Preparing European Nephrology for the next pandemic: lessons from the ERACODA collaboration.

Owing to the vulnerability of patients with chronic kidney disease to infectious diseases, the coronavirus disease 2019 (COVID-19) pandemic has been particularly devastating for the nephrology community. Unfortunately, the possibility of future COVID-19 waves or outbreaks of other infectious diseases with pandemic potential cannot be ruled out. The nephrology community made tremendous efforts to contain the consequences of the COVID-19 pandemic. Despite this, the COVID-19 pandemic has highlighted several shortcomings in our response to the pandemic and has taught us important lessons that can be utilized to improve our preparedness for any future health crises of a similar nature. In this article we draw lessons from the European Renal Association COVID-19 Database (ERACODA) project, a pan-European collaboration initiated in March 2020 to understand the prognosis of COVID-19 in patients on kidney function replacement therapy. We discuss the challenges faced in generating timely and robust evidence for informed management of patients with kidney disease and give recommendations for our preparedness for the next pandemic in Europe. Limited collaboration, the absence of common data architecture and the sub-optimal quality of available data posed challenges in our response to COVID-19. Aligning different research initiatives, strengthening electronic health records, and involving experts in study design and data analysis will be important in our response to the next pandemic. The European Renal Association may take a leading role in aligning research initiatives via its engagement with other scientific societies, national registries, administrators and researchers.

European Society of Organ Transplantation (ESOT) Consensus Statement on Prehabilitation for Solid Organ Transplantation Candidates.

There is increasingly growing evidence and awareness that prehabilitation in waitlisted solid organ transplant candidates may benefit clinical transplant outcomes and improve the patient's overall health and quality of life. Lifestyle changes, consisting of physical training, dietary management, and psychosocial interventions, aim to optimize the patient's physical and mental health before undergoing surgery, so as to enhance their ability to overcome procedure-associated stress, reduce complications, and accelerate post-operative recovery. Clinical data are promising but few, and evidence-based recommendations are scarce. To address the need for clinical guidelines, The European Society of Organ Transplantation (ESOT) convened a dedicated Working Group "Prehabilitation in Solid Organ Transplant Candidates," comprising experts in physical exercise, nutrition and psychosocial interventions, to review the literature on prehabilitation in this population, and develop recommendations. These were discussed and voted upon during the Consensus Conference in Prague, 13-15 November 2022. A high degree of consensus existed amongst all stakeholders including transplant recipients and their representatives. Ten recommendations were formulated that are a balanced representation of current published evidence and real-world practice. The findings and recommendations of the Working Group on Prehabilitation for solid organ transplant candidates are presented in this article.

Organ transplants of the future: planning for innovations including xenotransplantation.

The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen-free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first-in-human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first-in-human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders.

Estimating Time to ESRD in Children With CKD.

RATIONALE & OBJECTIVE: The KDIGO (Kidney Disease: Improving Global Outcomes) guideline for chronic kidney disease (CKD) presented an international classification system that ranks patients' risk for CKD progression. Few data for children informed guideline development. STUDY DESIGN: Observational cohort study. SETTINGS & PARTICIPANTS: Children aged 1 to 18 years enrolled in the North American Chronic Kidney Disease in Children (CKiD) cohort study and the European Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) trial. PREDICTOR: Level of estimated glomerular filtration rate (eGFR) and proteinuria (urine protein-creatinine ratio [UPCR]) at study entry. OUTCOME: A composite event of renal replacement therapy, 50% reduction in eGFR, or eGFR<15mL/min/1.73m2. eGFR was estimated using the CKiD-derived "bedside" equation. ANALYTICAL APPROACH: Accelerated failure time models of the composite outcome using a conventional generalized gamma distribution. Likelihood ratio statistics of nested models were used to amalgamate levels of similar risk. RESULTS: Among 1,232 children, median age was 12 (IQR, 8-15) years, median eGFR was 47 (IQR, 33-62) mL/min/1.73m2, 60% were males, and 13% had UPCRs>2.0mg/mg at study entry. 6 ordered stages with varying combinations of eGFR categories (60-89, 45-59, 30-44, and 15-29mL/min/1.73m2) and UPCR categories (<0.5, 0.5-2.0, and >2.0mg/mg) described the risk continuum. Median times to event ranged from longer than 10 years for eGFRs of 45 to 90mL/min/1.73m2 and UPCRs<0.5mg/mg to 0.8 years for eGFRs of 15 to 30mL/min/1.73m2 and UPCRs>2mg/mg. Children with glomerular disease were estimated to have a 43% shorter time to event than children with nonglomerular disease. Cross-validation demonstrated risk patterns that were consistent across the 10 subsample validation models. LIMITATIONS: Observational study, used cross-validation rather than external validation. CONCLUSIONS: CKD staged by level of eGFR and proteinuria characterizes the timeline of progression and can guide management strategies in children.

