Clinicopathological Differences between Right and Left Colorectal Cancer by Sex.

Background: Until now, studies on colorectal cancer (CRC) have focused on clinicopathological characteristics based on location without considering sex differences. However, as men and women have fundamentally different physiological characteristics, research results in the clinical field are limited. We aimed to elucidate the differences in the clinicopathological characteristics between right-sided CRC (RCC) and left-sided CRC (LCC) according to sex. Methods: We classified 1492 South Korean patients with no history of colon surgery between July 2005 and June 2015 based on tumor location and sex. For these patients, differences in the clinical characteristics according to sex were compared using univariate and multivariate analyses. Results: Of the 1269 patients, 951 (74.9%) had LCC, and 318 (25.1%) had RCC, making LCC approximately three times more common than RCC. When sex was not taken into account, patients with RCC had significantly higher rates of anemia and undifferentiated cancers than the rates in those with LCC. Even considering sex, anemia and undifferentiated cancer were more prevalent in RCC than in LCC in both men and women. In contrast, age over 65 years and abnormal white blood cell count differed between RCC and LCC only in women. Conclusions: The clinicopathologic characteristics of CRC vary according to the location and sex. Therefore, sex must be considered as a fundamental characteristic of personalized treatment.

A Mechanistic and Preclinical Assessment of BioRestore Bioactive Glass as a Synthetic Bone Graft Extender and Substitute for Osteoinduction and Spine Fusion.

STUDY DESIGN: Preclinical animal study. OBJECTIVE: Evaluate the osteoinductivity and bone regenerative capacity of BioRestore bioactive glass. SUMMARY OF BACKGROUND DATA: BioRestore is a Food and Drug Administration (FDA)-approved bone void filler that has not yet been evaluated as a bone graft extender or substitute for spine fusion. METHODS: In vitro and in vivo methods were used to compare BioRestore with other biomaterials for the capacity to promote osteodifferentiation and spinal fusion. The materials evaluated (1) absorbable collagen sponge (ACS), (2) allograft, (3) BioRestore, (4) Human Demineralized Bone Matrix (DBM), and (5) MasterGraft. For in vitro studies, rat bone marrow-derived stem cells (BMSC) were cultured on the materials in either standard or osteogenic media (SM, OM), followed by quantification of osteogenic marker genes (Runx2, Osx, Alpl, Bglap, Spp1) and alkaline phosphatase (ALP) activity. Sixty female Fischer rats underwent L4-5 posterolateral fusion (PLF) with placement of 1 of 5 implants: (1) ICBG from syngeneic rats; (2) ICBG+BioRestore; (3) BioRestore alone; (4) ICBG+Allograft; or (5) ICBG+MasterGraft. Spines were harvested 8 weeks postoperatively and evaluated for bone formation and fusion via radiography, blinded manual palpation, microCT, and histology. RESULTS: After culture for 1 week, BioRestore promoted similar expression levels of Runx2 and Osx to cells grown on DBM. At the 2-week timepoint, the relative ALP activity for BioRestore-OM was significantly higher (P<0.001) than that of ACS-OM and DBM-OM (P<0.01) and statistically equivalent to cells grown on allograft-OM. In vivo, radiographic and microCT evaluation showed some degree of bridging bone formation in all groups tested, with the exception of BioRestore alone, which did not produce successful fusions. CONCLUSIONS: This study demonstrates the capacity of BioRestore to promote osteoinductivity in vitro. In vivo, BioRestore performed similarly to commercially available bone graft extender materials but was incapable of producing fusion as a bone graft substitute. LEVEL OF EVIDENCE: Level V.

Waste to Energy: Steam explosion-based torrefaction process to produce solid biofuel for power generation utilizing various waste biomasses.

