Prognostic Value of Tumor-Associated Macrophages According to Histologic Locations and Hormone Receptor Status in Breast Cancer

Tumor-associated macrophages (TAMs) are involved in tumor progression by promoting epithelial-mesenchymal transition (EMT), tumor cell invasion, migration and angiogenesis. However, in breast cancer, the clinical relevance of the TAM infiltration according to distinct histologic locations (intratumoral vs. stromal) and hormone receptor status is unclear. We investigated the significance of the levels of TAM infiltration in distinct histologic locations in invasive breast cancer. We also examined the relationship of the TAM levels with the clinicopathologic features of tumors, expression of EMT markers, and clinical outcomes. Finally, we analyzed the prognostic value of TAM levels according to hormone receptor status. High levels of infiltration of intratumoral, stromal and total TAMs were associated with high histologic grade, p53 overexpression, high Ki-67 proliferation index and negative hormone receptor status. Infiltration of TAMs was also correlated with overexpression of vimentin, smooth muscle actin and alteration of β-catenin. Overall, a high level of infiltration of intratumoral TAMs was associated with poor disease-free survival, and was found to be an independent prognostic factor. In subgroup analyses by hormone receptor status, a high level of infiltration of intratumoral TAM was an independent prognostic factor in the hormone receptor-positive subgroup, but not in the hormone-receptor negative subgroup. Our findings suggest that intratumoral TAMs play an important role in tumor progression in breast cancer, especially in the hormone receptor-positive group, and the level of TAM infiltration may be used as a prognostic factor and even a therapeutic target in breast cancer.     

Clinical Correlates of Mass Effect in Autosomal Dominant Polycystic Kidney Disease

Mass effect from polycystic kidney and liver enlargement can result in significant clinical complications and symptoms in autosomal dominant polycystic kidney disease (ADPKD). In this single-center study, we examined the correlation of height-adjusted total liver volume (htTLV) and total kidney volume (htTKV) by CT imaging with hepatic complications (n = 461) and abdominal symptoms (n = 253) in patients with ADPKD. “Mass-effect” complications were assessed by review of medical records and abdominal symptoms, by a standardized research questionnaire. Overall, 91.8% of patients had 4 or more liver cysts on CT scans. Polycystic liver disease (PLD) was classified as none or mild (htTLV < 1,600 mL/m); moderate (1,600 ≤ htTLV <3,200 mL/m); and severe (htTLV ≥ 3,200 mL/m). The prevalence of moderate and severe PLD in our patient cohort was 11.7% (n = 54/461) and 4.8% (n = 22/461), respectively, with a female predominance in both the moderate (61.1%) and severe (95.5%) PLD groups. Pressure-related complications such as leg edema (20.4%), ascites (16.6%), and hernia (3.6%) were common, and patients with moderate to severe PLD exhibited a 6-fold increased risk (compared to no or mild PLD) for these complications in multivariate analysis. Similarly, abdominal symptoms including back pain (58.8%), flank pain (53.1%), abdominal fullness (46.5%), and dyspnea/chest-discomfort (44.3%) were very common, and patients with moderate to severe PLD exhibited a 5-fold increased risk for these symptoms. Moderate to severe PLD is a common and clinically important problem in ~16% of patients with ADPKD who may benefit from referral to specialized centers for further management.     

A Novel Cascade Classifier for Automatic Microcalcification Detection

In this paper, we present a novel cascaded classification framework for automatic detection of individual and clusters of microcalcifications (μC). Our framework comprises three classification stages: i) a random forest (RF) classifier for simple features capturing the second order local structure of individual μCs, where non-μC pixels in the target mammogram are efficiently eliminated; ii) a more complex discriminative restricted Boltzmann machine (DRBM) classifier for μC candidates determined in the RF stage, which automatically learns the detailed morphology of μC appearances for improved discriminative power; and iii) a detector to detect clusters of μCs from the individual μC detection results, using two different criteria. From the two-stage RF-DRBM classifier, we are able to distinguish μCs using explicitly computed features, as well as learn implicit features that are able to further discriminate between confusing cases. Experimental evaluation is conducted on the original Mammographic Image Analysis Society (MIAS) and mini-MIAS databases, as well as our own Seoul National University Bundang Hospital digital mammographic database. It is shown that the proposed method outperforms comparable methods in terms of receiver operating characteristic (ROC) and precision-recall curves for detection of individual μCs and free-response receiver operating characteristic (FROC) curve for detection of clustered μCs.     

