Radiofrequency ablation: mechanisms and clinical applications.

Radiofrequency ablation (RFA), a form of thermal ablation, employs localized heat to induce protein denaturation in tissue cells, resulting in cell death. It has emerged as a viable treatment option for patients who are ineligible for surgery in various diseases, particularly liver cancer and other tumor-related conditions. In addition to directly eliminating tumor cells, RFA also induces alterations in the infiltrating cells within the tumor microenvironment (TME), which can significantly impact treatment outcomes. Moreover, incomplete RFA (iRFA) may lead to tumor recurrence and metastasis. The current challenge is to enhance the efficacy of RFA by elucidating its underlying mechanisms. This review discusses the clinical applications of RFA in treating various diseases and the mechanisms that contribute to the survival and invasion of tumor cells following iRFA, including the roles of heat shock proteins, hypoxia, and autophagy. Additionally, we analyze| the changes occurring in infiltrating cells within the TME after iRFA. Finally, we provide a comprehensive summary of clinical trials involving RFA in conjunction with other treatment modalities in the field of cancer therapy, aiming to offer novel insights and references for improving the effectiveness of RFA.

Assessing the predictive value of pre- and post-operative inflammatory markers in patients undergoing total knee arthroplasty.

BACKGROUND AND OBJECTIVE: Total Knee Arthroplasty (TKA) has proven highly effective in improving quality of life for patients with severe knee conditions. Despite advancements, surgical complications such as periprosthetic joint infections (PJIs) pose risks. The potential predictive value of pre- and post-operative inflammatory markers like neutrophil-to-lymphocyte ratio (NLR), D-dimer, and albumin levels on surgical outcomes is garnering attention. There is a growing interest in leveraging these markers to enhance patient selection and outcome prediction in the context of TKA.Focusing on the natural course of these markers, and the incidence of PJIs and to refine perioperative care strategies, improve patient outcomes, and identify high-risk patients for targeted intervention. METHODS: The study included 94 patients who underwent total knee arthroplasty (TKA) between 2019 and 2023. Blood tests were conducted before surgery and at 1, 3, 7, and 15 days after surgery to assess various parameters including white blood cell count, neutrophils, lymphocytes, platelets, hemoglobin, C-reactive protein, D-dimers, total protein, albumin, and total cholesterol values and ratios. RESULTS: Following total knee arthroplasty (TKA), key observations in blood markers included a sharp rise in white blood cell (WBC) counts from 5.81 to 10.22 (*10^9/L) on the first day post-surgery, with levels returning close to preoperative values by day-15. Neutrophil counts similarly increased from 3.46 to 8.50 (*10^9/L) on day-1, decreasing to 4.01 by day-15. Hemoglobin levels significantly decreased from 115.70 g/L to 90.62 by day-3 before improving to 100.30 by day-15. C-reactive protein (CRP) levels also saw a significant rise from 6.15 mg/L to a peak of 47.07 on day-3, then reducing to 10.55 by day-15, indicating a response to inflammation. CONCLUSION: Following total knee arthroplasty (TKA), a significant initial postoperative increase in white blood cell count, neutrophils, and C-reactive protein levels, indicative of an acute inflammatory response, before returning towards baseline values by day 15. Hemoglobin levels displayed a notable dip post-surgery, gradually improving by the study's end. These patterns emphasize the dynamic nature of inflammatory and hematological responses after TKA, highlighting their potential role in predicting surgical outcomes and guiding postoperative care.

The CoV-Y domain of SARS-CoV-2 Nsp3 interacts with BRAP to stimulate NF-κB signaling and induce host inflammatory responses.

