Depletion of proteasome subunit PSMD1 induces cancer cell death via protein ubiquitination and DNA damage, irrespective of p53 status.

Hepatocellular carcinoma (HCC) is characterized by high incidence and fatality rates worldwide. In our exploration of prognostic factors in HCC, the 26s proteasome subunit, non-ATPase 1 (PSMD1) protein emerged as a significant contributor, demonstrating its potential as a therapeutic target in this aggressive cancer. PSMD1 is a subunit of the 19S regulatory particle in the 26S proteasome complex; the 19S particle controls the deubiquitination of ubiquitinated proteins, which are then degraded by the proteolytic activity of the complex. Proteasome-targeting in cancer therapy has received significant attention because of its practical application as an established anticancer agent. We investigated whether PSMD1 plays a critical role in cancer owing to its prognostic significance. PSMD1 depletion induced cell cycle arrest in G2/M phase, DNA damage and apoptosis of cancer cells, irrespective of the p53 status. PSMD1 depletion-mediated cell death was accompanied by an increase in overall protein ubiquitination. These phenotypes occurred exclusively in cancer cells, with no effects observed in normal cells. These findings indicate that PSMD1 depletion-mediated ubiquitination of cellular proteins induces cell cycle arrest and eventual death in cancer cells, emphasizing PSMD1 as a potential therapeutic target in HCC.

Comparison of blood parameters according to fecal detection of Mycobacterium avium subspecies paratuberculosis in subclinically infected Holstein cattle.

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) causes a chronic and progressive granulomatous enteritis and economic losses in dairy cattle in subclinical stages. Subclinical infection in cattle can be detected using serum MAP antibody enzyme-linked immunosorbent assay (ELISA) and fecal polymerase chain reaction (PCR) tests. OBJECTIVES: To investigate the differences in blood parameters, according to the detection of MAP using serum antibody ELISA and fecal PCR tests. METHODS: We divided 33 subclinically infected adult cattle into three groups: seronegative and fecal-positive (SNFP, n = 5), seropositive and fecal-negative (SPFN, n = 10), and seropositive and fecal-positive (SPFP, n = 18). Hematological and serum biochemical analyses were performed. RESULTS: Although the cows were clinically healthy without any manifestations, the SNFP and SPFP groups had higher platelet counts, mean platelet volumes, plateletcrit, lactate dehydrogenase levels, lactate levels, and calcium levels but lower mean corpuscular volume concentration than the SPFN group (p < 0.017). The red blood cell count, hematocrit, monocyte count, glucose level, and calprotectin level were different according to the detection method (p < 0.05). The SNFP and SPFP groups had higher red blood cell counts, hematocrit and calprotectin levels, but lower monocyte counts and glucose levels than the SPFN group, although there were no significant differences (p > 0.017). CONCLUSIONS: The cows with fecal-positive MAP status had different blood parameters from those with fecal-negative MAP status, although they were subclinically infected. These findings provide new insights into understanding the mechanism of MAP infection in subclinically infected cattle.

A Cell-Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer-Specific Synthetic Lethality.

Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof-of-principle evidence is presented that a cell-penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene-addicted cancer cells through transcription activity-independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2-p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome-wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C-resistant cancers. This study enhances the understanding of ACP52C-induced cancer-specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

Development and application of novel peptide-formulated nanoparticles for treatment of atopic dermatitis.

Atopic dermatitis is a chronic inflammatory skin condition that is characterized by skin inflammation, itching, and redness. Although various treatments can alleviate symptoms, they often come with side effects, highlighting the need for new treatments. Here, we discovered a new peptide-based therapy using the intra-dermal delivery technology (IDDT) platform developed by Remedi Co., Ltd (REMEDI). The platform screens and identifies peptides derived from proteins in the human body that possess cell-penetrating peptide (CPP) properties. We screened over 1000-peptides and identified several derived from the Speckled protein (SP) family that have excellent CPP properties and have anti-inflammatory effects. We assessed these peptides for their potential as a treatment for atopic dermatitis. Among them, the RMSP1 peptide showed the most potent anti-inflammatory effects by inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways while possessing CPP properties. To further improve efficacy and stability, we developed a palmitoylated version called Pal-RMSP1. Formulation studies using liposomes (Pal-RMSP1 LP) and micelles (Pal-RMSP1 DP) demonstrated improved anti-inflammatory effects in vitro and enhanced therapeutic effects in vivo. Our study indicates that nano-formulated Pal-RMSP1 could have the potential to become a new treatment option for atopic dermatitis.

