Development of the PROMIS pediatric stigma and extension to the PROMIS pediatric stigma: skin item banks.

PURPOSE: To develop the PROMIS Pediatric Stigma (PPS) and Skin (PPS-Skin) by constructing a common metric for measuring stigma in children with various conditions, while capturing the unique features of each condition. METHODS: Data from 860 children, ages 8-17, with a diagnosis of epilepsy, pNF (neurofibromatosis type 1 associated neurofibroma plexform), MD (muscular dystrophy), cancer, or skin conditions recruited from three projects were analyzed. Children with epilepsy, pNF and MD (sample-1) completed the original 18-item Neuro-QoL Stigma, while children with cancer and skin conditions (e.g., atopic dermatitis, psoriasis, and genetic skin disorders; sample-2) completed a 16-item version and 6 additional skin related items. Exploratory factor analysis (EFA) and confirmatory analysis (CFA) were used to evaluate unidimensionality of 24 stigma items. Differential item functioning (DIF) was used to evaluate measurement equivalence on group, gender, age, and conditions. Item response theory model (IRT) was used to construct the final measure. RESULTS: Sufficient unidimensionality was supported by both EFA and CFA. No items showed significant DIF indicating stable measurement properties across groups of comparison. All items fit the IRT model and were able to be calibrated together to form the PPS which consists of 18 core items. The PPS-Skin (18 cores items + 6 skin items) was developed by calibrating 6 skin items onto the common metric as the PPS. CONCLUSIONS: We used IRT techniques to successfully develop the PPS and the PPS-Skin, which share a common metric and account for unique and common concerns related to chronic conditions.

A case of severe nivolumab-induced lichen planus pemphigoides in a child with metastatic spitzoid melanoma.

Dermatologic reactions are among the most common adverse events of antiprogrammed cell death-1 (anti-PD-1) monoclonal antibodies agents and include maculopapular rash, psoriasiform rash, lichenoid eruptions, autoimmune bullous disorders, and vitiligo. Here, we present a case of a 12-year-old African American male with metastatic spitzoid melanoma treated with nivolumab who developed a mild lichenoid eruption that progressed to a severe case of lichen planus pemphigoides (LPP). Management was complex given the patient's age and history and included hospitalization for intravenous steroids, an intensive topical steroid regimen, methotrexate, and discontinuation of nivolumab. This case illustrates a rare but dramatic progression from a mild LP-like eruption to severe bullous lichenoid eruption, most consistent with LPP, as well as the diagnostic and treatment challenges in the setting of a pediatric patient on nivolumab.

Racial Ethnic Disparities in Youth With Type 1 Diabetes Participating in Diabetes Summer Camps.

OBJECTIVE: Diabetes camps are beneficial for campers and include benefits such as increases in diabetes knowledge, glycemic control, and psychological functioning. Racial/ethnic minority youth are likely to have poorer disease management and glycemic control. We hypothesized that minority youth with type 1 diabetes have reduced participation in diabetes summer camps. RESEARCH DESIGN AND METHODS: We analyzed deidentified data from 5,256 campers with type 1 diabetes who participated in a network of 48 American Diabetes Association-affiliated summer camps in 2018, and we compared participation rates by racial/ethnic category to the most recent SEARCH for Diabetes in Youth study prevalence rates. RESULTS: Camper demographics were significantly different than in the general population of children with type 1 diabetes (P < 0.001). Minority youth were more likely to attend day camp, be first-time campers, and request financial aid, and they were less likely to be on insulin pump therapy or use continuous glucose monitors. CONCLUSIONS: Racial/ethnic minority youth with diabetes are underrepresented in diabetes camps nationwide.

Multiple basal cell carcinomas in Gorlin Syndrome treated with pulsed dye laser.

This is an observational study demonstrating the effectiveness of pulsed dye laser (PDL) as a treatment of basal cell carcinomas (BCC) in patients with Gorlin Syndrome. Over 200 BCCs localized to the head, neck, trunk, and extremities of a patient suffering from Gorlin Syndrome were successfully treated with PDL without subsequent scarring. PDL is a simple and rapid modality to destroy BCCs arising in patients with Gorlin Syndrome resulting in a preferable cosmetic outcome.