Non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome. It consists of multiple domains that perform critical functions during the viral life cycle. CoV-Y is the most C-terminal domain of Nsp3, and it exhibits evolutionary conservation across diverse CoVs; however, the exact biological function of CoV-Y remains unclear. Here, we determined the crystal structure of CoV-Y of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp3 using the single-wavelength anomalous diffraction method. We revealed the interaction between CoV-Y and the host BRCA1-associated protein (BRAP) using immunoprecipitation-mass spectrometry experiments. This interaction was subsequently confirmed in cellular assays, and the precise binding-regions between these two proteins were clarified. We found that this interaction is conserved in SARS-CoV and Middle East respiratory syndrome coronavirus. Next, we demonstrated that CoV-Y enhances IκBα and IκBß phosphorylation and promotes the nuclear translocation of the downstream NF-κB members p50 and p65 through binding to BRAP. The CoV-Y-BRAP interaction can upregulate the transcript levels of the host inflammatory cytokines. Overall, our findings illustrate the biological function of CoV-Y for the first time and provide novel insights into coronavirus regulation of host inflammatory responses, as well as a possible target for antiviral drug development.

Nanomechanics of wild-type and mutant dimers of the inner-ear tip-link protein protocadherin 15.

Mechanical force controls the opening and closing of mechanosensitive ion channels atop the hair bundles of the inner ear. The filamentous tip link connecting transduction channels to the tallest neighboring stereocilium modulates the force transmitted to the channels and thus changes their probability of opening. Each tip link comprises four molecules: a dimer of protocadherin 15 (PCDH15) and a dimer of cadherin 23, all of which are stabilized by Ca2+ binding. Using a high-speed optical trap to examine dimeric PCDH15, we find that the protein's mechanical properties are sensitive to Ca2+ and that the molecule exhibits limited unfolding at a physiological Ca2+ concentration. PCDH15 can therefore modulate its stiffness without undergoing large unfolding events under physiological conditions. The experimentally determined stiffness of PCDH15 accords with published values for the stiffness of the gating spring, the mechanical element that controls the opening of mechanotransduction channels. When PCDH15 exhibits a point mutation, V507D, associated with nonsyndromic hearing loss, unfolding events occur more frequently under tension and refolding events occur less often than for the wild-type protein. Our results suggest that the maintenance of appropriate tension in the gating spring is critical to the appropriate transmission of force to transduction channels, and hence to hearing.

Unlocking PD-1 antibody resistance: The MUC1 DNA vaccine augments CD8+ T cell infiltration and attenuates tumour suppression.

In light of increasing resistance to PD1 antibody therapy among certain patient populations, there is a critical need for in-depth research. Our study assesses the synergistic effects of a MUC1 DNA vaccine and PD1 antibody for surmounting PD1 resistance, employing a murine CT26/MUC1 colon carcinoma model for this purpose. When given as a standalone treatment, PD1 antibodies showed no impact on tumour growth. Additionally, there was no change observed in the intra-tumoural T-cell ratios or in the functionality of T-cells. In contrast, the sole administration of a MUC1 DNA vaccine markedly boosted the cytotoxicity of CD8+ T cells by elevating IFN-γ and granzyme B production. Our compelling evidence highlights that combination therapy more effectively inhibited tumour growth and prolonged survival compared to either monotherapy, thus mitigating the limitations intrinsic to single-agent therapies. This enhanced efficacy was driven by a significant alteration in the tumour microenvironment, skewing it towards pro-immunogenic conditions. This assertion is backed by a raised CD8+/CD4+ T-cell ratio and a decrease in immunosuppressive MDSC and Treg cell populations. On the mechanistic front, the synergistic therapy amplified expression levels of CXCL13 in tumours, subsequently facilitating T-cell ingress into the tumour setting. In summary, our findings advocate for integrated therapy as a potent mechanism for surmounting PD1 antibody resistance, capitalizing on improved T-cell functionality and infiltration. This investigation affords critical perspectives on enhancing anti-tumour immunity through the application of innovative therapeutic strategies.

STING agonist inflames the cervical cancer immune microenvironment and overcomes anti-PD-1 therapy resistance.

