Oral Colchicine and Low-Dose Aspirin Combination Therapy for Non-elderly, Non-severe, Early Time From Onset, Adult Outpatients with Coronavirus Disease 2019 (COVID-19) during "The Fifth Pandemic Wave" in Japan.

BACKGROUND: Treatment with antiviral drugs for non-severe, early time from onset, adult outpatients with Coronavirus Disease 2019 (COVID-19) had not been established in 2021. However, some new variants of SARS-CoV-2 had caused rapid exacerbation and hospitalization among non-elderly outpatients with COVID-19, contributing to widespread crises within healthcare systems. METHODS: From July to October 2021, we urgently assessed a therapeutic program using oral colchicine (1.0 mg loading dose, followed approximately half a day later by 0.5 mg twice daily for 5 days, and then 0.5 mg once daily for 4 days) and low-dose aspirin (100 mg once daily for 10 days), for non-elderly, non-severe, early time from onset, adult outpatients with COVID-19. To verify its effectiveness, we set loxoprofen as a control arm, and com parison of these two arms was performed. The primary outcomes were hospitalization, criticality, and death rates. RESULTS: Thirty-eight patients (23 receiving colchicine and low-dose aspirin [CA]; 15 receiving loxoprofen [LO]) were evaluated. Hospitalization rate was lower in the CA group (1/23; 4.3%) than in the LO group (2/15; 13.3%); however, no significant difference was found between the two groups (p=0.34). No critical cases, deaths, or severe adverse events were found in either group. CONCLUSIONS: Our CA regimen did not show superiority over LO treatment. However, our clinical experience should be recorded as part of community health care activities carried out in Kurume City against the unprece dented COVID-19 pandemic.

STING activator 2'3'-cGAMP enhanced HSV-1-based oncolytic viral therapy.

Oncolytic viruses (OVs) can selectively replicate in tumor cells and remodel the microenvironment of immunologically cold tumors, making them a promising strategy to evoke antitumor immunity. Similarly, agonists of the stimulator of interferon genes (STING)-interferon (IFN) pathway, the main cellular antiviral system, provide antitumor benefits by inducing the activation of dendritic cells (DC). Considering how the activation of the STING-IFN pathway could potentially inhibit OV replication, the use of STING agonists alongside OV therapy remains largely unexplored. Here, we explored the antitumor efficacy of combining an HSV-1-based OV, C-REV, with a membrane-impermeable STING agonist, 2'3'-GAMP. Our results demonstrated that tumor cells harbor a largely defective STING-IFN pathway, thereby preventing significant antiviral IFN induction regardless of the permeability of the STING agonist. In vivo, the combination therapy induced more proliferative KLRG1-high PD1-low CD8+ T-cells and activated CD103+ DC in the tumor site and increased tumor-specific CD44+ CD8+ T-cells in the lymph node. Overall, the combination therapy of C-REV with 2'3'-cGAMP elicited antitumor immune memory responses and significantly enhanced systemic antitumor immunity in both treated and non-treated distal tumors.

Acanthopanax senticosus ameliorates steatohepatitis through HNF4 alpha pathway activation in mice.

Non-alcoholic fatty liver disease is a common liver disease worldwide, and is associated with dysregulation of lipid metabolism, leading to inflammation and fibrosis. Acanthopanax senticosus Harms (ASH) is widely used in traditional medicine as an adaptogen food. We examined the effect of ASH on steatohepatitis using a high-fat diet mouse model. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet with ASH extract (ASHE). After 6 weeks, liver RNA transcriptome sequencing (RNA-Seq) was performed, followed by Ingenuity Pathway Analysis (IPA). Our findings revealed that mice fed a high-fat diet with 5% ASHE exhibited significantly reduced liver steatosis. These mice also demonstrated alleviated inflammation and reduced fibrosis in the liver. IPA of RNA-Seq indicated that hepatocyte nuclear factor 4 alpha (HNF4 alpha), a transcription factor, was the activated upstream regulator (P-value 0.00155, z score = 2.413) in the liver of ASHE-fed mice. Adenosine triphosphate binding cassette transporter 8 and carboxylesterase 2, downstream targets of HNF4 alpha pathway, were upregulated. Finally, ASHE-treated HepG2 cells exposed to palmitate exhibited significantly decreased lipid droplet contents. Our study provides that ASHE can activate HNF4 alpha pathway and promote fat secretion from hepatocytes, thereby serving as a prophylactic treatment for steatohepatitis in mice.

