Do human polyoma viruses and human immunodeficiency virus share common co‐receptors?

Host and/or viral factors involved in human polyomavirus (HPoV) infection in persons living with HIV remain unknown. A hypothesis is outlined suggesting the importance of the co‐receptors CCR5, CCR2, and CXCR4 not only for HIV, but also for HPoV. Functionally capable receptors coded by wild‐type (wt) genotypes could facilitate internalization of HPoV in the cell resulting in brain and/or kidney infection/s in HIV infected individuals. Forty‐nine Bulgarians with HIV, all treated by HAART, without neurological and/or kidney disorders, were tested for JCV and BKV and genotyped for CCR5 (CCR5del32), CCR2 (CCR2‐64I), and CXCR4 (SDF1‐3′A). In 27/49 (55.1%) individuals a co‐infection with HPoV was identified—BKV in 12/49 (24.5%), JCV—in another 12/49 (24.5%), and both viruses—in 3/49 (6.1%). A high frequency of wt CCR5 was found in patients with HPoV (91.7% for BKV and JCV and in 100% with both viruses). V/V of CCR2 was presented in 75% for BKV and JCV and in 66.7% for BKV plus JCV. SDF1‐3′G/G predominated in JCV infected patients (75%), while G/A and A/A genotypes were more frequent in patients with BKV (41.7%). Also, 21/22 (95.4%) persons without HPoV infection were heterozygous for SDF1 and CCR2. The number of individuals bearing wt of all co‐receptors in the group of persons not infected with HPoV was lower (P = 0.03) than that with polymorphism/s in one or two genes (SDF1 and CCR2) in the same group. The results suggest a probable role of co‐receptors used by HIV to facilitate infection with HPoV. J. Med. Virol. 82:8–13, 2010. © 2009 Wiley‐Liss, Inc.     

Is human kallikrein-11 in gastric cancer treated with surgery and adjuvant chemoradiotherapy associated with survival?

Human kallikreins (hKs) have been reported to be involved in human cancers, and several hKs are promising biomarkers of various cancers, such as prostate, ovarian, breast, and testicular cancer. In the present study, we aimed to evaluate the prognostic value of immunohistochemical expression of hK11 in patients with gastric cancer. The study included 55 (36 men and 19 women; 58 ± 10 years of mean age) patients with gastric cancer treated with surgery and adjuvant chemoradiotherapy. Tissue sections were evaluated immunohistochemically with a monoclonal anti-hK11 antibody. Of the 55 patients, 35 (63.6%) were hK11-positive and 20 (36.4%) were hK11-negative. Disease-free and overall survival rates were significantly higher in patients with hK11 positive than in those with hK-11 negative expression (24 months vs. 11 months, p: 0.043; 29 months vs. 13 months, p: 0.038, respectively). In conclusion, hK11 expression in gastric cancer appears to be associated with a better prognosis. hK11 may be a prognostic biomarker of gastric cancer. On the other hand, it is needed to elucidate the mechanisms underlying the regulation of hK11 expression in gastric cancer.     

T cell‐mediated immune responses in human newborns: ready to learn?

Infections with intracellular pathogens are often more severe or more prolonged in young infants suggesting that T cell-mediated immune responses are different in early life. Whereas neonatal immune responses have been quite extensively studied in murine models, studies of T cell-mediated immunity in human newborns and infants are scarce. Qualitative and quantitative differences when compared with adult immune responses have been observed but on the other hand mature responses to certain vaccines and infectious pathogens were demonstrated during the postnatal period and even during foetal life. Herein, we review the evidence suggesting that under appropriate conditions of stimulation, protective T cell-mediated immune responses could be induced by vaccines in early life.     

Role of tumor‐associated macrophages in human malignancies: friend or foe?

Tumor‐associated macrophages (TAMs) play a pivotal role in tumor growth in human malignancies. Published studies have analyzed the relationship between TAM infiltration and the prognosis of patients for many human tumors. Most studies reported a positive correlation between TAM density and a poor prognosis. Studies focusing on macrophage phenotypes emphasized the protumor role of M2 anti‐inflammatory macrophages in many types of human tumors. However, TAMs influence tumor progression in various ways that depend on differences in tumor sites, histology, and microenvironments. In this review, we summarize the function of TAMs in various human malignancies by reviewing the data provided in studies of TAMs in human malignancies.     

First‐year growth in children with Noonan syndrome: Associated with feeding problems?

