity in 5 patients without postural exophthalmos was improved postoperatively. The imaging examination results showed no difference in the malformed vascular area before and after the treatment in the exophthalmos group [384.0 (329.0, 458.0) mm2 vs. 330.5 (271.6, 356.7) mm2; Z=-1.26, P=0.208], but a significantly decreased area after the treatment in the non-exophthalmos group [960.8 (822.1, 1058.3) mm2 vs. 311.6 (164.6, 361.6) mm2; Z=-2.67, P=0.008]. All patients had no obvious local or systemic adverse reactions during the follow-up. The pathology reports showed vascular malformations in all 15 specimens obtained from the exophthalmos group, as well as vascular malformations in 41.0% (16/39) of specimens and venous lymphatic malformations in 59.0% (23/39) of specimens from the non-exophthalmos group. Thirty-nine patients had complete remission (67.2%), 19 patients had partial remission (32.8%), and the effective treatment rate was 100%. Conclusion: Bleomycin lavage combined with N-butyl-2-cyanoacrylate glue embolization can achieve good therapeutic effects on orbital vascular malformations.

[A case report of orbital epithelioid hemangioendothelioma].

A 70-year-old male patient, who had a right upper eyelid tumor excision 4 years ago, complained of eyelid swelling and ptosis for 3 months. Orbital CT and MRI showed an orbital cystic lesion with hemorrhage in the right eye. The tumor was resected under general anesthesia. The pathological diagnosis was epithelioid hemangioendothelioma. (Chin J Ophthalmol, 2021, 57:696-698).

[The imaging signs and significances of the enlargement of the infraorbital nerve and the frontal nerve in orbital lymphoproliferative diseases].

Objective: To describe imaging signs of infraorbital nerve enlargement (IONE) and frontal nerve enlargement (FNE) in orbital lymphoproliferative diseases (LPDs), and to explore the diagnostic value and differential diagnostic role of the signs. Methods: A retrospective case series study. The data of 222 cases (262 eyes) of LPDs and 95 cases (134 eyes) of inflammatory pseudotumors (IPs) pathologically confirmed by the Peking University People's Hospital and the Third Medical Center of the Chinese PLA General Hospital from January 2013 to December 2018 were analyzed. The LPDs were lymphoma (including atypical lymphoid hyperplasia) in 91 cases (110 eyes) and reactive lymphoid hyperplasia (RLH) in 131 cases (152 eyes). The patients with LPD included 101 males and 121 females, aged (58±17) years, and the patients with IP included 44 males and 51 females, aged (49±21) years. All patients underwent orbital CT or MRI with T1 weighted imaging, T2 weighted imaging and enhanced T1 weighted imaging scanning. Slice thickness was 3 mm. In the coronal CT or MRI, the criterion for determining IONE was the inferior orbital nerve diameter greater than the optic nerve, and the criterion for determining FNE was the forehead nerve diameter equal to or greater than the optic nerve. The pathological types and imaging features of nerve enlargement were recorded. The incidence rates of different pathological types were compared using chi-square test. Results: The enlarged nerves showed homogeneous soft tissue density on CT images, accompanied with enlarged bony infraorbital nerve grooves (foramina). MRI showed moderate signals of T1 and T2 weighted imaging, with clear boundaries and obvious enhancement, which could spread to the pterygopalatine fossa and the cranial cavity. The accompanying images included the enlargement of lacrimal glands or extraocular muscles, intraorbital mass or sinuses opacity. The IONE and/or FNE were found in 12 patients with LPD, but were not found in any patients with IP. The difference was statistically significant (12/222 vs. 0/95, χ²=5.337, P=0.021). Among the cases with nerve enlargement, there were 2 cases of diffuse large B cell lymphoma and 10 cases of RLH (2/91 vs. 10/131, χ²=3.103, P=0.078), as well as 7 cases of IgG4-related ophthalmic disease (IgG4-ROD) and 3 cases of non-IgG4-ROD (7/28 vs. 3/103, χ2=15.232, P=0.000). Conclusions: Lymphoma and RLH can express IONE and/or FNE, in which the IgG4-ROD is the most common and specific type. CT and MRI scans can show enlarged nerves and accompanying signs. Neural thickening can also be applied as a discrimination marker of LPDs and IPs. (Chin J Ophthalmol, 2020, 56: 832-838).