Induction of SGK1 via glucocorticoid-influenced clinical outcome of triple-negative breast cancer patients.

PURPOSE: Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive breast malignancy. Glucocorticoid (GC)-glucocorticoid receptor (GR) pathway plays a pivotal role in the cellular responses to various stresses including chemotherapy. Serum- and glucocorticoid-induced kinase-1 (SGK1) is known as an important downstream effector molecule in the GR signaling pathway, we attempted to explore its clinicopathological and functional significance in TNBC in which GR is expressed. METHODS: We first immunolocalized GR and SGK1 and correlated the results with clinicopathological variables and clinical outcome in 131 TNBC patients. We also evaluated the effects of SGK1 on the cell proliferation and migration in TNBC cell lines with administration of dexamethasone (DEX) to further clarify the significance of SGK1. RESULTS: The status of SGK1 in carcinoma cells was significantly associated with adverse clinical outcome in TNBC patients examined and was significantly associated with lymph node metastasis, pathological stage, and lymphatic invasion of the patients. In particular, SGK1 immunoreactivity was significantly associated with an increased risk of recurrence in GR-positive TNBC patients. Subsequent in vitro studies also demonstrated that DEX promoted TNBC cell migration and the silencing of gene expression did inhibit the cell proliferation and migration of TNBC cells under DEX treatment. CONCLUSIONS: To the best of our knowledge, this is the first study to explore an association between SGK1 and clinicopathological variables and clinical outcome of TNBC patients. SGK1 status was significantly positively correlated with adverse clinical outcome of TNBC patients and promoted carcinoma cell proliferation and migration of carcinoma cells.

Postoperative Adjuvant Anastrozole for 10 or 5 Years in Patients With Hormone Receptor-Positive Breast Cancer: AERAS, a Randomized Multicenter Open-Label Phase III Trial.

PURPOSE: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS). PATIENTS AND METHODS: This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818). RESULTS: We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups. CONCLUSION: Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.

Allergenicity and Bioavailability of Nickel Nanoparticles Compared to Nickel Microparticles in Mice.

Metal allergy is a common disease that afflicts many people. Nevertheless, the mechanism underlying metal allergy development has not been completely elucidated. Metal nanoparticles might be involved in the development of a metal allergy, but the associated details are unknown. In this study, we evaluated the pharmacokinetics and allergenicity of nickel nanoparticles (Ni-NPs) compared with those of nickel microparticles (Ni-MPs) and nickel ions. After characterizing each particle, the particles were suspended in phosphate-buffered saline and sonicated to prepare a dispersion. We assumed the presence of nickel ions for each particle dispersion and positive control and orally administered nickel chloride to BALB/c mice repeatedly for 28 days. Results showed that compared with those in the Ni-MP administration group (MP group), the Ni-NP administration group (NP group) showed intestinal epithelial tissue damage, elevated serum interleukin (IL)-17 and IL-1ß levels, and higher nickel accumulation in the liver and kidney. Additionally, transmission electron microscopy confirmed the accumulation of Ni-NPs in the livers of both the NP and nickel ion administration groups. Furthermore, we intraperitoneally administered a mixed solution of each particle dispersion and lipopolysaccharide to mice and then intradermally administered nickel chloride solution to the auricle after 7 days. Swelling of the auricle was observed in both the NP and MP groups, and an allergic reaction to nickel was induced. Particularly in the NP group, significant lymphocytic infiltration into the auricular tissue was observed, and serum IL-6 and IL-17 levels were increased. The results of this study showed that in mice, Ni-NP accumulation in each tissue was increased after oral administration and toxicity was enhanced, as compared to those with Ni-MPs. Orally administered nickel ions transformed into nanoparticles with a crystalline structure and accumulated in tissues. Furthermore, Ni-NPs and Ni-MPs induced sensitization and nickel allergy reactions in the same manner as that with nickel ions, but Ni-NPs induced stronger sensitization. Additionally, the involvement of Th17 cells was suspected in Ni-NP-induced toxicity and allergic reactions. In conclusion, oral exposure to Ni-NPs results in more serious biotoxicity and accumulation in tissues than Ni-MPs, suggesting that the probability of developing an allergy might increase.

Histopathology of non-mass-like breast lesions on ultrasound.

