Pemphigoid gestationis: report of a case with umbilical artery Doppler assessment

BACKGROUND: Pemphigoid gestationis is a rare autoimmune disorder of pregnancy characterized clinically by a pruritic, papular rash and in some cases intrauterine growth restriction and premature delivery. The growth disorder is secondary to antibody deposition in the placental bed, with resultant placental insufficiency. The appropriate fetal assessment required during these gestations remains uncertain. The use of serial Doppler velocimetry of the umbilical arteries has not been reported to date in this disorder. CASE: A woman had pemphigoid and progressively decreasing umbilical artery end-diastolic flow over a period of weeks without documented fetal growth restriction. Delivery was finally prompted by reversal of end-diastolic flow. CONCLUSION: We suggest that parturients with this condition undergo frequent umbilical artery Doppler studies to document end-diastolic velocity even without the ultrasound finding of intrauterine growth restriction.     

Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells

Introduction

Resistance to anti-estrogen therapies is a major cause of disease relapse and mortality in estrogen receptor alpha (ERα)-positive breast cancers. Tamoxifen or estrogen withdrawal increases the dependence of breast cancer cells on Notch signalling. Here, we investigated the contribution of Nicastrin and Notch signalling in endocrine-resistant breast cancer cells.

Methods

We used two models of endocrine therapies resistant (ETR) breast cancer: tamoxifen-resistant (TamR) and long-term estrogen-deprived (LTED) MCF7 cells. We evaluated the migratory and invasive capacity of these cells by Transwell assays. Expression of epithelial to mesenchymal transition (EMT) regulators as well as Notch receptors and targets were evaluated by real-time PCR and western blot analysis. Moreover, we tested in vitro anti-Nicastrin monoclonal antibodies (mAbs) and gamma secretase inhibitors (GSIs) as potential EMT reversal therapeutic agents. Finally, we generated stable Nicastrin overexpessing MCF7 cells and evaluated their EMT features and response to tamoxifen.

Results

We found that ETR cells acquired an epithelial to mesenchymal transition (EMT) phenotype and displayed increased levels of Nicastrin and Notch targets. Interestingly, we detected higher level of Notch4 but lower levels of Notch1 and Notch2 suggesting a switch to signalling through different Notch receptors after acquisition of resistance. Anti-Nicastrin monoclonal antibodies and the GSI PF03084014 were effective in blocking the Nicastrin/Notch4 axis and partially inhibiting the EMT process. As a result of this, cell migration and invasion were attenuated and the stem cell-like population was significantly reduced. Genetic silencing of Nicastrin and Notch4 led to equivalent effects. Finally, stable overexpression of Nicastrin was sufficient to make MCF7 unresponsive to tamoxifen by Notch4 activation.

Conclusions

ETR cells express high levels of Nicastrin and Notch4, whose activation ultimately drives invasive behaviour. Anti-Nicastrin mAbs and GSI PF03084014 attenuate expression of EMT molecules reducing cellular invasiveness. Nicastrin overexpression per se induces tamoxifen resistance linked to acquisition of EMT phenotype. Our finding suggest that targeting Nicastrin and/or Notch4 warrants further clinical evaluation as valid therapeutic strategies in endocrine-resistant breast cancer.     

Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families

The genetic aetiology of familial aggregations of breast cancer and sarcomas has been elucidated only in part. In this study, 23 unrelated individuals from families with one case of sarcoma and at least one case of breast cancer were screened for mutations in the TP53, BRCA1 and BRCA2 genes. Families were classified according to their conformity to the criteria defining the Li-Fraumeni syndrome (LFS), Li-Fraumeni-like (LFL) syndrome and hereditary breast/ovarian cancer (HBOC). Germline TP53 mutations were identified in three instances (13%), including one LFS and two LFL families, while none of the non-LFS/non-LFL families had a TP53 mutation. Three cases (13%), including one with a TP53 mutation, carried BRCA2 mutations. Of these, two were observed in LFL/HBOC families and the other one in a non-LFS/non-LFL/HBOC family, while none of the non-HBOC families tested positive. These findings suggest that the screening of BRCA2, in addition to TP53, may be appropriate for the molecular characterisation of breast cancer/sarcoma families, with practical implications for counselling and clinical management.     