Systematic Review and Meta-analysis Comparing Topical Corticosteroids With Vehicle/Moisturizer in Childhood Atopic Dermatitis.

PROBLEM: To determine the safety and efficacy of topical corticosteroid versus vehicle/moisturizer in children under 2 years old (<2 y). ELIGIBILITY CRITERIA: A systematic review and meta-analysis searching PubMed MEDLINE, Embase, Web of Science, Cochrane Database of Controlled Trials, Cochrane Database of Systematic Reviews, DARE, NHS Economic Evaluation, CINAHL, GREAT, and Clinicaltrials.gov. We selected randomized controlled trials (RCTs) comparing topical corticosteroids to vehicle/moisturizer and included children <2 y. Two authors extracted data. SAMPLE: Only one study limited analyses to children <2 y, so our review included participants older than 2 years. Twelve RCTs were included with 2224 participants. Ten studies were industry-sponsored. RESULTS: The proportion of responders to topical corticosteroid across studies was 0.65 (95% CI, 0.54-0.74), as compared to vehicle/moisturizer 0.32 (95% confidence interval (CI), 0.20-0.48). The proportion of adverse events were similar between groups (topical steroids 0.17 (95% CI, 0.08-0.33) vs. vehicle/moisturizer 0.12 (CI 0.02-0.42)). High heterogeneity in treatment response occurred across studies that could not be explained by potential moderators. Mild adrenal suppression occurred in 4 of 157 measured participants (3%) receiving topical corticosteroids. Limitations include the few RCTs on this topic, the inclusion of participants >2 y and outcome measures and reporting methods rarely met CONSORT guidelines. CONCLUSIONS: Topical corticosteroids trended to being more effective and equally safe to vehicle/moisturizers, but generalizability is limited given the dearth of well-designed studies focused on children <2 y. Adverse events from vehicle/moisturizer may be greater than topical corticosteroid due to under treatment. IMPLICATIONS: Further work is needed in this age group.

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature.

BACKGROUND: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. OBJECTIVE: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. METHODS: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). RESULTS: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α-coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN-γ, OASL, and TH2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17-regulated gene expression (IL17F and IL36A/IL36B/IL36G). CONCLUSION: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36-targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.

Sleep disturbance in children with moderate/severe atopic dermatitis: A case-control study.

BACKGROUND: Sleep is disturbed in 60% of children with atopic dermatitis (AD). OBJECTIVE: To characterize sleep in a cohort of children with moderate-to-severe AD and determine methods for assessment of sleep disturbance. METHODS: A case-control study compared children age 6 to 17 years who have moderate-to-severe AD with age- and sex-matched healthy controls. Participants wore actigraphy watches and completed sleep- and disease-specific questionnaires. RESULTS: Nineteen patients with AD and 19 controls completed the study. The patients with AD experienced wake after sleep onset (WASO) for 103 plus or minus 55 minutes as compared with 50 plus or minus 27 minutes in the controls (P < .01). They had a higher frequency of restless sleep, daytime sleepiness, difficulty falling back to sleep at night, and teacher-reported daytime sleepiness. Disease severity correlated well with WASO (total SCORing Atopic Dermatitis score: r = 0.61, P < .01; objective SCORing Atopic Dermatitis score: r = 0.58, P = .01; and Eczema Area and Severity Index: r = 0.68, P < .01). The Children's Dermatology Life Quality Index sleep question correlated with WASO (r = 0.52, P = .03), but self-reported itch severity did not (r = 0.28, P = .30). LIMITATIONS: The study cohort was small. CONCLUSION: Children with moderate-to-severe AD experience more WASO and lower sleep efficiency than healthy controls but similar bedtime and wake time, sleep duration, and sleep onset latency.

Protein expression of DNA damage repair proteins dictates response to topoisomerase and PARP inhibitors in triple-negative breast cancer.

