Split isobaric analog state in 55Ni: case of strong isospin mixing.

Study of ß+ decay of the exotic Tz=-3/2 nucleus 55Cu, via delayed γ rays, has revealed a strongly isospin mixed doublet (4599-4579 keV) in 55Ni, which represents the fragmented and previously unknown isobaric analog of the ground state of 55Cu. The observed small log ft values to both states in the doublet confirm the superallowed Fermi ß decay. The near degeneracy of a pair of 3/2- levels in 55Ni results in the strong isospin mixing. The isospin mixing matrix element between the T=3/2 and T=1/2 levels is inferred from the experiment to be 9(1) keV, which agrees well with the matrix element of the charge symmetry breaking shell model Hamiltonian of Ormand and Brown. A precise value of the half-life of 55Cu at 57(3) ms was also obtained.

SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.

We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.

[Prevalence of diabetes and associated factors in Hainan centenarians].

Objective: To investigate basic characteristics of diabetes prevalence and associated factors in centenarians in Hainan province of China. Methods: All the subjects were from China Hainan Centenarian Cohort Study. A total of 1 002 centenarians were included in the final analysis, who were divided into three groups: diabetes group, impaired fasting glucose (IFG) group, and normal glucose group according to the guideline. Results: The average age of centenarians was (102.77±2.55) years, and the proportion of females was 82.0%. There were 95 centenarians who suffered from diabetes, and the prevalence rate was 9.5%. There were 81 centenarians who had IFG, and the prevalence rate was 8.1%. The mean fasting plasma glucose (FPG) level of centenarians was (5.12±1.44) mmol/L, while 43.5% of centenarians had FPG levels ranging from 4.00 to 5.00 mmol/L and 22.1% of centenarians had the FPG levels ranging from 5.00 to 6.00 mmol/L. Increased triglyceride level and abdominal obesity might be associated with the risk for diabetes. Conclusion: The glycometabolism in centenarians in Hainan was better than that in other age groups, and no gender specific difference was observed.

[Distribution characteristics of blood lipid profile in Hainan centenarians].

Objective: To explore the prevalence of lipid profile and the influencing factors of dyslipidemia in centenarians in Hainan province, and provide basic data for the study of the lipid profile in centenarians. Methods: The data of this study were from the baseline data of China Hainan Centenarian Cohort Study from June 2014 to December 2016. A total of 1 002 centenarians were recruited. According to the guidelines for the prevention and treatment of dyslipidemia in Chinese adults in 2016, the prevalence of lipid profile were described and the prevalence of dyslipidemia with different clinical classifications were compared, and the main influencing factors were analyzed. Results: The median levels of TC, TG, LDL-C and HDL-C were 4.60 mmol/L, 1.05 mmol/L, 2.77 mmol/L and 1.41 mmol/L, respectively, in centenarians in Hainan. Blood lipid profile level was higher in females than in males. With the increase of BMI, TC, TG and LDL-C increased significantly, while HDL-C decreased significantly. The total prevalence of dyslipidemia was 19.1%. Smoking, BMI and area distribution were the main influencing factors of dyslipidemia. Conclusion: The prevalence of dyslipidemia in centenarians in Hainan was at a low level compared with other countries, and the blood lipid profile level was higher in females than in males.

[Relationship between obesity related anthropometric indicators and depression risk in Hainan centenarians].