Children with Noonan syndrome show rapid decline of growth in the first year of life and feeding problems are present in over 50%. The aim of this study was to explore whether growth decelerates because of feeding problems or other Noonan syndrome‐related factors. We performed a retrospective, longitudinal cohort study of clinically and genetically diagnosed subjects with Noonan syndrome (n = 143). Questionnaires about the phenotypic–genotypic profile and reported feeding problems were sent to eligible subjects. Data on first‐year growth was obtained from growth charts. Ninety‐one participants were excluded because of different criteria. A total of 52 subjects with Noonan syndrome were included. The largest decline in weight and length standard deviation score (SDS) occurred in the first 2.5 months after birth (−1.93 and −1.15, respectively), with feeding problems causing a decline of 0.57 SDS in the remaining months. At 1 year, children with feeding problems were on average 290 g lighter and 0.8 cm shorter than children without feeding problems. Weight gain was also negatively influenced by having a PTPN11 mutation (n = 39) and a higher gestational age, whereas children of parents with Noonan syndrome and with a higher birth weight gained more weight. Growth in length was reduced by having cardiac surgery and a higher gestational age, but positively influenced by birth length and maternal height. Growth in children with Noonan syndrome is impaired right after birth and only partially associated with feeding problems. In addition, several specific Noonan syndrome‐related factors seem to influence growth in the first year.     

Nuclear translocation of β‐catenin and decreased expression of epithelial cadherin in human papillomavirus‐positive tonsillar cancer: an early event in human papillomavirus‐related tumour progression?

Stenner M, Yosef B, Huebbers C U, Preuss S F, Dienes H‐P, Speel E‐J M, Odenthal M & Klussmann J P (2011) Histopathology 58 , 1117–1126 Nuclear translocation of β‐catenin and decreased expression of epithelial cadherin in human papillomavirus‐positive tonsillar cancer: an early event in human papillomavirus‐related tumour progression? Aims: High‐risk human papillomaviruses (HPVs) constitute an important risk factor for tonsillar cancer. This study describes changes in cell adhesion molecules during metastasis of HPV‐related and HPV‐unrelated tonsillar carcinomas. Methods and results: We examined 48 primary tonsillar carcinoma samples (25 HPV‐16 DNA‐positive, 23 HPV‐16 DNA‐negative) and their respective lymph node metastases for their HPV status and for the expression of p16, epithelial cadherin (E‐cadherin), β‐catenin, and vimentin. A positive HPV‐specific polymerase chain reaction finding correlated significantly with p16 overexpression in both primary tumours and their metastases (P < 0.0001 for both). In HPV‐unrelated carcinomas, the expression of E‐cadherin was significantly lower in metastases than in primary tumours (P < 0.001). In contrast, the expression of nuclear β‐catenin was significantly higher in metastases than in primary tumours (P = 0.016). In HPV‐related carcinomas, nuclear localization of β‐catenin expression was already apparent in primary tumours (P = 0.030). The expression of vimentin significantly correlated with the grading of the primary tumour (P = 0.021). Conclusions: Our data indicate that the down‐regulation of E‐cadherin and the up‐regulation of nuclear β‐catenin expression might be crucial steps during tumour progression of tonsillar carcinomas, being already present in primary tumours in HPV‐driven carcinomas, but becoming apparent in HPV‐unrelated tumours later in the process of metastasis.     

Does increase in DNA repair allow “Tolerance‐to‐Insult” in chemical carcinogenesis? Skin tumor experiments with MGMT‐overexpressing mice

Several genotoxicity endpoints have been evaluated to define nonlinear dose‐responses for S_N1 and S_N2 alkylating genotoxicants. Dose‐response studies acknowledging the process of multistage tumorigenesis are important; however, data pertaining nonlinearity are not yet available. In this communication, the role of DNA repair in the dose‐response relationship for benign papillomas was examined using the two‐stage skin carcinogenesis protocol. The data obtained with O⁶‐methylguanine‐DNA methyltransferase (MGMT) overexpressing mice in which papillomas were induced by a single topical treatment with N‐methyl‐N‐nitrosourea (MNU) followed by promotion with 12‐O‐tetradecanoylphorbol‐13‐acetate are reported. As MGMT efficiently protects cells from mutations by repairing O⁶‐methylguanine, a miscoding lesion induced by MNU, the question whether MGMT is able to nullify carcinogenic lesions to an extent where they would be considered nonhazardous has been addressed. It is shown here that MGMT overexpression significantly protects against, but does not completely nullify, the effect of MNU in tumor initiation. The possible mechanisms involved have also been discussed. Environ. Mol. Mutagen. 55:145–150, 2014. © 2013 Wiley Periodicals, Inc.     