Currently, humankind is facing a serious environmental and climate crisis, which has accelerated the research on producing bioenergy from waste biomass as a carbon-neutral feedstock. In this study, the aim was to develop an upcycling strategy for waste biomass to solid-type biofuel conversion for power generation. Various types of waste biomass (i.e., waste wood after lumbering, sawdust-type mushroom waste wood, kudzu vine, and empty fruit bunches from palm) were used as sustainable feedstocks for steam explosion-based torrefaction. The reaction conditions were optimized for each waste biomass by controlling the severity index (Ro); the higher heating value increased proportional to the Ro increase. Additionally, component analysis revealed that steam explosion torrefaction mainly degraded hemicellulose, and most of the torrefied waste biomass met the Bio-Solid Refuse Fuel quality standard. The results provide not only a viable waste-to-energy strategy but also insights to address global climate change.

Preclinical Efficacy of Peripheral Nerve Regeneration by Schwann Cell-like Cells Differentiated from Human Tonsil-Derived Mesenchymal Stem Cells in C22 Mice.

Charcot-Marie-Tooth disease (CMT) is a hereditary disease with heterogeneous phenotypes and genetic causes. CMT type 1A (CMT1A) is a type of disease affecting the peripheral nerves and is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene. Human tonsil-derived mesenchymal stem cells (TMSCs) are useful for stem cell therapy in various diseases and can be differentiated into Schwann cell-like cells (TMSC-SCs). We investigated the potential of TMSC-SCs called neuronal regeneration-promoting cells (NRPCs) for peripheral nerve and muscle regeneration in C22 mice, a model for CMT1A. We transplanted NRPCs manufactured in a good manufacturing practice facility into the bilateral thigh muscles of C22 mice and performed behavior and nerve conduction tests and histological and ultrastructural analyses. Significantly, the motor function was much improved, the ratio of myelinated axons was increased, and the G-ratio was reduced by the transplantation of NRPCs. The sciatic nerve and gastrocnemius muscle regeneration of C22 mice following the transplantation of NRPCs downregulated PMP22 overexpression, which was observed in a dose-dependent manner. These results suggest that NRPCs are feasible for clinical research for the treatment of CMT1A patients. Research applying NRPCs to other peripheral nerve diseases is also needed.

A supramolecular polymer-collagen microparticle slurry for bone regeneration with minimal growth factor.

Recombinant bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive growth factor that can promote bone regeneration for challenging skeletal repair and even for ectopic bone formation in spinal fusion procedures. However, serious clinical side effects related to supraphysiological dosing highlight the need for advances in novel biomaterials that can significantly reduce the amount of this biologic. Novel biomaterials could not only reduce clinical side effects but also expand the indications for use of BMP-2, while at the same time lowering the cost of such procedures. To achieve this objective, we have developed a slurry containing a known supramolecular polymer that potentiates BMP-2 signaling and porous collagen microparticles. This slurry exhibits a paste-like consistency that stiffens into an elastic gel upon implantation making it ideal for minimally invasive procedures. We carried out in vivo evaluation of the novel biomaterial in the rabbit posterolateral spine fusion model, and discovered efficacy at unprecedented ultra-low BMP-2 doses (5 µg/implant). This dose reduces the growth factor requirement by more than 100-fold relative to current clinical products. This observation is significant given that spinal fusion involves ectopic bone formation and the rabbit model is known to be predictive of human efficacy. We expect the novel biomaterial can expand BMP-2 indications for difficult cases requiring large volumes of bone formation or involving patients with underlying conditions that compromise bone regeneration.

Significance of 8-OHdG Expression as a Predictor of Survival in Colorectal Cancer.

The incidence of colorectal cancer (CRC) is increasing worldwide. 8-hydroxy-2'-deoxyguanosine (8-OHdG), one of the most prevalent DNA alterations, is known to be upregulated in several carcinomas; however, 8-OHdG has not been used to predict the prognosis of patients with CRC. We aimed to determine 8-OHdG levels in patients with CRC using immunohistochemistry and conducted a survival analysis according to the pathological stage. The 5-year event-free survival (EFS) and disease-specific survival (DSS) hazard ratios (HRs) of the low 8-OHdG subgroup were 1.41 (95% confidence interval (CI): 1.01-1.98, p = 0.04) and 1.60 (95% CI: 1.12-2.28, p = 0.01), respectively. When tumor node metastasis (TNM) staging and 8-OHdG expression were combined, the 5-year EFS and DSS HRs of patients with CRC with low 8-OHdG expression cancer at the same TNM stage (stage Ⅲ/Ⅳ) were 1.51 (95% CI: 1.02-2.22, p = 0.04) and 1.64 (95% CI: 1.09-2.48, p = 0.02), respectively, compared to those with high 8-OHdG expression cancer, indicating a poor prognosis. Therefore, low 8-OHdG expression is a significant predictive factor for 5-year EFS and DSS in patients with CRC, and it can serve as an essential biomarker of CRC.