Computed Tomographic Angiography Used for Localization of the Cutaneous Perforators and Selection of Anterolateral Thigh Flap "Bail-Out" Branches.

BACKGROUND: The purpose of this study was to evaluate the territory supplied by the lateral circumflex femoral artery for the consistency of a proximal perforator that could be used as an alternative pedicle for the anterolateral thigh flap if a tedious intramuscular course is encountered during elevation of the perforator used to develop the initial surgical plan. It is hypothesized that a consistent "bail-out" perforator supplying the proximal thigh would facilitate a simpler anterolateral thigh flap harvest, with minimal modification to flap design. METHODS: Computed tomographic images of 9 fresh cadavers were imported using Materialize's Interactive Medical Imaging Control System software to create surface-rendered 3-dimensional reconstructions of 15 lower limbs. Perforators emerging proximally and laterally to a 3-cm radius circle drawn at the midpoint of the anterior superior iliac spine and superolateral patella were considered potential bail-out perforators and evaluated for their number emerging diameter, length, course, and location relative to the anterior superior iliac spine. RESULTS: An average of 2.9 ± 1.8 perforators per limb were identified. Mean pedicle length was 111 ± 20 mm, measured from the origin in the lateral circumflex femoral artery to where the perforators emerged through the deep fascia directly overlying the thigh muscles. Average diameter at origin in the lateral circumflex femoral artery was 2.8 ± 0.8 mm, and that at emergence through the deep fascia was 1.1 ± 0.3 mm. Vessel course was predominantly musculocutaneous (90%). CONCLUSIONS: A significant bail-out perforator routinely supplies the proximal anterolateral thigh and may be used as an alternative vascular pedicle for an anterolateral thigh flap if a tedious intramuscular course is encountered during elevation of a perforator identified within the conventional landmarks (3-cm radius circle at the midpoint of the anterior superior iliac spine and superolateral patella).

Peritoneal-pericardial communication in an adolescent on peritoneal dialysis.

BACKGROUND: Dialysate leakage into the pericardium is a rare but potentially life-threatening complication of peritoneal dialysis (PD). There has been one reported pediatric case of spontaneous peritoneo-pericardial fistula in a 2-year-old boy with tissue fragility due to malnutrition and two reported adult cases in PD patients with a history of previous cardiac surgery and/or pericardiocentesis. CASE-DIAGNOSIS/TREATMENT: We describe a 15-year-old girl with end-stage renal disease secondary to granulomatosis with polyangiitis, with recurrent pericardial effusions secondary to a peritoneo-pericardial fistula while on continuous cycling peritoneal dialysis (CCPD). She had previously presented with chylous pericardial effusion that required pericardiocentesis and subsequently developed recurrent pericardial effusions when she was commenced on CCPD 9 months later. Pericardial fluid chemistry revealed a sterile, serous fluid containing 15.1 mmol/L of glucose and <0.11 mmol/L of triglycerides. Peritoneal scintigraphy with Tc-99m labeled sulfur colloid injected intra-peritoneally confirmed the presence of a peritoneo-pericardial fistula. The pericardial effusions resolved upon switching the patient to hemodialysis (HD). CONCLUSIONS: Our case of recurrent pericardial effusions in a child on PD secondary to a peritoneo-pericardial fistula highlights the need for close follow-up in patients with a history of previous pericardiocentesis who are commenced on PD.

Reverse Radial Artery Flap Perforator Anatomy and Clinical Applications.

The pedicled reverse radial forearm flap is a well-known option for the treatment of a variety of soft tissue wounds including dorsal hand wounds. We document the number, emerging diameter, length from origin, course, and location of all perforators of the radial artery in a series of 6 fresh human cadavers after whole body lead oxide and gelatin injection to confirm and comprehensively document the anatomy of the radial artery perforators. This data provide an anatomic basis for a modification to the reversed radial forearm flap used to decrease venous congestion in the postoperative period. Two case reports are presented to provide clinical demonstration of the importance of this modification.

