Overhydration measured by bioimpedance analysis and the survival of patients on maintenance hemodialysis: a single-center study

AbstractBackgroundBioimpedance analysis (BIA) helps measuring the constituents of the body noninvasively. Prior studies suggest that BIA-guided fluid assessment helps to predict survival in dialysis patients. We aimed to evaluate the clinical usefulness of BIA for predicting the survival rate of hemodialysis patients in Korea.MethodsWe conducted a single-center retrospective study. All patients were diagnosed with end-stage renal disorder and started maintenance hemodialysis between June 2009 and April 2014. BIA was performed within the 1st week from the start of hemodialysis. The patients were classified into 2 groups based on volume status measured by the body composition monitor (BCM; Fresenius): an overhydrated group [OG; overhydration/extracellular water (OH/ECW) >15%] and a nonoverhydrated group (NOG; OH/ECW ≤15%).ResultsA total of 344 patients met the inclusion criteria. Of these, 252 patients (73.3%) were categorized into the OG and 92 patients (26.7%) into the NOG. Age- and sex-matching patients were selected with a rate of 2:1. Finally, 160 overhydrated patients and 80 nonoverhydrated patients were analyzed. Initial levels of hemoglobin and serum albumin were significantly lower in the OG. During follow-up, 43 patients from the OG and 7 patients from the NOG died (median follow-up duration, 24.0 months). The multivariate-adjusted all-cause mortality was significantly increased in the OG (odds ratio, 2.569; P = 0.033) and older patients (odds ratio, 1.072/y; P < 0.001). No significant difference of all-cause or disease-specific admission rate was observed between the 2 groups.ConclusionThe ratio of OH/ECW volume measured with body composition monitor is related to the overall survival of end-stage renal disorder patients who started maintenance hemodialysis

Olfactory marker protein regulates prolactin secretion and production by modulating Ca2+ and TRH signaling in lactotrophs

Olfactory marker protein (OMP) is a marker of olfactory receptor-mediated chemoreception, even outside the olfactory system. Here, we report that OMP expression in the pituitary gland plays a role in basal and thyrotropin-releasing hormone (TRH)-induced prolactin (PRL) production and secretion. We found that OMP was expressed in human and rodent pituitary glands, especially in PRL-secreting lactotrophs. OMP knockdown in GH4 rat pituitary cells increased PRL production and secretion via extracellular signal-regulated kinase (ERK)1/2 signaling. Real-time PCR analysis and the Ca2+ influx assay revealed that OMP was critical for TRH-induced PRL secretion. OMP-knockout mice showed lower fertility than control mice, which was associated with increased basal PRL production via activation of ERK1/2 signaling and reduced TRH-induced PRL secretion. However, both in vitro and in vivo results indicated that OMP was only required for hormone production and secretion because ERK1/2 activation failed to stimulate cell proliferation. Additionally, patients with prolactinoma lacked OMP expression in tumor tissues with hyperactivated ERK1/2 signaling. These findings indicate that OMP plays a role in PRL production and secretion in lactotrophs through the modulation of Ca2+ and TRH signaling. © 2018 The Author(s).1

TonEBP recognizes R-loops and initiates m6A RNA methylation for R-loop resolution

R-loops are three-stranded, RNA???DNA hybrid, nucleic acid structures produced due to inappropriate processing of newly transcribed RNA or transcription-replication collision (TRC). Although R-loops are important for many cellular processes, their accumulation causes genomic instability and malignant diseases, so these structures are tightly regulated. It was recently reported that R-loop accumulation is resolved by methyltransferase-like 3 (METTL3)-mediated m6A RNA methylation under physiological conditions. However, it remains unclear how R-loops in the genome are recognized and induce resolution signals. Here, we demonstrate that tonicity-responsive enhancer binding protein (TonEBP) recognizes R-loops generated by DNA damaging agents such as ultraviolet (UV) or camptothecin (CPT). Single-molecule imaging and biochemical assays reveal that TonEBP preferentially binds a R-loop via both 3D collision and 1D diffusion along DNA in vitro. In addition, we find that TonEBP recruits METTL3 to R-loops through the Rel homology domain (RHD) for m6A RNA methylation. We also show that TonEBP recruits RNaseH1 to R-loops through a METTL3 interaction. Consistent with this, TonEBP or METTL3 depletion increases R-loops and reduces cell survival in the presence of UV or CPT. Collectively, our results reveal an R-loop resolution pathway by TonEBP and m6A RNA methylation by METTL3 and provide new insights into R-loop resolution processes

The Therapeutic Effect of STAT3 Signaling-Suppressed MSC on Pain and Articular Cartilage Damage in a Rat Model of Monosodium Iodoacetate-Induced Osteoarthritis