Clinicopathologic Significance of Heat Shock Protein 60 as a Survival Predictor in Colorectal Cancer.

The role of heat shock protein 60 (HSP60), a mitochondrial chaperone, in tumor progression or its anti-tumor effects remains controversial. This study aimed to confirm the possibility of using HSP60 as a prognostic marker in patients with colorectal cancer (CRC), considering TNM classification for precise prediction. HSP60 expression increased with differentiation and p53 mutations in patients. However, compared to patients with high HSP60 expression, patients with low HSP60 expression had event-free survival and disease-specific survival hazard ratios (HRs) of 1.42 and 1.69, respectively. Moreover, when the survival rate was analyzed by combining TNM classification and HSP60 expression, the prognosis was poor, particularly when HSP60 expression was low in the late/advanced stage. This pattern was also observed with HSP family D member 1, HSPD1, the gene that encodes HSP60. Low HSPD1 expression was linked to lower overall survival and relapse-free survival rates, with HRs of 1.80 and 1.87, respectively. When TNM classification and HSPD1 expression were considered, CRC patients with low HSPD1 expression and advanced malignancy had a poorer prognosis than those with high HSPD1 expression. Thus, HSPD1/HSP60 can be a useful biomarker for a sophisticated survival prediction in late- and advanced-stage CRC, allowing the design of individualized treatment strategies.

Lamin Filament Assembly Derived from the Atomic Structure of the Antiparallel Four-Helix Bundle.

The nucleoskeletal protein lamin is primarily responsible for the mechanical stability of the nucleus. The lamin assembly process requires the A11, A22, and ACN binding modes of the coiled-coil dimers. Although X-ray crystallography and chemical cross-linking analysis of lamin A/C have provided snapshots of A11 and ACN binding modes, the assembly mechanism of the entire filament remains to be explained. Here, we report a crystal structure of a coil 2 fragment, revealing the A22 interaction at the atomic resolution. The structure showed detailed structural features, indicating that two coiled-coil dimers of the coil 2 subdomain are separated and then re-organized into the antiparallel-four-helix bundle. Furthermore, our findings suggest that the ACN binding mode between coil 1a and the C-terminal part of coil 2 when the A11 tetramers are arranged by the A22 interactions. We propose a full assembly model of lamin A/C with the curvature around the linkers, reconciling the discrepancy between the in situ and in vitro observations. Our model accounts for the balanced elasticity and stiffness of the nuclear envelopes, which is essential in protecting the cellular nucleus from external pressure.

Biochemical and functional characterization of skeletal muscle cells differentiated from tonsil-derived mesenchymal stem cells.