Progressive brain atrophy in chronically infected and treated HIV+ individuals.

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry to map the annual rate of change of regional brain volumes (mean time interval 1.0 ± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9 years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue loss despite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.

A systematic review of long-term outcomes of patients with psychosis who received early intervention services.

Despite convincing evidence of short-term symptom control and functional recovery of patients with psychosis after receiving early intervention (EI) services, little is known about the long-term outcomes of EI for these patients. This review aims to evaluate the effectiveness of EI services in improving long-term outcomes of patients with psychosis. A systematic literature search was conducted on PubMed, PsycINFO, Scopus, Medline, CINAHL, BIOSIS, and EMBASE electronic databases to identify studies that evaluated long-term outcomes of patients with psychosis measured 5 years or beyond after entering the EI service. Of 13,005 articles returned from the search, 14 eligible articles reporting study cohorts from nine EI services in seven countries and regions were identified. Data on study design, patient characteristics, intervention components, and outcomes were extracted and reviewed. Only a few studies reported better longitudinal outcomes for negative symptoms, mortality, employment, and hospitalization in patients received EI services. However, results from cross-sectional measurements provided little evidence for long-term impacts of EI services on clinical and functional outcomes. A dilution effect of benefits over time was also demonstrated in several studies. This review highlights the gap in current EI service provision and suggests possible future directions for service improvement and further research.

Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis.

BACKGROUND: This preplanned subset analysis of the phase III MONET1 study aimed to determine whether motesanib combined with carboplatin/paclitaxel (C/P) would result in improved overall survival (OS) versus chemotherapy alone, in a subset of Asian patients with nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with nonsquamous NSCLC (stage IIIB/IV or recurrent) and no prior systemic therapy for advanced disease were randomized to IV carboplatin (AUC, 6 mg/ml min) and paclitaxel (200 mg/m2) for up to six 3-week cycles, plus either oral motesanib 125 mg q.d. or placebo. Primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: Two hundred twenty-seven Asian patients from MONET1 were included in this descriptive analysis. Median OS was 20.9 months in the motesanib plus C/P arm and 14.5 months in the placebo plus C/P arm (P=0.0223); median PFS was 7.0 and 5.3 months, respectively, (P=0.0004); and ORR was 62% and 27%, respectively, (P<0.0001). Grade≥3 adverse events were more common in the motesanib plus C/P arm versus placebo plus C/P (79% versus 61%). CONCLUSION: In this preplanned subset analysis of Asian patients with nonsquamous NSCLC, motesanib plus C/P significantly improved OS, PFS, and ORR versus placebo plus C/P. CLINICAL TRIAL NUMBER: NCT00460317.

Electrical impedance tomography in anaesthetised chickens (Gallus domesticus).