Objective: To analyze the association of waist circumference, BMI, waist-hip ratio, waist-height ratio, calf circumference and waist-calf circumference ratio (WCR) with depression risk in centenarians in Hainan province. Methods: A total of 1 002 centenarians in Hainan were selected by cluster sampling. GDS-15 was used to investigate the depression. Multivariate linear regression and logistic regression analyses were conducted to evaluate the correlation between anthropometric indicators and depression risk. Restricted cubic spline was used to analyze and visualize the linear relationship. Results: After adjusting demographic characteristics (gender, age, ethnic group, marital status, educational level and type of residence) and lifestyle (smoking and drinking), the standard ß of BMI, WC, WHR, WHtR, calf circumference and WCR associated with GDS-15 were -0.069, -0.032,0.009, -0.009, -0.099 and 0.060, respectively, and the P values of BMI and calf circumference were <0.05. With the increase of calf circumference, the risk of depression decreased, OR value was 0.94 (95% CI:0.90-0.98), and after adjustment, the results were still significant. Classified variable analysis indicated with the decrease of calf circumference and the increase of WCR, the risk of depression increased gradually, the trend P values were 0.038 and 0.042, respectively. Conclusion: Central obesity (waist circumference and WCR) and periphery obesity (calf circumference) have differed effects on depression in centenarians, and increased calf circumference is a protective factor for depression in female centenarians, attention should be paid to the mental health of the elderly women with lower calf circumference.

[Distribution characteristics of blood pressure in Hainan centenarians].

Objective: To explore the blood pressure levels and the influencing factors of hypertension among Hainan centenarians, and provide basic data for the further blood pressure related studies of the centenarian population. Methods: The baseline data were from China Hainan Centenarian Cohort Study (CHCCS). This cross-sectional data, based on the community population, was a complete sample study of centenarians, including questionnaire survey, physical examination and physiological index detection. A total of 1 002 centenarians were recruited to describe the blood pressure level. According to the guidelines for the prevention and treatment of hypertension in Chinese adults in 2018, the prevalence of hypertension was analyzed. Results: The median levels of systolic blood pressure, diastolic pressure and pulse pressure were 152.0, 76.0 and 76.5 mmHg, respectively. Blood pressure level was higher in females than in males. The prevalence of hypertension was 71.9%, mainly in isolated systolic hypertension with the prevalence of 60.1%. The results of multivariate analysis showed that the risk of hypertension in women was higher than that in men (OR=1.624, 95%CI: 1.155-2.283), and the risk of hypertension in the northern (OR=0.625, 95%CI: 0.434-0.901) and central areas (OR=0.586, 95%CI: 0.346-0.993) was lower than that of the Eastern. Conclusion: The prevalence of hypertension, mainly in isolated systolic hypertension, showing gender and regional distribution differences.

[Epidemiological investigation of a family clustering of COVID-19].

Objective: To investigate the epidemiological characteristics of a family clustering of COVID-19. Methods: Field epidemiological survey was conducted. Results: Case 1 of the long-term residents from Hubei province was the source of infection of this family clustering. There were 6 cases (from case 2 to case 7) infected in the whole incubation period. The incubation period was more than 14 days for 3 of the second-generation cases. Routes of transmission included respiratory droplets (from case 1 transmitted to case 6, from case 1 to her family members) and close contact (from case 1 to other cases in her family). All the age groups were generally susceptible, while elderly were easier to progress to critically ill. Besides respiratory symptoms, there were also gastrointestinal symptoms, of which diarrhea was the most common one. Conclusions: Family clustering had been an important part for COVID-19 cases.

Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex.

Immunophilins, a family of proteins that exhibit rotamase (peptidyl-prolyl cis-trans isomerase) activity in vitro, are expressed in many organisms and most tissues. Although some immunophilins can mediate the immunosuppressive actions of FK506, rapamycin, and cyclosporin A, the physiological role of the unligated proteins is not known. A 59-kilodalton member of the FK506- and rapamycin-binding class was found to associate in the absence of these drugs with two heat shock proteins (hsp90 and hsp70) and the glucocorticoid receptor (GR). Together, these proteins make up the inactive GR, thus biochemically linking two families of proteins proposed to be involved in protein folding and assembly as well as two potent immunosuppressive modalities.

Postoperative extended-volume external-beam radiation therapy in high-risk esophageal cancer patients: a prospective experience.