FOLFOXIRI-Bevacizumab or FOLFOX-Panitumumab in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Propensity Score-Based Analysis

BackgroundDoublets plus anti‐epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI‐bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI‐bevacizumab versus doublets plus anti‐EGFRs is available in left‐sided RAS/BRAF wild‐type mCRC.Materials and MethodsWe selected patients with left‐sided RAS and BRAF wild‐type mCRC treated with first‐line FOLFOX‐panitumumab or FOLFOXIRI‐bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score‐based analysis was performed to compare FOLFOXIRI‐bevacizumab with FOLFOX‐panitumumab.ResultsA total of 185 patients received FOLFOX‐panitumumab and 132 received FOLFOXIRI‐bevacizumab. Median progression‐free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI‐bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX‐panitumumab group (propensity score‐adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64–1.04; p = .11; propensity score‐adjusted HR for OS, 0.80; 95% CI, 0.59–1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI‐bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI‐bevacizumab and FOLFOX‐panitumumab are valuable treatment options in left‐sided RAS/BRAF wild‐type mCRC.Implications for PracticeA propensity score‐based analysis of five trials was performed to compare FOLFOX‐panitumumab versus FOLFOXIRI‐bevacizumab in left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI‐bevacizumab achieved numerically superior survival outcomes versus FOLFOX‐panitumumab. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group. These observations suggest that although doublet chemotherapy plus anti‐EGFRs remains the preferred treatment in patients with left‐sided RAS/BRAF wild‐type mCRC, FOLFOXIRI‐bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients’ preference and potential impact on quality of life.     

Volition and alcohol-risk reduction: the role of action orientation in the reduction of alcohol-related harm among college student drinkers

The present study examined the role of action orientation in health behavior change. Eighty-six binge drinking college students completed measures of alcohol use, alcohol-related consequences (e.g., driving drunk), motivation to change drinking, and action orientation. Alcohol use and consequences were reassessed 1 month later. Results showed that, although there was no significant change in alcohol quantity per occasion, students reported a significant decline in alcohol-related problems over time. Hierarchical regression analyses were conducted to examine whether action orientation was associated with changes in alcohol involvement. Controlling for alcohol problems and motivation to change at Time 1, those with higher dispositional action orientation showed fewer alcohol-related consequences at Time 2. These results suggest that those who are low in action orientation may have more difficulty enacting intentions to modify harmful health behaviors. The findings underscore the importance of volitional skills in interventions to promote change in health behavior.     

Endocapsular cellulomonas as a cause of persistent postoperative endophthalmitis

Sequestration of bacteria within the capsular fornices after cataract extraction with intraocular lens implantation can cause both acute and chronic inflammation. A case of persistent postoperative endophthalmitis caused by capsular sequestration of Cellulomonas is described. The patient underwent uncomplicated cataract extraction with intraocular lens implantation and subsequently developed acute postoperative endophthalmitis. Inflammation persisted despite several vitreous taps and the injection of intravitreal antibiotics. Definitive treatment required pars plana vitrectomy, intraocular lens explantation, capsular bag removal, and intravitreal and parenteral antibiotics. In patients with postoperative endophthalmitis, one must consider atypical organisms as the source and should consider explantation of the intraocular lens with capsular bag removal.     

Functional interaction between the N- and C-terminal domains of murine leukemia virus surface envelope protein

A series of murine leukemia viruses (MuLVs) with chimeric envelope proteins (Env) was generated to map functional interactions between the N- and the C-terminal domains of surface proteins (SU). All these chimeras have the 4070A amphotropic receptor-binding region flanked by various lengths of Moloney ecotropic N- and C-terminal Env. A charged residue, E49 (E16 on the mature protein), was identified at the N-terminals of Moloney MuLV SU that is important for the interaction with the C-terminal domain of the SU. The region that interacts with E49 was localized between junction 4 (R265 of M-MuLV Env) and junction 6 (L374 of M-MuLV Env) of SU. Sequencing the viable chimeric Env virus populations identified residues within the SU protein that improved the replication kinetics of the input chimeric Env viruses. Mutations in the C-domain of SU (G387E/R, L435I, L442P) were found to improve chimera IV4, which displayed a delayed onset of replication. The replication of AE6, containing a chimeric junction in the SU C-terminus, was improved by mutations in the N-domain (N40H, E80K), the proline-rich region (Q252R), or the transmembrane protein (L538N). Altogether, these observations provide insights into the structural elements required for Env function.     