A Comparative Analysis of Pain Control Methods after Ankle Fracture Surgery with a Peripheral Nerve Block: A Single-Center Randomized Controlled Prospective Study.

Background and Objectives: Patients experience severe pain after surgical correction of ankle fractures. Although their exact mechanism is unknown, dexamethasone and epinephrine increase the analgesic effect of anesthetics in peripheral nerve blocks. This study aimed to compare the postoperative pain control efficacy of peripheral nerve blocks with ropivacaine combined with dexamethasone/epinephrine and peripheral nerve blocks with only ropivacaine and added patient-controlled analgesia in patients with ankle fractures. Materials and Methods: This randomized, controlled prospective study included patients aged 18-70 years surgically treated for ankle fractures between December 2021 and September 2022. The patients were divided into group A (n = 30), wherein pain was controlled using patient-controlled analgesia after lower extremity peripheral nerve block, and group B (n = 30), wherein dexamethasone/epinephrine was combined with the anesthetic solution during peripheral nerve block. In both groups, ropivacaine was used as the anesthetic solution for peripheral nerve block, and this peripheral nerve block was performed just before ankle surgery for the purpose of anesthesia for surgery. Pain (visual analog scale), patient satisfaction, and side effects were assessed and compared between the two groups. Results: The patients' demographic data were similar between groups. Pain scores were significantly lower in group B than in group A postoperatively. Satisfaction scores were significantly higher in group B (p = 0.003). There were no anesthesia-related complications in either group. Conclusions: Dexamethasone and epinephrine as adjuvant anesthetic solutions can effectively control pain when performing surgery using peripheral nerve blocks for patients with ankle fractures.

Feasibility of 3D-Printed Locking Compression Plates with Polyether Ether Ketone (PEEK) in Tibial Comminuted Diaphyseal Fractures.

The applicability of a polyether ether ketone locking compression plate (PEEK LCP) fabricated using FDM (fused deposition modeling)-based 3D printing to treat actual patients was studied. Three different tests-bending, axial compression, and axial torsion-were conducted on tibial non-osteoporotic comminuted diaphyseal fracture samples fixed with the commercial titanium alloy LCP and 3D-printed PEEK LCP. Comparing the outcomes of these tests revealed that the commercial titanium alloy LCP underwent plastic deformation in the bending and axial torsion tests, though the LCP did not fail even when an external force greater than the maximum allowable load of the tibia fixture of the LCP was applied. Elastic deformation occurred in the 3D-printed PEEK LCP in the bending and axial torsion tests. However, deformation occurred even under a small external force, and its stiffness was 10% compared to commercial titanium alloy LCP. Thus, 3D-printed PEEK LCP can be applied to the fracture conditions in non-weight-bearing regions. The experimental results reveal detailed insights into the treatment of actual patients by considering the stiffness and high toughness of 3D-printed PEEK LCP.

Neurog1-Derived Peptides RMNE1 and DualPep-Shine Penetrate the Skin and Inhibit Melanin Synthesis by Regulating MITF Transcription.

