The impact of baseline [−2]proPSA-related indices on the prediction of pathological reclassification at 1 year during active surveillance for low-risk prostate cancer: the Japanese multicenter study cohort

Purpose

Active surveillance (AS) is one potential solution to avoiding the overtreatment of favorable prostate cancer. By handling the AS strategy more safely, tumor aggressiveness may be evaluated more accurately. The aim of the present study was to evaluate the predictive impact of baseline prostate-specific antigen (PSA) isoform [?2]proPSA (p2PSA)-related indices on the pathological reclassification at 1 year during an AS program.

Methods

Between 2002 and 2003, 134 males diagnosed with low-risk prostate cancer were registered in the Japanese multicenter study cohort as candidates for AS, and 118 (88 %) males actually proceeded to AS. Of the 118 patients, the 67 that underwent protocol biopsy at 1 year after beginning AS were enrolled in the present study. The predictive significance of various baseline clinicopathological features and p2PSA-related indices on pathological reclassification at 1 year after beginning AS were investigated.

Results

The pathological reclassification rate was 37.3 %. According to the univariate analysis, prostate volume (p = 0.049), number of biopsy cores (p = 0.047), percentage of positive biopsy cores (p = 0.023), p2PSA to free PSA ratio (%p2PSA) (p = 0.003) and prostate health index (phi) (p = 0.010) at baseline were significantly different between the reclassification and non-reclassification groups. By multivariate logistic regression analysis, baseline %p2PSA (p = 0.008) and phi (p = 0.008) were the only independent predictive factors for pathological upgrade at 1 year after AS commencement.

Conclusions

Baseline %p2PSA and phi may predict the pathological reclassification at 1 year after starting AS, which could be due to the under detection of clinically significant prostate cancer at AS enrollment.     

Identification of salivary metabolites for oral squamous cell carcinoma and oral epithelial dysplasia screening from persistent suspicious oral mucosal lesions

Clinical Oral Investigations - To identify salivary metabolite biomarkers to differentiate patients with oral squamous cell carcinoma and oral epithelial dysplasia (OSCC/OED) from those with...     

Descending aorta–external iliac artery bypass for middle aortic syndrome

We encountered a surgical case of middle aortic syndrome (MAS) in a 56-year-old man who had resistant hypertension. Computed tomography showed severe stenosis of the abdominal aorta from below the superior mesenteric artery to above the inferior mesenteric artery. Although bilateral renal artery stenosis was confirmed, renal function was within normal limits. A 10-mm vascular prosthetic graft was used to perform a descending aorta to left external iliac artery bypass. His hypertension was well controlled without medication. This extra-anatomic bypass may be a simple and useful approach for treating MAS if it is not necessary to reconstruct the renal artery or visceral artery.     

Helicase proteins DHX29 and RIG-I cosense cytosolic nucleic acids in the human airway system

The recognition of cytoplasmic nucleic acid is critical for innate immune responses against microbial infection and is responsible for autoimmunity induced by dead cells. Here, we report the identification of a unique cytosolic nucleic acid cosensor in human airway epithelial cells and fibroblasts: DEAH (Asp-Glu-Ala-His) box polypeptide 29 (DHX29), a member of the DExD/H (Asp-Glu-x-Asp/His)-box helicase family. Knocking down DHX29 by siRNA attenuated the ability of cells to mount type I IFN and IL-6 in response to cytosolic nucleic acids and various viruses by blocking the activation of interferon regulatory factor 3 and NF-κB-p65. The cytosolic nucleic acid sensing by DHX29 in human epithelial cells and fibroblasts is independent of stimulator of interferon genes but is dependent on retinoic acid-inducible gene 1 (RIG-I) and mitochondrial antiviral signaling protein (MAVS). DHX29 binds directly to nucleic acids and interacts with RIG-I and MAVS through its helicase 1 domain, activating the RIG-I–MAVS-dependent cytosolic nucleic acid response. These results suggest that DHX29 is a cytosolic nucleic acid cosensor that triggers RIG-I/MAVS-dependent signaling pathways. This study will have important implications in drug and vaccine design for control of viral infections and viral-induced pathology in the airway.Human airway epithelia interface with the outside air environment. Viruses, bacteria, and other airborne microorganisms frequently cause mild to serious infections in humans, which may cause or exacerbate many human diseases, including pneumonia, asthma, and chronic obstructive pulmonary disease (1). Recent studies demonstrated that in addition to providing a physical barrier, epithelia can sense viral infection. This ability is critical to subsequent activation of antiviral innate and adaptive immunity (2–8).In the past decade, various cytosolic nucleic acid sensors and their mechanisms of action have been uncovered. Cytosolic double-stranded RNA (dsRNA) polyinosinic:polycytidylic acid (poly I:C) and 5′-ppp-dsRNA, mimicking the virus-derived RNA, are sensed by RIG-I–like receptors (9–11), which signal through the adaptor protein mitochondrial antiviral signaling protein (MAVS) (also known as CARDIF, IPS-1, or VISA) (12–15). For double-stranded DNA (dsDNA), many sensors have been reported, including DAI, AIM2, RNA pol III, IFI16, DDX41, Mre11, DNA-PKcs/Ku70/Ku80, cGAS, LRRFIP1, HMGB1, LSm14A, and NLRP3 (16, 17). Some of these molecules depend on stimulator of interferon genes (STING) (also known as ERIS, MITA, or MYPS) as the signaling adaptor (18–22). Furthermore, in addition to RIG-I–like receptors, many other DExD/H helicase family members, such as DHX9, DHX36, DDX1, DDX21, DHX33, DDX3, and DDX60, have been reported to function in nucleic acid sensing (23–29). These reports suggest that, depending on the virus species, cell type, types of ligands, types of responses, and the response phase, cytosolic nucleic acids are sensed by various sensing molecules that lead to different downstream signaling (16, 17). Different cytosolic nucleic acid sensors also have been implicated in the sensing of viral infection in human airway epithelial and subepithelial cells (2–7).In this study, we systemically analyzed the function of 59 members of the DExD/H (Asp-Glu-x-Asp/His) helicase family in sensing nucleic acids in human airway-derived epithelial cells and fibroblasts. We report that in the human airway system, DHX29 is engaged in cytosolic nucleic acid and virus sensing as a cosensor of the RIG-I/MAVS pathway, independently of STING.     

Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study

Background

We recently reported the efficacy of indigo naturalis (IN) in patients with active ulcerative colitis (UC) in a randomized controlled trial (INDIGO study). However, few studies have been conducted to investigate whether IN is effective even in treatment-refractory cases, such as in those with steroid dependency and anti-TNF refractoriness.

Methods

In the INDIGO study, 86 patients with active UC were randomly assigned to an IN group (0.5–2.0 g daily) or placebo group. The rate of clinical response (CR), mucosal healing (MH), and change in fecal calprotectin (FCP) levels was compared between refractory [patients with steroid-dependent disease, previous use of anti-TNF-α, and concomitant use of immunomodulators (IM)] and non-refractory patients. We also analyzed factors predicting CR and MH at week 8.

Results

The rates of CR of IN group were significantly higher than placebo group, even in patients with steroid-dependent disease (p < 0.001), previous use of anti-TNF-α (p = 0.002), and concomitant use of IM (p = 0.013). The rates of MH in IN group were significantly higher than in placebo group in patients with steroid-dependent disease (p = 0.009). In the IN group, median FCP levels, at week 8, were significantly lower than baseline in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α (p < 0.001, respectively). Multivariate analysis indicated that the previous use of anti-TNF-α was not a predictive factor for CR and MH at week 8.

Conclusions

In a sub-analysis of data from a randomized placebo-controlled trial, we found that IN may be useful even in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α.

     

Activated microglia in a rat stroke model express NG2 proteoglycan in peri‐infarct tissue through the involvement of TGF‐β1

We investigated activated microglia in ischemic brain lesions from rats that had been subjected to transient middle cerebral artery occlusion. Activated microglia expressing NG2 chondroitin sulfate proteoglycan (NG2) were found only in the narrow zone (demarcation zone) that demarcated the peri‐infarct tissue and ischemic core. NG2^? activated microglia were abundantly distributed in the peri‐infarct tissue outside the demarcation zone. NG2⁺ microglia but not NG2^? microglia expressed both CD68 and a triggering receptor expressed on myeloid cells 2 (TREM‐2), suggesting that NG2⁺ microglia eliminated apoptotic neurons. In fact, NG2⁺ microglia often attached to degenerating neurons and sometimes internalized NeuN⁺ or neurofilament protein⁺ material. Kinetic studies using quantitative real‐time RT‐PCR revealed that expression of transforming growth factor‐β1 (TGF‐β1) was most evident in the ischemic core; with this marker produced mainly by macrophages located in this region. TGF‐β receptor mRNA expression peaked at 3 days post reperfusion (dpr) in the peri‐infarct tissue, including the demarcation zone. Primary cultured rat microglia also expressed the receptor mRNA. In response to TGF‐β1, primary microglia enhanced the expression of NG2 protein and TREM‐2 mRNA as well as migratory activity. A TGF‐β1 inhibitor, SB525334, abolished these effects. The present results suggest that TGF‐β1 produced in the ischemic core diffused toward the peri‐infarct tissue, driving activated microglial cells to eliminate degenerating neurons. Appropriate control of NG2⁺ microglia in the demarcation zone might be a novel target for the suppression of secondary neurodegeneration in the peri‐infarct tissue. GLIA 2014;62:185–198