NDRG3-mediated lactate signaling in hypoxia

Hypoxia is associated with many pathological conditions as well as the normal physiology of metazoans. We identified a lactate-dependent signaling pathway in hypoxia, mediated by the oxygen- and lactate-regulated protein NDRG family member 3 (NDRG3). Oxygen negatively regulates NDRG3 expression at the protein level via the PHD2/VHL system, whereas lactate, produced in excess under prolonged hypoxia, blocks its proteasomal degradation by binding to NDRG3. We also found that the stabilized NDRG3 protein promotes angiogenesis and cell growth under hypoxia by activating the Raf-ERK pathway. Inhibiting cellular lactate production abolishes NDRG3-mediated hypoxia responses. The NDRG3-Raf-ERK axis therefore provides the genetic basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases in addition to advancing our understanding of the normal physiology of hypoxia responses. [BMB Reports 2015; 48(6): 301-302]     

Trends in the Use of Nephron-Sparing Surgery over 7 Years: An Analysis Using the R.E.N.A.L. Nephrometry Scoring System

Objective

To analyze trends in the use of partial nephrectomy, we evaluated which individual factors of renal nephrometry score (RNS) influenced the operative approach bi-annually from 2008 to 2014.

Materials and Methods

We performed a retrospective review of renal cell carcinoma treated by surgery in 2008, 2010, 2012, and 2014. The complexity of renal masses was measured using the R.E.N.A.L. nephrometry scoring system with CT or MRI. Group comparison in terms of operation year and surgical type (partial nephrectomy versus radical nephrectomy) was performed. We developed a nomogram to quantitate the likelihood of selecting partial nephrectomy over radical nephrectomy.

Results

A total of 1106 cases (237 in 2008, 225 in 2010, 292 in 2012, and 352 in 2014) were available for the study. Over the study period, the proportion of partial nephrectomies performed increased steadily from 21.5% in 2008 to 66.5% in 2014 (p < 0.05). Furthermore, use of partial nephrectomy increased steadily in all RNS complexity groups (low, moderate, and high) (p < 0.05). In the analysis of individual components of RNS, values of the R and N components increased statistically by year in the partial nephrectomy group (p < 0.05). Average AUC was 0.920.

Conclusions

The proportion of partial nephrectomies performed sharply increased over the study period. Additionally, over the study period, more partial nephrectomies were performed for renal masses of larger size and closer to the collecting system and main renal vessels. A nomogram developed based on this recent data set provides significant predictive value for surgical decision making.     

Efficacy and Safety of Sorafenib Therapy on Metastatic Renal Cell Carcinoma in Korean Patients: Results from a Retrospective Multicenter Study

Objective

To evaluate the efficacy and safety of sorafenib for Korean patients with metastatic renal cell carcinoma (mRCC).

Methods

A total of 177 mRCC patients using sorafenib as first- (N = 116), second- (N = 43), and third-line (N = 18) therapies were enrolled from 11 Korean centers between 2006 and 2012. The patient characteristics, therapy duration, tumor response, disease control rate, and tolerability were assessed at baseline and at routine follow-ups, and the progression-free survival (PFS) and overall survival (OS) times and rates were analyzed.

Results

Among all patients, 18 (10.2%) stopped sorafenib treatment for a median of 1.7 weeks, including 15 (8.5%) who discontinued the drug, while 40 (22.6%) and 12 (6.8%) patients required dose reductions and drug interruptions, respectively. Severe adverse events (AEs) or poor compliance was observed in 64 (36.2%) patients, with 118 (7.4%) ≥grade 3 AEs. During the treatment, one myocardial infarction was observed. The number of ≥grade 3 AEs in the first-line sorafenib group was 71 (6.8% of the total 1048 AEs). During a median follow-up of 17.2 months, the radiologically confirmed best objective response rate, disease control rate, median PFS, and median OS were 22.0%, 53.0%, 6.4 months (95% confidence interval [CI], 5.2–8.9), and 32.6 months (95% CI, 27.3–63.8) for the total 177 sorafenib-treated patients, respectively, and 23.2%, 56.0%, 7.4 months (95% CI, 5.5–10.5), and not reached yet (95% CI, 1.0–31.1) for the first-line sorafenib group, respectively.

Conclusions

Sorafenib produced tolerable safety, with a ≥grade 3 AE rate of 7.4% and an acceptable disease control rate (53.0%) in Korean mRCC patients.     

