Protective effects of the phytogenic feed additive "comfort" on growth performance via modulation of hypothalamic feeding- and drinking-related neuropeptides in cyclic heat-stressed broilers.

Identification of alternatives to antibiotics in livestock and poultry is necessary. Fueled by consumer preferences, phytogenic feed additives are increasingly used in the food system; however, their mode of action is not well defined. Here, we used broiler chickens, in which appetite and feeding behavior regulation are controlled by complex mechanisms, to determine the effect of the phytogenic feed additive "comfort" (PFA-C) as well as its underlying molecular mechanisms on growth performance in heat-stressed broiler chickens. Heat stress significantly increased birds' core body temperature, water intake, and the hypothalamic expression of heat shock protein (HSP) 70, whereas it decreased feed intake, BW, and woody breast incidence. Phytogenic feed additive "comfort" supplementation downregulated the hypothalamic expression of HSP70, reduced core body temperature, increased feed and water intake, and improved BW in HS broilers. At molecular levels, the effect of PFA-C on growth performance seemed to be mediated by modulation of hypothalamic expression of melanocortin receptor 2, arginine vasopressin, aquaporin 2, and sodium and potassium-transporting ATPase subunit beta 1 polypeptides. In summary, PFA-C supplementation ameliorates heat stress productivity losses via a potential cytoprotective effect, reduction of hypothalamic intracellular stress, and modulation of hypothalamic feeding- and drinking-related polypeptide expression.

Identifi cation of the Underlying Genetic Factors of Skin Aging in a Korean Population Study.

Genetic polymorphisms may affect the molecular mechanisms underlying determination of skin type. So far, several genetic studies have been reported; however, very few studies have been conducted to examine the relationship between genotype and skin phenotypes. In this study, the genome sequences of individuals tested for five cosmetic characteristics (wrinkles, moisture content, pigmentation, oil content, and ensitivity) were determined, and we also conducted five genome-wide association studies (GWASs) to identify predictive markers. Some single-nucleotide polymorphisms (SNPs) within those genes were more frequent in individuals exhibiting stronger traits. GWASs revealed that two genome-wide significant SNPs within FCRL5 and OCA2 genes were associated with wrinkles and pigmentation, respectively (p < 5 × 10-8), and that genomewide SNPs in 21 genes (wrinkles: FCRL5, REEP3, ADSS, and SPTLC1; moisture: TBX4, TRPM3, CEMIP2, CTSH, and TTC39C; pigmentation: OCA2, NCLN, TNS1, CDC42BPA, HS3ST4, and UNCX; oil: SYN2, CNDP1, GAS6, INSR, and TNFRSF19; and sensitivity: CREB5) might be associated with five skin phenotypes. Among these, a genome-wide significant SNP (rs117381658) and the SNP located downstream of FCRL5, which encodes a member of the immunoglobulin receptor family, were associated with an increased risk of wrinkles (p = 1.52 × 10-8). The other genome-wide significant SNP (rs74653330) was associated with a decreased risk of pigmentation (p = 1.04 × 10-8), which is located in the coding region of OCA2 that encodes for a transporter of melanin. Our study reports genetic factors associated with skin cosmetology parameters in the Korean population. We hope our findings will provide a foundation for further genetic and molecular studies related to custom cosmetics. Based on these findings, the industry will be able to provide consumers with ingredients capable of palliating the lack of function associated in genes with SNPs.

An IFN-γ and TNF-α dual release fluorospot assay for diagnosing active tuberculosis.

OBJECTIVES: Currently available interferon (IFN)-γ-release assays (IGRA) cannot discriminate active tuberculosis (TB) from latent TB infection (LTBI), and so have limited clinical utility for diagnosing active TB. Since numbers of tumour necrosis factor (TNF)-α-producing T cells are highly correlated with active TB, we hypothesized that detecting IFN-γ- and/or TNF-α-producing T cells would overcome this limitation of IGRA. This study evaluated the diagnostic performances of the IFN-γ and TNF-α dual release fluorospot assay for active TB. METHODS: Adult patients with suspected TB including recent TB exposers were prospectively enrolled over a 28-month period. In addition to the conventional IGRA test (i.e. QuantiFERON-In-Tube), a fluorospot assay for detecting IFN-γ- and TNF-α-producing T cells was performed. The final diagnoses were classified by clinical category. Patients with confirmed or probable TB were regarded as active TB, and patients with not active TB were further classified as having not active TB with and without LTBI, based on the QuantiFERON-In-Tube results. RESULTS: A total of 153 patients including 45 with active TB and 108 with not active TB (38 LTBI vs. 70 not LTBI) were finally analysed. The sensitivity and specificity of the QuantiFERON-In-Tube assay for active TB were 84% (95% confidence interval (CI), 70-93) and 70% (95% CI 61-79), respectively. The IFN-γ/TNF-α dual release assay by fluorospot had substantially higher diagnostic specificity (94%) for diagnosing active TB than the IFN-γ single release assay (72%, p < 0.001), without compromising sensitivity (84% vs. 89%, p 0.79). CONCLUSIONS: The fluorospot-based IFN-γ/TNF-α dual release assay appears to be a simple and useful test for diagnosing active TB.