Background: Cervical cancer poses a significant global threat to women's health. However, current therapeutic interventions, such as radiotherapy, chemotherapy, surgical resection, and immune checkpoint inhibitors, face limitations in the advanced stages of the disease. Given the immunosuppressive microenvironment in cervical cancer, it is imperative to explore novel perspectives. In this regard, STING agonists have emerged as promising candidates. Methods: The expression profiles and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Prognostic analysis of STING downstream genes (CCL5, CXCL9, CXCL10) and immune infiltration analysis were conducted using Kaplan-Meier Plotter, ESTIMATE, and deconvo_CIBERSOR. Single-cell RNA-seq (scRNA-seq) analysis was conducted to evaluate the potential of MSA-2 in cervical cancer treatment employing SingleR, chi-squared test, and Gene Set Enrichment Analysis (GSEA). Cellular interaction analysis utilized the CellChat package to assess the potentiation of cellular interaction following MSA-2 administration. Murine tumor models involving U14 and TC-1, were conducted, and the IF of tissue was subsequently conducted to assess the tumor microenvironment status after treatment. Results: Prognosis in cervical cancer correlated with elevated expression of STING downstream genes, indicating prolonged survival and reduced recurrence. These genes positively correlated with immune infiltration, influencing stromal scores, immune scores, and estimate scores. Specific immune cell populations, including CD8+ T cells, M1-type macrophages, NK cells, and T follicular helper cells, were associated with STING downstream genes. scRNA-seq in a classic immune-excluded model revealed that MSA-2 exerts priming and activating functions on vital components within TME, and intensifies their intercellular communications. The in vivo assay ultimately demonstrated that MSA-2, either as a standalone treatment or in combination with anti-PD-1, effectively suppressed the growth of subcutaneous cervical tumors. Moreover, the combination strategy significantly augmented efficacy compared to anti-PD-1 monotherapy by eliciting a robust antitumor immune response. Conclusion: This study highlights the pivotal role of the STING pathway and the potential of MSA-2 in reshaping the immune microenvironment in cervical cancer. Combining MSA-2 with immune checkpoint inhibitors presents a transformative approach, holding promise for improved prognosis. Further investigations are warranted to explore the broader immune landscape and potential long-term effects of MSA-2 in cervical cancer treatment.

Novel bigels based on walnut oil oleogel and chitosan hydrogel: Preparation, characterization, and application as food spread.

This study developed new biphasic gel systems containing a walnut oil-based oleogel and a chitosan hydrogel and evaluated the application on food spread. The effects of different oleogelators [γ-oryzanol/ß-sitosterol (γ-ORY/ß-SIT), candelilla wax/span 65 (CW/SA), and mono- and diglycerides of fatty acids] were explored. Rheological analysis showed that γ-ORY/ß-SIT-based bigel had the strongest gel strength, but XRD confirmed that ß' crystal form (d = 3.72 Å, 4.12 Å) was predominantly in the CW/SA-based bigel, which was more appropriate for application as spread. The characteristics of CW/SA-based bigel with different oleogel fractions (40-80 wt%) were investigated. The microscopic images indicated that the hydrogels were dispersed as small droplets in the oleogels after oleogel fraction reaching 60 %. The highest crystallinity was achieved when the oleogel fraction was 60 %, and its oil binding capacity was 96.49 %. Textural analysis showed that the CW/SA-based bigel (OG-60 %) had similar properties with commercial spread B, and can be used as a partial replacement for spread B. Replacing 75 % of the commercial spread B with the bigel was found to be optimal and displayed acceptable sensory features. This study developed a healthy bigel based on walnut oil and provided the in-depth information for bigels as an alternative to plastic fats.

Genome-wide association study, population structure, and genetic diversity of the tea plant in Guizhou Plateau.

BACKGROUND: Guizhou Plateau, as one of the original centers of tea plant, has a profound multi-ethnic cultural heritage and abundant tea germplasm resources. However, the impact of indigenous community factors on the genetic diversity, population structure and geographical distribution of tea plant is still unclear. RESULTS: Using the genotyping-by-sequencing (GBS) approach, we collected 415 tea plant accessions from the study sites, estimated genetic diversity, developed a core collection, and conducted a genome-wide association study (GWAS) based on 99,363 high-quality single-nucleotide polymorphisms (SNPs). A total of 415 tea accessions were clustered into six populations (GP01, GP02, GP03, GP04, GP05 and GP06), and the results showed that GP04 and GP05 had the highest and lowest genetic diversity (Pi = 0.214 and Pi = 0.145, respectively). Moreover, 136 tea accessions (33%) were selected to construct the core set that can represent the genetic diversity of the whole collection. By analyzing seven significant SNP markers associated with the traits such as the germination period of one bud and two leaves (OTL) and the germination period of one bud and three leaves (OtL), four candidate genes possibly related to OTL and OtL were identified. CONCLUSIONS: This study revealed the impact of indigenous communities on the population structure of 415 tea accessions, indicating the importance of cultural practices for protection and utilization of tea plant genetic resources. Four potential candidate genes associated with the OTL and OtL of tea plant were also identified, which will facilitate genetic research, germplasm conservation, and breeding.

