Prognosticators of survival in patients with metastatic pancreatic cancer and ascites.

BACKGROUND: Identification of factors associated with survival after ascites diagnosis in metastatic pancreatic cancer (mPC) patients may guide treatment decisions and help to maintain quality of life in this highly symptomatic patient collective. PATIENTS AND METHODS: All patients treated for mPC at the Medical University of Vienna between 2010 and 2019 developing ascites throughout their course of disease were identified by retrospective chart review. General risk factors, metastatic sites, systemic inflammation and liver function parameters, as well as type of treatment after ascites diagnosis were investigated for associations with survival. RESULTS: One hundred and seventeen mPC patients with ascites were included in this study. Median time from mPC to ascites diagnosis was 8.9 months (range 0-99 months) and median overall survival (OS) after ascites diagnosis was 27.4 days (range 21.3-42.6 days). Identified prognostic factors at ascites diagnosis independently associated with an impaired OS were presence of liver metastases [hazard ratio (HR): 2.07, 95% confidence interval (CI) 1.13-3.79, P = 0.018), peritoneal carcinomatosis (HR: 1.74, 95% CI 1.11-2.71, P = 0.015), and portal vein obstruction (HR: 2.52, 95% CI 1.29-4.90, P = 0.007). Compared with best supportive care, continuation of systemic therapy after ascites diagnosis was independently associated with survival (HR: 0.35, 95% CI 0.20-0.61, P < 0.001) with a median OS of 62 days (95% CI 51-129 days, P < 0.001) versus 16 days (95% CI 11-24 days), respectively. CONCLUSIONS: Liver and peritoneal metastases as well as portal vein obstruction were found to be prognostic factors after ascites diagnosis in mPC patients. Continuation of systemic therapy after ascites diagnosis was associated with a longer OS, which needs to be evaluated in larger clinical trials including quality-of-life assessment.

Clinical risk factors for ascites in metastatic pancreatic cancer.

BACKGROUND: Malignant ascites is common in metastatic pancreatic cancer (mPC) and its management still remains a clinical challenge. Early identification of patients at risk for ascites development may support and guide treatment decisions. MATERIALS AND METHODS: Data of patients treated for mPC at the Medical University of Vienna between 2010 and 2019 were collected by retrospective chart review. Ascites was defined as clinically relevant accumulation of intraperitoneal fluid diagnosed by ultrasound or computer tomography scan of the abdomen. We investigated the association between general risk factors, metastatic sites, liver function, systemic inflammation as well as portal vein obstruction (PVO) and ascites development. RESULTS: Among 581 patients with mPC included in this study, 122 (21.0%) developed ascites after a median of 8.7 months after diagnosis of metastatic disease. The occurrence of ascites led to an 8.9-fold increased risk of death [confidence interval (CI) 7.2-11, P < 0.001] with a median overall survival of 1 month thereafter. Clinical risk factors for ascites were male sex [hazard ratio (HR) 1.71, CI 1.00-2.90, P = 0.048], peritoneal carcinomatosis (HR 6.79, CI 4.09-11.3, P < 0.001), liver metastases (HR 2.16, CI 1.19-3.91, P = 0.011), an albumin-bilirubin (ALBI) score grade 3 (HR 6.79, CI 2.11-21.8, P = 0.001), PVO (HR 2.28, CI 1.15-4.52, P = 0.019), and an elevated C-reactive protein (CRP) (HR 4.19, CI 1.58-11.1, P = 0.004). CONCLUSIONS: Survival after diagnosis of ascites is very limited in mPC patients. Male sex, liver and peritoneal metastases, impaired liver function, PVO, as well as systemic inflammation were identified as independent risk factors for ascites development in this uniquely large real-life patient cohort.

Structure of the RNA polymerase domain of E. coli primase.

All cellular organisms use specialized RNA polymerases called "primases" to synthesize RNA primers for the initiation of DNA replication. The high-resolution crystal structure of a primase, comprising the catalytic core of the Escherichia coli DnaG protein, was determined. The core structure contains an active-site architecture that is unrelated to other DNA or RNA polymerase palm folds, but is instead related to the "toprim" fold. On the basis of the structure, it is likely that DnaG binds nucleic acid in a groove clustered with invariant residues and that DnaG is positioned within the replisome to accept single-stranded DNA directly from the replicative helicase.

Structure of a murine leukemia virus receptor-binding glycoprotein at 2.0 angstrom resolution.

An essential step in retrovirus infection is the binding of the virus to its receptor on a target cell. The structure of the receptor-binding domain of the envelope glycoprotein from Friend murine leukemia virus was determined to 2.0 angstrom resolution by x-ray crystallography. The core of the domain is an antiparallel beta sandwich, with two interstrand loops forming a helical subdomain atop the sandwich. The residues in the helical region, but not in the beta sandwich, are highly variable among mammalian C-type retroviruses with distinct tropisms, indicating that the helical subdomain determines the receptor specificity of the virus.

