Biology of the estrogen receptor,GPR30, in triple negative breast cancer

Background

Triple-negative (TN) breast cancer lacks a known signaling pathway amenable to targeted therapy. The authors hypothesized that the G protein–coupled receptor GPR30 may be present in TN breast cancer and serve a role for tumor growth.

Methods

A retrospective pathology study and chart review were conducted. All patients aged ≤49 years from 2000 to 2008 were included (n = 24). Concurrent patients aged ≥50 years were randomly selected. Paraffin sections were stained for GPR30 and reviewed by a pathologist blinded to estrogen receptor and progesterone receptor status. Disease-free survival was analyzed versus age and receptor status. Means were compared using 2-sample t tests and proportions using chi-square analysis.

Results

Twenty-seven patients tested GPR30 positive and 21 GPR30 negative. Seventeen of 18 TN cancers tested positive for GPR30 (P < .0001). Recurrence at a mean follow-up of 36 months was 22.2% in the GPR30-positive group and 9.5% in the GPR30-negative group.

Conclusions

GPR30 is prevalent in TN breast cancer and associated with young age and possibly recurrence.     

SPAK Differentially Mediates Vasopressin Effects on Sodium Cotransporters

Activation of the Na⁺-K⁺-2Cl⁻-cotransporter (NKCC2) and the Na⁺-Cl⁻-cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conserved N-terminal threonine and serine residues, but the kinase pathways that mediate this action of vasopressin are not well understood. Two homologous Ste20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor–specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.The furosemide-sensitive Na⁺-K⁺-2Cl⁻-cotransporter (NKCC2) of the thick ascending limb (TAL) and the thiazide-sensitive Na⁺-Cl⁻-cotransporter (NCC) of the distal convoluted tubule (DCT) are key regulators of renal salt handling and therefore participate importantly in BP and extracellular fluid volume homeostasis.¹ Loss-of-function mutants in the SLC12A1/ A3 genes encoding NKCC2 and NCC cause salt-losing hypotension and hypokalemic alkalosis in Bartter’s and Gitelman’s syndromes,^2,3 whereas their overactivity may contribute to essential hypertension.^4,5 Recently, attention has been focused on the two closely related STE20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase 1 (OSR1), which can phosphorylate NKCC2 and NCC at their N-terminal conserved threonine or serine residues (T96, T101, and T114 of mouse NKCC2 and T53, T58, and S71 of mouse NCC) and thereby activate the transporters.^6–8 Despite the high homology between SPAK and OSR1 and their overlapping renal expression patterns, distinct roles along the nephron have been suggested based on data from SPAK-deficient and kidney-specific OSR1-deficient mice: deletion of SPAK primarily impairs the function of NCC, whereas deletion of OSR1 negatively affects NKCC2.^9–11 The complex functional properties of a WNK-SPAK/OSR1-N(K)CC interaction cascade are currently being defined.¹² Recently, arginine vasopressin (AVP), signaling via the V2 receptor (V2R), has been identified as an efficient activator of both cotransporters, affecting their luminal trafficking and phosphorylation.^13–18 Because plasma AVP levels may vary not only with the sleep-wake cycle or long-term physiologic challenges, but also with pulsatile changes over the short term, distinct, time-dependent responses may occur.¹⁹ SPAK and OSR1 are well placed to regulate distal NaCl reabsorption in response to AVP. Here we tested the role of SPAK in AVP-induced activation of NKCC2 and NCC, acutely and during long-term treatment. The results suggest that SPAK is an essential kinase that modulates distal nephron function in response to AVP stimulation.     

Migraine in Assiut Governorate,Egypt: epidemiology,risk factors,comorbid conditions and predictors of change from episodic to chronic migraine

Abstract

Objectives: Headache is one of the most common complaints in medicine. Epidemiological and population-based studies reported that migraine has a variable prevalence worldwide. This study was done to estimate the prevalence of migraine across various age groups in Assiut district, Egypt.

Methods: This is a door-to-door study. It included 4700 randomly selected individuals.

Results: Headache was reported in 1668 subjects (35.49%), of them, 87.65% (n = 1462) had primary headaches. Migraine prevalence was 10.51% with female-to-male ratio of 2.4:1 particularly in ages of 20–40 years. The mean age of patients was 31.46 ± 13.39 years and age at onset was 24.16 ± 12.10 years. Nearly, 63.5% had frequent attacks, 65.2% of the attacks were severe enough to stop daily activities and lasted for >1 day in 32.5% of females compared to 40.7% and 14.5% for males. Chronic or daily migraine was more in females (35.3% versus 20.7% for males). Approximately, 5.6% had chronic migraine and 1.2% had daily migraine from the start, while 24.2% had transformation from episodic to chronic migraine within 6.1 ± 4.4 years. Migraine was prevalent among those with middle educational levels and labor workers. The duration of migraine attacks was found to reduce with age but the chronic/daily migraine increased with age. Hypertension, anxiety, irritable bowel syndrome, and depression were common comorbidities with migraine.

