ERCC1, XPF and XPA-locoregional differences and prognostic value of DNA repair protein expression in patients with head and neck squamous cell carcinoma.

OBJECTIVES: Nucleotide excision repair protein expression has been claimed to be responsible for platinum-based chemotherapy resistance. ERCC1, XPF and XPA, core proteins in DNA repair, were evaluated regarding their prognostic value in patients with head and neck squamous cell carcinoma by looking at overall survival and time to recurrence. MATERIALS AND METHODS: Tissue microarrays were constructed from 453 cases of HNSCC, including 222 oral (49%), 126 oropharyngeal (27.8%) and 105 laryngeal (23.2%) tumours. There were 284 XPF, 293 XPA and 294 ERCC1 specimens evaluable for protein expression analysis after immunohistochemical workup. Expression levels were dichotomised into high- and low-expressing groups. Outcomes for overall survival (OS) and time to recurrence (TTR) were analysed using the Kaplan-Meier method. RESULTS: No correlation between ERCC1, XPA and XPF expression and OS was found by looking at the overall patient cohort. However, subsite analysis revealed that high ERCC1 expression was associated with a significantly inferior OS in patients with SCC of the oral cavity (p = 0.028) and showed an independent predictive value in multivariate analysis (p = 0.0123). High XPA expression showed a significantly increased OS in patients with oropharyngeal SCC (p = 0.0386). Regarding XPF, no impact on OS in any subsite could be shown. CONCLUSIONS: While high ERCC1 expression functions as a predictive marker with decreased OS in patients with squamous cell carcinoma of the oral cavity, high XPA expression shows an inverse effect in the subsite of the oropharynx, which has not been described previously. CLINICAL RELEVANCE: ERCC1 and XPA might be candidates to overcome chemotherapy resistance in subtypes of HNSCC.

Polyamines in human breast milk for preterm and term infants.

Maternal milk is the first source of exogenous polyamines for the newborn. Polyamines modulate gut maturation in neonates, but no studies are available on polyamine concentration in human milk of preterm babies, even though they could be important for their immature gut. The present study aimed to determine polyamine concentration in human breast milk of mothers with preterm or term infants during the first month of lactation. Human milk samples were obtained during the first month of lactation from twenty-seven mothers with preterm babies and twelve mothers with babies born at term. The polyamine concentration in human milk was quantified by HPLC. During the first month of lactation, the total polyamine concentration was significantly higher in preterm milk than in term milk samples (7590 (SD 4990) v. 4660 (SD 4830) nmol/l, respectively (P » 0·034)), as well as individual polyamine concentrations. Polyamine concentration in mature milk for preterm babies was significantly higher than that in mature milk for babies at term, and a similar trend was observed in colostrum and transition human milk. The spermidine/spermine ratio was higher in transition milk in preterm v. term samples, while in mature milk, the ratio was significantly lower in preterm than in term babies. In conclusion, the polyamine concentration was significantly higher in human milk for preterm than for term infants. This and the different spermidine/spermine ratios could influence the gut development of premature babies.

Stent Graft Placement by Pseudoaneurysm of the Hepatic Arteries: Efficacy and Patency Rate in Follow-up.

PURPOSE: To investigate efficacy and patency status of stent graft implantation in the treatment of hepatic artery pseudoaneurysm. MATERIALS AND METHODS: A retrospective analysis of patients who had undergone endovascular treatment of hepatic artery pseudoaneurysms between 2011 and 2020 was performed. Medical records were examined to obtain patients' surgical histories and to screen for active bleeding. Angiographic data on vascular access, target vessel, material used and technical success, defined as the exclusion of the pseudoaneurysm by means of a stent graft with sufficient control of bleeding, were collected. Vessel patency at follow-up CT was analyzed and classified as short-term (< 6 weeks), mid-term (between 6 weeks and 1 year), and long-term patency (> 1 year). In case of stent occlusion, collateralization and signs of hepatic hypoperfusion were examined. RESULTS: In total, 30 patients were included and of these, 25 and 5 had undergone stent graft implantation and coiling, respectively. In patients with implanted stent grafts, technical success was achieved in 23/25 patients (92%). Follow-up CT scans were available in 16 patients, showing stent graft patency in 9/16 patients (56%). Short-term, mid-term, and long-term short-term stent patency was found in 81% (13/16), 40% (4/10), and 50% (2/4). In patients with stent graft occlusion, 86% (6/7) exhibited maintenance of arterial liver perfusion via collaterals and 14% (1/7) exhibited liver abscess during follow-up. CONCLUSION: Stent graft provides an effective treatment for hepatic artery pseudoaneurysms. Even though patency rates decreased as a function of time, stent occlusion was mainly asymptomatic due to sufficient collateralization.