Molecular epidemiology and environmental contamination during an outbreak of parainfluenza virus 3 in a haematology ward.

BACKGROUND: Although fomites or contaminated surfaces have been considered as transmission routes, the role of environmental contamination by human parainfluenza virus type 3 (hPIV-3) in healthcare settings is not established. AIM: To describe an hPIV-3 nosocomial outbreak and the results of environmental sampling to elucidate the source of nosocomial transmission and the role of environmental contamination. METHODS: During an hPIV-3 outbreak between May and June 2016, environmental surfaces in contact with clustered patients were swabbed and respiratory specimens used from infected patients and epidemiologically unlinked controls. The epidemiologic relatedness of hPIV-3 strains was investigated by sequencing of the haemagglutinin-neuraminidase and fusion protein genes. FINDINGS: Of 19 hPIV-3-infected patients, eight were haematopoietic stem cell recipients and one was a healthcare worker. In addition, four had upper and 12 had lower respiratory tract infections. Of the 19 patients, six (32%) were community-onset infections (symptom onset within <7 days of hospitalization) and 13 (68%) were hospital-onset infections (≥7 days of hospitalization). Phylogenetic analysis identified two major clusters: five patients, and three patients plus one healthcare worker. Therefore, seven (37%) were classified as nosocomial transmissions. hPIV-3 was detected in 21 (43%) of 49 environmental swabs up to 12 days after negative respiratory polymerase chain reaction conversion. CONCLUSION: At least one-third of a peak season nosocomial hPIV-3 outbreak originated from nosocomial transmission, with multiple importations of hPIV-3 from the community, providing experimental evidence for extensive environmental hPIV-3 contamination. Direct contact with the contaminated surfaces and fomites or indirect transmission from infected healthcare workers could be responsible for nosocomial transmission.

MicroRNA-30a-5p (miR-30a) regulates cell motility and EMT by directly targeting oncogenic TM4SF1 in colorectal cancer.

PURPOSE: Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and many oncogenes and tumor suppressor genes are involved in CRC. MicroRNAs (miRNAs) are small non-coding RNAs that can negatively regulate gene expression. Previous studies have revealed that miRNAs regulate the development and progression of many cancers. In this study, we investigated the role of microRNA-30a-5p (miR-30a) in CRC and its unknown mechanisms. METHODS: qRT-PCR was used to detect miR-30a and TM4SF1 mRNA expression in CRC specimens and cell lines. CRC cell migration and invasion were assessed after transfection with miR-30a or TM4SF1 using wound healing and trans-well migration and invasion assays. Transmembrane-4-L-six-family protein (TM4SF1) was validated as a target of miR-30a in CRC through luciferase reporter assay and bioinformatics algorithms. Moreover, two EMT regulators, E-cadherin and VEGF, were also identified using Western blotting and immunohistochemistry. RESULTS: We found that miR-30a was down-regulated in CRC tumor tissues and cell lines, and miR-30a was inversely associated with advanced stage and lymph node metastatic status compared with normal tissues. miR-30a decreased migration and invasion in CRC cell lines, and miR-30a overexpression not only down-regulated TM4SF1 mRNA and protein expression, but also inhibited the expression of VEGF and enhanced expression of E-cadherin. We also showed that TM4SF1 was up-regulated in CRC tumor specimens compared with adjacent normal tissues, and TM4SF1 expression was significantly associated with advanced stage and lymph node status compared with adjacent normal tissues. CONCLUSIONS: These results suggest that miR-30a is an important regulator of TM4SF1, VEGF, and E-cadherin for CRC lymph node metastasis, a potential new therapeutic target in CRC.