Low contribution of PbO2-coated lead service lines to water lead contamination at the tap.

To determine if residential water sampling corroborates the expectation that formation of stable PbO2 coatings on lead service lines (LSLs) provides an effective lead release control strategy, lead profile sampling was evaluated for eight home kitchen taps in three U.S. cities with observed PbO2-coated LSLs (Newport, Rhode Island; Cincinnati and Oakwood, Ohio). After various water standing times, these LSLs typically released similar or lower peak lead levels (1 to 18 µg/L) than the lead levels from the respective kitchen faucets (1 to 130 µg/L), and frequently 50-80% lower than the lead levels typically reported from Pb(II)-coated LSLs in comparable published sampling studies. Prolonged stagnation (10-101 h) at the Cincinnati sites produced varying results. One site showed minimal (0-4 µg/L) increase in lead release from the PbO2-coated LSL, and persistence of free chlorine residual. However, the other site showed up to a 3-fold increase proportional to standing time, with essentially full depletion of the chlorine residual. Overall, lead release was consistently much lower than that reported in studies of Pb(II)-coated LSL scales, suggesting that natural formation of PbO2 in LSLs is an effective lead "corrosion" control strategy.

Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort.

BACKGROUND: Hepcidin, a key iron regulatory protein, is elevated in patients with chronic kidney disease (CKD). Its role in the development and progression of the anemia of CKD in children remains poorly defined. METHODS: Cross-sectional and longitudinal study in children aged 1-16 years with stage 2-4 CKD in the Chronic Kidney Disease in Children (CKiD) cohort (n = 133) with hepcidin measured at baseline and hemoglobin (HGB) measured annually at follow-up. Anemia was defined as HGB <5th percentile for age/sex OR treatment with an erythropoiesis-stimulating agent (ESA). RESULTS: Hepcidin levels correlated negatively with glomerular filtration rate (GFR; r = -0.22, p = 0.01) and positively with ferritin (r = 0.67, p < 0.001). At the lower end of the GFR spectrum at baseline (10th percentile, 27.5 mL/min/1.73 m(2)), higher hepcidin was associated with a 0.87 g/dL decrease in HGB during follow-up (95 % CI -1.69, -0.05 g/dL, p = 0.038). At higher GFR percentiles there was no significant association between baseline hepcidin and HGB during follow-up. Among 90 non-anemic subjects at baseline, 23.3 % developed incident anemia. In subjects with GFR ≤ the median, a higher hepcidin level was associated with an increased risk of incident anemia (at the 10th percentile GFR, HR 3.471, 95 % CI 1.228, 9.810, p = 0.019; at the 25th percentile GFR, HR 2.641, 95 % CI 1.213, 5.750, p = 0.014; at the 50th percentile GFR, HR 1.953, 95 % CI 1.011, 3.772, p = 0.046). Among subjects with GFR at the 75th percentile or above, incrementally higher baseline hepcidin was not associated with increased anemia risk. CONCLUSIONS: Higher hepcidin levels are associated with a decreased HGB and an increased risk of incident anemia, and this association is most significant among subjects with lower GFR.

Protein energy wasting in children with chronic kidney disease.

BACKGROUND: In adults with chronic kidney disease (CKD), protein-energy wasting (PEW) is a risk factor for hospitalization and death. However, PEW in children with CKD is not well characterized or defined. METHODS: Using data from the Chronic Kidney Disease in Children study, we assessed three alternate definitions of PEW using biochemical parameters, body and muscle mass measurements, and reported appetite as described in adults: (1) a minimal PEW definition (≥2 of the four criteria); (2) a standard PEW definition (≥3 of the four criteria); (3) a modified PEW definition (≥3 of the four criteria plus a pediatric-focused criterion of short stature or poor growth). RESULTS: Of the 528 children analyzed in this study (median age 12 years, median glomerular filtration rate 45 mL/min/1.73 m(2), 39% female, 18% African American), 7-20% met the spectrum of definitions for PEW. The unadjusted incidence rates for incident hospitalizations were 1.9-, 2.1-, and 2.2-fold higher for those children diagnosed with PEW using the minimal, standard, and modified definitions, respectively (P = 0.08, 0.09 and 0.03). Following adjustment, only the modified PEW definition, which added short stature or poor growth as a criterion, showed modest significance (P = 0.06). CONCLUSIONS: The inclusion of a criterion based on growth may augment the definition of PEW and improve risk discrimination in children with CKD.