Predicting the duration of chemotherapy-induced neutropenia: new scores and validation.

BACKGROUND: the objective of this study was to develop predictive models to classify febrile neutropenic patients into two groups, according to a prediction of the duration of the chemotherapy-induced neutropenia episode. PATIENTS AND METHODS: for this retrospective analysis, 106 patients with solid tumours and an episode of febrile neutropenia (FN) were eligible. A score was attributed to each chemotherapy treatment drug according to its expected toxicity. Three new scores were proposed based only on this classification. Two of them are a combination of the individual drug scores and the third one was built using statistical techniques such as cluster analysis and classification trees. RESULTS: statistical techniques produced the best score, distinguishing two groups of patients with statistically different neutropenia durations, with median durations until haematological recovery of absolute neutrophil count 2 × 10(9)/l of 4 versus 2 days (P < 0.001). CONCLUSIONS: our methodological approach based on statistical techniques identifies the patients who will need the longest times to recover from FN. The input of this predictive system is only the aggressiveness of the cytotoxic agents in a chemotherapy regimen. Our proposal succeeded in distinguishing two groups of patients and the results show better performance than other scores in previous studies.

Dynamic evaluation of neutrophil-to-lymphocyte ratio as prognostic factor in stage III non-small cell lung cancer treated with chemoradiotherapy.

PURPOSE: Locally advanced non-small cell lung cancer (LA-NSCLC) is frequently treated with chemoradiotherapy (CRT). Despite the efforts, long-term outcomes are poor, and novel therapies have been introduced to improve results. Biomarkers are needed to detect early treatment failure and plan future follow-up and therapies. Our aim is to evaluate the role of dynamics of neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced NSCLC treated with CRT. METHODS: We retrospectively reviewed patients diagnosed with LA-NSCLC receiving definitive CRT at our center from 2010 to 2015. Baseline and post-treatment NLR were collected from our center database. NLR was dichotomized (threshold = 4) and patients were divided into two groups based on the variation from baseline to post-treatment NLR. The prognostic role and association with response were examined with logistic regression and multivariate Cox regression model, respectively. RESULTS: Ninety-two patients were included. Our analysis shows that NLR after treatment is associated with response to treatment [OR in the multivariate analysis 4.94 (1.01-24.48); p value = 0.048]. Furthermore, NLR and ECOG are independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Specifically, PFS was 25.79 months for the good prognosis group and 12.09 for the poor prognosis group [HR 2.98 (CI 95% = 1.74-5.10), p < 0.001]; and OS was 42.94 months and 18.86 months, respectively [HR 2.81 (CI 95% = 1.62-4.90), p < 0.001]. CONCLUSION: Dynamics of NLR have a prognostic value in stage III NSCLC treated with definitive CRT. Pre- and post-CRT NLR should be evaluated in prospective clinical trials involving consolidation treatment with immunotherapy.

[Retinopathy of prematurity in the Murcia region of Spain. Incidence and severity]. / Retinopatía del prematuro en la región de Murcia (España). Incidencia y gravedad.

OBJECTIVE: To determine the incidence and severity of Retinopathy of Prematurity (ROP) in the Murcia region of Spain. METHODS: This was a retrospective study of all infants born preterm in the Murcia region during 2004, who were screened for ROP. Our screening criteria were: Infants with a gestational age

Molecular subtypes in early colorectal cancer associated with clinical features and patient prognosis.