Comparison of computed tomographic findings in pulmonary mucormycosis and invasive pulmonary aspergillosis.

Because there are no available molecular markers for pulmonary mucormycosis (PM), which has low culture sensitivity, early diagnosis and treatment rely heavily on imaging modes such as computed tomography (CT). However, there are limited data comparing CT findings for PM with those for invasive pulmonary aspergillosis (IPA). Adult patients who met the modified criteria for proven and probable PM (over an 11-year period) and IPA (over a 6-year period, owing to the availability of the galactomannan assay) according to the modified European Organization for Research and Treatment of Cancer/Mycosis Study Group definitions were retrospectively enrolled. IPA cases were selected at a 1 : 4 (PM/IPA) ratio. Thoracic CT scans were reviewed by two experienced radiologists blinded to the patients' demographics and clinical outcomes. A total of 24 patients with PM, including 20 (83%) with proven PM and four (17%) with probable PM, and 96 patients with IPA, including 12 (13%) with proven IPA and 84 (87%) with probable IPA, were eventually analysed. The reverse halo sign was more common in patients with PM (54%) than in those with IPA (6%, p < 0.001), whereas some airway-invasive features, such as clusters of centrilobular nodules, peribronchial consolidations, and bronchial wall thickening, were more common in patients with IPA (IPA 52% vs. PM 29%, p 0.04; IPA 49% vs. PM 21%, p 0.01; IPA 34% vs. PM 4%, p 0.003, respectively). The reverse halo sign was more common, and airway-invasive features were less common, in patients with PM than in those with IPA. These findings may help physicians to initiate Zygomycetes-active antifungal treatment earlier.

Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver.

The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression. This review will discuss the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages.

Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling.

Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells-macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.

Increased incidence of herpes zoster in the setting of cytomegalovirus preemptive therapy after kidney transplantation.

BACKGROUND: Herpes zoster (HZ) is a common infectious disease after kidney transplantation (KT). The incidence of HZ may increase during cytomegalovirus (CMV) preemptive therapy. We therefore evaluated the incidence, risk factors, and clinical outcomes of HZ after KT, according to the type of CMV prophylaxis used. METHODS: We retrospectively established a cohort of KT recipients who underwent transplantation from June 2008 to May 2010. Patients were categorized into 3 groups according to CMV prophylaxis regimen: Group A (preemptive therapy), Group B (universal prophylaxis <3 months), and Group C (universal prophylaxis >3 months). The incidence rate of HZ was compared in each group, and risk factors for HZ were identified. RESULTS: The incidence rate of HZ was 46.6 (95% confidence interval [CI] 31.4-66.5) per 1000 person-years. The incidence rate was higher in Group A than in Group C (80.0 vs. 13.0 per 1000 person-years; P = 0.001). Median onset time of HZ after KT was shorter in Group A than in Group B (0.9 vs. 9.9 months; P < 0.001) and Group C (0.9 vs. 14.8 months; P = 0.008). Post-herpetic neuralgia occurred in 7 patients (23%). No visceral involvement or death was related to HZ. By multivariate analysis, only female gender (corrected relative risk 1.59; 95% CI 1.09-2.00) was independently associated with HZ development. CONCLUSIONS: In the setting of CMV preemptive therapy, a differentiated varicella zoster virus-specific prophylaxis might be necessary for patients with HZ risk factors.

agr Dysfunction and persistent methicillin-resistant Staphylococcus aureus bacteremia in patients with removed eradicable foci.

PURPOSE: Persistent Staphylococcus aureus bacteremia (SAB) has been observed in patients with eradicated foci, but there are few studies of the risk factors and clinical outcomes of persistent bacteremia. This study determined the risk factors for persistent methicillin-resistant S. aureus (MRSA) bacteremia in patients without retained eradicable foci, including genotypic characteristics. METHODS: All adult SAB patients were investigated between 2008 and 2010. Persistent bacteremia was defined as bacteremia lasting >7 days after treatment and patients were monitored prospectively. The study included patients without retained eradicable foci, e.g., removed prosthetic devices and intravenous catheters removed after diagnosis, and those without metastatic infections. RESULTS: Persistent bacteremia occurred in 36 % (31/87) SAB patients with eradicated foci. There were no significant differences in successful defervescence (2.0 vs. 2.0 days, P = 0.55) and total length of hospital stay after bacteremia in the persistent bacteremia group and resolved bacteremia group (P = 0.32). The difference in MRSA bacteremia-related 30-day mortality with persistent bacteremia and resolved bacteremia was not significant (P = 0.12). However, agr dysfunction was higher in persistent bacteremia patients (94 %) than those with resolved bacteremia (75 %, P = 0.03). Multivariate analysis using a logistic regression model found that only agr dysfunction [odds ratio (OR) 4.83, 95 % confidence interval (CI) 1.02-22.89, P = 0.04] was an independent risk factor for persistent bacteremia. CONCLUSIONS: This study suggests that persistent bacteremia with eradicated foci might not adversely affect the outcome for MRSA bacteremia patients. agr dysfunction in S. aureus was significantly associated with persistent bacteremia.