Osteoarthritis (OA) is a degenerative disease that induces pain, cartilage deformation, and joint inflammation. Mesenchymal stem cells (MSCs) are potential therapeutic agents for treatment of OA. However, MSC therapy can cause excessive inflammation. Signal transducer and activator of transcription 3 (STAT3) modulates secretion of many proinflammatory cytokines. Experimental OA was induced by intra-articular (IA) injection of monosodium iodoacetate (MIA) to the right knee of rats. MSCs from OA patients (OA-MSCs) were treated with STA21, a small molecule that blocks STAT3 signaling, by IA or intravenous (IV) injection after MIA injection. Pain severity was quantified by assessment of secondary tactile allodynia using the von Frey assessment test. Cartilage degradation was measured by microcomputed tomography image analysis, histological analysis, and the Mankin score. Protein and gene expression was evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, and real-time polymerase chain reaction. MSCs increased production of proinflammatory cytokines under inflammatory conditions. STA21 significantly decreased expression of these proinflammatory molecules via inhibition of STAT3 activity but increased gene expression of molecules related to migration potential and immunomodulation in OA-MSCs. STAT3-inhibited OA-MSCs administrated by IV or IA injection decreased pain severity and cartilage damage in rats with MIA-induced OA rats by decreasing proinflammatory cytokines in the joints. Combined IA and IV-injected STAT3-inhibited OA-MSCs had an additive effect of pain relief in MIA-induced OA rats. STAT3 inhibition may optimize the therapeutic activities of MSCs for treating OA by attenuating pain and progression of MIA by inhibiting inflammation and cartilage damage

Methylsulfonylmethane Suppresses Breast Cancer Growth by Down-Regulating STAT3 and STAT5b Pathways

Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers

Stabilized Amorphous Calcium Carbonate as a Precursor of Microcoating on Calcite

Highly controlled biomineralization of calcium carbonate is via non-classical mesocrystallization of amorphous precursors. In the present study, a simple in vitro assay was developed to mimic the biological process, which involved stabilized amorphous calcium carbonate and a single crystal substrate of calcite. The microcoating layer formed on the calcite substrate displayed mesocrystalline characteristics, and the layers near the substrate were strongly influenced by the epitaxy to the substrate. This behavior was preserved even when the morphology of the coating layer was modified with poly(acrylic acid), a model anionic macromolecule. Interestingly, the extent of the epitaxy increased substantially with poly(ethylene imine), which barely affected the crystal morphology. The in vitro assay in the present study will be useful in the investigations of the biomineralization and bioinspired crystallization of calcium carbonate in general

Comparative Evaluation of the Efficacy of Combined Intramedullary Pinning with K-Wires Pinning in the Treatment of Fifth Metacarpal Neck Fractures versus Conventional Techniques—K-Wires Pinning and Intramedullary Pinning

Background and Objectives: Since the neck is the weakest part of the metacarpals, the most common metacarpal fracture is a neck fracture, a type which accounts for 38% of all hand fractures. Such fractures can be fixed using a variety of conventional techniques, including intramedullary pinning and K-wire pinning. However, conventional techniques involve complications, such as angulation, stiffness, and rotational deformity. The purpose of this study was to compare the usefulness of our new technique, combined intramedullary pinning with K-wire pinning (IPKP), with those of intramedullary pinning (IP) and K-wire pinning (KP). Materials and Methods: This was a single-center, randomized controlled trial conducted between January 2005 and April 2023. A total of 158 patients with acute displaced fractures of the fifth-metacarpal neck were randomly assigned to either the IPKP group (n = 48), the KP group (n = 60), or the IP group (n = 50). We radiographically evaluated angulation and shortening in three visits: pre-operatively, post-operatively, and at a 1-year follow-up. We clinically evaluated the ranges of motion and Quick-DASH scores to assess daily living performance and the cosmetic scores, using the SBSES score, to assess patients’ satisfaction with their cosmetic outcomes. Results: The IPKP group was superior to the KP group and the IP group regarding radiographical and clinical assessments at the 1-year follow-up visit. The angulation was 15.7° (±7.7) in the KP group, 17.0° (±5.9) in the IP group, and 12.6° (±2.5) in the IPKP group (p p = 0.42). Four patients (6.6%) in the KP group and two patients (4%) in the IP group were reported as having stiffness, while no patients were found to have stiffness in the IPKP group. The average Quick-DASH score was 2.3 (±0.5) in the KP group, 2.5 (±0.4) in the IP group, and 1.9 (±0.4) in the IPKP group (p > 0.05). The average cosmetic score was 3.7 (±1.2) in the KP group, 3.8 (±0.9) in the IP group, and 4.7 (±0.8) in the IPKP group (p Conclusions: With the IPKP technique, accurate reduction can be achieved to improve hand function and cosmetic outcomes