Do body‐related sensations make feel us better? Subjective well‐being is associated only with the subjective aspect of interoception

According to the proposition of several theoretical accounts, the perception of the bodily cues, interoceptive accuracy and interoceptive sensibility, has a significant positive impact on subjective well‐being. Others assume a negative association; however, empirical evidence is scarce. In this study, 142 young adults completed questionnaires assessing subjective well‐being, interoceptive sensibility, and subjective somatic symptoms and participated in measurements of proprioceptive accuracy (reproduction of the angle of the elbow joint), gastric sensitivity (water load test), and heartbeat tracking ability (Schandry task). Subjective well‐being showed weak to medium positive associations with interoceptive sensibility and weak negative associations with symptom reports. No associations with measures of interoceptive accuracy were found. Gastric sensitivity as opposed to heartbeat perception and proprioceptive accuracy moderated the association between interoceptive sensibility and well‐being. Thus, subjective well‐being is associated only with the self‐reported (perceived) aspect of interoception but not related to the sensory measures of interoceptive accuracy.     

Can interferon‐γ and interleukin‐10 balance be associated with severity of human Leishmania (Viannia) braziliensis infection?

Suitable levels of interferon (IFN)-gamma and interleukin (IL)-10 seem to favour the outcome of cutaneous leishmaniasis (CL), while high IFN-gamma and low IL-10 production are associated with severity of mucosal leishmaniasis (ML). Considering that cytokine balance is important for the maintenance of protective responses in leishmaniasis, our aim was to investigate leishmanial antigens-induced IFN-gamma and IL-10 levels maintained in healed individuals who had different clinical outcomes of Leishmania infection. Thirty-three individuals who recovered from L. braziliensis infection were studied: cured CL (CCL), cured ML (CML), spontaneous healing of CL (SH) or asymptomatic individuals (ASY). Cytokines were quantified by enzyme-linked immunosorbent assay (ELISA) in culture supernatants of L. braziliensis-stimulated peripheral blood mononuclear cells (PBMC). IFN-gamma levels were higher in CML (7593 +/- 5994 pg/ml) in comparison to SH (3163 +/- 1526 pg/ml), ASY (1313 +/- 1048 pg/ml) or CCL (1897 +/- 2087 pg/ml). Moreover, cured ML cases maintained significantly lower production of IL-10 (127 +/- 57.8 pg/ml) in comparison to SH (1373 +/- 244 pg/ml), ASY (734 +/- 233 pg/ml) or CCL (542 +/- 375 pg/ml). Thus, a high IFN-gamma/IL-10 ratio observed in CML can indicate unfavourable cytokine balance. On the other hand, no significant difference in the IFN-gamma/IL-10 ratio was observed when CCL individuals were compared to SH or ASY subjects. In conclusion, even after clinical healing, ML patients maintained a high IFN-gamma/IL-10 secretion profile in response to leishmanial antigens. This finding can explain a delayed down-modulation of exacerbated inflammatory responses, which can be related in turn to the necessity of prolonged therapy in ML management. Conversely, lower IFN-gamma/IL-10 balance observed in CCL, SH and ASY individuals can represent a better-modulated immune response associated with a favourable prognosis.     

Does C‐reactive protein independently predict mortality in adult community‐acquired bacteremia patients with known sepsis severity?

We evaluated whether sepsis severity and C‐reactive protein (CRP) level on admission prognostically corroborated or annulled each other in adult patients with incident community‐acquired bacteremia (Funen, Denmark, 2000–2008). We used logistic regression and area under the receiver operating characteristic curve (AUC) to evaluate 30‐day mortality in four models: (i) age, gender, comorbidity, bacteria, and ward. (ii) Model 1 and sepsis severity. (iii) Model 1 and CRP. (iv) Model 1, sepsis severity, and CRP. Altogether, 416 of 1999 patients died within 30 days. CRP independently predicted 30‐day mortality [Model 4, odds ratio (95% CIs) for 100 mg/L: 1.16 (1.06–1.27)], but it did not contribute to the AUC (Model 2 vs Model 4: p = 0.31). In the 963 non‐severe sepsis patients, CRP independently predicted 30‐day mortality [Model 4: 1.42 (1.20–1.69)] and it increased the AUC (Model 2 vs Model 4: p = 0.06), thus CRP contributed as much as sepsis severity to prognosis.