BACKGROUND AND PURPOSE: Extended-volume external-beam radiation therapy (RT) following esophagectomy is controversial. The present prospective study evaluates the feasibility of extended-volume RT treatment in high-risk esophagectomy patients with a cervical anastomosis receiving postoperative combined chemoradiation therapy. PATIENTS AND METHODS: From 2001 to 2006, 15 patients with resected esophageal cancer were prospectively accrued to this pilot study to evaluate the adverse effects of extended-volume RT. Postoperative management was carried out at London Regional Cancer Program. Eligibility criteria were pathology-proven esophageal malignancy (T3-4, N0-1), disease amenable to surgical resection, and esophagectomy with or without resection margin involvement. Patients with distant metastases (M1) and patients treated with previous RT were excluded. All 15 study patients received 4 cycles of 5-fluorouracil-based chemotherapy. External-beam RT was conducted using conformal computed tomography planning, with multi-field arrangement tailored to the pathology findings, with coverage of a clinical target volume encompassing the primary tumour bed and the anastomotic site in the neck. The radiation therapy dose was 50.40 Gy at 1.8 Gy per fraction. The RT was delivered concurrently with the third cycle of chemotherapy. The study outcomes-disease-free survival (DFS) and overall survival (OS)-were calculated by the Kaplan-Meier method. Treatment-related toxicities were assessed using the U.S. National Cancer Institute's Common Toxicity Criteria. RESULTS: The study accrued 10 men and 5 women of median age 64 years (range: 48-80 years) and TNM stages T3N0 (n = 1), T2N1 (n = 2), T3N1 (n = 11), and T4N1 (n = 1). Histopathology included 5 adenocarcinomas and 10 squamous-cell carcinomas. Resection margins were clear in 10 patients. The median follow-up time was 19 months (range: 3.5-53.4 months). Before radiation therapy commenced, delay in chemotherapy occurred in 20% of patients, and dose reduction was required in 13.3%. During the concurrent chemoradiation therapy phase, 20% of the patients experienced chemotherapy delay, and 6.6% experienced dose reduction. No patient experienced treatment-related acute and chronic esophagitis above grade 2. Disease recurred in 40% of the patients (6/15), and median time to relapse was 24 months. No tumour recurred at the anastomotic site. The median DFS was 23 months, and the median OS was 21 months. CONCLUSIONS: Extended-volume external-beam RT encompassing the tumour bed and the anastomotic site is feasible and safe for high-risk T3-4, N0-1 esophageal cancer patients after esophagectomy.

Intraspinal schwannoma and neurogenic bladder.

Most lumbar intradural schwannomas present initially as radiculopathies with sensory disturbances. However, neurogenic bladder dysfunction may be one of the earliest manifestations and can cause long-term disability. We present the case of a patient with a L3-4 schwannoma (newly diagnosed owing to recurrent urinary retention and urinary tract infection) who finally underwent surgical resection. Improvement of bladder sensation was documented by urodynamic study and the patient was subsequently weaned off her Foley catheter with satisfactory outcome.

Shape changes, exocytosis, and cytosolic free calcium changes in stimulated human eosinophils.

Essentially pure preparations of normal density eosinophils obtained from patients with hypereosinophilic syndrome (HES) were stimulated with complement factor 5a (C5a), platelet-activating factor (PAF), FMLP and neutrophil-activating peptide (NAP-1/IL-8). Three responses were studied, the transient rise in cytosolic free calcium concentration ([Ca2+]i) (derived from indo-1 fluorescence), shape changes (measured by laser turbidimetry), and exocytosis of eosinophil peroxidase (EPO) (assessed by H2O2/luminol-dependent chemiluminescence). Responses were obtained with all four agonists, but C5a and PAF were by far more potent than FMLP and NAP-1/IL-8, which induced only minor effects. Pretreatment of the cells with pertussis toxin attenuated [Ca2+]i changes, EPO release and, to a lesser extent, shape changes, indicating that GTP-binding proteins of Gi-type are involved in receptor-dependent signal transduction processes leading to these responses. A clear dissociation was observed in the control of the shape change response and EPO exocytosis. The shape change was not affected by Ca2+ depletion or treatment with the protein kinase inhibitor staurosporine, but exocytosis was prevented by Ca2+ depletion and markedly enhanced by staurosporine. The activation of the contractile system, leading to shape changes and motility, thus appears to be independent of the classical signal transduction pathway involving phospholipase C, a [Ca2+]i rise and protein kinase C activation. Exocytosis is, as expected, Ca2+ dependent and appears to be under a negative control involving protein phosphorylations.