There have been several investigations of non-mass-like (NML) lesions on ultrasound (US) since Uematsu first described this approach, and it is a relatively new concept for breast examination. However, the results have varied, and there have been only a few studies related to the detailed histopathology of NML lesions on US. Here, we review the histopathology of NML lesions. NML lesions are pathologically benign, atypical, or malignant. There are two major findings of NML lesions on US: architectural distortion and calcifications. Architectural distortion pathologically indicates a fibrous change with ductal proliferation, invasive breast carcinoma, and carcinoma in situ. Histopathologically, microcalcifications are seen in both benign and malignant lesions, and it is important to distinguish between these lesions among NML lesions, particularly fibrocystic changes including adenosis and hyperplasia in the case of benign lesions and carcinoma in situ (ductal and lobular) in the case of malignant lesions. The differential major points may be whether NML lesions are associated with abundant hyperechoic foci, which indicate comedo necrosis on histology. They are usually high-grade carcinoma in situ that may be positive for HER2 or triple negativity. A recent report indicated that low-grade carcinoma in situ showed better survival than higher-grade carcinoma in situ, which is often accompanied by comedo necrosis on histology, reflecting visible microcalcification on US. NML lesions are considered to include a certain rate of low-grade carcinoma in situ. Therefore, more caution may be needed when detecting and managing NML lesions to avoid overdiagnosis and overtreatment as a result of this recent "low-risk ductal carcinoma in situ" concept.

Effects of n-3 polyunsaturated fatty acid supplementation on quadriceps weakness immediately after total knee arthroplasty: a pilot, randomized, open-label clinical trial.

[Purpose] Severe quadriceps weakness immediately after total knee arthroplasty can be problematic. The n-3 long-chain polyunsaturated fatty acids have antioxidant and anti-inflammatory effects against ischemia-reperfusion injury, whereas n-6 long-chain polyunsaturated fatty acids exert pro-inflammatory effects, thereby promoting ischemia-reperfusion injury. [Participants and Methods] We explored the efficacy of preoperative n-3 long-chain polyunsaturated fatty acid supplementation against early quadriceps weakness among 20 patients scheduled for total knee arthroplasty (intervention group, n=10; control group, n=10). The intervention group received 645 mg of eicosapentaenoic acid) and 215 mg of docosahexaenoic acid daily for 30 days preoperatively. Serum eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were measured preoperatively. We compared serum derivatives of reactive oxygen metabolites as oxidative stress biomarkers, knee circumference, thigh volume, knee pain during the quadriceps strength test, and quadriceps strength preoperatively and 4 days postoperatively to quantify the change. [Results] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation significantly increased the (eicosapentaenoic acid+docosahexaenoic acid)/arachidonic acid ratio in the intervention group. A significantly lower increase in quadriceps weakness was exhibited in the intervention group than in the control group. However, changes in oxidative stress, knee/thigh swelling, and knee pain during strength testing did not significantly differ between the two groups. [Conclusion] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation exhibited beneficial effects on quadriceps weakness immediately after total knee arthroplasty.

Exploring the ethics of physical restraints: Students' questioning.

BACKGROUND: Physical restraints are routinely employed to ensure patient safety in Japanese acute care. Little is known about nursing students' perspectives and how they begin to question their value and knowledge in the face of restraint experiences in clinical practice. OBJECTIVE: To investigate nursing students' questions about patient restraints and how they understand the ethics of the use of restraints in nursing. RESEARCH DESIGN: Qualitative descriptive research using narrative analysis. PARTICIPANTS AND RESEARCH CONTEXT: Experiential data were generated and thematically analyzed from semi-structured interviews with 16 nursing students who had completed their bachelor's degree program requirements. ETHICAL CONSIDERATIONS: The study was approved by academic and clinical ethics agencies. Participants provided written informed consent. RESULTS: Physical restraints were encountered in 16 incidents, 3 with children and 13 with older patients with dementia. Students struggled to comprehend the policies and protocols of restraint use and worried their use was primarily for security rather than therapeutic purposes. Five themes were identified: (1). Questioning the tension between person-centered care, patient autonomy, and restraints, (2). Questioning the nature of restraints in which participants analyzed the policies and protocols around restraint use, (3). Questioning the professional nursing self whereby students reflected on how restraint use challenged their nursing values, and (4). Questioning professional nursing practice, in which students explored how restraints fit within a nursing perspective and positioned themselves as patient advocates. Students encountering physical restraints should ask questions based on values of patient-centeredness, autonomy, and advocacy. There is a need for education that facilitates reflection and questioning so that it informs students' ethical thinking which may enhance nurse advocacy to reduce restraint use. CONCLUSIONS: Restraints provide contexts in which students must face tensions between nursing values and clinical reality. Further research on nursing education strategies within non-psychiatric settings is needed to reduce physical restraints.