Anti-pigmentation peptides have been developed as alternative skin-lightening agents to replace conventional chemicals that have adverse effects on the skin. However, the maximum size of these peptides is often limited by their low skin and cell penetration. To address this issue, we used our intra-dermal delivery technology (IDDT) platform to identify peptides with hypo-pigmenting and high cell-penetrating activity. Using our cell-penetrating peptides (CPPs) from the IDDT platform, we identified RMNE1 and its derivative RMNE3, "DualPep-Shine", which showed levels of α-Melanocyte stimulating hormone (α-MSH)-induced melanin inhibition comparable to the conventional tyrosinase inhibitor, Kojic acid. In addition, DualPep-Shine was delivered into the nucleus and regulated the gene expression levels of melanogenic enzymes by inhibiting the promoter activity of microphthalmia-associated transcription factor-M (MITF-M). Using a 3D human skin model, we found that DualPep-Shine penetrated the lower region of the epidermis and reduced the melanin content in a dose-dependent manner. Furthermore, DualPep-Shine showed high safety with little immunogenicity, indicating its potential as a novel cosmeceutical ingredient and anti-pigmentation therapeutic agent.

Difference in Joint Stability Between Small Posterior Malleolar Fragments With Fixation and Those Without Fixation: A Biomechanical Cadaver Study.

The indication for the surgical treatment of ankle fractures that involve a posterior malleolar fragment remains controversial. This cadaver study assessed the biomechanical results of rotation stiffness of Haraguchi type 1 posterior malleolar fragments with or without cannulated screw fixation. Twelve anatomic lower-extremity specimens from 6 cadavers were tested. Six right legs were subjected to posterior malleolus osteotomy (Haraguchi type I) followed with (group A; n = 3) or without (group B; n = 3) fixation using a cannulated screw. Ankle joint stability was measured under both external rotation force and axial loading, and the passive resistive torque was measured in both groups. The mean torque value in group A was 0.1093 Nm/º, while that in group B was 0.0537 Nm/º. There was a significant intergroup difference (p = .004). In group B, the torque value was further increased in the latter rotation period (about 40-60 degrees). Group A proved more stable under experimental conditions than group B. Fixation in type I posterior malleolar fragments produced improved stability in ankle rotation, even for posterior malleolar fragments involving <25% of the articular surface, and has been considered an effective aid in treatment.

NPFFR2 Contributes to the Malignancy of Hepatocellular Carcinoma Development by Activating RhoA/YAP Signaling.

G protein-coupled receptors (GPCRs) are a diverse family of cell surface receptors implicated in various physiological functions, making them common targets for approved drugs. Many GPCRs are abnormally activated in cancers and have emerged as therapeutic targets for cancer. Neuropeptide FF receptor 2 (NPFFR2) is a GPCR that helps regulate pain and modulates the opioid system; however, its function remains unknown in cancers. Here, we found that NPFFR2 is significantly up-regulated in liver cancer and its expression is related to poor prognosis. Silencing of NPFFR2 reduced the malignancy of liver cancer cells by decreasing cell survival, invasion, and migration, while its overexpression increased invasion, migration, and anchorage-independent cell growth. Moreover, we found that the malignant function of NPFFR2 depends on RhoA and YAP signaling. Inhibition of Rho kinase activity completely restored the phenotypes induced by NPFFR2, and RhoA/F-Actin/YAP signaling was controlled by NPFFR2. These findings demonstrate that NPFFR2 may be a potential target for the treatment of hepatocellular carcinoma.

Selective cytotoxicity of a novel mitochondrial complex I inhibitor, YK-135, against EMT-subtype gastric cancer cell lines due to impaired glycolytic capacity.

Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancers have the worst prognosis due to their higher recurrence rate, higher probability of developing metastases and higher chemoresistance compared to those of other molecular subtypes. Pharmacologically actionable somatic mutations are rarely found in EMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screen using 37 gastric cancer cell lines and 48,467 synthetic smallmolecule compounds. We identified YK-135, a small-molecule compound that showed higher cytotoxicity toward EMT-subtype gastric cancer cell lines than toward non-EMT-subtype gastric cancer cell lines. YK-135 exerts its cytotoxic effects by inhibiting mitochondrial complex I activity and inducing AMP-activated protein kinase (AMPK)-mediated apoptosis. We found that the lower glycolytic capacity of the EMT-subtype gastric cancer cells confers synthetic lethality to the inhibition of mitochondrial complex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenone and phenformin) mimic the efficacy of YK-135, supporting our results. These findings highlight mitochondrial complex I inhibitors as promising therapeutic agents for EMT-subtype gastric cancers and YK-135 as a novel chemical scaffold for further drug development. [BMB Reports 2022; 55(12): 645-650].