Screening and Constructing of Novel Angiotensin I-Converting Enzyme Inhibiting Peptides from Walnut Protein Isolate and Their Mechanisms of Action: A Merged In Silico and In Vitro Study.

Angiotensin I-converting enzyme (ACE)-inhibiting peptides were isolated from walnut protein isolate (WPI) using ultrasound-assisted extraction. This study aimed to assess the impact of ultrasonic pretreatment on the physicochemical properties of WPI. The optimal extraction conditions for WPI were determined as a 15-min ultrasonic treatment at 400 W. Subsequently, the hydrolysate exhibiting the highest in vitro ACE-inhibiting activity underwent further processing and separation steps, including ultrafiltration, ion exchange chromatography, liquid chromatography-tandem mass spectrometry, ADMET screening, and molecular docking. As a result of this comprehensive process, two previously unidentified ACE-inhibiting peptides, namely Tyr-Ile-Gln (YIQ) and Ile-Tyr-Gln (IYQ), were identified. In addition, a novel peptide, Ile-Lys-Gln (IKQ), was synthesized, demonstrating superior ACE-inhibiting activity and temperature stability. In silico analysis estimated an in vivo utilization rate of 21.7% for IKQ. These peptides were observed to inhibit ACE through an anti-competitive mechanism, with molecular docking simulations suggesting an interaction mechanism involving hydrogen bonding. Notably, both IYQ and IKQ peptides exhibited no discernible toxicity to HUVECs cells and promoted nitric oxide (NO) generation. These findings underscore the potential of ultrasonicated WPI in the separation of ACE-inhibiting peptides and their utility in the development of novel ACE inhibitors for functional food applications.

IMPA2 promotes basal-like breast cancer aggressiveness by a MYC-mediated positive feedback loop.

Basal-like breast cancer (BLBC) is the most aggressive subtype with poor prognosis; however, the mechanisms underlying aggressiveness in BLBC remain poorly understood. In this study, we showed that in contrast to other subtypes, inositol monophosphatase 2 (IMPA2) was dramatically increased in BLBC. Mechanistically, IMPA2 expression was upregulated due to copy number amplification, hypomethylation of IMPA2 promoter and MYC-mediated transcriptional activation. IMPA2 promoted MI-PI cycle and IP3 production, and IP3 then elevated intracellular Ca2+ concentration, leading to efficient activation of NFAT1. In turn, NFAT1 up-regulated MYC expression, thereby fulfilling a positive feedback loop that enhanced aggressiveness of BLBC cells. Knockdown of IMPA2 expression caused the inhibition of tumorigenicity and metastasis of BLBC cells in vitro and in vivo. Clinically, high IMPA2 expression was strongly correlated with large tumor size, high grade, metastasis and poor survival, indicating poor prognosis in breast cancer patients. These findings suggest that IMPA2-mediated MI-PI cycle allows crosstalk between metabolic and oncogenic pathways to promote BLBC progression.

Nanomechanics of wild-type and mutant dimers of the tip-link protein protocadherin 15.