IgG4-related Inflammatory Pseudotumor with Imaging Findings Similar to Meningioma.

IgG4-related inflammatory pseudotumor is a feature of IgG4-related disease and develops in various organs. Intracranial IgG4-related inflammatory pseudotumor is rare, and data on the clinical course and response to treatment are insufficient in the literature. We herein report a patient with IgG4-related inflammatory pseudotumor who had magnetic resonance imaging findings similar to meningioma. Tumorectomy was discontinued because of the intraoperative rapid diagnosis, which revealed the infiltration of lymphocytes and plasma cells. She received oral prednisolone therapy for IgG4-related inflammatory pseudotumor, and the tumor size had significantly decreased after six months of treatment.

A Bioelectrical Impedance Analysis for the Assessment of Muscle Atrophy in Patients with Chronic Inflammatory Demyelinating Polyneuropathy.

Objective Muscle atrophy is observed in a subset of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Its manifestation is associated with a poor functional prognosis and poor response to immunomodulatory therapies. We evaluated muscle atrophy in patients with CIDP using a bioelectrical impedance analysis (BIA). Methods We enrolled 12 patients with CIDP for a BIA of muscle atrophy. Of these 12 patients, 10 were diagnosed with typical CIDP, 1 with multifocal acquired demyelinating sensory and motor neuropathy, and 1 with distal acquired demyelinating symmetric neuropathy. All 12 patients underwent a series of assessments and evaluations, including a BIA and computed tomography (CT). A correlation was found between the skeletal muscle mass determined by the BIA and that found using CT of the muscles. Results The BIA provided values for each patient's skeletal muscle mass index (SMI) ranging from 4.1 to 8.1 kg/m2. Four of the patients with CIDP had SMI values below the threshold for sarcopenia. CT of the patients' muscles provided scores indicating grades of muscle atrophy in the upper and lower extremities. A comparison of the outcomes from these two measures showed a good correlation between their muscle atrophy ratings (p<0.05). Conclusion We found that a BIA and muscle CT provided muscle atrophy assessments of equivalent accuracy. Therefore, a BIA can be a simple alternative to muscle CT that is suitable for regular use in daily clinical practice as a reliable tool for assessing muscle atrophy in patients with CIDP.

Metformin enhances the antitumor activity of oncolytic herpes simplex virus HF10 (canerpaturev) in a pancreatic cell cancer subcutaneous model.

Oncolytic virus (OV) therapy is a promising cancer immunotherapy, especially for cold tumors by inducing the direct lysis of cancer cells and initiation of potent antitumor response. Canerpaturev (C-REV) is an attenuated oncolytic herpes simplex virus-1, which demonstrated a potent antitumor effect in various preclinical models when used either alone or combined. Metformin is a commonly prescribed antidiabetic drug that demonstrated a potent immune modulator effect and antitumor response. We combined C-REV with metformin in a low immunogenic bilateral murine tumor model to enhance C-REV's antitumor efficacy. In vitro, metformin does not enhance the C-REV cell cytotoxic effect. However, in in vivo model, intratumoral administration of C-REV with the systemic administration of metformin led to synergistic antitumor effect on both sides of tumor and prolonged survival. Moreover, combination therapy increased the effector CD44+ CD8+ PD1- subset and decreased the proportion of terminally-differentiated CD103+ KLRG-1+ T-regulatory cells on both sides of tumor. Interestingly, combination therapy efficiently modulates conventional dendritic cells type-1 (cDC1) on tumors, and tumor-drained lymph nodes. Our findings suggest that combination of C-REV and metformin enhances systemic antitumor immunity. This study may provide insights into the mechanism of action of OV therapy plus metformin combination against various tumor models.

Relationship between Standing Trunk Extension Angle and Medial Elbow Injuries in Young Baseball Pitchers.