The applicability of electrical impedance tomography (EIT) in birds is unknown. This study aimed to evaluate the use of EIT in anaesthetised chickens in four recumbency positions. Four adult Hyline chickens were anaesthetised with isoflurane in oxygen, and intubated endotracheally for computed tomography (CT). A rubber belt was placed around the coelom caudal to the shoulder joint. A chicken-specific finite element (FE) model, which is essential to generate anatomically accurate functional EIT images for analysis, was constructed based on the CT images obtained at the belt level. Ten additional chickens were anaesthetised with the same protocol. An EIT electrode belt was placed at the same location. The chickens were breathing spontaneously and positioned in dorsal, ventral, right and left lateral recumbency in a randomised order. For each recumbency, raw EIT data were collected over 2 min after 13 min of stabilisation. The data were reconstructed into functional EIT images. EIT variables including tidal impedance variation (TIV), centre of ventilation right to left (CoVRL) and ventral to dorsal (CoVVD), right to left (RL) ratio, impedance change (ΔZ) and eight regional impedance changes including the dorsal, central-dorsal, central-ventral and ventral regions of the right and left regions were analysed. Four breathing patterns (BrP) were observed and categorised based on the expiratory curve. A linear mixed model was used to compare EIT variables between recumbencies. Fisher's exact test was used to compare the frequencies of breathing patterns for each recumbency. The ΔZ observed was synchronous to ventilation, and represented tidal volume of the cranial air sacs as confirmed by CT. Significant differences were found in CoVVD and regional impedance changes between dorsal and ventral recumbencies (P < 0.05), and in CoVRL, RL ratio and regional impedance changes between right and left recumbencies (P < 0.05), which suggested a tendency for the distribution of ventilation to shift towards non-dependent air sacs. No differences were found for TIV and respiratory rate between recumbencies. Recumbency had a significant effect on the frequencies of each of the four BrPs (P = 0.001). EIT can monitor the magnitude and distribution of ventilation of the cranial air sacs in different recumbencies in anaesthetised chickens.

A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer.

BACKGROUND: Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. PATIENTS AND METHODS: Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). RESULTS: In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). CONCLUSIONS: Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.

A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer.

BACKGROUND: We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS: Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.

A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel-carboplatin (CP) plus motesanib or bevacizumab. PATIENTS AND METHODS: Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs). RESULTS: ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C(max) and C(min) values were consistent with its pharmacokinetic properties observed in previous studies. CONCLUSIONS: The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study.

Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV.

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date. Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide. Design, Setting, and Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019. Main Outcomes and Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status. Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] ß = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] ß = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] ß = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] ß = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004). Conclusions and Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.

MicroRNA-124 inhibits cell invasion and epithelial-mesenchymal transition by directly repressing Snail2 in gastric cancer.

OBJECTIVE: MicroRNAs (miRNAs) act as critical regulators of genes expression involved in tumor biological processes. The study aimed to investigate the clinical significance and biological role of miR-124 in gastric cancer (GC). PATIENTS AND METHODS: MiR-124 expression was analyzed from 88 GC tissues and adjacent normal tissues by quantitative Real-time PCR (qRT-PCR). Kaplan-Meier curves and log-rank test was used to evaluate the association between miR-124 and the over survival (OS) time of GC patients. MTT assays and transwell invasion assays were performed to assess cell proliferation and invasion. The relationship between miR-124 and Snail2 expression was analyzed by dual luciferase reporter assay. Western blot analyses were performed to detect the relative protein expression. RESULTS: We found that miR-124 expression was significantly reduced in GC tissue samples when compared to the adjacent normal tissues (p<0.05). Lower miR-124 was found to be associated with tumor size (p=0.001), lymphatic metastasis (p=0.008) and TNM stage (p=0.015). Furthermore, patients who have lower miR-124 predicted poor OS time (p<0.05). Function studies suggested that cell proliferation and invasion ability of GC cells were inhibited by up-regulation of miR-124 expression. Moreover, we demonstrated that Snail2 was a direct target of miR-124. Meanwhile, miR-124 inhibited Epithelial-Mesenchymal Transition (EMT) process by repressing the Snail2 expression in GC cells. CONCLUSIONS: MiR-124 acted as a tumor suppressor in GC and may be a useful target for GC treatment.

Loss of Rb and Myc activation co-operate to suppress cyclin D1 and contribute to transformation.