Patients with metastatic triple-negative breast cancer (TNBC) have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising therapeutic option for these tumors. The TNBC tumor type has been associated with BRCA mutations, and inhibitors of Poly (ADP-ribose) polymerase (PARP), a family of proteins that facilitates DNA repair, have been shown to effectively kill BRCA defective tumors by preventing cells from repairing DNA damage, leading to a loss of cell viability and clonogenic survival. Here we present preclinical efficacy results of combining the PARP inhibitor, ABT-888, with CPT-11, a topoisomerase I inhibitor. CPT-11 binds to topoisomerase I at the replication fork, creating a bulky adduct that is recognized as damaged DNA. When DNA damage was stimulated with CPT-11, protein expression of the nucleotide excision repair enzyme ERCC1 inversely correlated with cell viability, but not clonogenic survival. However, 4 out of the 6 TNBC cells were synergistically responsive by cell viability and 5 out of the 6 TNBC cells were synergistically responsive by clonogenic survival to the combination of ABT-888 and CPT-11. In vivo, the BRCA mutant cell line MX-1 treated with CPT-11 alone demonstrated significant decreased tumor growth; this decrease was enhanced further with the addition of ABT-888. Decrease in tumor growth correlated with an increase in double strand DNA breaks as measured by γ-H2AX phosphorylation. In summary, inhibiting two arms of the DNA repair pathway simultaneously in TNBC cell lines, independent of BRCA mutation status, resulted in un-repairable DNA damage and subsequent cell death.

Abrogating phosphorylation of eIF4B is required for EGFR and mTOR inhibitor synergy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive disease. They have a high rate of relapse and often develop resistance to standard chemotherapy. Many TNBCs have elevated epidermal growth factor receptor (EGFR) but are resistant to EGFR inhibitors as monotherapy. In this study, we sought to find a combination therapy that could sensitize TNBC to EGFR inhibitors. Phospho-mass spectrometry was performed on the TNBC cell line, BT20, treated with 0.5 µM gefitinib. Immunoblotting measured protein levels and phosphorylation. Colony formation and growth assays analyzed the treatment on cell proliferation, while MTT assays determined the synergistic effect of inhibitor combination. A Dual-Luciferase reporter gene plasmid measured translation. All statistical analysis was done on CalucuSyn and GraphPad Prism using ANOVAs. Phospho-proteomics identified the mTOR pathway to be of interest in EGFR inhibitor resistance. In our studies, combining gefitinib and temsirolimus decreased cell growth and survival in a synergistic manner. Our data identified eIF4B, as a potentially key fragile point in EGFR and mTOR inhibitor synergy. Decreased eIF4B phosphorylation correlated with drops in growth, viability, clonogenic survival, and cap-dependent translation. Taken together, these data suggest EGFR and mTOR inhibitors abrogate growth, viability, and survival via disruption of eIF4B phosphorylation leading to decreased translation in TNBC cell lines. Further, including an mTOR inhibitor along with an EGFR inhibitor in TNBC with increased EGFR expression should be further explored. Additionally, translational regulation may play an important role in regulating EGFR and mTOR inhibitor synergy and warrant further investigation.

Dasatinib is synergistic with cetuximab and cisplatin in triple-negative breast cancer cells.

BACKGROUND: Patients presenting with triple-negative breast cancers (TNBCs) have a poorer prognosis compared with those with other subtypes of breast cancer. The majority of TNBCs overexpress epidermal growth factor receptor (EGFR). However, EGFR inhibition as a monotherapy, as with the monoclonal antibody cetuximab, is ineffective. Src family tyrosine kinases play a critical role in signal transduction downstream of growth factor receptors and are involved in the development of EGFR inhibitor resistance. We hypothesize that dasatinib, an Src family tyrosine kinase inhibitor, may help overcome EGFR resistance to cetuximab, and in combination with cisplatin may enhance growth inhibition and apoptosis and reduce metastatic potential. METHODS: Growth inhibition, apoptosis, cell migration and invasion, and effects on EGFR, Akt, and mitogen-activated protein kinase phosphorylation were examined in a panel of breast cancer cell lines, including seven TNBC cell lines. RESULTS: Six out of seven TNBC cell lines demonstrated a synergistic interaction using the triple-drug combination, compared with only two TNBC cell lines with the cisplatin and cetuximab combination. An induction of apoptosis and decrease in EGFR and mitogen-activated protein kinase phosphorylation, and thus resensitization to EGFR inhibition, was observed using the three-drug treatment regimen. A significant reduction (P < 0.001) in tumor cell migration and invasion was also found following dasatinib treatment alone or in combination. CONCLUSIONS: These findings may have important clinical implications in treating TNBC patients whose tumors co-overexpress both EGFR and c-Src. Identification of this subset of patients may be beneficial in the design of a clinical trial using this treatment regimen.