PURPOSE: After surgical resection, an ample prognosis variability among stages is observed. Multiple prognostic factors are individually studied and some CRC classifiers have been proposed. Not one have been implemented into clinical practice. METHODS/PATIENTS: We classified 105 patients with resected CRC (stage I-III) into five molecular subtypes using BRAFV600E and RAS (KRAS; NRAS) status, and the expression of DNA mismatch repair (MMR) proteins (MLH1 and MSH2). Clinicopathological features and DFS) of distincts groups were evaluated. RESULTS AND CONCLUSIONS: RAS and BRAFV600E mutations were detected in 43.8 and 11.4% of patients, respectively. 19% of tumours had lack of expression of any MMR proteins reflecting a system deficiency (dMMR). Patients with any RAS mutation had lower DFS that patients with RAS wild type (wt) (40.23 vs 45.26 months; p value = 0.035). Of a total of five molecular subtypes, three were MMR proficient (pMMR): RAS mutated (39%), BRAFV600E mutated (6.7%) and RAS/BRAFV600E wt (35.2%); and two were dMMR: BRAFV600E mutated (4.8%) and BRAFV600E wt (14.3%). Left side tumours were more frequently observed in pMMR/RAS and BRAFV600E wt subtype, and right side tumours in dMMR subtypes. Among the three pMMR subtypes, a benefit survival was observed for patients without any mutation in BRAFv600E or RAS oncogenes (median of DFS = 45.5 vs 40.98 months in RAS mutated group; p = 0.084 and vs 34.13 in BRAFv600E mutated group; p = 0.031). Molecular classification using these biomarkers can be useful to identify groups with differences in prognosis.

Lipid transport across the intestinal epithelial cell. Effect of colchicine.

Rats injected with colchicine (0.5 mg/100 g of body weight) 1 h before ingestion of a margarine emulsion (1 g in 2 ml of saline) do not show the rise in plasma triacylglycerol concentration found in controls during the subsequent hours. The effect of colchicine is more dramatic when the experiment is performed after prior administration of Triton WR-1339, a substance known to inhibit the catabolism of lipoproteins. Colchicine-treated rats also showed a five-fold increase in the content of triacylglycerol in proximal jejunum, when compared to controls. These results are consistent with the idea that colchicine interferes with the intracellular phase of fat absorption, suggesting that the microtubular-microfilamentous system could be involved in the release of chylomicrons from the intestinal cell into the circulation.

Early response to the effect of iron fortification in the Venezuelan population.

In Venezuela a severe economic crisis beginning in 1983 provoked a progressive reduction of the quality and quantity of food consumed by the low socioeconomic strata of the population. In these strata, which represent > or = 80% of the Venezuelan population, we had seen a continuous increase in the prevalence of iron deficiency during that recent decade. As a result, in 1993 the Venezuela Government created the Special Commission for Enrichment of Foods. That same year a fortification program began in which precooked yellow and white maize and wheat flours were enriched with 20 and 50 mg Fe (as ferrous fumarate)/kg flour, respectively. The corn flour was also enriched with vitamin A, thiamine, riboflavin, and niacin, whereas the wheat flour was enriched with these same vitamins, except vitamin A. These two cereals represent 45% of the total energy consumed daily by the low socioeconomic strata of the population. A preliminary survey carried out in Caracas in 1994 in a population of 307 children aged 7, 11, and 15 y showed that the prevalence of iron deficiency determined by measuring the serum ferritin concentration and the prevalence of anemia were reduced from 37% and 19%, respectively, in 1992 to 15% and 10%, respectively in 1994.

The relationship between iron deficiency and anemia in Venezuelan children.

The iron status of 3228 subjects from the nutrition survey Proyecto Venezuela was studied. The sample included children from 1 to 16 y of age grouped by age and sex. Values for three indicators of iron status were compared: hemoglobin concentration, serum ferritin concentration, and percentage saturation of serum transferrin. In all groups there was a strong overlap in the hemoglobin concentration distribution curves for non-iron-deficient and iron-deficient subjects classified as such according to the other two indexes. The prevalence of iron deficiency ranged from 35% in 1-3 y olds to 10% in adolescent males, the values being almost identical in the nonanemic group compared with the total population. In the different groups, 80-97% of the subjects with abnormal values of at least one of these two indexes were not anemic. The difficulties involved in establishing a state of iron deficiency according to these indexes are discussed.