Mechanical force controls the opening and closing of mechanosensitive ion channels atop the hair bundles of the inner ear. The filamentous tip link connecting transduction channels to the tallest neighboring stereocilium modulates the force transmitted to the channels and thus changes their probability of opening. Each tip link comprises four molecules: a dimer of protocadherin 15 and a dimer of cadherin 23, all of which are stabilized by Ca2+ binding. Using a high-speed optical trap to examine dimeric PCDH15, we find that the protein's configuration is sensitive to Ca2+ and that the molecule exhibits limited unfolding at a physiological Ca2+ concentration. PCDH15 can therefore modulate its stiffness without undergoing large unfolding events in physiological Ca2+ conditions. The experimentally determined stiffness of PCDH15 accords with published values for the stiffness of the gating spring, the mechanical element that controls the opening of mechanotransduction channels. When PCDH15 has a point mutation, V507D, associated with non-syndromic hearing loss, unfolding events occur more frequently under tension and refolding events occur less often than in the wild-type protein. Our results suggest that the maintenance of appropriate tension in the gating spring is critical to the appropriate transmission of force to transduction channels, and hence to hearing.

Dexamethasone and dexmedetomidine as adjuvants to ropivacaine do not prolong analgesia in wound infiltration for lumbar spinal fusion: a prospective randomized controlled study.

BACKGROUND AND OBJECTIVES: Local anesthetics (LAs) are widely used to infiltrate into surgical wounds for postoperative analgesia. Different adjuvants like dexamethasone and dexmedetomidine, when added to LA agents, could improve and prolong analgesia. The aim of this trial was to evaluate the analgesic efficacy and opioid-sparing properties of dexamethasone and dexmedetomidine when added to ropivacaine for wound infiltration in transforaminal lumbar interbody fusion (TLIF). METHODS: We conducted a controlled study among 68 adult patients undergoing TLIF, which was prospective, randomized and double-blind in nature. The participants were divided into four equal groups at random. Group R was given 150 mg of 1% ropivacaine (15 mL) and 15 mL of normal saline. Group R + DXM received 150 mg of 1% ropivacaine (15 mL) and 10 mg of dexamethasone (15 mL). Group R + DEX received 150 mg of 1% ropivacaine (15 mL) and 1 µg/kg of dexmedetomidine (15 mL). Lastly, group R + DXM + DEX was given 150 mg of 1% ropivacaine (15 mL), 10 mg of dexamethasone and 1 µg/kg of dexmedetomidine (15 mL). The primary focus was on the length of pain relief provided. Additionally, secondary evaluations included the amount of hydromorphone taken after surgery, the numerical rating scale and safety assessments within 48 h after the operation. RESULTS: Based on the p value (P > 0.05), there was no significant variance in the duration of pain relief or the total usage of hydromorphone after surgery across the four groups. Similarly, the numerical rating scale scores at rest and during activity at 6-, 12-, 24- and 48-h post-surgery for all four groups showed no difference (P > 0.05). However, the incidence of delayed anesthesia recovery was slightly higher in group R + DEX and group R + DXM + DEX when compared to group R or group R + DXM. Furthermore, there were no significant differences between the four groups in terms of vomiting, nausea, dizziness or delayed anesthesia recovery. CONCLUSION: For wound infiltration in TLIF, the addition of dexamethasone and dexmedetomidine to ropivacaine did not result in any clinically significant reduction in pain or opioid consumption and could prompt some side effects.

Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.

Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long-proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

Revealing the impact of CD70 expression on the manufacture and functions of CAR-70 T-cells based on single-cell transcriptomics.

BACKGROUND: Chimeric antigen receptor-modified T cells (CAR T-cells) have shown exhilarative clinical efficacy for hematological malignancies. However, a shared antigen pool between healthy and malignant T-cells remains a concept to be technically and clinically explored for CAR T-cell therapy in T-cell cancers. No guidelines for engineering CAR T-cells targeting self-expressed antigens are currently available. METHOD: Based on anti-CD70 CAR (CAR-70) T-cells, we constructed CD70 knock-out and wild-type CAR (CAR-70KO and CAR-70WT) T-cells and evaluated their manufacturing and anti-tumor capability. Single-cell RNA sequencing and TCR sequencing were performed to further reveal the underlying differences between the two groups of CAR T-cells. RESULTS: Our data showed that the disruption of target genes in T-cells before CAR transduction advantaged the expansion and cell viability of CAR T-cells during manufacturing periods, as well as the degranulation, anti-tumor efficacy, and proliferation potency in response to tumor cells. Meanwhile, more naïve and central memory phenotype CAR+ T-cells, with higher TCR clonal diversity, remained in the final products in KO samples. Gene expression profiles revealed a higher activation and exhaustion level of CAR-70WT T-cells, while signaling transduction pathway analysis identified a higher level of the phosphorylation-related pathway in CAR-70KO T-cells. CONCLUSION: This study evidenced that CD70 stimulation during manufacturing process induced early exhaustion of CAR-70 T-cells. Knocking-out CD70 in T-cells prevented the exhaustion and led to a better-quality CAR-70 T-cell product. Our research will contribute to good engineering CAR T-cells targeting self-expressed antigens.

