Interactions of insulin and estrogen in the regulation of cell proliferation and carcinogenesis

Equilibrium of sexual steroids and metabolic processes has close correlations. Insulin is a potent regulator of human sexual steroid hormone production and modulates their signals at receptor level. Insulin resistance and excessive insulin production provoke hyperandrogenism and estrogen deficiency in women resulting not only in anovulatory dysfunction but also a high risk for cardiovascular diseases and cancer. Physiologic functions of all female organs have higher estrogen demand as compared with men. In healthy women estrogen predominance against androgens is a favor in their reproductive period, which means a strong defense against insulin resistance and its complications. However, in postmenopausal cases the increasing prevalence of insulin resistance and type-2 diabetes associated with estrogen deficiency and androgen excess, result in a gender specific higher risk for precancerous lesions and cancer as compared with men. Estrogen has beneficial effect on the energy metabolism, glucose homeostasis and on the lipid metabolism of liver and of peripheral tissues as well. A moderate or severe decrease in serum estrogen level enhances the prevalence of insulin resistant states. In premenopausal women long or irregular menstrual cycles are predictors for the risk of insulin resistance and type-2 diabetes. Moreover, in postmenopausal estrogen deficient cases elevated fasting glucose, increased body weight and abdominal fat deposition are often observed progressively with age in correlation with an impaired glucose tolerance. In the rare cases of estrogen deficient men severe type-2 diabetes seems to be a characteristic complication. Upon becoming familiar with the cancer risk of insulin resistance and estrogen deficiency, there would be plenty of possibilities for primary cancer prevention. In patients with cancer the treatment of hormonal and metabolic disturbances may become effective adjuvant therapy.     

The altered expression of syndecan 4 in the uninvolved skin of venous leg ulcer patients may predispose to venous leg ulcer

Syndecan 4 (SDC4), a heparan sulfate proteoglycan, and neuropilin 1 (NRP1), a transmembrane receptor, are both involved in normal wound healing, but little is known about their possible role in venous leg ulcer pathogenesis. We aimed to investigate whether there are any expression abnormalities and/or gene polymorphisms of SDC4 and NRP1 associated with venous leg ulcer. SDC4 showed significantly lower mRNA and protein expression in the uninvolved dermis of venous leg ulcer patients ( n =15) compared with controls ( n =15; p =0.0136), while NRP1 showed no expression abnormalities. None of the examined SDC4 and NRP1 polymorphisms showed a difference in their allelic distribution between leg ulcer patients ( n =92) and controls ( n =92). We hypothesize that SDC4 may play an essential role not only in the inflammation and tissue formation phases of normal wound healing, but its expression abnormalities observed in the uninvolved dermis of venous leg ulcer patients may contribute to venous leg ulcer development.     

Solid papillary carcinoma of the breast with an associated Cytokeratin 7‐ negative Paget's disease of the nipple. Report of a first case

Solid papillary carcinoma (SPC) is a rare neoplasm of the breast showing a distinct morphology, neuroendocrine differentiation and should be divided into invasive and in situ subtype according to the current 2012 WHO classification of breast tumors. Here, we describe a case of a pure SPC, invasive‐type, in a 31‐years old female with an associated mammary Paget's disease (MPD) of the nipple showing a rare, CK7‐negative immune phenotype, which has not been reported so far. This unusual differential diagnosis should be added to the rare condition of CK7‐negative Paget's disease of the breast and complement a new feature to the characterization of SPC.     

Regulatory role of capsaicin-sensitive peptidergic sensory nerves in the proteoglycan-induced autoimmune arthritis model of the mouse

Objective

The regulatory role of capsaicin-sensitive peptidergic sensory nerves has been shown in acute inflammation, but little is known about their involvement in T/B-cell driven autoimmune arthritis. This study integratively characterized the function of these nerve endings in the proteoglycan-induced chronic arthritis (PGIA), a translational model of rheumatoid arthritis.