Comparison of the QuantiFERON-TB Gold In-Tube test with the tuberculin skin test for detecting latent tuberculosis infection prior to hematopoietic stem cell transplantation.

A total of 244 patients including 100 (41%) autologous hematopoietic stem cell transplant (HCT) recipients and 144 (59%) allogeneic HCT recipients were enrolled over a 28-month period. During the study period, no prophylaxis for latent tuberculosis (TB) infection was administrated. Of these, 201 (82%) had Bacillus Calmette-Guérin (BCG) scars or prior histories of BCG vaccination. The tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) test were performed simultaneously in all 244 patients. TST indurations were ≥ 5 mm in 39 of these patients (15%), and in 25 (10%) indurations were ≥ 10 mm. In addition, 40 (16%) had positive QFT-GIT outcomes, and 34 (14%) indeterminate outcomes. If the 34 patients with indeterminate QFT-GIT results were excluded from the overall agreement analysis, the agreement between the TST results (induration size ≥ 5 mm) and the QFT-GIT results in the 210 patients with clear QFT results was poor (κ = 0.08, 95% confidence interval [CI] -0.06 to 0.24), as it was for the patients with indurations ≥ 10 mm (κ = 0.15, 95% CI -0.004 to 0.31). During follow up, 2 patients developed TB after HCT. The incidence of TB in the patients with positive QFT-GIT outcomes was 2.80 per 100 person-years (95% CI 0.07-15.81), whereas among those with positive TST (≥ 5 mm) results, it was 0 per 100 person-years (95% CI 0-8.00). However, this finding should be cautiously interpreted because of the relatively short follow up and the fact that the sample size of the study cohort did not have adequate power. In conclusion, our data show that, although the frequencies of positive outcomes in the 2 TB screening tests were similar, the overall agreement between the TST and the QFT-GIT test was poor, regardless of BCG vaccination history.

Analysis of initial and follow-up CT findings in patients with invasive pulmonary aspergillosis after solid organ transplantation.

AIM: To assess initial and follow-up CT findings of invasive pulmonary aspergillosis (IPA) in solid organ transplant (SOT) recipients using new diagnostic criteria, and to compare initial CT findings of survivors with those of patients who died. MATERIALS AND METHODS: Forty-six adult SOT patients who met the 2008 EORTC/MSG criteria for proven or probable invasive pulmonary aspergillosis were assessed. Initial CT findings of the 21 survivors and 15 patients who died of IPA-related causes were compared using the internationally recognized thoracic glossary of terms. The extents of the largest lesions in each of 18 surviving were measured and changes of those lesions were recorded. RESULTS: Consolidation or mass was the most common finding, observed in 33 of 46 patients (72%), followed by large nodules (59%), ground-glass opacity (50%), and infarcted consolidation (48%). Consolidation or mass was significantly less frequent in survivors than in patients who died (62% versus 93%). Cavitation was more common (43% versus 13%), and significantly smaller (7.5 cm(2) versus 19 cm(2), p = 0.014) in survivors. Follow-up CT in survivors showed that the halo sign resolved rapidly within 4 weeks. The extent of consolidation, infarcted consolidation, and internal low-density area decreased gradually with time to reduce to half the size in 3 weeks. Large nodules persisted for the first 7 days (84%), followed by slow regression. CONCLUSION: Consolidation or mass is the most common CT finding of IPA in SOT recipients. Absence of consolidation or mass and presence of small cavities may be associated with better prognosis. The time for resolution of each pattern after treatment varies.

Chromosomally integrated human herpesvirus-6 in transplant recipients.