Type II DNA topoisomerases.

Type II DNA topoisomerases are enzymes capable of passing one DNA duplex through another. A combination of structural and biochemical analyses is illuminating the mechanistic details of this transport reaction, revealing the sites of DNA and nucleotide binding and the existence of large-scale domain motions.

Recent developments in DNA topoisomerase II structure and mechanism.

Type II DNA topoisomerases are enzymes that are capable of transporting one duplex DNA through another. Recent experimental results, including the structure of a fragment of yeast topoisomerase II, have provided new insights into the mechanism of the strand passage reaction. Other results have begun to define the role of ATP in the catalytic cycle and illuminate how DNA breaks mediated by topoisomerase II can occur.

Crystal structure of the N-terminal domain of the DnaB hexameric helicase.

BACKGROUND: The hexameric helicase DnaB unwinds the DNA duplex at the Escherichia coli chromosome replication fork. Although the mechanism by which DnaB both couples ATP hydrolysis to translocation along DNA and denatures the duplex is unknown, a change in the quaternary structure of the protein involving dimerization of the N-terminal domain has been observed and may occur during the enzymatic cycle. This N-terminal domain is required both for interaction with other proteins in the primosome and for DnaB helicase activity. Knowledge of the structure of this domain may contribute to an understanding of its role in DnaB function. RESULTS: We have determined the structure of the N-terminal domain of DnaB crystallographically. The structure is globular, highly helical and lacks a close structural relative in the database of known protein folds. Conserved residues and sites of dominant-negative mutations have structurally significant roles. Each asymmetric unit in the crystal contains two independent and identical copies of a dimer of the DnaB N-terminal domain. CONCLUSIONS: The large-scale domain or subunit reorientation that is seen in DnaB by electron microscopy might result from the formation of a true twofold symmetric dimer of N-terminal domains, while maintaining a head-to-tail arrangement of C-terminal domains. The N-terminal domain of DnaB is the first region of a hexameric DNA replicative helicase to be visualized at high resolution. Comparison of this structure to the analogous region of the Rho RNA/DNA helicase indicates that the N-terminal domains of these hexameric helicases are structurally dissimilar.

Structure of DNA topoisomerases.

Over the last several years topoisomerases have finally begun to yield to high-resolution structural studies. These models have greatly aided our understanding of the mechanisms of topoisomerase catalysis and drug interactions. This review will cover advances in the structural biology of topoisomerases and discuss their implications for topoisomerase function.

DNA replication at high resolution.

Several decades of research have delineated the roles of many proteins central to DNA replication. Here we present a structural perspective of this work spanning the past 15 years and highlight several recent advances in the field.

Divalent metal cofactor binding in the kinetic folding trajectory of Escherichia coli ribonuclease HI.

Proteins often require cofactors to perform their biological functions and must fold in the presence of their cognate ligands. Using circular dichroism spectroscopy. we investigated the effects of divalent metal binding upon the folding pathway of Escherichia coli RNase HI. This enzyme binds divalent metal in its active site, which is proximal to the folding core of RNase HI as defined by hydrogen/deuterium exchange studies. Metal binding increases the apparent stability of native RNase HI chiefly by reducing the unfolding rate. As with the apo-form of the protein, refolding from high denaturant concentrations in the presence of Mg2+ follows three-state kinetics: formation of a rapid burst phase followed by measurable single exponential kinetics. Therefore, the overall folding pathway of RNase HI is minimally perturbed by the presence of metal ions. Our results indicate that the metal cofactor enters the active site pocket only after the enzyme reaches its native fold, and therefore, divalent metal binding stabilizes the protein by decreasing its unfolding rate. Furthermore, the binding of the cofactor is dependent upon a carboxylate critical for activity (Asp10). A mutation in this residue (D10A) alters the folding kinetics in the absence of metal ions such that they are similar to those observed for the unaltered enzyme in the presence of metal.

Interhemispheric integration of information in a surface estimation task.

Normal subjects were asked to estimate the total surface of two black spots presented tachistoscopically, either both to the right or both to the left visual field, or bilaterally to either visual field. Performance was highest with unilateral left visual field presentation and lowest with bilateral presentation of the spots. Interhemispheric integration varied with the quantitative relation between the stimuli in the left and right visual fields. Errors may be due in part to an insufficient cooperation of the left hemisphere and/or to an ignorance of the right hemisphere and/or to an unreliable transfer by the cerebral commissures.

Interhemispheric cooperation and activation in integration of verbal information.