Methods

Peptidergic afferents were defunctionalized by resiniferatoxin (RTX) pretreatment in BALB/c mice, PGIA was induced by repeated antigen challenges. Hind paw volume, arthritis severity, grasping ability and the mechanonociceptive threshold were monitored during the 17-week experiment. Myeloperoxidase activity, vascular leakage and bone turnover were evaluated by in vivo optical imaging. Bone morphology was assessed using micro-CT, the intertarsal small joints were processed for histopathological analysis.

Results

Following desensitization of the capsaicin-sensitive afferents, ankle edema, arthritis severity and mechanical hyperalgesia were markedly diminished. Myeloperoxidase activity was lower in the early, but increased in the late phase, whilst plasma leakage and bone turnover were not altered. Desensitized mice displayed similar bone spurs and erosions, but increased trabecular thickness of the tibia and bony ankylosis of the spine. Intertarsal cartilage thickness was not altered in the model, but desensitization increased this parameter in both the non-arthritic and arthritic groups.

Conclusion

This is the first integrative in vivo functional and morphological characterization of the PGIA mouse model, wherein peptidergic afferents have an important regulatory function. Their overall effect is proinflammatory by increasing acute inflammation, immune cell activity and pain. Meanwhile, their activation decreases spinal ankylosis, arthritis-induced altered trabecularity, and cartilage thickness in small joints.

     

Presence of Endogenous PACAP-38 Ameliorated Intestinal Cold Preservation Tissue Injury

Cold preservation tissue injury remains an unsolved problem during small intestinal transplantation. Pituitary adenylate cyclase-activating polypeptide (PACAP) plays a central role in the intestinal physiology. The aim of our study was to compare the cold ischemic injury in wild-type and PACAP-38 deficient mice after small bowel cold storage. Cold ischemia was produced with small bowel preservation in a University of Wisconsin solution at 4°C in wild-type (n = 35) mice for 1 h (GI), for 3 h (GII), and for 6 h (GIII); and in PACAP-38 deficient (n = 35) mice for 1 h (GIV), for 3 h (GV), and for 6 h (GVI). Small bowel biopsies were collected after laparotomy (Control) and at the end of the ischemia periods. To determine oxidative stress parameters, malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. In PACAP-38 deficient animals, tissue lipid peroxidation was elevated. These changes were significant after 6 h (153.04 ± 7.2) compared to sham-operated (110.44 ± 5.5) and compared to wild-type results (120.0 ± 1.1 μmol/g, p < 0.05). Meanwhile, the capacity and activity of the endogenous antioxidant system decreased significantly after 3 and 6 h preservation (GSH: 808.7 ± 5.2; 720.4 ± 8.7 vs. 910.4 ± μmol/g; SOD: 125.1 ± 1.4; 103.3 ± 1.9 vs. 212.11 ± 5.8 IU/g). Qualitative and quantitative histological results showed destruction of the mucous, submucous layers, and crypts in PACAP-38 deficient mice compared to wild-type tissues. These processes depended on the time of the cold preservation periods. Our present study showed that the presence of PACAP-38 in the small bowel tissue has a key role in the protection against intestinal cold preservation injury.     

T-cell synapse formation depends on antigen recognition but not CD3 interaction: studies with TCR:ζ, a candidate transgene for TCR gene therapy

