ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells.

PURPOSE: ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that has shown clinical activity against EGFR-expressing tumors. Our aim was to explore the effects of ZD1839 in breast cancer cell lines expressing different levels of EGFR and the closely related HER2 receptor. EXPERIMENTAL DESIGN: We studied the growth-inhibitory effects of ZD1839 in a series of breast carcinoma cell lines. In HER2-overexpressing BT-474 breast cancer cells, we studied the effects of ZD1839 on cell growth and heterodimerization of receptors under basal and ligand-stimulated conditions. RESULTS: ZD1839 was an equally potent inhibitor of growth in breast cancer cells expressing high levels of EGFR and HER2. In BT-474 breast cancer cells, ZD1839 abolished EGF- and heregulin-induced activation of ErbB receptors and downstream signaling molecules. Because ZD1839 does not inhibit the HER2 tyrosine kinase in vitro, and because heregulin is a ligand that activates HER2 by binding to HER3 and HER4 but does not bind to the EGFR, our findings suggested that ZD1839 interfered with HER2 function in intact cells. Searching for mechanisms, we report that ZD1839 induces the formation of inactive unphosphorylated EGFR/HER2 and EGFR/HER3 heterodimers. Furthermore, ZD1839 completely abolishes basal and heregulin-induced formation of active phosphorylated HER2/HER3 heterodimers. CONCLUSIONS: ZD1839 inhibits the growth of HER2-overexpressing breast cancer cells, possibly by sequestration of HER2 and HER3 receptors in an inactive heterodimer configuration with the EGFR. Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors.     

Prevention of central venous catheter-related bloodstream infections using non-technologic strategies.

OBJECTIVE: To evaluate the incidence of nosocomial bacteremias related to the use of non-impregnated central venous catheters (CVCs) when only non-technologic strategies were used to prevent them. DESIGN: This was a prospective study of infectious complications of CVCs placed in intensive care unit (ICU) patients from April 1997 to December 2001. SETTING: The medical-surgical ICU of a tertiary-care, university-affiliated hospital in Argentina. METHODS: We studied all patients admitted to the ICU using non-impregnated CVCs. Maximal sterile barrier precautions (ie, use of cap, mask, sterile gown, sterile gloves, and large sterile drape), strict handwashing, preparation of the patients' skin with antiseptic solutions, insertion and management of catheters by trained personnel, and continuing quality improvement programs aimed at appropriate insertion and maintenance of catheters were employed. RESULTS: During the study period, 2,525 patients were admitted to the ICU. Eight hundred sixty-eight patients had 1,037 CVCs inserted. The number of CVC-related bloodstream infections (BSIs), acquired in the ICU, was 2.7 per 1,000 CVC-days (13 nosocomial CVC-related BSIs during 4,770 days of CVC use). Microorganisms isolated included methicillin-susceptible Staphylococcus aureus (n = 6), methicillin-resistant S. aureus (n = 2), coagulase-negative methicillin-resistant Staphylococcus (n = 2), Escherichia coli (n = 1), Klebsiella pneumoniae (n = 1), and Enterobacter cloacae (n = 1). CONCLUSIONS: A low rate of catheter-related BSI was achieved without antimicrobial-impregnated catheters. The incidence of CVC-associated bacteremias corresponded to the 10th to 20th percentile range of the National Nosocomial Infections Surveillance System hospitals for the same type of ICU.     

Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma

In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non‐endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low‐grade, non‐ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE‐positive endometrioid endometrial carcinomas (EECs). We performed exome‐sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling‐related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA‐repair‐related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co‐occurrence (RAD50‐KMT2D and RAD50‐SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.     

Systemic Autoimmune Diseases in Patients Hospitalized with COVID-19 in Spain: A Nation-Wide Registry Study

We aimed to evaluate the clinical outcome of Systemic Autoimmune Diseases (SADs) patients hospitalized with COVID-19 in Spain, before the introduction of SARS-CoV-2 vaccines. A nationwide, retrospective and observational analysis of the patients admitted during 2020, based on the ICD10 codes in the National Registry of Hospital Discharges, was performed. Among 117,694 patients, only 892 (0.8%) presented any type of SAD before COVID-19-related admission: Sjogren’s Syndrome constituted 25%, Systemic Vasculitides 21%, Systemic Lupus Erythematosus 19%, Sarcoidosis 17%, Systemic Sclerosis 11%, Mixed and Undifferentiated Connective Tissue Disease 4%, Behçet’s Disease 4% and Inflammatory Myopathies 2%. The in-hospital mortality rate was higher in SAD individuals (20% vs. 16%, p < 0.001). After adjustment by baseline conditions, SADs were not associated with a higher mortality risk (OR = 0.93, 95% CI 0.78–1.11). Mortality in the SADs patients was determined by age (OR = 1.05, 95% CI 1.04–1.07), heart failure (OR = 1.67, 95% CI 1.10–2.49), chronic kidney disease (OR = 1.29, 95% CI 1.05–1.59) and liver disease (OR = 1.97, 95% CI 1.13–3.44). In conclusion, the higher COVID-19 mortality rate seen in SADs patients hospitalized in Spain in 2020 was related to the higher burden of comorbidities, secondary to direct organ damage and sequelae of their condition. Whilst further studies should evaluate the impact of baseline immunosuppression on COVID-19 outcomes in this population, efforts should be focused on the optimal management of SAD to minimize the impact of the organ damage that has been shown to determine COVID-19 prognosis.     