Subjects had to judge the semantic relation between two tachistoscopically presented German adjectives. In Exp. I, the two words were projected simultaneously, either both to the left visual field (i.e. to the right hemisphere, LVF-RH), or both to the right visual field (i.e. to the left hemisphere, RVF-LH), or one word to each visual field (i.e. to both hemispheres, EVF-BH). The results yielded a significantly higher performance in the condition EVF-BH than in the two unilateral conditions, without a significant difference between the latter two conditions. In Exp. II, the two words were shown successively. With bilateral presentation, a distinction was made as to whether the left visual field (EVF-BH-L) or the right visual field (EVF-BH-R) was stimulated first. The significantly highest performance was shown in conditions RVF-LH and EVF-BH-R compared with the condition EVF-BH-L, and the significantly poorest performance in the condition LVF-RH compared with the condition EVF-BH-L. The results provide evidence for (1) an intrahemispheric interference with simultaneous unilateral presentation, (2) a cooperative interhemispheric interaction with simultaneous bilateral presentation, and (3) an interhemispheric priming effect with successive bilateral presentation when the left hemisphere was stimulated first.

Bilateral processing of numbers: parallel processing versus functional unity.

Thirty-six normal subjects had to add two numbers ranging from 3 to 9 which were presented tachistoscopically. The two numbers were displayed either unilaterally to the left or right visual field, or bilaterally with one number to the left and one to the right visual field. They were represented as two word names, two dot clusters, or two bargraphs, or the two numbers were represented inconsistently in two different of these representations. The results showed that bilateral processing of a word and a bargraph was performed without visible interactions, and the hemispheres performed independently. When the display included a dot cluster, however, its processing (sequential vs. holistic) appeared to depend on the type of stimulus processed by the contralateral hemisphere, indicating strong interhemispheric interactions.

Ketamine-fentanyl-midazolam infusion for the control of symptoms in terminal life care.

In this report, we describe nine terminally ill patients with metastatic cancer who were treated with an intravenous infusion consisting of ketamine (2 mg/ml)/fentanyl (5 micrograms/ml)/midazolam (0.1 mg/ml) (K/F/M) to control pain after traditional analgesic therapies were unsuccessful. In addition to pain, all patients exhibited some symptoms of cognitive compromise and agitation. After initiation of the K/F/M infusion, all patients exhibited some degree of qualitative improvement in these symptoms as well as in overall pain control. We feel that these observations warrant reporting of the efficacy of this infusion for the treatment of uncontrolled pain and agitation in terminally ill patients when the traditional methods of pain control are inadequate.

A pronounced cognitive style improves interhemispheric integration: by hemispheric differentiation or by hemispheric similarity?

Under conditions of tachistoscopic stimulation normal subjects were presented visuospatial stimulus pairs which had to be integrated interhemispherically. The presence of a pronounced cognitive style improves the interhemispheric integration of this type of information. Two interpretations are discussed. The first explains the observed improvement with a qualitative division of labour, with one highly specialized and one just transmitting hemisphere, i.e., with hemispheric differentiation. The second emphasizes the relatively high capacity of the "subordinate" hemisphere in information processing, i.e., hemispheric similarity.

Fixation accuracy and perceptual asymmetry for consonants.

Fixation accuracy was related to perception of laterally presented consonants. Small left-eye fixation inaccuracy influenced perceptual performance of 8 men and 8 women.

Interhemispheric integration of compound nouns: effects of stimulus arrangement and mode of presentation.

Normal subjects had to name German compound nouns which were presented tachistoscopically. The compound nouns were displayed either unilaterally to the left or right visual field or bilaterally with one element to each visual field. In the bilateral condition a distinction was made as to whether familiar or unfamiliar arrangement of the elements was used. Representation in print was compared with pictorial representation of the compound nouns. A right visual-field superiority was observed with printed representation, but no laterality effects with pictorial representation. Bilateral processing was superior to unilateral processing. Within the bilateral conditions, the familiar arrangement of the elements yielded a significantly better performance than unfamiliar arrangement. This difference can be explained by reading habits and/or by different styles of interhemispheric integration.

Role of interstimulus and stimulus-hemisphere compatibility in the process of interhemispheric integration.

Normal subjects had to name German compound nouns which were presented tachistoscopically. The compound nouns were displayed either unilaterally to the left or right visual field, or bilaterally with one element to the left and one to the right visual field. A distinction was made between the bilateral conditions as to whether the representation of the elements, printed and/or pictorial, included a high or low interstimulus and a high or low stimulus-hemisphere compatibility. Analysis indicated firstly a superiority of the left hemisphere for the naming of compound nouns in mixed print and pictorial representation. Secondly, the performance in the bilateral conditions was moderated by stimulus-hemisphere compatibility. In the process of interhemispheric integration stimulus-hemisphere compatibility proved more crucial than interstimulus compatibility. Analyses of errors further illustrated hemispheric behaviour.

[Rickets-like bone changes in goat kids fed with artificial milk intended for calves]. / Rachitisachtige botveranderingen bij met kunstmelk-voeder voor kalveren opgefokte geitelammeren.

In a large commercial goat farm rickets-like symptoms were diagnosed in goat kids. The disease was probably caused by the synthetic milk which was freely available to the kids. The milk feed was for calves and had a calcium-phosphorus ratio of 0.83:1.