EGFR Tyrosine 845 Phosphorylation-Dependent Proliferation and Transformation of Breast Cancer Cells Require Activation of p38 MAPK.

Phosphorylation of epidermal growth factor receptor (EGFR) on tyrosine 845 by c-Src has been shown to be important for cell proliferation and migration in several model systems. This cross talk between EGFR and Src family kinases (SFKs) is one mechanism for resistance to EGFR inhibitors both in cell models and in the clinic. Here, we show that phosphorylation of tyrosine 845 on EGFR is required for proliferation and transformation using several cell models of breast cancer. Overexpression of EGFR-Y845F or treating cells with the SFK inhibitor dasatinib abrogated tyrosine 845 phosphorylation, yet had little to no effect on other EGFR phosphorylation sites or EGFR kinase activity. Abrogation of Y845 phosphorylation inhibited cell proliferation and transformation, even though extracellular signal-regulated kinase (ERK) and Akt remained active under these conditions. Importantly, cotransfection of mitogen-activated protein kinase (MAPK) kinase 3 and p38 MAPK restored cell proliferation in the absence of EGFR tyrosine 845 phosphorylation. Taken together, these data demonstrate a novel role for p38 MAPK signaling downstream of EGFR tyrosine 845 phosphorylation in the regulation of breast cancer cell proliferation and transformation and implicate SFK inhibitors as a potential therapeutic mechanism for overcoming EGFR tyrosine kinase inhibitor resistance in breast cancer.

Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met.

INTRODUCTION: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown clinical efficacy in lung, colon, and pancreatic cancers. In lung cancer, resistance to EGFR TKIs correlates with amplification of the hepatocyte growth factor (HGF) receptor tyrosine kinase Met. Breast cancers do not respond to EGFR TKIs, even though EGFR is overexpressed. This intrinsic resistance to EGFR TKIs in breast cancer does not correlate with Met amplification. In several tissue monoculture models of human breast cancer, Met, although expressed, is not phosphorylated, suggesting a requirement for a paracrine-produced ligand. In fact, HGF, the ligand for Met, is not expressed in epithelial cells but is secreted by fibroblasts in the tumor stroma. We have identified a number of breast cancer cell lines that are sensitive to EGFR TKIs. This sensitivity is in conflict with the observed clinical resistance to EGFR TKIs in breast cancers. Here we demonstrate that fibroblast secretion of HGF activates Met and leads to EGFR/Met crosstalk and resistance to EGFR TKIs in triple-negative breast cancer (TNBC). METHODS: The SUM102 and SUM149 TNBC cell lines were used in this study. Recombinant HGF as well as conditioned media from fibroblasts expressing HGF were used as sources for Met activation. Furthermore, we co-cultured HGF-secreting fibroblasts with Met-expressing cancer cells to mimic the paracrine HGF/Met pathway, which is active in the tumor microenvironment. Cell growth, survival, and transformation were measured by cell counting, clonogenic and MTS assays, and soft agar colony formation, respectively. Student's t test was used for all statistical analysis. RESULTS: Here we demonstrate that treatment of breast cancer cells sensitive to EGFR TKIs with recombinant HGF confers a resistance to EGFR TKIs. Interestingly, knocking down EGFR abrogated HGF-mediated cell survival, suggesting a crosstalk between EGFR and Met. HGF is secreted as a single-chain pro-form, which has to be proteolytically cleaved in order to activate Met. To determine whether the proteases required to activate pro-HGF were present in the breast cancer cells, we utilized a fibroblast cell line expressing pro-HGF (RMF-HGF). Addition of pro-HGF-secreting conditioned fibroblast media to TNBC cells as well as co-culturing of TNBC cells with RMF-HGF fibroblasts resulted in robust phosphorylation of Met and stimulated proliferation in the presence of an EGFR TKI. CONCLUSIONS: Taken together, these data suggest a role for Met in clinical resistance to EGFR TKIs in breast cancer through EGFR/Met crosstalk mediated by tumor-stromal interactions.