Possible beneficial effect of high-dose intravenous steroid therapy in acute demyelinating disease and transverse myelitis.

Intravenous steroid followed by oral prednisone was administered to patients with Guillain-Barré syndrome (five), acute transverse myelitis (three), and multiple sclerosis in acute relapse (seven). Preliminary experience with each of these disorders revealed prompt clinical improvement in some patients. The approach used in this uncontrolled study deserves further investigation.

HIV-1-induced cytopathogenicity in cell culture despite very decreased amounts of fusion-competent viral glycoprotein.

In order to examine the potential role of env-induced membrane fusion in the cytopathogenic properties of HIV-1 in cell culture, the effects of mutations within the proteolytic cleavage site of gp160, which result in a reduction but not a complete absence of proteolytic processing have been further studied. Cells expressing the mutant glycoproteins were shown to be severely reduced in their capacity to form syncytia. However, viruses encoding these glycoproteins could infect cell culture cells, albeit with delayed kinetics, and, at late infection time points, resulted in complete cytolysis of the infected culture. Since amplification by polymerase chain reaction and direct sequencing of the DNA in the infected cultures confirmed the presence of the mutant and the absence of revertant DNA, this shows that the amount of fusion competent viral glycoprotein does not influence HIV-1 cytopathogenicity, but rather that other parameters must be involved in inducing cell death.

Generation of lymphocyte cell lines coexpressing CD4 and wild-type or mutant HIV type 1 glycoproteins: implications for HIV type 1 Env-induced cell lysis.

To gain more insight into the processes leading to HIV-1 Env-induced cell death, we aim to coexpress stably wild-type and relevant mutant variants of both HIV-1 Env and human CD4 in lymphocyte cell lines. Here we report on the generation and characterization of several cell lines inducibly or constitutively expressing wild-type or cleavage-defective HIV-1 glycoproteins and human CD4 either singly or in combination. Coexpression of CD4 and wild-type Env led to the formation of multinucleated syncytia, to growth arrest and cell death, effects that all could be prevented by cultivation in the presence of monoclonal antibodies that inhibit cell surface membrane fusion. Cell lines coexpressing CD4 and mutated, noncleavable Env, detectable at the cell surface and still retaining CD4-binding capacity, were not retarded in their growth and cytolysis did not occur. These results indicate that cell lysis requires cell surface interaction of CD4 and gp120/41 and cleavage of gp160 to gp120 and gp41.

Slow cortical potentials during retention of object, spatial, and verbal information.

We used event related potentials (ERPs) to examine both the specificity and the timing of slow cortical scalp potentials (SPs) elicited by the retention of object, spatial, and verbal information in working memory (WM). Participants performed a modified delayed matching task in which a task cue presented in the middle of the delay interval indicated what type of information had to be retained for a subsequent comparison with the test stimulus. The first experiment used nameable objects and spatial locations as stimuli. The retrieval mode (visual vs. verbal) was manipulated by presenting either figural information or printed words as test stimuli. Transient ensembles of frontal and parieto-occipital slow waves with different scalp topographies for object and spatial information were evoked as a function of task cues. When words rather than objects were used as test stimuli highly similar, though more pronounced, fronto-parietal slow wave patterns were obtained. The second experiment using unfamiliar objects and non-nameable spatial locations indicated that neither the left frontal negative SP nor the posterior SPs are exclusively related to verbal working memory operations. The results indicate that a parietal negative SP reflects processes of spatial selective attention whereas a parieto-occipital positive SP indexes the retention of visual object information. Left frontal negative SPs are generated by a compound of higher order frontal control processes and vary as a function of information type.

Gestalt perception modulates early visual processing.