Purpose: The purpose of this study was to investigate the relationship between the standing trunk extension angle and medial elbow injuries. Subjects and methods: The study participants were 90 male baseball pitchers (10−12 years) belonging to youth baseball teams. Pitching elbow injuries were evaluated by an orthopedic surgeon using ultrasound scans and physical examination findings. A single optical three-dimensional motion analysis system was used for the trunk extension measurements, with three-dimensional coordinates captured. The overall, upper, and lower trunk angles were then analyzed. Results: Trunk extension angle during standing trunk extension was significantly smaller among participants who were positive for medial elbow injuries on ultrasound scans (positive: 71.4° ± 10.3°; negative: 75.7° ± 9.2°; t = 2.05, p < 0.05). The upper trunk extension angle was significantly smaller than the lower trunk extension angle among participants who were positive for medial elbow injuries on physical examination (upper: 33.0° ± 6.9°; lower: 41.2° ± 8.2°; t = −2.42, p < 0.05). Conclusions: Trunk extension angle during standing trunk extension is associated with medial elbow injuries. Evaluating the trunk extension angle as multiple segments rather than a single rigid body is valuable.

Orem's nursing self-care deficit theory: A theoretical analysis focusing on its philosophical and sociological foundation.

BACKGROUND: The self-care deficit nursing theory (SCDNT) advocated by Dorothea E. Orem is widely known and used in nursing practice worldwide. However, its broader philosophical and sociological context is often ignored. DESIGN: The theoretical analysis of Orem's SCDNT reported in this article focuses on four aspects of the theory: its essential structure/core values, affirmation of nursing as a practical science, philosophical foundations, and the sociological context surrounding its development. RESULTS: By interpreting the SCDNT from a philosophical and sociological viewpoint, it can be concluded that Orem established human-to-human nursing as a science premised on the existence of human beings as the central value of the theory. Moreover, Orem emphasized that the human-to-human relationship necessarily precedes the nurse-patient interface. CONCLUSION: The new interpretation and evaluation perspectives presented in this report may further the understanding of Orem's SCDNT. Moreover, they highlight the multifaceted aspects of nursing practice and role of person-to-person relationships as the basis of the SCDNT.

A scoping review of alternative methods of delivering ethics education in nursing.

AIM: We conducted a scoping review of nursing ethics education to examine educational formats that go beyond traditional lectures. DESIGN: This study was a scoping review. METHODS: We used seven databases and relevant search terms, including nursing ethics, morals, values, nursing students and nursing ethics education. RESULTS: Of 5,190 papers, 14 quasi-experimental studies met the inclusion criteria. All papers examined practices and self-study added to traditional lecture styles (i.e. the control group). Five practices emerged as follows: combined web (i.e. Internet) and lecture, web-based self-study, simulation, group learning and analysing ethical issues. The purpose, method and evaluation method differed based on the country in which the study was conducted. These educational interventions yielded significant differences in knowledge and in nursing students' critical thinking and ethical sensitivity postintervention. Multi-faceted ethics education will lay the foundation for effective practical training and practice.

S-1 facilitates canerpaturev (C-REV)-induced antitumor efficacy in a triple-negative breast cancer model.

Canerpaturev (C-REV) is a highly attenuated, replication-competent, mutant strain of oncolytic herpes simplex virus type 1 that may be an effective new cancer treatment option. S-1, an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, is used as a key chemotherapeutic agent for metastatic recurrent breast cancer. Although the antitumor effects of oncolytic viruses combined with 5-FU in vivo have been reported, the detailed mechanisms are unknown. Here, we investigated the antitumor mechanism of the combination of C-REV and S-1 in triple-negative breast cancer (TNBC) in the context of tumor immunity. The combined effect of C-REV and S-1 was evaluated in a bilateral tumor model of murine TNBC 4T1 in vivo. S-1 enhanced the TNBC growth inhibitory effects of C-REV, and decreased the number of tumor-infiltrating, myeloid-derived suppressor cells (MDSCs), which suppress both innate and adaptive immune responses. Moreover, C-REV alone and in combination with S-1 significantly increased the number of CD8+ T cells in the tumor and the production of interferon γ (IFNγ) from these cells. Our findings indicate that C-REV suppresses TNBC tumor growth by inducing the expansion of effector CD8+ T cell subsets in tumors in which S-1 can inhibit MDSC function. Our study suggests that MDSCs may be an important cellular target for breast cancer treatment. The combination of C-REV and S-1 is a new approach that might be directly translated into future clinical trials against TNBC.