INTRODUCTION/AIMS: Human tonsils are a readily accessible source of stem cells for the potential treatment of skeletal muscle disorders. We reported previously that tonsil-derived mesenchymal stem cells (TMSCs) can differentiate into skeletal muscle cells (SKMCs), which renders TMSCs promising candidates for cell therapy for skeletal muscle disorders. However, the functional properties of the myocytes differentiated from mesenchymal stem cells have not been clearly evaluated. In this study we investigated whether myocytes differentiated from TMSCs (skeletal muscle cells derived from tonsil mesenchymal stem cells [TMSC-SKMCs]) exhibit the functional characteristics of SKMCs. METHODS: To test the insulin reactivity of TMSC-SKMCs, the expression of glucose transporter 4 (GLUT4) and phosphatidylinositol 3-kinase/Akt was analyzed after the cells were treated for 30 minutes with 100 nmol/L insulin in normal or high-glucose medium. We also examined whether these cells formed a neuromuscular junction (NMJ) when cocultured with motor neurons, and whether they were stimulated by electrical signals using whole-cell patch clamping. RESULTS: Skeletal muscle cells derived from tonsil mesenchymal stem cells expressed SKMC markers, such as MYOD, MYH3, MYH8, TNNI1, and TTN, at high levels, and exhibited a multinucleated cell morphology and a myotube-like shape. The expression of the acetylcholine receptor and GLUT4 was confirmed in TMSC-SKMCs. In addition, these cells exhibited insulin-mediated glucose uptake, NMJ formation, and transient changes in cell membrane action potential, all of which are representative functions of human SKMCs. DISCUSSION: Tonsil-derived mesenchymal stem cells can be functionally differentiated into SKMCs and may have potential for clinical application for the treatment of skeletal muscle disorders.

Literature review on the interdisciplinary biomarkers of multi-target and multi-time herbal medicine therapy to modulate peripheral systems in cognitive impairment.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by the deposition of amyloid-beta (Aß) peptide and neurofibrillary tangles in the brain. The approved drug for AD has certain limitations such as a short period of cognitive improvement effect; moreover, the development of drug for AD therapeutic single target for Aß clearance in brain ended in failure. Therefore, diagnosis and treatment of AD using a multi-target strategy according to the modulation of the peripheral system, which is not only limited to the brain, is needed. Traditional herbal medicines can be beneficial for AD based on a holistic theory and personalized treatment according to the time-order progression of AD. This literature review aimed to investigate the effectiveness of herbal medicine therapy based on syndrome differentiation, a unique theory of traditional diagnosis based on the holistic system, for multi-target and multi-time treatment of mild cognitive impairment or AD stage. Possible interdisciplinary biomarkers including transcriptomic and neuroimaging studies by herbal medicine therapy for AD were investigated. In addition, the mechanism by which herbal medicines affect the central nervous system in connection with the peripheral system in an animal model of cognitive impairment was reviewed. Herbal medicine may be a promising therapy for the prevention and treatment of AD through a multi-target and multi-time strategy. This review would contribute to the development of interdisciplinary biomarkers and understanding of the mechanisms of action of herbal medicine in AD.

Epifluorescence Microscopy with Image Analysis as a Promising Method for Multispecies Biofilm Quantification.

Epifluorescence microscopy with image analysis was evaluated as a biofilm quantification method (i.e., quantification of surface area colonized by biofilms), in comparison with crystal violet (CV) staining. We performed different experiments to generate multispecies biofilms with natural and artificial bacterial assemblages. First, four species were inoculated daily in 16 different sequences to form biofilms (surface colonization, 0.1%-56.6%). Second, a 9-species assemblage was allowed to form biofilms under 10 acylase treatment episodes (33.8%-55.6%). The two methods comparably measured the quantitative variation in biofilms, exhibiting a strong positive relationship (R2 ≥ 0.7). Moreover, the two methods exhibited similar levels of variation coefficients. Finally, six synthetic and two natural consortia were allowed to form biofilms for 14 days, and their temporal dynamics were monitored. The two methods were comparable in quantifying four biofilms colonizing ≥18.7% (R2 ≥ 0.64), but not for the other biofilms colonizing ≤ 3.7% (R2 ≤ 0.25). In addition, the two methods exhibited comparable coefficients of variation in the four biofilms. Microscopy and CV staining comparably measured the quantitative variation of biofilms, exhibiting a strongly positive relationship, although microscopy cannot appropriately quantify the biofilms below the threshold colonization. Microscopy with image analysis is a promising approach for easily and rapidly estimating absolute quantity of multispecies biofilms.

Long-term adaptation of two anammox granules with different ratios of Candidatus Brocadia and Candidatus Jettenia under increasing salinity and their application to treat saline wastewater.