Human herpesvirus-6 (HHV-6) is unique among human herpesviruses because of its ability to integrate into chromosomes. This entity, termed chromosomally integrated HHV-6 (CIHHV-6), is often mistaken for active infection and treated unnecessarily. The clinical significance of CIHHV-6 in transplant recipients is not defined. Herein, the clinical characteristics of 7 liver transplant patients with CIHHV-6 from our recent study, together with 14 other published cases of CIHHV-6 were reviewed. Of the 21 cases, CIHHV-6B was reported most commonly among solid organ transplant recipients, while CIHHV-6A was mostly seen in allogeneic hematopoietic stem cell recipients. None of the 21 patients developed clinical symptoms related to HHV-6 after transplantation. However, antiviral therapy was administered to 5 asymptomatic patients mistaken to have HHV-6 infection because of their very high HHV-6 DNA levels, 3 who developed symptomatic cytomegalovirus disease, and 1 with graft-versus-host disease that was mistaken for HHV-6 infection. In patients who received antiviral therapy, there was no apparent decline in HHV-6 DNA load, although change in viral kinetics is difficult to discern in the setting of high baseline HHV-6 DNA load. Clinicians should be aware of this entity of CIHHV-6 so that antiviral therapy can be considered in the proper clinical context.

Diagnostic yield of the cytomegalovirus (CMV) antigenemia assay and clinical features in solid organ transplant recipients and hematopoietic stem cell transplant recipients with CMV pneumonia.

Data are limited on the value of non-invasive diagnostic methods, such as the cytomegalovirus (CMV) antigenemia assay, and the clinical features of CMV pneumonia in patients who have undergone solid organ transplant (SOT) compared with those who have had hematopoietic stem cell transplant (HSCT). All adult patients with suspected CMV pneumonia, who had received SOT or HSCT in a tertiary hospital during a 5-year period, were retrospectively enrolled. CMV pneumonia was defined as clinical and radiographic evidence of pneumonia in association with the isolation of CMV in viral cultures of bronchoalveolar lavage or lung tissue specimens, or with the identification of CMV in lung tissue. In total, 36 patients with CMV pneumonia were identified. Of these, 29 (80%) had received SOT and 7 (20%) had received HSCT. The incidence of CMV pneumonia in the patients with SOT (3.0 per 1000 person-years [95% confidence interval {CI} 0.6-8.7]) was lower than in those with HSCT (17.0 per 1000 person-years [95% CI 9.9-27.2], P = 0.003) and CMV-related mortality showed a tendency to have lower mortality in patients with SOT (10% [3/29]) than with HSCT (43% [3/7], P = 0.07). The overall sensitivity of the CMV assay (≥ 1/200,000 leukocytes) in patients with CMV pneumonia was 69% (95% CI 52-84%). The CMV antigenemia test is of limited value in diagnosing CMV pneumonia, given the high cost of false-negative diagnoses of CMV pneumonia.

The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53.

The orphan nuclear receptor TR3 (NR41A and Nur77) is overexpressed in most lung cancer patients and is a negative prognostic factor for patient survival. The function of TR3 was investigated in non-small-cell lung cancer A549 and H460 cells, and knockdown of TR3 by RNA interference (siTR3) inhibited cancer cell growth and induced apoptosis. The prosurvival activity of TR3 was due, in part, to formation of a p300/TR3/ specificity protein 1 complex bound to GC-rich promoter regions of survivin and other Sp-regulated genes (mechanism 1). However, in p53 wild-type A549 and H460 cells, siTR3 inhibited the mTORC1 pathway, and this was due to activation of p53 and induction of the p53-responsive gene sestrin 2, which subsequently activated the mTORC1 inhibitor AMP-activated protein kinase α (AMPKα) (mechanism 2). This demonstrates that the pro-oncogenic activity of TR3 in lung cancer cells was due to inhibition of p53 and activation of mTORC1. 1,1-Bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) is a recently discovered inhibitor of TR3, which mimics the effects of siTR3. DIM-C-pPhOH inhibited growth and induced apoptosis in lung cancer cells and lung tumors in murine orthotopic and metastatic models, and this was accompanied by decreased expression of survivin and inhibition of mTORC1 signaling, demonstrating that inactivators of TR3 represent a novel class of mTORC1 inhibitors.

Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer.