Characterization of Inclusion Size Distributions in Steel Wire Rods

The control of inclusions in steel components is essential to guarantee strong performance. The reliable characterization of inclusion populations is essential not only to evaluate the quality of the components but also to allow the use of analytical procedures for the comparison and discrimination of inclusion populations. In this work, inclusion size distributions in wire rod specimens from six plant-scale heats were measured and analyzed. For the measurements, the metallographic procedure specified in the ASTM E2283 standard was used. The population density function (PDF) approach and the extreme value statistical procedure specified in the ASTM E2283 standard were used to analyze the whole size distribution and the upper tail of the size distribution, respectively. The PDF approach allowed us to identify differences among inclusion size distributions and showed that new inclusions were not formed after the liquid steel treatment process. The extreme value statistical procedure led to the prediction of the maximum inclusion length for each heat, which was used for the statistical discrimination of heats. Furthermore, the estimation of the probability of finding an inclusion larger than a given inclusion size using the extreme value theory allowed us to order the heats for different critical inclusion sizes.     

Evaluation of the Performance of Atomic Diffusion Additive Manufacturing Electrodes in Electrical Discharge Machining

Atomic Diffusion Additive Manufacturing (ADAM) is an innovative Additive Manufacturing process that allows the manufacture of complex parts in metallic material, such as copper among others, which provides new opportunities in Rapid Tooling. This work presents the development of a copper electrode manufactured with ADAM technology for Electrical Discharge Machining (EDM) and its performance compared to a conventional electrolytic copper. Density, electrical conductivity and energy-dispersive X-ray spectroscopy were performed for an initial analysis of both ADAM and electrolytic electrodes. Previously designed EDM experiments and optimizations using genetic algorithms were carried out to establish a comparative framework for both electrodes. Subsequently, the final EDM tests were carried out to evaluate the electrode wear rate, the roughness of the workpiece and the rate of material removal for both electrodes. The EDM results show that ADAM technology enables the manufacturing of functional EDM electrodes with similar material removal rates and rough workpiece finishes to conventional electrodes, but with greater electrode wear, mainly due to internal porosity, voids and other defects observed with field emission scanning electron microscopy.     

Visible and Quantifiable Improvement in Skin Roughness and Texture Using a High Power Non-ablative 1540-nm Fractional Erbium: Glass Laser

BackgroundNon-ablative fractional laser treatments for improving skin tone and rejuvenation have become increasingly popular due to short downtime and fewer side effects compared to ablative treatments.Objective We sought to determine the efficacy of a non-ablative 1540-nm fractional erbium: glass laser in improving skin roughness and skin texture.MethodsThe forehead, cheek, and nasal areas of 15 patients were treated for five monthly sessions using a 7x7 pixel tip (1.21cm² affective area, approximately 300 microns diameter per pixel), fluence of 2,500 to 3,000 mJ/pulse (40–62 mJ/Pixel), and three stacked pulses were emitted at a rate of 1Hz for three passes per treatment session. Measurements of skin roughness, skin roughness area, and maximum skin depth were collected using a 3D imaging system. Improvement in skin parameters was calculated by comparing the measurements prior to treatment and 12 weeks after completion.ResultsAll 15 patients showed significant improvement in all three measured parameters (p<0.001) with no significant side effects.LimitationsThe limitations of this study include the small number of patients and the narrow range of skin tone (Fitzpatrick Skin Types II–IV).ConclusionOur results suggest that monthly treatments with a non-ablative 1540-nm fractional Erbium:glass laser appear to be safe and effective for skin texture and roughness.     

Association between Adherence to the Mediterranean Diet and Anthropometric and Health Variables in College-Aged Males

The present study aimed to verify the association between adherence to the Mediterranean diet (MD) and anthropometric and health variables. Four-hundred-and-ninety-five college-aged males aged 18–25 participated in this cross-sectional research. The KIMED (Mediterranean Diet Quality Index for children and adolescents) was used to assess the adherence to MD. The following variables were also assessed: body mass (BM), height (HE), body mass index (BMI), body fat percentage (%FAT), lean mass (LEAN), abdominal girth (AG), waist-to-hip ratio (WHR), oxygen saturation (SPO2), systolic blood pressure (SBP), diastolic blood pressure (DBP), double product (DP), and fasting blood glucose (GLU). The results showed that adherence to MD presented a strong negative correlation with most of the anthropometric parameters (BM: r = −0.571; BMI: r = −0.614; %FAT: r = −0.558; and AG: r = −0.564), a moderate or weak correlation with most of the health variables (GLU: r = −0.407; SBP: r = −0.238; DBP: r = −0.217, and DP: r = −0.265) and LEAN (r = −0.497), and a very weak correlation with WHR (r = −0.090). Many anthropometric parameters (BM, BMI, %FAT, LEAN, AG, WHR) present significant correlations with health variables (SBP, DBP, DP, and GLU). We conclude that greater adherence to Mediterranean diet is associated with healthier values of the selected anthropometric and health parameters. Since most of the anthropometric and health parameters present significant correlations among themselves, this finding could be useful in medical diagnosis, health monitoring, and risk detection. Based on the level of adherence to Mediterranean diet and the KIDMED found in the present study, and considering the prevalence of obesity in the Middle East, it is imperative to implement nutritional interventions with the target population of this research to prevent nutrition-related diseases and promote public health.