Nitrogen removal in saline wastewater is a challenge of the anaerobic ammonium oxidation (anammox) process, which is dominated by freshwater anammox bacteria (FAB). Candidatus Brocadia and Candidatus Jettenia, the most widely used FABs, have been separately applied and evaluated for their ability to treat saline wastewater. To understand the effect of salinity on nitrogen removal capability when they present together in an anammox granule, we compared two anammox granules: GRN1 was evenly dominated by Ca. Brocadia (42 %) and Ca. Jettenia (43 %), while GRN2 was dominated with mostly Ca. Brocadia (90 %) and a small amount of Ca. Jettenia (1 %). Each granule was inoculated into a continuous column reactor to treat artificial wastewater containing 150 mg NH4+-N/L and 150 mg NO2--N/L under increasing saline conditions for 250 days. GRN1 showed superior and more stable nitrogen removal than GRN2 under saline conditions of up to 15 g NaCl/L. Under high-saline conditions, both the granules' sizes decreased (larger GRN1 than GRN2 in initial). The mass percent of Na salt increased (more in GRN2) and mineral contents decreased more in GRN1. High-throughput sequencing for microbial community analysis showed that Planctomycetes in GRN1 (85 %) and GRN2 (92 %) decreased to 14 % and 12 %, respectively. The ratio of Ca. Brocadia and Ca. Jettenia in GRN1 changed to 37 % and 63 %, respectively, whereas the ratio in GRN2 (99 % and 1 %, respectively) did not change. Both salt-adapted granules were applied to the two-stage partial nitritation and anammox (PN/A) process to treat high strength ammonium (400 mg/L) wastewater under high saline condition (15 g NaCl/L). The PN/A process containing GRN1 showed more stable nitrogen removal performance during approximately 100 days of operation. These results suggest that the anammox granules evenly dominated by two FABs, Ca. Brocadia and Ca. Jettenia, would be advantageous to treat high-strength NH4+ wastewater under high-saline conditions.

Feeding strategy for single-stage deammonification to treat moderate-strength ammonium under low free ammonia conditions.

Single-stage deammonification (SSD) processes have been successfully operated using the step-feeding strategy to treat high-strength NH4+ (>300 mg/L), but often failed to treat moderate-strength NH4+ (100-300 mg/L). Because it is hard to maintain the free ammonia (FA) above 1 mg/L, which is a concentration in which the activity of NO2- oxidizing bacteria (NOB) can be selectively suppressed. In this study, to evaluate the effectiveness of the step-feeding strategy on the long-term stability of treating moderate-strength NH4+, two SSD sequential-batch reactors (SBRs) were operated under one-step feeding and multi-step feeding strategies. The one-step feeding SBR achieved a higher nitrogen removal efficiency (86 %), nitrogen removal rate (0.61 kg/m3/d), and COD removal efficiency (95 %) than the multi-step feeding SBR (73 %, 0.39 kg/m3/d, and 95 %, respectively). This means the appropriate FA to selectively suppress NOB activity was successfully maintained in the one-step feeding SBR (FA > 1 mg/L). Therefore, it the necessary to apply a step feed strategy that can be maintained above FA (1 mg/L) from the start-up of operation to treat moderate-strength NH4+.

Green and Sustainable Hot Melt Adhesive (HMA) Based on Polyhydroxyalkanoate (PHA) and Silanized Cellulose Nanofibers (SCNFs).

Polyhydroxyalkanoate (PHA), with a long chain length and high poly(4-hydroxybutyric acid) (P4HB) ratio, can be used as a base polymer for eco-friendly and biodegradable adhesives owing to its high elasticity, elongation at break, flexibility, and processability; however, its molecular structures must be adjusted for adhesive applications. In this study, surface-modified cellulose nanofibers (CNFs) were used as a hydrophobic additive for the PHA-based adhesive. For the surface modification of CNFs, double silanization using tetraethyl orthosilicate (TEOS) and methyltrimethoxysilane (MTMS) was performed, and the thermal and structural properties were evaluated. The hydrophobicity of the TEOS- and MTMS-treated CNFs (TMCNFs) was confirmed by FT-IR and water contact angle analysis, with hydrophobic CNFs well dispersed in the PHA. The PHA-CNFs composite was prepared with TMCNFs, and its morphological analysis verified the good dispersion of TMCNFs in the PHA. The tensile strength of the composite was enhanced when 10% TMCNFs were added; however, the viscosity decreased as the TMCNFs acted as a thixotropic agent. Adding TMCNFs to PHA enhanced the flowability and infiltration ability of the PHA-TMCNFs-based adhesive, and an increase in the loss tangent (Tan δ) and adjustment of viscosity without reducing the adhesive strength was also observed. These changes in properties can improve the flowability and dispersibility of the PHA-TMCNFs adhesive on a rough adhesive surface at low stress. Thus, it is expected that double-silanized CNFs effectively improve their interfacial adhesion in PHA and the adhesive properties of the PHA-CNFs composites, which can be utilized for more suitable adhesive applications.