Endospore surface properties of commonly used Bacillus anthracis surrogates vary in aqueous solution.

The hydrophobic character and electrophoretic mobility (EPM) of microorganisms are vital aspects of understanding their interactions with the environment. These properties are fundamental in fate-and-transport, physiological, and virulence studies, and thus integral in surrogate selection. Hydrophobic and electrostatic forces are significant contributors to particle and microorganism mobility in the environment. Herein, the surface properties of commonly used Bacillus anthracis surrogate endospores were tested under comparable conditions with respect to culture, endospore purification, buffer type and strength. Additionally, data is presented of endospores suspended in dechlorinated tap water to evaluate the surrogates in regard to a breach of water infrastructure security. The surface properties of B. anthracis were found to be the most hydrophobic and least electronegative among the six Bacillus species tested across buffer strength. The effect of EPM on hydrophobicity varies in a species-specific manner. This study demonstrates that surrogate surface properties differ and care must be taken when choosing the most suitable surrogate. Moreover, it is shown that Bacillus thuringensis best represents Bacillus anthracis-Sterne with respect to both EPM and hydrophobicity across all test buffers.

Management of anemia in children receiving chronic peritoneal dialysis.

Little information exists regarding the efficacy, modifiers, and outcomes of anemia management in children with CKD or ESRD. We assessed practices, effectors, and outcomes of anemia management in 1394 pediatric patients undergoing peritoneal dialysis (PD) who were prospectively followed in 30 countries. We noted that 25% of patients had hemoglobin levels below target (<10 g/dl or <9.5 g/dl in children older or younger than 2 years, respectively), with significant regional variation; levels were highest in North America and Europe and lowest in Asia and Turkey. Low hemoglobin levels were associated with low urine output, low serum albumin, high parathyroid hormone, high ferritin, and the use of bioincompatible PD fluid. Erythropoiesis-stimulating agents (ESAs) were prescribed to 92% of patients, and neither the type of ESA nor the dosing interval appeared to affect efficacy. The weekly ESA dose inversely correlated with age when scaled to weight but did not correlate with age when normalized to body surface area. ESA sensitivity was positively associated with residual diuresis and serum albumin and inversely associated with serum parathyroid hormone and ferritin. The prevalence of hypertension and left ventricular hypertrophy increased with the degree of anemia. Patient survival was positively associated with achieved hemoglobin and serum albumin and was inversely associated with ESA dose. In conclusion, control of anemia in children receiving long-term PD varies by region. ESA requirements are independent of age when dose is scaled to body surface area, and ESA resistance is associated with inflammation, fluid retention, and hyperparathyroidism. Anemia and high ESA dose requirements independently predict mortality.

Canadian Society of Nephrology commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD.

The KDIGO (Kidney Disease: Improving Global Outcomes) 2012 clinical practice guideline for anemia management in patients with chronic kidney disease provides the structural and evidence base for the Canadian Society of Nephrology commentary on this guideline's relevancy and application to the Canadian health care system. While in general agreement, we provide commentary on 11 of the 61 KDIGO guideline statements. Specifically, we agreed that a therapeutic trial of iron is appropriate in cases in which a reduction in erythropoiesis-stimulating agent (ESA) dosage or avoidance of ESA and transfusion is desired, transferrin saturations are >30%, and ferritin concentrations are >500 µg/L. However, we concluded that there is insufficient evidence to support an upper target or threshold for ferritin and transferrin saturation levels. We agree with the initiation of ESA treatment when hemoglobin (Hb) level is 90-100 g/L; however, we specifically state that an acceptable range for Hb level is 95-115 g/L, with a target of 100-110 g/L, and add caution to individualization above this range due to concerns regarding the safety of ESAs. We agree that ESAs should be used with considerable caution in patients with active malignancy, history of stroke, or history of malignancy, and we suggest initiating ESA therapy at Hb level of 90 g/L and to aim for a Hb level in the range of 90-105 g/L. The reader is encouraged to note the level of evidence and review the entire KDIGO anemia guideline to interpret the guideline statements and commentary appropriately.

Echo-Doppler assessment of the biophysical properties of the aorta in children with chronic kidney disease.