Hepatitis B virus X increases immune cell recruitment by induction of chemokine SDF-1

Hepatitis B virus X protein is a major factor in the HBV-induced disease developments. Stromal cell-derived factor-1 is a small cytokine that is strongly chemotactic for lymphocytes. We explored the role of HBx on recruitment of HBV-induced virus-nonspecific immune cells into liver. Immune cell recruitment and SDF-1 expression level significantly increased in livers of HBx-transgenic mice and X-box binding protein-1 significantly increased SDF-1 gene expression. Finally, we confirmed that immune cell recruitment into liver tissues of HBx-TG mice was diminished by a chemokine receptor antagonist. Therefore, HBx increases ER stress-dependent SDF-1 expression and induces HBV-induced immune cell recruitment into liver.     

Inhibitory role of Id1 on TGF-β-induced collagen expression in human dermal fibroblasts

Inhibitor of DNA binding 1 (Id1) is a basic helix-loop-helix (bHLH) protein that has a variety of functional roles in cellular events including differentiation, cell cycle and cancer development. In addition, it has been demonstrated that Id1 is related with TGF-β and Smad signaling in various biological conditions. In this study, we investigated the effect of Id1 on TGF-β-induced collagen expression in human dermal fibroblasts. When Id1-b isoform was overexpressed, TGF-β-induced collagen expression was markedly inhibited. Consistent with this result, Id1-b significantly inhibited TGF-β-induced collagen gel contraction. In addition, Id1-b inhibited TGF-β-induced phosphorylation of Smad2 and Smad3. Finally, immunohistochemistry showed that Id1 expression was decreased in fibrotic skin diseases while TGF-β signaling was increased. Together, these results suggest that Id1 is an inhibitory regulator on TGF-β-induced collagen expression in dermal fibroblasts.     

Neurotropic and neuroprotective activities of the earthworm peptide Lumbricusin

We recently isolated a polypeptide from the earthworm Lumbricus terrestris that is structurally similar to defensin, a well-known antibacterial peptide. An 11-mer antibacterial peptide (NH₂-RNRRWCIDQQA), designated Lumbricusin, was synthesized based on the amino acid sequence of the isolated polypeptide. Since we previously reported that CopA3, a dung beetle peptide, enhanced neuronal cell proliferation, we here examined whether Lumbricusin exerted neurotropic and/or neuroprotective effects. Lumbricusin treatment induced a time-dependent increase (∼51%) in the proliferation of human neuroblastoma SH-SY5Y cells. Lumbricusin also significantly inhibited the apoptosis and decreased viability induced by treatment with 6-hydroxy dopamine, a Parkinson’s disease-mimicking agent. Immunoblot analyses revealed that Lumbricusin treatment increased ubiquitination of p27^Kip1 protein, a negative regulator of cell-cycle progression, in SH-SY5Y cells, and markedly promoted its degradation. Notably, adenoviral-mediated over-expression of p27^Kip1 significantly blocked the antiapoptotic effect of Lumbricusin in 6-hydroxy dopamine-treated SH-SY5Y cells. These results suggest that promotion of p27^Kip1 degradation may be the main mechanism underlying the neuroprotective and neurotropic effects of Lumbricusin.     

The PDZ-binding motif of the avian NS1 protein affects transmission of the 2009 influenza A(H1N1) virus

By nature of their segmented RNA genome, influenza A viruses (IAVs) have the potential to generate variants through a reassortment process. The influenza nonstructural (NS) gene is critical for a virus to counteract the antiviral responses of the host. Therefore, a newly acquired NS segment potentially determines the replication efficiency of the reassortant virus in a range of different hosts. In addition, the C-terminal PDZ-binding motif (PBM) has been suggested as a pathogenic determinant of IAVs. To gauge the pandemic potential from human and avian IAV reassortment, we assessed the replication properties of NS-reassorted viruses in cultured cells and in the lungs of mice and determined their transmissibility in guinea pigs. Compared with the recombinant A/Korea/01/2009 virus (rK09; 2009 pandemic H1N1 strain), the rK09/VN:NS virus, in which the NS gene was adopted from the A/Vietnam/1203/2004 virus (a human isolate of the highly pathogenic avian influenza H5N1 virus strains), exhibited attenuated virulence and reduced transmissibility. However, the rK09/VN:NS-PBM virus, harboring the PBM in the C-terminus of the NS1 protein, recovered the attenuated virulence of the rK09/VN:NS virus. In a guinea pig model, the rK09/VN:NS-PBM virus showed even greater transmission efficiency than the rK/09 virus. These results suggest that the PBM in the NS1 protein may determine viral persistence in the human and avian IAV interface.