CD137 deficiency because of two novel biallelic TNFRSF9 mutations in a patient presenting with severe EBV-associated lymphoproliferative disease.

Objectives: Increasing evidence indicates that some germline genetic mutations that impair pathways required for robust host immune surveillance against EBV infection may result in an extremely high susceptibility to EBV-associated lymphoproliferative disease (EBV+ LPD). TNFRSF9 encodes a vital costimulatory molecule that enhances CD8+ T-cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from TNFRSF9 heterozygous mutations has been identified. Methods: Here, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous TNFRSF9 mutations [NM_001561.5: c.208 + 1->AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV+ LPD. Immunophenotyping and in vitro assays of lymphocyte function and NK cell activity were performed. Results: Biallelic TNFRSF9 mutations resulted in markedly reduced or abrogated expression of CD137 on activated T, B and NK cells. CD8+ T cells from the patient had impaired activation, reduced expression/release of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), perforin and granzyme B, and diminished cytotoxic activity. Functional experiments identified both variations were hypomorphic mutations and played a contributing role in CD137 deficiency and the development of EBV+ LPD. Conclusion: Our study expands the genetic spectrum and clinical phenotype of patients with CD137 deficiency and provides additional evidence that the TNFRSF9 gene plays a critical role in host immune responses to EBV infection.

Recovery of Li and Co in Waste Lithium Cobalt Oxide-Based Battery Using H1.6Mn1.6O4.

H1.6Mn1.6O4 lithium-ion screen adsorbents were synthesized by soft chemical synthesis and solid phase calcination and then applied to the recovery of metal Li and Co from waste cathode materials of a lithium cobalt oxide-based battery. The leaching experiments of cobalt and lithium from cathode materials by a citrate hydrogen peroxide system and tartaric acid system were investigated. The experimental results showed that under the citrate hydrogen peroxide system, when the temperature was 90 °C, the rotation speed was 600 r·min-1 and the solid-liquid ratio was 10 g·1 L-1, the leaching rate of Co and Li could reach 86.21% and 96.9%, respectively. Under the tartaric acid system, the leaching rates of Co and Li were 90.34% and 92.47%, respectively, under the previous operating conditions. The adsorption results of the lithium-ion screen showed that the adsorbents were highly selective for Li+, and the maximum adsorption capacities were 38.05 mg·g-1. In the process of lithium removal, the dissolution rate of lithium was about 91%, and the results of multiple cycles showed that the stability of the adsorbent was high. The recovery results showed that the purity of LiCl, Li2CO3 and CoCl2 crystals could reach 93%, 99.59% and 87.9%, respectively. LiCoO2 was regenerated by the sol-gel method. XRD results showed that the regenerated LiCoO2 had the advantages of higher crystallinity and less impurity.

The role of the PLA2G6 gene in neurodegenerative diseases.

PLA2G6-associated neurodegeneration (PLAN) represents a continuum of clinically and genetically heterogeneous neurodegenerative disorders with overlapping features. Usually, it encompasses three autosomal recessive diseases, including infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (NBIA) 2A, atypical neuronal dystrophy with childhood-onset or NBIA2B, and adult-onset dystonia-parkinsonism form named PARK14, and possibly a certain subtype of hereditary spastic paraplegia. PLAN is caused by variants in the phospholipase A2 group VI gene (PLA2G6), which encodes an enzyme involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation. In this review, we discuss PLA2G6 gene structure and protein, functional findings, genetic deficiency models, various PLAN disease phenotypes, and study strategies in the future. Our primary aim is to provide an overview of genotype-phenotype correlations of PLAN subtypes and speculate on the role of PLA2G6 in potential mechanisms underlying these conditions.