Conclusions: We believe that the work done in this study is informative as it determined the actual prevalence of migraine across various age groups and the important predictors of change in the severity, duration, and frequency of migraine in our locality.     

Structural,optical and dielectric properties of Cu1.5Mn1.5O4 spinel nanoparticles

In this study, a Cu_1.5Mn_1.5O₄ spinel was successfully synthesized by a sol–gel method at 500 °C for 5 h and characterized by different techniques. X-ray diffraction (XRD), Fourier transformation infrared (FTIR) spectroscopy and Raman spectroscopic analyses confirmed the formation of a spinel cubic structure with the Fd$\bar{3}$m space group. The SEM proves that the grain size of our compound is of the order of 48 nm. Crystallite sizes determined from three estimates are closer to the grain size obtained from the SEM, indicating the single domain nature of the sample. The optical properties of UV-visible spectroscopy for our sample showed that the gap value is equal to 3.82 eV, making our compound a good candidate for optoelectronic applications. For electrical properties, impedance spectroscopy was performed at a frequency range of 40 ≤ frequency ≤ 10⁶ Hz. This suggested hoping conduction due to three theoretical models. The latter can be attributed to the correlated barrier hopping (CBH) model in region I, overlapping large polaron tunneling (OLPT) in region II and non-overlapping small polaron tunneling (NSPT) mechanism in region III. One dielectric relaxation is detected from the dielectric impedance and modulus, attributed to grain contributions. This behavior was confirmed by both Nyquist and Argand''s plots of dielectric impedance at different measuring temperatures.

In this study, a Cu_1.5Mn_1.5O₄ spinel was successfully synthesized by a sol–gel method at 500 °C for 5 h and characterized by different techniques.     

Doxycycline hydrochloride-metronidazole solid lipid microparticles gels for treatment of periodontitis: development,in-vitro and in-vivo clinical evaluation

Objective: To formulate solid lipid microparticles (SLMs) encapsulating doxycycline hydrochloride (DH) and metronidazole (MT) for the treatment of periodontal diseases.

Methods: SLMs were prepared applying hot homogenization method, using different types of lipids and stabilized with various types and concentrations of surfactants. The optimized formula was subjected to freeze-drying followed by incorporation into poloxamer gel. Microbiological and clinical evaluation of the selected SLMs on patients suffering from periodontal diseases was performed.

Results: SLMs could entrap high percentage of both drugs (81.14% and 68.75 % for doxycycline hydrochloride and metronidazole respectively). Transmission electron microscopy images of SLMs showed nearly spherical particles. Freeze-dried SLMs showed satisfactory stability for three months. Combined drugs were molecularly dispersed in SLMs. Incorporation of the freeze-dried SLMs powder in poloxamer gel could control the drugs release for 72 h. In-vivo study revealed effective and safe use of SLMs gel for periodontitis treatment. Significant improvement in both microbiological and clinical parameters was observed as compared to scaling and root planing alone.

Conclusion: The formulated SLMs gel offers an applicable dosage form that can be injected directly into the periodontal pocket as adjunctive to scaling and root planing.     

Association between RANTES polymorphisms and asthma severity among Tunisian children

The chemokine known as RANTES (regulated upon activation, normal T cells expressed and secreted) is an important element for the chemotaxis at the site of allergic inflammation. Many studies have made an interesting link between RANTES polymorphisms and asthma, showing that the variant in the promoter region is associated with high risk of asthma and severe airway obstruction. We conducted a case-control and family study aiming at identifying the relationship between polymorphisms (-28 C/G and -403 G/A) and haplotypes in the RANTES gene with asthma and severity. The results of the case control study suggest an association between alleles level of -28 C/G and -403 G/A promoter polymorphism (p = 0.01) (p = 0.00175) and asthma. Univariate analysis of the RANTES polymorphisms show an increased prevalence of the AC and AG haplotypes in asthmatics (p = 0.014) and (p = 0.015) respectively. Our data suggest that -28 C/G and -403 G/A polymorphisms within the RANTES promoter region play an important role in asthma predisposition and in the severity of airway obstruction.     

Protective effects of Mentha piperita Linn on benzo[a]pyrene-induced lung carcinogenicity and mutagenicity in Swiss albino mice

The Editor-in-Chief has retracted the published paper "ProtectiveEffects of