C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells.

Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)-TBK1-IRF3-IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS-STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection.

Association between Preoperative Long-Chain Polyunsaturated Fatty Acids and Oxidative Stress Immediately after Total Knee Arthroplasty: A Pilot Study.

Quadriceps muscle atrophy following total knee arthroplasty (TKA) can be caused by tourniquet-induced ischemia-reperfusion (IR) injury, which is often accompanied by oxidative stress and inflammatory responses. n-3 long-chain polyunsaturated fatty acids (LCPUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert antioxidant and anti-inflammatory effects against IR injury, whereas n-6 LCPUFAs, particularly arachidonic acid (AA), exhibit pro-inflammatory effects and promote IR injury. This study aimed to examine whether preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio are associated with oxidative stress immediately after TKA. Fourteen eligible patients with knee osteoarthritis scheduled for unilateral TKA participated in this study. The levels of serum EPA, DHA, and AA were measured immediately before surgery. Derivatives of reactive oxygen metabolites (d-ROMs) were used as biomarkers for oxidative stress. The preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio were found to be significantly negatively correlated with the serum d-ROM levels at 96 h after surgery, and the rate of increase in serum d-ROM levels between baseline and 96 h postoperatively. This study suggested the preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio can be negatively associated with oxidative stress immediately after TKA.

Oncolytic herpes simplex virus HF10 (canerpaturev) promotes accumulation of CD8+ PD-1- tumor-infiltrating T cells in PD-L1-enriched tumor microenvironment.

Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a "cold" tumor into a "hot" tumor with high CD8+ T-cell infiltration. CD8+ T-cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD-L1 expression persists on tumor or immune cells. In this study, we found that canerpaturev (C-REV) treatment significantly suppressed tumor growth, even though it induced a significant increase in PD-L1 expression in tumors in vivo as well as persistence of high PD-L1 expression on antigen-presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C-REV treatment increased the abundance of activated CD8+ PD-1- tumor-infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+ PD-1high TILs into the tumor was observed in the control group. Moreover, the difference in PD-1 expression was observed only in tumors after treatment with C-REV, whereas most CD8+ T cells in the spleen, tumor-draining lymph nodes and blood were PD-1-negative, and this did not change after C-REV treatment. In addition, changes in expression of T-cell immunoglobulin and mucin-domain containing-3 and T-cell immune-receptor with Ig and ITIM domains were not observed on CD8+ TILs after C-REV treatment. Taken together, our findings may reveal mechanisms that allow OVs to trigger an antitumor immune response, irrespective of a PD-L1-enriched tumor microenvironment, by recruitment of CD8+ PD-1- TILs.

Acanthopanax senticosus Harms extract causes G0/G1 cell cycle arrest and autophagy via inhibition of Rubicon in human liver cancer cells.

Acanthopanax senticosus (Rupr. et Maxim) Harms (ASH), also known as Siberian ginseng or eleuthero, is a hardy shrub native to China, Korea, Russia and the northern region of Japan. ASH is used for the treatment of several diseases such as heart disease, hypertension, rheumatoid arthritis, allergies, chronic bronchitis, diabetes and cancer. In the present study, the inhibitory effect of the root extract of ASH (ASHE) on HuH­7 and HepG2 liver cancer cells was examined. ASHE suppressed liver cancer cell proliferation by inducing cell cycle arrest at the G0/G1 phase, as well as apoptosis, as indicated by the increased number of Annexin V and 7­AAD­positive cells. Furthermore, the expression of LC3­II, an autophagy marker, in these cells also increased post treatment with ASHE. LC3­II induction was further enhanced by co­treatment with chloroquine. Fluorescence and transmission electron micrographs of ASHE­treated liver cancer cells showed the presence of an increased number of autophagic vesicles. A decreased protein expression level of run domain Beclin­1­interacting and cysteine­rich domain­containing, an autophagy inhibitor, with no change in RUBCN mRNA expression was observed, indicating activation of the autophagosome­lysosome fusion step of autophagy. In conclusion, ASHE exerts cytostatic activity on liver cancer cells via both apoptosis and autophagy, and may serve as a potential therapeutic agent for management of liver cancer and autophagy­related diseases.