We examined whether early visual processing reflects perceptual properties of a stimulus in addition to physical features. We recorded event-related potentials (ERPs) of 13 subjects in a visual classification task. We used four different stimuli which were all composed of four identical elements. One of the stimuli constituted an illusory Kanizsa square, another was composed of the same number of collinear line segments but the elements did not form a Gestalt. In addition, a target and a control stimulus were used which were arranged differently. These stimuli allow us to differentiate the processing of colinear line elements (stimulus features) and illusory figures (perceptual properties). The visual N170 in response to the illusory figure was significantly larger as compared to the other collinear stimulus. This is taken to indicate that the visual N170 reflects cognitive processes of Gestalt perception in addition to attentional processes and physical stimulus properties.

Serum immunoglobulins in Guillain-Barré syndrome.

Serum major class immunoglobulin concentrations were measured in 162 patients with Guillain-Barré Syndrome (GBS) and 85 normal controls. Significant elevations of IgM, A and G were found in the GBS group. Forty-four of 162 GBS patients (27%) had IgM concentrations greater than two standard deviations above the control mean. GBS patients with high serum IgM were young and 68% showed serologic evidence of recent infection with DNA core agents, cytomegalovirus, Epstein-Barr virus, or Mycoplasma pneumoniae. Longitudinal studies in seven patients with elevated serum IgM revealed that clinical improvement was accompanied by a marked decline in serum IgM. IgA and IgG changes were less consistent. Our findings indicate that the serum immunoglobulin response in GBS is polyclonal and follows the usual pattern seen in infections and other conditions with an immune component.

Studies on lysophospholipases, V. The action of lysolecithin-hydrolyzing enzymes on lecithins and 1-acyl lysolecithins with varying fatty acid chain-length.

The activity of two purified lysolecithin-hydrolyzing enzymes on homologous series of synthetic lecithins containing two identical fatty acyl chains and of 1-acyl-lysolecithins has been measured as a function of substrate concentration. In general, enzymatic activity toward lecithins decreased with increasing chain length. Maximal hydrolysis rates for the lysolecithin series were measured with 1-dodecanoyllysolecithin. In this series increased affinities for substrates with increasing acyl-chain length was noticed. In the substrate concentration versus enzymatic velocity curves no breaks were observed at the critical micelle concentration of the various substrates. The initial site of attack during hydrolysis of short-chain lecithins was determined using 1-octanoyl-2pentanoyl-lecithin, 1-hexanoyl-2-hexyllecithin and 1 -hexyl-2-hexanoyllecithin. Both enzymes exhibited a pronounced preference for hydrolysis of the acyl ester bond at the 1-position. Especially the enzyme from beef pancreas seems to be suitable for the enzymatic preparation of 2-acyl lysolecithins from the corresponding short-chain lecithins.

Study of group-specific proteins in mammalian cells transformed by Rous sarcoma virus.

Lysates of various mammalian RSV-transformed cells labelled with 35S-methionine were tested for the presence of gs proteins and for the size of these molecules by means of antisera, using sodium dodecyl sulphate--polyacrylamide slab gel electrophoresis. In no case was the presence of gs proteins detected in the analyzed immunoprecipitates; only in RSH-mix cells a quantitative difference in the contrast of a 70 000-molecular weight protein was found. The autoradiograms of simultaneously tested immunoprecipitates of lysates of RSV-transformed chicken cells clearly showed the presence of p27 and after a short-term labelling also of the gs precursor molecule (pr76). The cause of the failure in detecting gs proteins by the used method in two mammalian RSV-transformed lines, in which the gs antigens were previously detected by complement fixation test, are discussed.

LIPSIA--a new software system for the evaluation of functional magnetic resonance images of the human brain.

This paper describes the non-commercial software system LIPSIA that was developed for the processing of functional magnetic resonance images (fMRI) of the human brain. The analysis of fMRI data comprises various aspects including filtering, spatial transformation, statistical evaluation as well as segmentation and visualization. In LIPSIA, particular emphasis was placed on the development of new visualization and segmentation techniques that support visualizations of individual brain anatomy so that experts can assess the exact location of activation patterns in individual brains. As the amount of data that must be handled is enormous, another important aspect in the development LIPSIA was the efficiency of the software implementation. Well established statistical techniques were used whenever possible.