T-cell receptors (TCRs) can be genetically modified to improve gene-engineered T-cell responses, a strategy considered critical for the success of clinical TCR gene therapy to treat cancers. TCR:ζ, which is a heterodimer of TCRα and β chains each coupled to complete human CD3ζ, overcomes issues of mis-pairing with endogenous TCR chains, shows high surface expression and mediates antigen-specific T-cell functions in vitro. In the current study, we further characterized TCR:ζ in gene-engineered T cells and assessed whether this receptor is able to interact with surface molecules and drive correct synapse formation in Jurkat T cells. The results showed that TCR:ζ mediates the formation of synaptic areas with antigen-positive target cells, interacts closely with CD8α and MHC class I (MHCI), and co-localizes with CD28, CD45 and lipid rafts, similar to WT TCR. TCR:ζ did not closely associate with endogenous CD3ε, despite its co-presence in immune synapses, and TCR:ζ showed enhanced synaptic accumulation in T cells negative for surface-expressed TCR molecules. Notably, synaptic TCR:ζ demonstrated lowered densities when compared with TCR in dual TCR T cells, a phenomenon that was related to both extracellular and intracellular CD3ζ domains present in the TCR:ζ molecule and responsible for enlarged synapse areas.     

Modulation of the risk of coronary sclerosis/myocardial infarction by the interaction between factor XIII subunit A Val34Leu polymorphism and fibrinogen concentration in the high risk Hungarian population

INTRODUCTION: The results on the association of factor XIII (FXIII) A subunit (FXIII-A) Val34Leu polymorphism with the risk of myocardial infarction (MI) are rather inconclusive. The original paper and confirmatory reports demonstrated a protective effect of the mutation, but results demonstrating the lack of protection have also been published. Gene-gene and gene-environmental interactions have been proposed to be responsible for the opposing results. As the rate of change in fibrin clot permeability with increasing fibrinogen concentrations decreased stepwise with increasing number of Leu34 alleles it was proposed that the protection by Val34Leu polymorphism become effective only at higher fibrinogen concentrations. However, this hypothesis has not been tested on patients with coronary artery disease. PATIENTS AND METHODS: 955 consecutive patients admitted for coronary angiography were categorized according to the presence or absence of significant coronary sclerosis (CS) and according to positive or negative history of MI. The frequency of FXIII-A Val34Leu polymorphism, and a number of risk factors, including fibrinogen were determined in the patients. FXIII-A Val34Leu polymorphism was also investigated in a population control group of 1146 subjects. RESULTS: The presence of FXIII-A Leu34 allele or homozygous Leu34 genotype did not change the risk of CS or MI in the general Hungarian population. However, when patients with fibrinogen level in the upper quartile were separately investigated, the Leu34 allele provided a statistically significant protection against MI. CONCLUSIONS: Fibrinogen concentration modulates the effect of Leu34 allele on the risk of MI; its protective effect emerges at increasing fibrinogen concentration.     

Relationship between relative aerobic power and echocardiographic characteristics in male athletes

The relationship between relative aerobic power (rel.VO(2)max) as a generally accepted indicator of endurance capacity and certain characteristics of the athlete's heart, such as body-size related (relative) left ventricular (LV) diastolic wall thickness (WTd), internal diameter (LVIDd), muscle mass (MM), WTd/IDd, heart rate (HR), fractional shortening (FS) and E/A ratio, were investigated in 346 young males (18-35 years, 291 athletes of various events and 55 nonathletic control subjects). Rel.VO(2)max was measured by spiroergometry; cardiac characteristics were determined by two-dimensionally guided M-mode and Doppler-echocardiography. When the groups were pooled, correlation of rel.VO(2)max with the cardiac parameters was significant: LVMM.BSA(-1.5)= 0.413, LVWTd.BSA(-0.5)= 0.327, LVIDd.BSA(-0.5)= 0.292, HR =-0.434, E/A = 0.272 (P < 0.001), but no significant relationship was seen with FS and WTd/IDd. In the endurance trained group, rel. VO(2)max correlated significantly with LVMM.BSA(-1.5), LVWT.BSA(-0.5), HR, and E/A, in the ballgame players with LVMM.BSA(-1.5), LVWT.BSA(-0.5), and E/A, in the power-and-sprint event athletes with HR and E/A. In the control group, no significant relationship was observed. Results indicate that in athletes having higher endurance capacity maximal oxygen consumption depends largely on cardiac condition, while in athletes with a lower endurance capacity it can be limited by peripheral conditions.