Exosomal Communication Between the Tumor Microenvironment and Innate Immunity and Its Therapeutic Application.

Exosomes, which are well-known nanoscale extracellular vesicles, are multifunctional biomaterials derived from endosomes and perform various functions. The exosome is a critical material in cell-cell communication. In addition, it regulates the pathophysiological conditions of the tumor microenvironment in particular. In the tumor microenvironment, exosomes play a controversial role in supporting or killing cancer by conveying biomaterials derived from parent cells. Innate immunity is a crucial component of the host defense mechanism, as it prevents foreign substances, such as viruses and other microbes and tumorigenesis from invading the body. Early in the tumorigenesis process, the innate immunity explicitly recognizes the tumor via Ags and educates the adaptive immunity to eliminate it. Recent studies have revealed that exosomes regulate immunity in the tumor microenvironment. Tumor-derived exosomes regulate immunity against tumor progression and metastasis. Furthermore, tumor-derived exosomes regulate polarization, differentiation, proliferation, and activation of innate immune cells. Exosomes produced from innate immune cells can inhibit or support tumor progression and metastasis via immune cell activation and direct cancer inhibition. In this study, we investigated current knowledge regarding the communication between tumor-derived exosomes and innate immune cell-derived exosomes (from macrophages, dendritic cells, NK cells, and neutrophils) in the tumor microenvironment. In addition, we discussed the potential development of exosomal immunotherapy using native or engineered exosomes against cancer.

Functional outcomes of residual varus alignment versus mechanical alignment in total knee arthroplasty for varus osteoarthritis: A preferred reporting items for systematic reviews and meta-analyses-compliant meta-analysis.

BACKGROUND: One in five patients with mechanical alignment (MA) after total knee arthroplasty (TKA) was reportedly dissatisfied. As constitutional varus knees are common, restoring the patients' natural residual varus (RV) alignment is as an appealing alternative to neutral MA. This meta-analysis aimed to evaluate the effects of RV alignment on the functional outcomes compared with those of MA in TKA for the knees with varus osteoarthritis. METHODS: The MEDLINE/PubMed, Cochrane Library, and EMBASE databases were comprehensively searched for papers comparing the effects of RV alignment and MA on the functional outcomes from the time of inception of the databases to July 2020. Studies comparing the functional outcomes in the knees subjected to TKA with RV alignment (case group) and MA (control group) were included. The Knee Society knee and functional scores (KSKS and KSFS, respectively), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Oxford knee score (OKS), and forgotten joint score (FJS) were compared. RESULTS: Seven studies were finally included; all studies showed a low risk of selection bias and provided detailed demographic data. The pooled mean difference in the KSKS (0.06, 95% confidence interval [CI]: -0.14 to 0.27; p = 0.55) and KSFS (0.08, 95% CI: -0.08 to 0.35; p = 0.56) between RV alignment and MA did not significantly differ. The pooled mean differences in the WOMAC (-0.25, 95% CI: -0.57 to 0.07; p = 0.12), OKS (0.06, 95% CI: -0.15 to 0.27; p = 0.56), and FJS (0.41, 95% CI: -0.18 to 1.00; p = 0.18) between the groups were not significant. CONCLUSION: The beneficial effects of RV alignment on the functional outcomes are limited compared to those of MA in TKA for varus osteoarthritis to date. Currently, TKA with neutral MA should be considered as the gold standard.

Snail acetylation by autophagy-derived acetyl-coenzyme A promotes invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells.