A targeted enzyme approach to sensitization of tyrosine kinase inhibitor-resistant breast cancer cells.

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors. Here, we investigate the cause of this sustained phosphorylation and the molecular basis for the ineffectiveness of gefitinib. We show that reactive oxygen species (ROS), known to damage cellular macromolecules and to modulate signaling cascades in a variety of human diseases including cancers, appear to play a critical role in mediating EGFR TKI-resistance. Furthermore, elimination of these ROS through use of a cell-penetrating catalase derivative sensitizes the cells to gefitinib. These results suggest a new approach for the treatment of TKI-resistant breast cancer patients specifically, the targeting of ROS and attendant downstream oxidative stress and their effects on signaling cascades.

Lipid raft localization of EGFR alters the response of cancer cells to the EGFR tyrosine kinase inhibitor gefitinib.

Epidermal growth factor receptor (EGFR) is overexpressed in many cancer types including ~30% of breast cancers. Several small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR have shown clinical efficacy in lung and colon cancers, but no benefit has been noted in breast cancer. Thirteen EGFR expressing breast cancer cell lines were analyzed for response to EGFR TKIs. Seven were found to be EGFR TKI resistant; while shRNA knockdown of EGFR determined that four of these cell lines retained the requirement of EGFR protein expression for growth. Interestingly, EGFR localized to plasma membrane lipid rafts in all four of these EGFR TKI-resistant cell lines, as determined by biochemical raft isolation and immunofluorescence. When lipid rafts were depleted of cholesterol using lovastatin, all four cell lines were sensitized to EGFR TKIs. In fact, the effects of the cholesterol biosynthesis inhibitors and gefitinib were synergistic. While gefitinib effectively abrogated phosphorylation of Akt- and mitogen-activated protein kinase in an EGFR TKI-sensitive cell line, phosphorylation of Akt persisted in two EGFR TKI-resistant cell lines, however, this phosphorylation was abrogated by lovastatin treatment. Thus, we have shown that lipid raft localization of EGFR correlates with resistance to EGFR TKI-induced growth inhibition and pharmacological depletion of cholesterol from lipid rafts decreases this resistance in breast cancer cell lines. Furthermore, we have presented evidence to suggest that when EGFR localizes to lipid rafts, these rafts provide a platform to facilitate activation of Akt signaling in the absence of EGFR kinase activity.

EGFR/Met association regulates EGFR TKI resistance in breast cancer.

Breast cancers show a lack of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), despite 30% of tumors expressing EGFR. The mechanism of this resistance is unknown; however, we have recently shown that Met kinase activity compensates for loss of EGFR kinase activity in cell culture models. Met has been implicated in the pathogenesis of breast tumors and therefore may cooperate with EGFR for tumor growth. Here we have found that EGFR phosphorylation and cell proliferation is in part regulated by Met expression. In addition, we found that Met constitutive phosphorylation occurred independent of the Met ligand hepatocyte growth factor (HGF). Ligand-independent Met phosphorylation is mediated by Met amplification, mutation, or overexpression and by Met interaction with other cell surface molecules. In SUM229 breast cancer cells, we found that Met was not amplified or mutated, however it was overexpressed. Met overexpression did not directly correlate with ligand-independent Met phosphorylation as the SUM229 cell line was the only Met expressing breast cancer line with constitutive Met phosphorylation. Interestingly, Met expression did correlate with EGFR expression and we identified an EGFR/Met complex via co-immunoprecipitation. However, we only observed Met constitutive phosphorylation when c-Src also was part of this complex. Ligand-independent phosphorylation of Met was decreased by down regulating EGFR expression or by inhibiting c-Src kinase activity. Lastly, inhibiting EGFR and Met kinase activities resulted in a synergistic decrease in cell proliferation, supporting the idea that EGFR and Met functionally, as well as physically interact in breast cancer cells to regulate response to EGFR inhibitors.