Chronic kidney disease (CKD) is known to cause increased arterial stiffness, which is an important independent risk factor for adverse cardiovascular events. The purpose of this study was to assess the vascular properties of the aorta (AO) in a group of children with CKD using a noninvasive echocardiography (echo)-Doppler method. We studied 24 children with stages 2 through 5 CKD and 48 age-matched controls. Detailed echocardiographic assessment and echo-Doppler pulse wave velocity (PWV) was performed. Indices of arterial stiffness, including characteristic (Zc) and input (Zi) impedances, elastic pressure-strain modulus (Ep), and arterial wall stiffness index, were calculated. CKD patients underwent full nephrology assessment, and an iohexol glomerular filtration rate was performed, which allowed for accurate assignment of the CKD stage. CKD patients had greater median systolic blood pressure (114 vs. 110 mmHg; p < 0.04) and pulse pressure (51 vs. 40 mmHg; p < 0.001) compared with controls. PWV was similar between groups (358 vs. 344 cm s(-1); p = 0.759), whereas Zi (182 vs. 131 dyne s cm(-5); p < 0.001), Zc (146 vs. 138 dyne s cm(-5); p = 0.05), and Ep (280 vs. 230 mmHg; p < 0.02) were significantly greater in CKD than in controls. Although load-dependent measures of arterial stiffness were greater in non-dialysis dependent CKD patients, PWV was not increased compared with controls. This suggests that the increased arterial stiffness may not be permanent in these pediatric patients with kidney disease.

International plastic surgery missions: a framework for resident education using the CanMEDS competencies.

Residency education has shifted over the past decade in an attempt to graduate well-rounded physicians. There is a recognition that a physician's abilities must extend beyond medical knowledge. The Royal College of Physicians and Surgeons of Canada introduced the CanMEDS physician competency framework in 2005. The framework provides 7 areas of competencies that are aimed at providing improved patient care. These competencies are medical expert, communicator, collaborator, manager, health advocate, scholar, and professional. Teaching and evaluating many of these competencies is often challenging for residency training programs. We believe that international surgical missions provide a prime opportunity to teach and evaluate all CanMEDS' roles.Plastic surgery is a field with many different organizations involved in international surgery. Many plastic surgery training programs offer opportunities for residents to become involved in these international surgical missions. Through these trips, residents gain surgical experience, see a variety and volume of clinical cases, and have the opportunity to travel to a foreign country and experience different cultures. We believe that international plastic surgery surgical missions also provide an exceptional micro environment for the teaching of CanMEDS roles. Using examples from residents' personal experiences on international plastic surgery missions to China, Mali, and Cambodia, we describe the benefits of these missions in transferring the CanMEDS competencies to resident training.

Breast reduction scars: a prospective survey of patient preferences.

BACKGROUND: Studies have shown that scarring is a primary reason for patient dissatisfaction with reduction mammaplasty. OBJECTIVES: The authors prospectively evaluated patient preferences for the 3 most common breast reduction scar patterns: horizontal, vertical, and Wise. METHODS: Sixty-six patients were recruited for the study before receiving their reduction mammaplasty consultation. Each patient was shown line drawings and postoperative photographs of the 3 breast reduction techniques and scored the scars on a modified 10-point Likert scale (1 = unacceptable; 10 = acceptable). The survey responses had no impact on the patients' medical care. A nonparametric Friedman test was used to compare the mean scores, and univariate generalized linear regression analysis was performed to adjust for confounding factors. Post hoc analysis was performed using the Bonferroni method. Significance was set at P < .001. RESULTS: Sixty patients completed the study. The mean preference ranking was significantly higher for the horizontal scar pattern versus vertical and Wise (P < .001). The mean score difference between the horizontal and Wise patterns was 2.982. The mean difference between the horizontal and vertical patterns was 2.27. There was no significant difference in preference between the vertical and Wise patterns. Linear regression analysis showed that age, body mass index, and torso/bra size had no significant effect on preference. CONCLUSIONS: To our knowledge, this is the first study designed to prospectively evaluate patient preferences regarding postoperative scars. Results indicate that the horizontal technique is preferable with respect to scar placement.