BACKGROUND: Autophagy is elevated in metastatic tumors and is often associated with active epithelial-to-mesenchymal transition (EMT). However, the extent to which EMT is dependent on autophagy is largely unknown. This study aimed to identify the mechanisms by which autophagy facilitates EMT. METHODS: We employed a liquid chromatography-based metabolomic approach with kirsten rat sarcoma viral oncogene (KRAS) and liver kinase B1 (LKB1) gene co-mutated (KL) cells that represent an autophagy/EMT-coactivated invasive lung cancer subtype for the identification of metabolites linked to autophagy-driven EMT activation. Molecular mechanisms of autophagy-driven EMT activation were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting analysis, immunoprecipitation, immunofluorescence staining, and metabolite assays. The effects of chemical and genetic perturbations on autophagic flux were assessed by two orthogonal approaches: microtubule-associated protein 1A/1B-light chain 3 (LC3) turnover analysis by Western blotting and monomeric red fluorescent protein-green fluorescent protein (mRFP-GFP)-LC3 tandem fluorescent protein quenching assay. Transcription factor EB (TFEB) activity was measured by coordinated lysosomal expression and regulation (CLEAR) motif-driven luciferase reporter assay. Experimental metastasis (tail vein injection) mouse models were used to evaluate the impact of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) or ATP citrate lyase (ACLY) inhibitors on lung metastasis using IVIS luciferase imaging system. RESULTS: We found that autophagy in KL cancer cells increased acetyl-coenzyme A (acetyl-CoA), which facilitated the acetylation and stabilization of the EMT-inducing transcription factor Snail. The autophagy/acetyl-CoA/acetyl-Snail axis was further validated in tumor tissues and in autophagy-activated pancreatic cancer cells. TFEB acetylation in KL cancer cells sustained pro-metastatic autophagy in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner. Pharmacological inhibition of this axis via CAMKK2 inhibitors or ACLY inhibitors consistently reduced the metastatic capacity of KL cancer cells in vivo. CONCLUSIONS: This study demonstrates that autophagy-derived acetyl-CoA promotes Snail acetylation and thereby facilitates invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells and that inhibition of the autophagy/acetyl-CoA/acetyl-Snail axis using CAMKK2 or ACLY inhibitors could be a potential therapeutic strategy to suppress metastasis of KL lung cancer.

Risk factors for postoperative pneumonia in patients undergoing hip fracture surgery: a systematic review and meta-analysis.

BACKGROUND: Postoperative pneumonia (POP) is a devastating complication that can frequently occur after hip fracture surgery. This study aimed to quantitatively and comprehensively summarize the risk factors for POP following hip fracture surgery. METHODS: PubMed, Embase, and Cochrane Library were systematically searched for studies assessing risk factors for POP following hip fracture surgery. The pooled odds ratio (OR) and standardized mean difference (SMD) between patients with and without POP were calculated. Evidence was assessed using the Newcastle-Ottawa scale. RESULTS: Ten studies including 37,130 patients with hip fractures were selected. POP occurred in 1768 cases with an accumulated incidence of 7.8% (95% confidence interval [CI]: 0.061-0.094). Advanced age (SMD: 0.50, 95% CI: 0.10-0.90), male sex (OR: 1.50, 95% CI: 1.12-2.01), American Society of Anesthesiologists physical status scale ≥3 (OR: 3.17, 95% CI: 1.25-8.05), chronic obstructive pulmonary disease (OR: 2.05, 95% CI: 1.43-2.94), coronary heart disease (OR: 1.82, 95% CI: 1.27-2.60), arrhythmia (OR: 1.49, 95% CI: 1.04-2.15), congestive heart failure (OR: 1.41, 95% CI: 1.14-1.75), chronic kidney disease (OR: 2.09, 95% CI: 1.28-3.41), and cerebrovascular accident (OR: 2.14, 95% CI: 1.60-2.85) were risk factors for POP. Hemoglobin (SMD: -0.14, 95% CI: - 0.25 to - 0.03), albumin (SMD: -0.97, 95% CI: - 1.54--0.41), blood urea nitrogen (SMD: 0.20, 95% CI: 0.03-0.37), alanine aminotransferase (SMD: 0.27, 95% CI: 0.10-0.44), arterial oxygen pressure (SMD: -0.49, 95% CI: - 0.71--0.27), time from injury to surgery (SMD: 0.13, 95% CI: 0.08-0.17), and surgery within 48 h (OR: 3.74, 95% CI: 2.40-5.85) were associated with the development of POP. CONCLUSION: Patients with the aforementioned risk factors should be identified preoperatively, and related prophylaxis strategies should be implemented to prevent POP following hip fracture surgery.