The human POK family members are transcription factors with a POZ domain and zinc-fingers that act primarily as transcriptional repressors. Several members of this family are involved in oncogenesis and this prompted us to assess whether expression levels of individual POK family members are associated with clinical outcomes in cancer. We have observed that ZBTB4 (zinc-finger and BTB domain containing 4) is downregulated in breast cancer patients, and that its expression is significantly correlated with relapse-free survival. Further integrative analysis of mRNA and microRNA (miR) expression data from the NCI-60 cell lines revealed an inverse correlation between ZBTB4 and oncogenic miRs derived from the miR-17-92 cluster and its paralogs. The experimental results using MDA-MB-231 and MCF-7 human breast cancer cells confirm that miRNAs derived from these clusters, containing miR-17-5p, miR-20a, miR-106a, miR-106b and miR-93, negatively regulate ZBTB4 expression. Overexpression of ZBTB4 or restoration of ZBTB4 by using an antagomir inhibit growth and invasion of breast cancer cells, and this effect is due, in part, to ZBTB4-dependent repression of the specificity protein 1 (Sp1), Sp3 and Sp4 genes, and subsequent downregulation of several Sp-dependent oncogenes, in part, through competition between ZBTB4 and Sp transcription factors for GC-rich promoter sequences. These results confirm that ZBTB4 functions as a novel tumor-suppressor gene with prognostic significance for breast cancer survival, and the oncogenic miR-17-92/ZBTB4/Sp axis may be a potential therapeutic target.

Comparison of higher dose and lower dose ganciclovir for cytomegalovirus prophylaxis in seropositive heart transplant recipients.

BACKGROUND: We performed a retrospective historical cohort study to compare the efficacy of higher dose (HD, 10 mg/kg/day for 2 weeks, followed by 5 mg/kg/day intravenously for 2 weeks) and lower dose (LD, 5 mg/kg/day for 4 weeks) ganciclovir (GCV) for cytomegalovirus (CMV) prophylaxis in seropositive heart transplant recipients. METHODS: All consecutive patients undergoing heart transplantation (HT) between June 1999 and January 2008 at our institution were enrolled. All recipients were seropositive for CMV before HT. Before October 2005, 72 patients received the HD regimen and after October 2005, 36 patients received the LD regimen. We followed up all patients for 1 year. RESULTS: In the HD group 43 of 72 patients (60%) developed CMV infections vs. 21 of 36 patients (58%) in the LD group (P=0.89). CMV diseases occurred in 4 patients of the HD group (6%) and 4 patients of the LD group (11%) (P=0.44). The incidence of acute rejection was not significantly different between the 2 groups (14% vs. 6%; P=0.33). Among patients who completed 4-week courses of prophylaxis, 32 of 58 patients (55%) in the HD group developed CMV infections vs. 18 of 30 patients (60%) in the LD group (P=0.66). CMV diseases occurred in 3 patients of the HD group (5%) and 4 of the LD group (13%) (P=0.22). Acute rejection incidence did not differ significantly between the 2 groups (17% vs. 7%; P=0.21). CONCLUSIONS: LD GCV for CMV prophylaxis may not be inferior to the HD regimen in seropositive HT recipients.

MERTK polymorphisms associated with risk of haematological disorders among Korean SLE patients.

OBJECTIVE: The MER receptor tyrosine kinase (MERTK) gene is critical for the efficient clearance of apoptotic cells and has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the genetic polymorphisms in MERTK to evaluate it as a potential candidate gene for a host genetic study of SLE and clinical manifestations in patients with SLE. METHODS: By resequencing the coding and flanking regions of the MERTK gene in 24 unrelated Koreans, 37 polymorphisms were identified. Based on gene position, minor allele frequency and inter-single-nucleotide polymorphism (SNP) linkage disequilibrium, six of these polymorphisms were selected for subsequent genotyping and association analysis with the risk of SLE and haematological disorders in 350 Korean SLE patients and 330 controls. RESULTS: Although no significant associations with the risk of SLE were found, logistic regression analyses revealed that variants +465C > G (P = 0.05) and +130215insdelT (P = 0.0005) were significantly associated with decreased risk of leucopenia in SLE patients. Further, +465C > G, +95616G > A, +123157A > G and the haplotype ht1 also showed significant associations (P = 0.006-0.05) with a decreased risk of lymphopenia in SLE patients. CONCLUSION: Our findings suggest that polymorphisms in MERTK might be one of the genetic risk factors for presenting leucopenia and lymphopenia in SLE patients.