Structure of Bacillus subtilis superoxide dismutase.

The sodA gene of Bacillus subtilis was expressed in Escherichia coli, purified and crystallized. The crystal structure of MnSOD was solved by molecular replacement with four dimers per asymmetric unit and refined to an R factor of 21.1% at 1.8 A resolution. The dimer structure is very similar to that of the related enzyme from B. anthracis. Larger structural differences were observed with the human MnSOD, which has one less helix in the helical domain and a longer loop between two beta-strands and also showed differences in three amino acids at the intersubunit interface in the dimer compared with the two bacterial MnSODs. These structural differences can be exploited in the design of drugs that selectively target the Bacillus enzymes.

Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases.

PURPOSE: To study the use of chemotherapy for Merkel cell carcinoma (MCC) of the skin. PATIENTS AND METHODS: Twenty-five cases of MCC were treated at the London Regional Cancer Center between 1987 and 1997. Thirteen cases treated with chemotherapy were reviewed with 191 cases from the literature. RESULTS: At presentation, 24 patients had localized skin lesions (stage I) and one had locoregional involvement (stage II). Among the nine cases with recurrent nodal disease, six had chemotherapy as a component of salvage treatment. They were all free of disease at a median of 19 months (range, 12 to 37 months). In contrast, two patients who had salvage radiotherapy alone died of disease. Overall survival (OS) and disease-free survival (DFS) were 59% and 43%, respectively, at two years. Median OS and DFS were 29 months (range, 1 to 133 months) and 9 months (range, 1 to 133 months), respectively. Nodal disease developed in 12 (50%) of 24 patients with stage I disease, and distant metastases developed in six (25%) of 24. Including those from the literature, there were 204 cases treated with chemotherapy. Cyclophosphamide/doxorubicin (or epirubicin)/vincristine combination +/- prednisone was the most commonly used chemotherapy regimen (47 cases), with an overall response rate of 75.7% (35.1% complete, 35. 1% partial, and 5.4% minor responses). Etoposide/cisplatin (or carboplatin) was the next most commonly used regimen (27 cases), with an overall response rate of 60% (36% complete and 24% partial responses). The difference in response rate was not statistically significant (P =.19). Among the 204 cases, there were seven (3.4%) toxic deaths. CONCLUSION: Chemoradiation for locally recurrent or advanced disease may be an option for patients with a good performance status.

Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial.

PURPOSE: To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM). PATIENTS AND METHODS: One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). RESULTS: All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02). CONCLUSION: There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.

Genetic analysis of the colicin V secretion pathway.

Colicin V (ColV) is peptide antibiotic secreted by Escherichia coli through a dedicated exporter composed of three proteins, CvaA, CvaB, and TolC. ColV secretion is independent of the E. coli general secretory pathway (Sec) but requires an N-terminal export signal specific for the CvaAB/TolC exporter. ColV secretion was characterized using genetic and biochemical methods. When the ColV N-terminal extension is replaced with the OmpA signal sequence, the Sec system can localize ColV to the periplasm. Periplasmic ColV is lethal to cells lacking the ColV immunity protein, Cvi. Based on this result, a genetic assay was designed to monitor for the presence of periplasmic ColV during normal CvaAB/TolC mediated secretion. Results indicate that low levels of ColV may be present in the periplasm during secretion. Precursor and mature ColV were also characterized from the wild-type system and in various exporter mutant backgrounds using immunoprecipitation. ColV processing is rapid in wild-type cells, and CvaA and CvaB are critical for processing to occur. In contrast, processing occurs normally, albeit more slowly, in a TolC mutant.