Two distinct receptor-binding domains of human glycyl-tRNA synthetase 1 displayed on extracellular vesicles activate M1 polarization and phagocytic bridging of macrophages to cancer cells.

Macrophages play important roles in cancer microenvironment. Human cytosolic glycyl-tRNA synthetase (GARS1) was previously shown to be secreted via extracellular vesicles (EVs) from macrophages to trigger cancer cell death. However, the effects of GARS1-containing EVs (GARS1-EVs) on macrophages as well as on cancer cells and the working mechanisms of GARS1 in cancer microenvironment are not yet understood. Here we show that GARS1-EVs induce M1 polarization and facilitate phagocytosis of macrophages. GARS1-EVs triggers M1 polarization of macrophage via the specific interaction of the extracellular cadherin subdomains 1-4 of the cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) with the N-terminal WHEP domain containing peptide region of GARS1, and activates the RAF-MEK-ERK pathway for M1 type cytokine production and phagocytosis. Besides, GARS1 interacted with cadherin 6 (CDH6) of cancer cells via its C-terminal tRNA-binding domain to induce cancer cell death. In vivo model, GARS1-EVs showed potent suppressive activity against tumor initiation via M1 type macrophages. GARS1 displayed on macrophage-secreted extracellular vesicles suppressed tumor growth in dual mode, namely through pro-apoptotic effect on cancer cells and M1 polarization effect on macrophages. Collectively, these results elucidate the unique tumor suppressive activity and mechanism of GARS1-EVs by activating M1 macrophage via CELSR2 as well as by direct killing of cancer cells via CDH6.

Function and therapeutic development of exosomes for cancer therapy.

Exosomes are extracellular vesicles, 50-150 nm in diameter, released by most cells. Exosomes contain several intracellular components, including DNA, RNA, and proteins, which reflect the parent cell's status and contribute to intercellular communication. Cancers are associated with high morbidity and mortality rates worldwide. Owing to a high survival rate, cancer treatment by immune modulation of the tumor microenvironment has recently received a lot of attention. Exosomes' role in immunological control is also being studied extensively. Exosomes play a role in cancer-immune cell communication. Through intracellular communication, exosomes promote tumor growth, metastasis, angiogenesis, and drug resistance. In addition, innate immune cell-derived exosomes and adaptive immune cell exosomes have an anti-tumorigenic activity. Exosome-related tumor microenvironment drugs are being developed, including inhibitors of exosomal release, tumor-derived exosomes, and immune cell-derived exosome engineering, although there are still some obstacles to overcome. We describe in this review the significance of exosomes in the tumor microenvironment. We also summarize current studies on anticancer immune drug development and the challenges in developing exosome-related drugs.

Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure.

Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR1-5). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds 1-20 of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (1-10) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (11-20) showed poor anticancer effect. Compound 10, having the highest cytotoxic effect (48 h, HT29 IC50 = 6.223 µM, HCT116 IC50 = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound 10 inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound 10 increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds 11 and 13 had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities.

A novel vertebroplasty technique using a larger-diameter needle for thoracolumbar osteoporotic vertebral compression fracture.