Cyclin D1 can bind and phosphorylate the product (pRb) of the retinoblastoma gene (RB-1) and recent evidence suggests pRb, in turn, may regulate cyclin D1 protein expression. In transformed cell lines, loss of pRb activity strongly correlates with a decrease in cyclin D1 protein expression, and conversely, introduction of pRb can induce cyclin D1 promoter activity. We show here that pRb does not regulate cyclin D1 directly as basal and serum-stimulated levels of cyclin D1 protein and kinase activity are similar in wildtype and pRb-deficient primary mouse embryonic fibroblasts (MEFs). These observations suggest that the suppression of cyclin D1 in pRb-minus tumour cell lines requires both loss of pRb and at least one additional genetic event. We have determined that constitutive, ectopic Myc expression in pRb-deficient, but not wildtype, MEFs suppresses cyclin D1 protein expression and kinase activity. Regulation is evident at either the level of RNA or protein expression. Phenotypically, pRb-deficient MEFs consistently exhibited a delayed growth response in comparison to wildtype MEFs. This growth delay is abrogated in pRb-deficient MEFs which are expressing ectopic Myc protein, coincident with the loss of cyclin D1 protein expression. Moreover, these cells exhibit an increased proliferative capacity, and they no longer show contact inhibition. Our results support a cross-regulatory mechanism between Myc, pRb and cyclin D1 and suggest a novel role for cyclin D1 in tumorigenesis.

Nuclear localization conferred by the pocket domain of the retinoblastoma gene product.

The tumor suppressor Rb is a nuclear phosphoprotein that controls cell growth and differentiation by modulating the activity of certain transcription factors. Transport of Rb to the nucleus is affected by both a bipartite nuclear localization signal (NLS) in the C-terminus of the protein and a central domain, termed A/B or pocket, through which Rb interacts with transcription factors and viral oncoproteins. Mutations in either the A or B subdomains of the pocket render a NLS-deficient Rb completely cytoplasmic. Fusing the A/B domain of Rb to the Escherichia coli beta-galactosidase, to create betagal-A/B, confers nuclear localization upon this bacterial protein. Moreover, co-expression with the adenovirus oncoprotein, E1A, further augments nuclear localization of betagal-A/B. These findings provide direct evidence that the pocket domain of Rb is not only required but also sufficient to induce nuclear transport by a 'piggyback' mechanism. Thus, nuclear localization of Rb is dictated by two independent and autonomous domains: (i) the bipartite NLS and (ii) the pocket domain. We suggest that via these domains, Rb chaperons and co-compartmentalizes with its associated factors and preempts their activity prior to nuclear transport.

African elephant myoglobin with an unusual autoxidation behavior: comparison with the H64Q mutant of sperm whale myoglobin.

Elephant myoglobins both from Asian and African species have a glutamine in place of the usual distal (E7) histidine at position 64. We have isolated native oxymyoglobin directly from the skeletal muscle of African elephant (Loxodonta africana), and examined the autoxidation rate of oxymyoglobin (MbO2) to metmyoglobin (metMb) as a function of pH in 0.1 M buffer at 25 degreesC. As a result, African elephant MbO2 was found to be equally resistant to autoxidation as sperm whale myoglobin. However, the elephant myoglobin exhibited a distinct rate saturation below pH 6. Kinetic analysis of the pH profiles for the autoxidation rate has disclosed that African elephant MbO2 does not show any proton-catalyzed process, such as the one that can play a dominant role in the autoxidation reaction of sperm whale myoglobin by involving the distal histidine as its catalytic residue. Such a greater stability of African elephant MbO2 at low pH could be explained almost completely by the single H64Q mutation of sperm whale myoglobin. In African elephant aqua-metmyoglobin the Soret band was considerably broadened so as to produce another peak in the pentacoordinate 395 nm region. This unique spectral feature was therefore analyzed to show that the myoglobin is in equilibrium between two species, depending upon the presence or absence of a water molecule at the sixth coordinate position.

Skeletal muscle mitogen-activated protein kinases and ribosomal S6 kinases. Suppression in chronic diabetic rats and reversal by vanadium.