Antibodies to cytoplasmic sequences of cloned liver growth hormone (GH) receptors recognize GH receptors associated with tyrosine kinase activity.

GH stimulates tyrosyl phosphorylation of GH receptors in 3T3-F442A fibroblasts, and highly purified GH receptor preparations exhibit tyrosine kinase activity. Paradoxically, however, the GH receptor cloned from liver exhibits no sequence similarity to receptors with known signal transduction mechanisms, including those exhibiting ligand-activated tyrosine kinase activity. These observations raise the possibility that there are two kinds of receptors for GH: the first represented by the cloned liver GH receptor, and the second by a tyrosine kinase-containing GH receptor. To inquire into the possibility of two distinct GH receptors, we determined whether the cloned liver GH receptor shares structural similarities with the tyrosine kinase-associated GH receptor. When the cloned rabbit liver GH receptor is expressed in human kidney 293 cells, it migrates with a mol wt appropriate for the tyrosine kinase-associated GH receptor, despite the calculated mol wt of the cloned GH receptor being 60,000 smaller than that of the tyrosine kinase-associated GH receptor. The recognition of tyrosine kinase-associated GH receptor by antipeptide antibodies to three different epitopes on the cytoplasmic domain of the cloned liver GH receptor was also tested. Tyrosyl phosphorylated [125I]human GH-receptor complexes were prepared by immunoprecipitation with phosphotyrosyl-binding antibody; this subpopulation of GH-receptor complexes was recognized by all three antipeptide antibodies. The antibodies also recognized similarly isolated tyrosyl phosphorylated GH-receptor complexes, which had been further phosphorylated in solution on tyrosyl residues upon addition of [gamma 32P] ATP. Furthermore, highly purified GH receptors prepared by sequential immunoprecipitation using phosphotyrosyl-binding antibody and any one of the three antipeptide antibodies incorporated 32P into tyrosyl residues upon the addition of [gamma 32P] ATP. These results provide evidence that tyrosine kinase-associated GH receptors share sequence similarity in the cytoplasmic domain with the cloned liver GH receptor. The cloned GH receptor and the tyrosine kinase-associated GH receptor, therefore, are likely to be the same receptor or related receptor isoforms.

Characterization of the phospholipase C gene of Pseudomonas aeruginosa cloned in Escherichia coli.

We have cloned a 4.9-kb fragment of Pseudomonas aeruginosa DNA containing the structural gene of phospholipase C (PLC), by inserting it into the BamHI site of plasmid pBR322. Strains of Escherichia coli carrying this recombinant plasmid produce PLC, but expression of the gene differs from that in P. aeruginosa in two respects: (i) synthesis of the enzyme appears to be constitutive, i.e., not repressible by the presence of inorganic phosphate in the growth medium, and (ii) most of the enzyme remains associated with the outer membrane instead of being secreted. Insertion mutagenesis at a unique restriction site within the PLC gene destroyed the ability of the plasmid to code, in maxicells, for phospholipase C activity and for an Mr 80000 polypeptide.

Orientation and expression of the cloned hemolysin gene of Pseudomonas aeruginosa.

The structural gene for Pseudomonas aeruginosa hemolysin, carried on recombinant plasmid pSL2 and cloned in Escherichia coli, was analyzed by insertional and deletional mutagenesis. Expression of the hemolysin was blocked by insertion of transposon Tn5 into different locations. Two of the mutants allowed detectable synthesis of truncated hemolysin polypeptides of two different sizes and thus defined the structural gene. The location of the hemolysin gene in the recombinant plasmid, and the direction of transcription, were further established by nuclease BAL 31 digestion, and by construction of gene fusions between hemolysin and beta-galactosidase. Evidently, the tet promoter contributed to the majority of the expression of cloned hemolysin gene, but the Pseudomonas promoter was present in the cloned DNA and was functional in E. coli since inactivation of the tet promoter either by Tn5 insertion or by deletion decreased synthesis of the 80-kDal hemolysin but did not fully abolish it.