ABSTRACT: Percutaneous vertebroplasty (VP) and kyphoplasty (KP) are well-established minimally invasive surgical procedures for the treatment of osteoporotic vertebral compression fractures (OVCF). However, some drawbacks have been reported regarding these procedures, including height loss, cement leakage, and loss of the restored height after balloon deflation. We performed a novel VP technique to minimize these limitations of conventional procedures. This study aimed to compare radiological and clinical outcomes of our method using a larger-diameter needle versus conventional VP (using a smaller needle) for thoracolumbar OVCF.From April 2016 to May 2017, 107 consecutive patients diagnosed with thoracolumbar OVCF were enrolled. Patients were divided into two groups: group 1 underwent conventional VP, i.e., using a smaller diameter needle, and group 2 underwent VP through a modified method with a larger-diameter needle. For radiological evaluation, parameters related to anterior vertebral height (AVH) and segmental angle were assessed using plain standing radiographs, and patient-reported outcomes were evaluated using the visual analog scale. Cement injection amount and leakage pattern were also analyzed. Group 2 showed a larger anterior vertebral height change than group 1 immediately postoperatively and one year postoperatively. The 1-year postoperatively-AVH maintained better in group 2 than in group 1. Group 2 showed more significant improvement of segmental angle immediately postoperatively than group 1 (3.15° in group 1 vs 9.36° in group 2). IYPo-visual analog scale significantly improved in both groups, with greater improvement in group 2 (3.69 in group 1 vs 5.63 in group 2). A substantially larger amount of cement was injected, with a lower leakage rate in group 2 than in group 1.A novel VP technique using a larger-diameter needle showed superior radiological and clinical outcomes than conventional VP. Therefore, it can be considered a useful treatment option for OVCF.

Clinical Outcomes of Biportal Endoscopic Interlaminar Decompression with Oblique Lumbar Interbody Fusion (OLIF): Comparative Analysis with TLIF.

Oblique lumbar interbody fusion (OLIF) improves the spinal canal, with favorable clinical outcomes. However, it may not be useful for treating concurrent, severe central canal stenosis (SCCS). Therefore, we added biportal endoscopic spinal surgery (BESS) after OLIF, evaluated the combined procedure for one-segment fusion with clinical outcomes, and compared it to open conventional TLIF. Patients were divided into two groups: Group A underwent BESS with OLIF, and Group B were treated via TLIF. The length of hospital stay (LOS), follow-up period, operative time, estimated blood loss (EBL), fusion segment, complications, and clinical outcomes were evaluated. Clinical outcomes were measured using Visual Analog Scale (VAS) scores, Oswestry Disability Index (ODI) scores, and the modified Macnab criteria. All the clinical parameters improved significantly after the operation in Group A. The only significant between-group difference was that the EBL was significantly lower in Group A. At the final follow-up, no clinical parameter differed significantly between the groups. No complications developed in either group. We suggest that our combination technique is a useful, alternative, minimally invasive procedure for the treatment of one-segment lumbar SCCS associated with foraminal stenosis or segmental instability.

Posterior tibial slope is a modifiable predictor of relatively large extension gaps in total knee arthroplasty for degenerative osteoarthritis.

BACKGROUND: During total knee arthroplasty (TKA) for osteoarthritis, the sagittal gap imbalance (SGI) with a relatively large extension gap is an important surgical challenge. We determined the predictors of SGI with a relatively large extension gap and evaluated the surgical outcomes of knees with SGI. METHODS: 551 consecutive cases of primary TKA for osteoarthritis were retrospectively reviewed. The cohort was divided into two groups according to the SGI and statistically matched according to baseline characteristics via the inverse probability of treatment weighting method. Multiple linear and logistic regression analyses were performed to determine the predictors of sagittal gap difference (SGD) and SGI. Intergroup differences in clinical and radiological outcomes were analyzed. RESULTS: Of all the knees included, 8.5% (n = 45) presented with SGI with a relatively large extension gap and required femoral sagittal balancing to manage SGI. The hyperextension angle (HA), preoperative joint line convergence angle (JLCA), and the change in posterior tibial slope (PTS) significantly correlated to SGD and predicted SGI with a relatively large extension gap. SGI group showed significant changes in femoral posterior condylar offset and joint line height compared to those without SGI (1.48 vs -0.45, 1.37 vs -0.51, respectively). Postoperative ROM and knee society knee scores were lower in SGI group. CONCLUSION: Knees requiring sagittal balancing to manage SGI with a relatively large extension gap is not uncommon in TKA for osteoarthritic knees. The change in PTS is an independent and modifiable predictor of SGI.