MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways

Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two 'oncomirs' may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.     

A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness

Ca2+ enters the stereocilia of hair cells through mechanoelectrical transduction channels opened by the deflection of the hair bundle and is exported back to endolymph by an unusual splicing isoform (w/a) of plasma-membrane calcium-pump isoform 2 (PMCA2). Ablation or missense mutations of the pump cause deafness, as described for the G283S mutation in the deafwaddler (dfw) mouse. A deafness-inducing missense mutation of PMCA2 (G293S) has been identified in a human family. The family also was screened for mutations in cadherin 23, which accentuated hearing loss in a previously described human family with a PMCA2 mutation. A T1999S substitution was detected in the cadherin 23 gene of the healthy father and affected son but not in that of the unaffected mother, who presented instead the PMCA2 mutation. The w/a isoform was overexpressed in CHO cells. At variance with the other PMCA2 isoforms, it became activated only marginally when exposed to a Ca2+ pulse. The G293S and G283S mutations delayed the dissipation of Ca2+ transients induced in CHO cells by InsP3. In organotypic cultures, Ca2+ imaging of vestibular hair cells showed that the dissipation of stereociliary Ca2+ transients induced by Ca2+ uncaging was compromised in the dfw and PMCA2 knockout mice, as was the sensitivity of the mechanoelectrical transduction channels to hair bundle displacement in cochlear hair cells.     

Outcomes of human immunodeficiency virus-infected and -exposed children undergoing surgery—a prospective study

Aim

Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) is a worldwide pandemic. Mother-to-child transmission programs should theoretically minimize vertical transfer of the virus, but with variable effectiveness of implementation a significant number of children become infected and may present for emergency, diagnostic, and elective surgery. The aim of this study was to prospectively document the clinical presentation, the spectrum of pathology, and surgical outcomes of patients presenting to our hospital. This formed part of a pilot study of a collaborative international working group studying HIV infection in children, which included the Buzzi Children's Hospital Milan, Italy; the University of San Diego, California, USA; and the Red Cross War Memorial Children's Hospital and University of Cape Town, School of Adolescent and Child Health, Cape Town, South Africa.

Method

Clinical data from all children admitted to the surgical service of the Red Cross War Memorial Children's Hospital between July 2004 and December 2006 with either a history of HIV exposure (born to an HIV-infected mother) or confirmation of HIV infection by ELISA or polymerase chain reaction was collected. The clinical course was documented prospectively for the duration of admission and subsequent follow-up as recorded in case records review. The spectrum of pathology, surgical intervention, outcome, complications, World Health Organization stage of AIDS, and type of antiretroviral therapy were all noted. Comparative outcomes and subgroup analysis were not done in this part of the study.

Results

One hundred and thirteen patients were included in the study over the 30-month period. The average age was 24 months (1 day to 11 years). Seventy-nine (70%) of the 113 patients were infected and 34 (30%) were exposed, 9 of whom subsequently tested negative. Of the infected group, 53 (67%) patients were on antiretroviral therapy. The extent of disease in the infected group of patients according to the 2006 World Health Organization criteria was as follows: stage 1, 4 (5%); stage 2, 12 (15%); stage 3, 51 (65%); and stage 4, 12 (15%). All patients had nutritional assessments and were plotted on growth curves. Sixty-two (54%) were found to be malnourished and 41 (36%) of the children were found to have comorbid disease processes.Eighteen patients (16%) were treated with antibiotics or conservative therapy alone. The remaining 95 patients (84%) underwent an average of 1.6 procedures (range, 1-35), 59 (52%) in an elective manner and 36 (31%) as an emergency. When assessing the relationship of HIV to the presenting disease state, 58 (73.4%) had HIV-related diseases and 52 (46%) presented with sepsis.A total of 29 (25%) patients had surgical complications of which 6 (20%) were not considered to be HIV related. Nine (31%) had, in retrospect, incorrect management of the presenting disease, leaving 14 (48%) who potentially had HIV-related complications of poor wound healing and sepsis. A total of 100 (88%) were discharged alive, 6 (5.3%) died, and 7 (6 %) were lost to follow-up. Long-term follow-up of 50 patients for an average of 8 months revealed one further mortality.

Conclusion

Human immunodeficiency virus-positive and -exposed patients present a unique challenge in management which is complicated by concomitant disease and poor nutrition. These patients require an expanded differential diagnosis. We believe that, although on the surface there may be a higher complication rate, this needs to be confirmed in an expanded comparative cohort study, which is underway and that patients should still receive the benefit of full surgical intervention.     

Encrusted pyelitis. Lithiasic disease with infectious etiology

We report on two new cases of encrusted pielitis, a lithiasic disease of infectious ethiology--Corynebacterium of D group-. The clinic diagnostic is difficult and this disease develops in immunosuppressed patients, mainly in renal transplanted ones. One of our two cases is diagnosed in a patient with a transplanted kidney and the other one develops the disease within her native kidneys. We remark on the clinic features and therapeutic options.     

Clinical variability of cardio-facio-cutaneous syndrome: report of two additional cases

We describe two new cases of cardio-facio-cutaneous (CFC) syndrome, and underline the clinical variability of the CFC phenotype in our two patients presenting with border-line psychomotor development. The first patient showed some additional clinical manifestations, such as cryptorchidism and scoliosis, and the second one had atypical skin lesions.     

1-year postactivation results for sequentially implanted bilateral cochlear implant users.

OBJECTIVE: Evaluate speech recognition in quiet and in noise for a group of 12 children, all of whom underwent sequential bilateral cochlear implantation at various ages (range, 1 yr, 8 mo to 9 yr, 6 mo at time of second implant). STUDY DESIGN: Retrospective. SETTING: Outpatient cochlear implant clinic. PATIENTS: Children who underwent sequential bilateral cochlear implantation. INTERVENTION: Rehabilitative. MAIN OUTCOME MEASURES: Speech recognition in quiet was evaluated for each ear separately using single-word speech recognition assessments (Multisyllabic Lexical Neighborhood Test and Early Speech Perception Test) via recorded presentation. Speech recognition in noise was assessed for each ear separately and in the bilateral condition by obtaining a spondee recognition threshold in the presence of speech-weighted noise presented at 45 dB hearing level. The primary outcome measure for speech recognition in noise assessment was the signal-to-noise ratio for 50% performance, which was calculated by determining the difference between the presentation level of the noise and the presentation level at which the speech recognition threshold was obtained. The results of these assessments were contrasted between children receiving their second cochlear implant before 4 years of age and children receiving their second cochlear implant after 4 years of age. RESULTS: A statistically significant difference for speech recognition scores in quiet was obtained between the early-implanted ear and the late-implanted ears for children receiving their second cochlear implant after 4 years of age. There was not a statistically significant difference in speech recognition scores in quiet between the early-implanted and late-implanted ears of children receiving their second cochlear before 4 years of age. Both groups of children possessed better speech recognition scores in noise (statistically significant at an alpha = 0.05) in the bilateral condition relative to either unilateral condition. However, there was not a statistically significant relationship between speech recognition performance in noise and the duration of deafness of the later implanted ear. CONCLUSION: Bilateral cochlear implantation allowed for better speech recognition in noise relative to unilateral performance for a group of 12 children who underwent sequential bilateral cochlear implantation at various ages. There was not a statistically significant relationship between speech recognition in noise benefit, which was defined as the difference in performance between the first implanted ear and the bilateral condition and the age at which the second implant was received. Children receiving bilateral cochlear implants younger than 4 years of age achieved better speech recognition in quiet performance for the later implanted ear as compared with children receiving their second cochlear implant after 4 year of age.