Variability of target volume delineation in cervical esophageal cancer.

PURPOSE: Three-dimensional (3D) conformal radiation therapy (CRT) assumes and requires the precise delineation of the target volume. To assess the consistency of target volume delineation by radiation oncologists, who treat esophageal cancers, we have performed a transCanada survey. MATERIALS AND METHODS: One of three case presentations, including CT scan images, of different stages of cervical esophageal cancer was randomly chosen and sent by mail. Respondents were asked to fill in questionnaires regarding treatment techniques and to outline boost target volumes for the primary tumor on CT scans, using ICRU-50 definitions. RESULTS: Of 58 radiation oncologists who agreed to participate, 48 (83%) responded. The external beam techniques used were mostly anterior-posterior fields, followed by a multifield boost technique. Brachytherapy was employed by 21% of the oncologists, and concurrent chemotherapy by 88%. For a given case, and the three volumes defined by ICRU-50 (i.e., gross tumor volume [GTV], clinical target volume [CTV], and planning target volume [PTV]) we determined: 1. The total length in the cranio-caudal dimension; 2. the mean diameter in the transverse slice that was located in a CT slice that was common to all participants; 3. the total volume for each ICRU volume; and 4. the (5, 95) percentiles for each parameter. The PTV showed a mean length of 14.4 (9.6, 18.0) cm for Case A, 9.4 (5.0, 15.0) cm for Case B, 11.8 (6.0, 16.0) cm for Case C, a mean diameter of 6.4 (5.0, 9.4) cm for Case A, 4.4 (0.0, 7.3) cm for Case B, 5.2 (3.9, 7.3) cm for Case C, and a mean volume of 320 (167, 840) cm3 for Case A and 176 (60, 362) cm3 for Case C. The results indicate variability factors (95 percentile divided by 5 percentile values) in target diameters of 1.5 to 2.6, and in target lengths of 1.9 to 5.0. CONCLUSION: There was a substantial inconsistency in defining the planning target volume, both transversely and longitudinally, among radiation oncologists. The potential benefits of 3D treatment planning with high-precision dose delivery could be offset by this inconsistency in target-volume delineation by radiation oncologists. This may be particularly important for multicenter clinical trials, for which quality assurance of this step will be essential to the interpretation of results.

Radiation treatment for cervical esophagus: patterns of practice study in Canada, 1996.

PURPOSE: To assess the patterns of practice among Canadian radiation oncologists who treat esophageal cancers, using a trans-Canada survey, completed at the end of 1996. METHODS AND MATERIALS: One of 3 case presentations of different stages of cervical esophageal cancer was randomly assigned and sent to participating radiation oncologists by mail. Respondents were asked to fill in questionnaires regarding treatment techniques and to outline target volumes for the boost phase of radiotherapy. Radiation oncologists from 26 of 27 (96%) of all Canadian centers participated. RESULTS: High-energy X-rays (>/= 10 MV) were employed by 68% of the respondents in part of the treatment course. The majority (83%) of the radiation oncologists used at least two phases of treatment. Very few, 10 of 59 (17%), responses started with multifield treatment. The most frequently used prescription dose was 60 Gy/30 fractions/6 weeks, given with concurrent chemotherapy. Dose prescriptions were to the isocenter in 39 of 48 (81%) or to a particular isodose line in 9 of 48 (19%) of respondents. CONCLUSION: There was a variety of radiation treatment techniques in this trans-Canada survey. The majority of the patients had combined cisplatin-based chemoradiation. The isocenter was not used consistently as a dose prescription point.