Structural basis for the interaction between unfarnesylated progerin and the Ig-like domain of lamin A/C in premature aging disorders.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by C-terminally truncated lamin A, termed as the pre-progerin product. Progerin is a C-terminally farnesylated protein derived from pre-progerin, which causes nuclear deformation at the inner-nuclear membrane. As an alternative or additional mechanism, a farnesylation-independent abnormal interaction between the C-terminus of progerin and Ig-like domain has been proposed. However, the molecular mechanism underlying the role of unfarnesylated C-terminus of pre-progerin in HGPS remains largely unknown. In this study, we determined the crystal structures of C-terminal peptide of progerin and Ig-like domain of lamin A/C. Results showed that the C-terminal cysteine residue of progerin forms a disulfide bond with the only cysteine residue of the Ig-like domain. This finding suggested that unfarnesylated progerin can form a disulfide bond with the Ig-like domain in the lamin meshwork. The Alphafold2-assisted docking structure showed that disulfide bond formation was promoted by a weak interaction between the groove of Ig-like domain and the unfarnesylated C-terminal tail region of progerin. Our results provide molecular insights into the normal aging process as well as premature aging of humans.

Transplantation of Differentiated Tonsil-Derived Mesenchymal Stem Cells Ameliorates Murine Duchenne Muscular Dystrophy via Autophagy Activation.

BACKGROUND: Skeletal muscles play many important roles in the human body and any malfunction or disorder of the skeletal muscles can lead to a reduced quality of life. Some skeletal dysfunctions are acquired, such as sarcopenia but others are congenital. Duchenne muscular dystrophy (DMD) is one of the most common forms of hereditary muscular dystrophy and is caused by a deficiency of the protein, Dystrophin. Currently, there is no clear treatment for DMD, there are only methods that can alleviate the symptoms of the disease. Mesenchymal stem cells, including tonsil-derived mesenchymal stem cells (TMSCs) have been shown to differentiate into skeletal muscle cells (TMSC-myocyte) and can be one of the resources for the treatment of DMD. Skeletal muscle cell characteristics of TMSC-myocytes have been confirmed through changes in morphology and expression of skeletal muscle markers such as Myogenin, Myf6, and MYH families after differentiation. MEOTHDS: Based on these characteristics, TMSC-myocytes have been transplanted into mdx mice, a mouse model of DMD, to investigate whether they can help improve the symptoms of DMD. The red fluorescent protein gene was transduced into TMSC (TMSC-R) for tracking transplanted cells. RESULTS: Prior to transplantation (TP), it was confirmed whether TMSC-R-myocytes had the same differentiation potential as TMSC-myocytes. Increased expression of dystrophin and autophagy markers in the TP group compared with the sham group was confirmed in the gastrocnemius muscle 12 weeks after TP. CONCLUSION: These results demonstrate muscle regeneration and functional recovery of mdx via autophagy activation following TMSC-myocyte TP.

Cyclin-dependent kinase 1 depolymerizes nuclear lamin filaments by disrupting the head-to-tail interaction of the lamin central rod domain.