IQGAP1 protein binds human epidermal growth factor receptor 2 (HER2) and modulates trastuzumab resistance.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-25% of breast cancers. Increased HER2 expression is an adverse prognostic factor and correlates with decreased patient survival. HER2-positive (HER2(+)) breast cancer is treated with trastuzumab. Unfortunately, some patients are intrinsically refractory to therapy, and many who do respond initially become resistant within 1 year. Understanding the molecular mechanisms underlying HER2 signaling and trastuzumab resistance is essential to reduce breast cancer mortality. IQGAP1 is a ubiquitously expressed scaffold protein that contains multiple protein interaction domains. By regulating its binding partners IQGAP1 integrates signaling pathways, several of which contribute to breast tumorigenesis. We show here that IQGAP1 is overexpressed in HER2(+) breast cancer tissue and binds directly to HER2. Knockdown of IQGAP1 decreases HER2 expression, phosphorylation, signaling, and HER2-stimulated cell proliferation, effects that are all reversed by reconstituting cells with IQGAP1. Reducing IQGAP1 up-regulates p27, and blocking this increase attenuates the growth inhibitory effects of IQGAP1 knockdown. Importantly, IQGAP1 is overexpressed in trastuzumab-resistant breast epithelial cells, and reducing IQGAP1 both augments the inhibitory effects of trastuzumab and restores trastuzumab sensitivity to trastuzumab-resistant SkBR3 cells. These data suggest that inhibiting IQGAP1 function may represent a rational strategy for treating HER2(+) breast carcinoma.

MAPK scaffold IQGAP1 binds the EGF receptor and modulates its activation.

Cellular responses produced by EGF are mediated through the receptor (EGFR) and by various enzymes and scaffolds. Recent studies document IQGAP1 as a scaffold for the MAPK cascade, binding directly to B-Raf, MEK, and ERK and regulating their activation in response to EGF. We previously showed that EGF is unable to activate B-Raf in cells lacking IQGAP1. However, the mechanism by which IQGAP1 links B-Raf to EGFR was unknown. Here we report that endogenous EGFR and IQGAP1 co-localize and co-immunoprecipitate in cells. EGF has no effect on the association, but Ca(2+) attenuates binding. In vitro analysis demonstrated a direct association mediated through the IQ and kinase domains of IQGAP1 and EGFR, respectively. Calmodulin disrupts this interaction. Using a mass spectrometry-based assay, we show that EGF induces phosphorylation of IQGAP1 Ser(1443), a residue known to be phosphorylated by PKC. This phosphorylation is eliminated by pharmacological inhibition of either EGFR or PKC and transfection with small interfering RNA directed against the PKCα isoform. In IQGAP1-null cells, EGF-stimulated tyrosine phosphorylation of EGFR is severely attenuated. Normal levels of autophosphorylation are restored by reconstituting wild type IQGAP1 and enhanced by an IQGAP1 S1443D mutant. Collectively, these data demonstrate a functional interaction between IQGAP1 and EGFR and suggest that IQGAP1 modulates EGFR activation.

Calmodulin binds HER2 and modulates HER2 signaling.

Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of receptor tyrosine kinases, has defined roles in neoplastic transformation and tumor progression. Overexpression of HER2 is an adverse prognostic factor in several human neoplasms and, particularly in breast cancer, correlates strongly with a decrease in overall patient survival. HER2 stimulates breast tumorigenesis by forming protein-protein interactions with a diverse array of intracellular signaling molecules, and evidence suggests that manipulation of these associations holds therapeutic potential. To modulate specific HER2 interactions, the region(s) of HER2 to which each target binds must be accurately identified. Calmodulin (CaM), a ubiquitously expressed Ca(2+) binding protein, interacts with multiple intracellular targets. Interestingly, CaM binds the juxtamembrane region of the epidermal growth factor receptor, a HER2 homolog. Here, we show that CaM interacts, in a Ca(2+)-regulated manner, with two distinct sites on the N-terminal portion of the HER2 intracellular domain. Deletion of residues 676-689 and 714-732 from HER2 prevented CaM-HER2 binding. Inhibition of CaM function or deletion of the CaM binding sites from HER2 significantly decreased both HER2 phosphorylation and HER2-stimulated cell growth. Collectively, these data suggest that inhibition of CaM-HER2 interaction may represent a rational therapeutic strategy for the treatment of patients with breast cancer. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

Microbial survey of a full-scale, biologically active filter for treatment of drinking water.

The microbial community of a full-scale, biologically active drinking water filter was surveyed using molecular techniques. Nitrosomonas, Nitrospira, Sphingomonadales, and Rhizobiales dominated the clone libraries. The results elucidate the microbial ecology of biological filters and demonstrate that biological treatment of drinking water should be considered a viable alternative to physicochemical methods.