Anti-ribosomal P protein antibodies and insomnia correlate with depression and anxiety in patients suffering from systemic lupus erythematosus.

Objective: Anxiety and depression in patients with systemic lupus erythematosus (SLE) complicate clinical treatment and can seriously affect prognosis. The present study aims to investigate the effects of the anti-ribosomal P protein antibody (anti-RibP) in the peripheral blood and insomnia on the severity of anxiety and depression in case of SLE. The study compared both the results of the investigation on the objective perceptions of physicians concerning mood changes in patients with SLE and the results of self-rating scales that were completed by the enrolled patients. The conclusion of the comparation is used to determine the probability of the accurate detection of anxiety and depression by physicians. The study aims to assist in the early detection in clinical practice of abnormal emotions in patients with SLE and to summarize common clinical interventions for anxiety and depression. Method: The relationship between anxiety and depression was evaluated by the Zung self-rating anxiety/depression scale (SAS/SDS). Basic information (e.g., blood type, smoking history, drinking history, educational background, duration of illness), the insomnia severity index (ISI) results, and anti-RibP in the peripheral blood, were investigated in 107 patients with SLE in northeastern China to further analyze the correlation between the severity of depression and anti-RibP, together with the consistency between results of the questionnaire for physicians and the self-rating scale for patients. Results: Gender, smoking history, drinking history, educational background, and duration of illness were correlated with the SAS/SDS scores (P < 0.05). Family history had a significant effect on the SAS score (P = 0.031), while the SDS score was significantly correlated with blood type (P = 0.021). The ISI score was significantly and positively correlated with the SAS/SDS score (P < 0.001). The titer of anti-RibP showed a correlation with the SDS score (P < 0.05) but not with the SAS score (P = 0.198). The titer of anti-RibP was significantly higher in patients with major depression compared with those with no depression, patients with mild depression, and those with moderate depression (P < 0.001). Conclusion: Anxiety and depression in patients with SLE were correlated with sleeping, educational background, blood type, smoking history, and alcohol consumption. Although anti-RibP was not significantly correlated with anxiety, it indicated a significant correlation with major depression. Clinicians were more accurate in assessing anxiety compared with depression.

Combination of novel oncolytic herpesvirus with paclitaxel as an efficient strategy for breast cancer therapy.

BACKGROUND: New strategies are needed to improve the treatment of patients with breast cancer (BC). Oncolytic virotherapy is a promising new tool for cancer treatment but still has a limited overall durable antitumor response. A novel replicable recombinant oncolytic herpes simplex virus type 1 called VG161 has been developed and has demonstrated antitumor effects in several cancers. Here, we explored the efficacy and the antitumor immune response of VG161 cotreatment with paclitaxel (PTX) which as a novel oncolytic viral immunotherapy for BC. METHODS: The antitumor effect of VG161 and PTX was confirmed in a BC xenograft mouse model. The immunostimulatory pathways were tested by RNA-seq and the remodeling of tumor microenvironment was detected by Flow cytometry analysis or Immunohistochemistry. Pulmonary lesions were analyzed by the EMT6-Luc BC model. RESULTS: In this report, we demonstrate that VG161 can significantly represses BC growth and elicit a robust antitumor immune response in a mouse model. The effect is amplified when combined with PTX treatment. The antitumor effect is associated with the infiltration of lymphoid cells, including CD4+ T cells, CD8+ T cells, and NK cells (expressing TNF and IFN-γ), and myeloid cells, including macrophages, myeloid-derived suppressor cells, and dendritic cell cells. Additionally, VG161 cotreatment with PTX showed a significant reduction in BC lung metastasis, which may result from the enhanced CD4+ and CD8+ T cell-mediated responses. CONCLUSIONS: The combination of PTX and VG161 is effective for repressing BC growth by inducing proinflammatory changes in the tumor microenvironment and reducing BC pulmonary metastasis. These data will provide a new strategy and valuable insight for oncolytic virus therapy applications in primary solid or metastatic BC tumors.