Met and c-Src cooperate to compensate for loss of epidermal growth factor receptor kinase activity in breast cancer cells.

Breast cancers are not responsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), although 30% of breast cancers overexpress EGFR. The mechanism of intrinsic resistance to EGFR TKIs in breast cancer is the focus of current studies. Here, we observed that EGFR remains tyrosine phosphorylated in breast cancer cells that proliferate in the presence of EGFR TKIs. In one such cell line, SUM229, inhibiting c-Src kinase activity with either a dominant-negative c-Src or a c-Src TKI decreased EGFR phosphorylation on Tyr(845), Tyr(992), and Tyr(1086) in the presence of EGFR TKIs. Conversely, overexpressing wild-type (wt) c-Src in the EGFR TKI-sensitive breast cancer cell line SUM149 increased EGFR kinase-independent EGFR tyrosine phosphorylation. In addition, in the presence of EGFR TKIs, inhibiting c-Src kinase activity decreased cell growth in SUM229 cells, and overexpressing wt-c-Src increased cell growth in SUM149 cells. We identified the receptor tyrosine kinase Met to be responsible for activating c-Src in SUM229 cells. Inhibiting Met kinase activity with a small molecule inhibitor decreased c-Src phosphorylation and kinase activation. In addition, inhibiting Met kinase activity in SUM229 cells decreased EGFR tyrosine phosphorylation and growth in the presence of EGFR TKIs. Stimulating Met kinase activity in SUM149 cells with hepatocyte growth factor increased EGFR tyrosine phosphorylation and cell growth in the presence of EGFR TKIs. These data suggest a Met/c-Src-mediated signaling pathway as a mediator of EGFR tyrosine phosphorylation and cell growth in the presence of EGFR TKIs.

Effects of diets enriched in omega-3 and omega-6 polyunsaturated fatty acids on offspring sex-ratio and maternal behavior in mice.

There have been many trials describing the effects of polyunsaturated fatty acids (PUFA) on fecundity, neonatal development, and maternal behavior in humans, but few controlled studies in rodents. We examined the effects of a maternal diet high in omega 3 (N-3) or omega 6 (N-6) PUFA on NIH Swiss mice. Female mice were ad libitum fed one of three complete and balanced diets (N-3, enriched in menhaden oil; N-6, enriched in corn oil; C, control diet, Purina 5015) from age 4 wk until the end of the study. Mice were bred at approximately 19 wk and 27 wk of age, providing a total of 838 pups from 129 litters in two experiments. After weaning their pups from parity 1, behavior of dams was assessed on elevated-plus and open-field mazes. Although the fraction of male pups from the N-3 and C groups was not different from 0.5, dams on the N-6 diet birthed more daughters than sons (213 vs. 133; P < 0.001). Although maternal stress has been reported to favor birth of daughters, the behavior of N-6 dams was not different from controls. By contrast, the N-3 dams displayed greater anxiety, spending less time in the open arms and more time in the closed arms of the elevated maze and traveling less distance and exhibiting less exploratory behavior in the open field (P < 0.05). N-3 dams tended to produce smaller litters than C dams, and N-3-suckled pups gained less weight (P < 0.05). In conclusion, the N-3 diet had negative effects on murine fecundity and maternal behavior, whereas the N-6 diet favored birth of daughters.

Operative treatment of unstable pediatric pelvis and acetabular fractures.

The management of unstable pediatric pelvic and acetabular fractures continues to be controversial. Recent reports have suggested that closed management of unstable pelvic and acetabular fractures can result in significant long-term morbidity. The purpose of this study was to evaluate the results of operative stabilization of unstable pelvic and acetabular fractures in children and adolescents. Eighteen patients less than 16 years of age with unstable pelvic and acetabular fractures were treated operatively over a 7-year period. Fracture healing, time to union, complications, and functional outcome were assessed. All fractures healed by 10 weeks. No patients suffered wound complications, infection, or growth arrest at an average follow-up of 30 months. These results support operative fixation of unstable pediatric pelvic and acetabular fractures to restore pelvic symmetry and periarticular anatomy. Favorable clinical results can be achieved with a low incidence of complications.