Nuclear lamins maintain the nuclear envelope structure by forming long linear filaments via two alternating molecular arrangements of coiled-coil dimers, known as A11 and A22 binding modes. The A11 binding mode is characterized by the antiparallel interactions between coil 1b domains, whereas the A22 binding mode is facilitated by interactions between the coil 2 domains of lamin. The junction between A11- and A22-interacting dimers in the lamin tetramer produces another parallel head-tail interaction between coil 1a and the C-terminal region of coil 2, called the ACN interaction. During mitosis, phosphorylation in the lamin N-terminal head region by the cyclin-dependent kinase (CDK) complex triggers depolymerization of lamin filaments, but the associated mechanisms remain unknown at the molecular level. In this study, we revealed using the purified proteins that phosphorylation by the CDK1 complex promotes disassembly of lamin filaments by directly abolishing the ACN interaction between coil 1a and the C-terminal portion of coil 2. We further observed that this interaction was disrupted as a result of alteration of the ionic interactions between coil 1a and coil 2. Combined with molecular modeling, we propose a mechanism for CDK1-dependent disassembly of the lamin filaments. Our results will help to elucidate the cell cycle-dependent regulation of nuclear morphology at the molecular level.

AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells.

Our team has previously reported a series of quinazoline-based lapatinib hybrids as potent kinase-targeting anticancer agents. Among them, AF8c showed a relatively safe profile in colorectal cancer (CRC) cells. In this study, we delineate a novel anticancer activity of AF8c in CRC cells. AF8c mediated p53-dependent apoptosis of CRC cells via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), among others. The silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of a CRC mice model with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. In comparison with lapatinib, AF8c showed higher cellular antiproliferative activity at the tested concentrations in CRC cells and synergized TRAIL effects in CRC cells. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC cells. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC.

Toward Improving Working Conditions to Enhance Professionalism of Convention Workers: Focusing on the Difference between Job Satisfaction and Job Performance According to Professionalism Perception.

In recent years, the importance of professionalism of convention workers has been rapidly emerging. Therefore, the purpose of this study is to establish a strategy for strengthening the professionalism of convention workers. For this, the study investigates if there are any differences in job satisfaction and job performance based on the segmented groups of professionalism perception of convention workers. The results of factor analysis showed six underlying dimensions of professionalism perception of convention workers. Cluster analysis showed that there were different segmented groups of professionalism perception: high level (cluster 1), low level (cluster 2), moderate level (cluster 3). Lastly, MANOVA showed that there were differences in job satisfaction and job performance among the segmented groups. More theoretical and practical implications are discussed in the conclusion.

Determination of methanogenesis by nutrient availability via regulating the relative fitness of methanogens in anaerobic digestion.

Response of microbial community to nutrient availability in anaerobic digestion (AD) remains elusive. Prokaryotic communities in AD batch cultures with 0, 1, 3, 5, 7, 11, 15, 20, and 25 g/L peptone were monitored using massive parallel sequencing and quantitative PCR over a 34-day experimental period. Methane production displayed a hump-shaped response to the nutrient gradient (peaking at 15 g/L peptone). Moreover, total and acetoclastic methanogens showed hump-shaped responses (both peaking at 11 g/L peptone). However, prokaryotic population increased with nutrient concentration (linear regression, R2 = 0.86) while diversity decreased (R2 = 0.94), and ordination analysis showed a gradual succession of community structure along the first axis. Network analysis revealed that extent of interspecific interactions (e.g., edge number and clustering coefficient) exhibited a hump-shaped response. The combined results indicate that abundant species became more dominated with increasing nutrient, which can result in a gain or loss of interspecific interaction within the community. Network module analysis showed that one module dominated the network at each nutrient level (comprising 41%-65% of the nodes), indicating that AD community formed a core microbial guild. The most abundant phylotypes, Macellibacteroides and Butyricicoccaceae, were consistently negative with acetoclastic methanogens in the dominant modules. Their predominance at ≥15 g/L peptone can explain the hump-shaped responses of methanogenesis and methanogens. Collectively, methanogenesis and microbial network exhibited hump-shaped responses, although microbial community exhibited monotonic responses. Therefore, nutrient availability can determine the methanogenesis through regulating the relative fitness of methanogens within the community.