The mitogen-activated protein (MAP) kinases and ribosomal S6 protein kinases in the skeletal muscle of insulin-resistant long-term (2 and 6 months' duration) diabetic rats were investigated to understand further the changes in insulin intracellular signaling pathways that accompany diabetes. The effects of insulin-mimetic vanadium compounds on the activity of these kinases were also examined. In the insulin-resistant 2-month diabetic rats, the basal activities of MAP kinases were relatively unchanged, while the basal activities of S6 kinases were significantly increased. Intravenous injection of insulin moderately activated both the 42-kDa MAP kinase (p42mapk) and a 44-kDa MAP kinase (p44erk1) in the 2-month control rats but not in the 2-month diabetic rats. Insulin treatment markedly stimulated the activity of a novel 31-kDa S6 kinase and the previously described 90-kDa ribosomal S6 kinase encoded by one of the rsk genes (p90rsk) in the 2-month control rats, while the effect was substantially reduced in the diabetic rats. In the 6-month diabetic rats, the basal phosphotransferase activities of both MAP kinases were depressed threefold or greater. This correlated with reductions in the amount of immunoreactive p42mapk and p44erk1 proteins in extracts from the diabetic rats. The basal activity of the 31-kDa S6 kinase activity was also reduced fourfold in the 6-month diabetic rats. Treatment of the 2-month diabetic rats with vanadyl sulfate resulted in euglycemia, prevented the increase in the basal activity of S6 kinase, and improved the activation of S6 kinase by insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

BMSCs transplantation improves cognitive impairment via up-regulation of hippocampal GABAergic system in a rat model of chronic cerebral hypoperfusion.

Bone marrow mesenchymal stem cells (BMSCs) transplantation can ameliorate cognitive impairment in chronic ischemic brain injury, but the underlying mechanism is poorly understood. It is considered that the hippocampus holds the capabilities of memory consolidation and spatial navigation, and the gamma amino butyric acid (GABA)ergic system plays an important role in the control of learning and memory processes. Herein, we investigated whether transplantation of BMSCs could improve cognitive impairment via regulating the hippocampal GABAergic system in a rat model of chronic cerebral hypoperfusion. Animals treated with permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO) (a rat model of chronic cerebral hypoperfusion) received intravenous injections of BMSCs or saline as experimental group and control group I, the sham-operated rats received intravenous injections of BMSCs or saline as the sham group and control group II. Four weeks later, the Morris Water Maze was employed to evaluate the cognitive changes of each group, immunohistochemistry and western blotting was used to investigate the GABAergic system expression including GABA, glutamic acid decarboxylase 67 (GAD67) or GABA(B) receptor 1 (GABA(B)R1) in the hippocampus. Our results showed that the 2VO model presented decreased capacities of learning and memory and down-regulated the expression of GABA, GAD67 or GABA(B)R1 in the hippocampal CA1 subfield in comparison to the sham group (P<0.05), while administration of BMSCs (experimental group) manifested increased performances of learning sessions and probe tasks, as well as up-regulated expression of GABA, GAD67 or GABA(B)R1 compared with the control group I (P<0.05). Collectively, these findings suggest that transplantation of BMSCs is capable of improving cognitive impairment via up-regulating the hippocampal GABAergic system in a rat model of chronic cerebral hypoperfusion. Hence, BMSCs transplantation could serve as an important tool for cell therapy in chronic cerebral hypoperfusion disorders.

Simulations using a drug-disease modeling framework and phase II data predict phase III survival outcome in first-line non-small-cell lung cancer.

Simulations were performed for carboplatin/paclitaxel (C/P) plus motesanib or bevacizumab vs. C/P as first-line treatment for advanced non-small-cell lung cancer (NSCLC) using a published drug-disease model. With 700 patients in each arm, simulated hazard ratios for motesanib (0.87; 95% confidence interval [CI], 0.71-1.1) and bevacizumab (0.89; 95% CI, 0.73-1.1) agreed with results from the respective phase III studies but did not discriminate between failed and successful studies. The current model may require further enhancement to improve its utility for predicting phase III outcomes.