Ethanol sensitivity and tolerance in long-term memory mutants of Drosophila melanogaster

Background:  It has become increasingly clear that molecular and neural mechanisms underlying learning and memory and drug addiction are largely shared. To confirm and extend these findings, we analyzed ethanol-responsive behaviors of a collection of Drosophila long-term memory mutants.
Methods:  For each mutant, sensitivity to the acute uncoordinating effects of ethanol was quantified using the inebriometer. Additionally, 2 distinct forms of ethanol tolerance were measured: rapid tolerance, which develops in response to a single brief exposure to a high concentration of ethanol vapor; and chronic tolerance, which develops following a sustained low-level exposure.
Results:  Several mutants were identified with altered sensitivity, rapid or chronic tolerance, while a number of mutants exhibited multiple defects.
Conclusions:  The corresponding genes in these mutants represent areas of potential overlap between learning and memory and behavioral responses to alcohol. These genes also define components shared between different ethanol behavioral responses.     

Breast cancer neoplastic seeding in the setting of image-guided needle biopsies of the breast

Purpose

Cathepsin S (CTSS) is expressed in a variety of cancers and stimulates tumor progression. However, the regulatory mechanism and role of CTSS in breast cancer progression are poorly understood. The aim of this study was to examine the relationships between CTSS expression and breast cancer grade and stage, and the signaling molecules involved in CTSS expression.

Methods

Immunohistochemical staining was performed in tissue microarray sections of 1451 human invasive breast cancer samples to determine epithelial (E-CTSS) and stromal CTSS (S-CTSS) expression. Gene and protein expression levels in human breast cancer cell lines were measured by polymerase chain reaction and western blotting. Small interfering RNA transfection and a Matrigel transwell invasion assay were used to confirm the signaling pathways regulating CTSS expression.

Results

In patient tumor tissue blocks, high grade, late stage, and triple negativity were associated with elevated CTSS protein expression, and expression levels were related to the clinical outcomes of patients with invasive breast cancer. CTSS expression was also higher in triple-negative breast cancer (TNBC) cell lines than in hormone-responsive cells, and CTSS expression patterns matched those of tryptophan hydroxylase 1 (TPH1) and 5-hydroxytryptamine receptor 7 (5-HT₇). Treatment of TNBC cells (MDA-MB-231 and HCC-1395) with 5-HT significantly enhanced CTSS protein expression, whereas pharmacological inhibition or knockdown of 5-HT₇ significantly inhibited its expression. Correspondingly, cancer cell invasion was increased by 5-HT treatment and suppressed by 5-HT₇ knockdown. The expression of CTSS was regulated by PI3K/Akt and Ras/Raf/MAPK signaling pathways, and these signaling pathways were stabilized by HSP90 and enhanced by the 5-HT₇ receptor-dependent autocrine effect of 5-HT in TNBC cells.

Conclusion

Our findings suggest CTSS as a candidate target for development of a strategy to inhibit breast cancer invasion, and indicate that HSP90 and 5-HT₇ (regulators of CTSS) should be considered as alternative targets for the management of TNBC invasion and metastasis.

     

Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma

RATIONALE: One-quarter to one-third of individuals with asthma smoke, which may affect response to therapy and contribute to poor asthma control. OBJECTIVES: To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke. METHODS: In a multicenter, placebo-controlled, double-blind, double-dummy, crossover trial, 44 nonsmokers and 39 light smokers with mild asthma were assigned randomly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast. MEASUREMENTS AND MAIN RESULTS: Primary outcome was change in prebronchodilator FEV(1) in smokers versus nonsmokers. Secondary outcomes included peak flow, PC(20) methacholine, symptoms, quality of life, and markers of airway inflammation. Despite similar FEV(1), bronchodilator response, and sensitivity to methacholine at baseline, subjects with asthma who smoked had significantly more symptoms, worse quality of life, and lower daily peak flow than nonsmokers. Adherence to therapy did not differ significantly between smokers and nonsmokers, or between treatment arms. Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein (ECP) in both smokers and nonsmokers, but increased FEV(1) (170 ml, p = 0.0003) only in nonsmokers. Montelukast significantly increased a.m. peak flow in smokers (12.6 L/min, p = 0.002), but not in nonsmokers. CONCLUSIONS: In subjects with mild asthma who smoke, the response to inhaled corticosteroids is attenuated, suggesting that adjustments to standard therapy may be required to attain asthma control. The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting. Larger prospective studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke.