Understanding the Anatomy of Retroperitoneal Interfascial Space: Implications for Regional Anesthesia.

BACKGROUND: Fascial plane block techniques have evolved considerably in recent years. Unlike the conventional peripheral nerve block methods, the fascial plane block's effect can be predicted based on fascial anatomy and does not require a clear vision of the target nerves. The anatomy of the retroperitoneal interfascial space is complex, since it comprises multiple compartments, including the transversalis fascia (TF), the retroperitoneal fasciae (RF), and the peritoneum. For this reason, an in-depth, accurate understanding of the retroperitoneal interfascial space's anatomical characteristics is necessary for perceiving the related regional blocks and mechanisms that lie underlie the dissemination of local anesthetics (LAs) outside or within the various retroperitoneal compartments. OBJECTIVES: This review aims to summarize the retroperitoneum's anatomical characteristics and elucidate the various communications among different interfascial spaces as well as their clinical significance in regional blocks, including but not limited to the anterior quadratus lumborum block (QLB), the fascia iliaca compartment block (FICB), the transversalis fascia plane block (TFPB), and the preperitoneal compartment block (PCB). STUDY DESIGN: This is a narrative review of pertinent studies on the use of retroperitoneal spaces in regional anesthesia (RA). METHODS: We conducted searches in multiple databases, including PubMed, MEDLINE, and Embase, using "retroperitoneal space," "transversalis fascia," "renal fascia," "quadratus lumborum block," "nerve block," and "liquid diffusion" as some of the keywords. RESULTS: The anatomy of the retroperitoneal interfascial space has a significant influence on the injectate spread in numerous RA blocking techniques, particularly the QLB, FICB, and TFPB approaches. Furthermore, the TF is closely associated with the QLB, and the extension between the TF and iliac fascia offers a potential pathway for LAs. LIMITATIONS: The generalizability of our findings is limited by the insufficient number of randomized controlled trials (RCTs). CONCLUSIONS: Familiarity with the anatomy of the retroperitoneal fascial space could enhance our understanding of peripheral nerve blocks. By examining the circulation in the fascial space, we may gain a more comprehensive understanding of the direction and degree of injectate diffusion during RA as well as the block's plane and scope, possibly resulting in effective analgesia and fewer harmful clinical consequences.

[Ilizarov technique combined with center of rotation dome-shaped osteotomy for the treatment of juvenile distal femoral valgus deformity].

OBJECTIVE: To investigate the effect of Ilizarov technique combined with rotational center dome-shaped osteotomy in the treatment of juvenile distal femoral valgus deformity. METHODS: A retrospective study was conducted to analyze the clinical data of 11 patients with valgus deformity of the distal femur who had been admitted and followed up completely from January 2016 to October 2020. There were 7 males and 4 females. The 6 patients were on the right side and 5 patients were on the left side. The age ranged from 10 to 14 years old. The center of roration of angulation(CORA) was identified at the distal femur deformity, and dome-shaped osteotomy was performed with the CORA as the midpoint. The annular external fixator was installed according to the needle threading principle of Ilizarov external fixation, and the distal femur was cut off. The valgus deformity under visual inspection of the distal femur was corrected immediately, and the external fixator was fixed and maintained. The residual deformity and shortening were corrected according to the force line and length of the lower limbs suggested by the weight-bearing full-length anteroposterior and lateral X-rays of both lower limbs. RESULTS: All 11 patients were followed up for 13 to 25 months. The time of wearing external fixator was 12 to 17 weeks. In the last follow-up, both lower limbs were measured by the weight-bearing full-length anteroposterior and lateral X-rays, and the length of both lower limbs of 11 patients were equal, and the deformities were corrected. The score of hospital for special surgery (HSS) was used to evaluate the knee function, all of which were excellent. CONCLUSION: The Ilizarov technique was applied in the treatment of distal femoral valgus deformity in adolescents using a rotating central dome-shaped osteotomy. Visual femoral valgus deformity was corrected immediately during the operation. After the operation, residual deformities and shortening were dynamically adjusted and corrected according to the force line and shortening degree of lower extremities indicated by the weight-bearing anteroposterior and lateral radiographs of both lower limbs, with minimal damage and fast recovery.

Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR-mediated DNA damage response.

Despite active clinical trials on the use of Oleandrin alone or in combination with other drugs for the treatment of solid tumors, the potential synergistic effect of Oleandrin with radiotherapy remains unknown. This study reveals a new mechanism by which Oleandrin targets ATM and ATR kinase-mediated radiosensitization in lung cancer. Various assays, including clonogenic, Comet, immunofluorescence staining, apoptosis and Cell cycle assays, were conducted to evaluate the impact of oleandrin on radiation-induced double-strand break repair and cell cycle distribution. Western blot analysis was utilized to investigate alterations in signal transduction pathways related to double-strand break repair. The efficacy and toxicity of the combined therapy were assessed in a preclinical xenotransplantation model. Functionally, Oleandrin weakens the DNA damage repair ability and enhances the radiation sensitivity of lung cells. Mechanistically, Oleandrin inhibits ATM and ATR kinase activities, blocking the transmission of ATM-CHK2 and ATR-CHK1 cell cycle checkpoint signaling axes. This accelerates the passage of tumor cells through the G2 phase after radiotherapy, substantially facilitating the rapid entry of large numbers of inadequately repaired cells into mitosis and ultimately triggering mitotic catastrophe. The combined treatment of Oleandrin and radiotherapy demonstrated superior inhibition of tumor proliferation compared to either treatment alone. Our findings highlight Oleandrin as a novel and effective inhibitor of ATM and ATR kinase, offering new possibilities for the development of clinical radiosensitizing adjuvants.

NCAPD2 augments the tumorigenesis and progression of human liver cancer via the PI3K­Akt­mTOR signaling pathway.

Non­SMC condensin I complex subunit D2 (NCAPD2) is a newly identified oncogene; however, the specific biological function and molecular mechanism of NCAPD2 in liver cancer progression remain unknown. In the present study, the aberrant expression of NCAPD2 in liver cancer was investigated using public tumor databases, including TNMplot, The Cancer Genome Atlas and the International Cancer Genome Consortium based on bioinformatics analyses, and it was validated using a clinical cohort. It was revealed that NCAPD2 was significantly upregulated in liver cancer tissues compared with in control liver tissues, and NCAPD2 served as an independent prognostic factor and predicted poor prognosis in liver cancer. In addition, the expression of NCAPD2 was positively correlated with the percentage of Ki67+ cells. Finally, single­cell sequencing data, gene­set enrichment analyses and in vitro investigations, including cell proliferation assay, Transwell assay, wound healing assay, cell cycle experiments, cell apoptosis assay and western blotting, were carried out in human liver cancer cell lines to assess the biological mechanisms of NCAPD2 in patients with liver cancer. The results revealed that the upregulation of NCAPD2 enhanced tumor cell proliferation, invasion and cell cycle progression at the G2/M­phase transition, and inhibited apoptosis in liver cancer cells. Furthermore, NCAPD2 overexpression was closely associated with the phosphatidylinositol 3­kinase (PI3K)­Akt­mammalian target of rapamycin (mTOR)/c­Myc signaling pathway and epithelial­mesenchymal transition (EMT) progression in HepG2 and Huh7 cells. In addition, upregulated NCAPD2 was shown to have adverse effects on overall survival and disease­specific survival in liver cancer. In conclusion, the overexpression of NCAPD2 was shown to lead to cell cycle progression at the G2/M­phase transition, activation of the PI3K­Akt­mTOR/c­Myc signaling pathway and EMT progression in human liver cancer cells.

Compensatory mutations potentiate constructive neutral evolution by gene duplication.

The functions of proteins generally depend on their assembly into complexes. During evolution, some complexes have transitioned from homomers encoded by a single gene to heteromers encoded by duplicate genes. This transition could occur without adaptive evolution through intermolecular compensatory mutations. Here, we experimentally duplicated and evolved a homodimeric enzyme to determine whether and how this could happen. We identified hundreds of deleterious mutations that inactivate individual homodimers but produce functional enzymes when coexpressed as duplicated proteins that heterodimerize. The structure of one such heteromer reveals how both losses of function are buffered through the introduction of asymmetry in the complex that allows them to subfunctionalize. Constructive neutral evolution can thus occur by gene duplication followed by only one deleterious mutation per duplicate.

Shenqi Fuzheng Injection Reduces Cisplatin-Induced Kidney Injury via cGAS/STING Signaling Pathway in Breast Cancer Mice Model.

Background: Shenqi Fuzheng Injection (SQFZ) is a traditional Chinese medicine injection consists of extracts of Codonopsis pilosula and Astragalus mongholicus. Combining SQFZ with conventional chemotherapy may improve the therapeutic efficacy and reduce side-effects of chemotherapy. However, the mechanisms of SQFZ reducing cisplatin-induced kidney injury are still unclear. Methods: The main compounds of SQFZ were identified via UPLC-Q-TOF-MS technique. Using multiple databases to predict potential targets for SQFZ. We established a breast cancer model by injecting 4T1 cells into mice. Tumor growth and body weight were observed. Serum blood urea nitrogen (BUN), creatinine (CRE), and glutathione (GSH) levels were measured. The extent of their kidney injury was measured by hematoxylin-eosin staining (HE). Cell apoptosis was identified using Hoechst33258 staining, flow cytometry and TUNEL. We evaluated H2AX and stimulator of interferon genes (STING) expression by immunohistochemistry (IHC), and assessed apoptosis-associated proteins by Western blotting analysis. We also evaluated mitochondrial function. The secretion of the inflammatory cytokines in serum was observed using ELISA assay. The effect of the STING pathway in HK-2 renal tubular epithelial cells exposed to cisplatin alone or combined with SQFZ. Results: The potential targets of SQFZ on kidney injury mainly related to inflammatory responses, oxidation and antioxidant, apoptosis as well as IFN signaling pathway. Cisplatin significantly reduced animal weight, while there were no changes in the combination SQFZ and cisplatin. SQFZ counteracted cisplatin-induced BUN and CRE elevation. SQFZ ameliorated the oxidative stress induced by cisplatin. It diminished cisplatin-induced apoptosis and mitochondrial DNA damage and reversed cisplatin-induced cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/STING signaling pathway activation. It also improved the mitochondrial dysfunction induced by cisplatin. Conclusions: The results of the present study suggested that SQFZ effectively reduced cisplatin-induced kidney injury by inhibiting cGAS/STING signaling pathway.

Impact of COVID-19 pandemic on routine childhood vaccinations.

Routine pediatric vaccination is one of the most effective public health inter-ventions for the control of a number of fatal diseases. However, during the coronavirus disease 2019 pandemic, routine pediatric vaccination rates were severely affected by disruptions of health services and vaccine confidence issues. Governments and the United Nations have taken measures to re-establish routine pediatric vaccination, while additional efforts are needed to catch up and develop plans to ensure routine vaccination services for the future pandemics.

Specific and cumulative infection burden and mild cognitive impairment and dementia: A population-based study.

Infection by pathogenic microbes is widely hypothesized to be a risk factor for the development of neurocognitive disorders and dementia, but evidence remains limited. We analyzed the association of seropositivity to 11 common pathogens and cumulative infection burden with neurocognitive disorder (mild cognitive impairment and dementia) in a population-based cohort of 475 older individuals (mean age = 67.6 y) followed up over 3-5 years for the risk of MCI-dementia. Specific seropositivities showed a preponderance of positive trends of association with MCI-dementia, including for Plasmodium, H. pylori, and RSV (p < 0.05), as well as Chickungunya, HSV-2, CMV and EBV (p > 0.05), while HSV-1 and HHV-6 showed equivocal or no associations, and Dengue and VZV showed negative associations (p < 0.05) with MCI-dementia. High infection burden (5 + cumulated infections) was significantly associated with an increased MCI-dementia risk in comparison with low infection burden (1-3 cumulative infections), adjusted for age, sex, and education. Intriguingly, for a majority (8 of 11) of pathogens, levels of antibody titers were significantly lower in those with MCI-dementia compared to cognitive normal individuals. Based on our observations, we postulate that individuals who are unable to mount strong immunological responses to infection by diverse microorganisms, and therefore more vulnerable to infection by greater numbers of different microbial pathogens or repeated infections to the same pathogen in the course of their lifetime are more likely to develop MCI or dementia. This hypothesis should be tested in more studies.

Sustained release of brimonidine from conjunctival sac insert to reduce intraocular pressure for glaucoma treatment.

BACKGROUND: Glaucoma is one of the major irreversible blinding eye diseases in the world. Reducing intraocular pressure (IOP) is the primary treatment option, and taking eye drops daily is the common method. However, short drug duration and poor bioavailability of eye drops may lead to unsatisfied therapeutic effects and inadequate patient compliance. METHODS: A brimonidine-loaded silicone rubber insert (BRI@SR@PT) was prepared by loading brimonidine into a surface-modified silicone rubber ring, followed by polydopamine/thermoplastic polyurethane coatings. The physical properties, in vitro cytocompatibility and drug release of BRI@SR@PT were investigated. The BRI@SR@PT was administrated in the conjunctival sac of rabbit eyes, and its in vivo drug release, IOP-lowering efficacy and biosafety were assessed. RESULTS: The BRI@SR@PT presented great thermal stability and excellent elasticity. The BRI@SR@PT was able to release BRI sustainably for 28 days with little toxicity in vitro. Compared to BRI eye drops, the BRI@SR@PT effectively lowered IOP for 21 days based on the sustained BRI release with great biosafety when administrated in conjunctival sac of rabbit eyes in a noninvasive fashion. CONCLUSIONS: The conjunctival sac insert (BRI@SR@PT), as a promising drug-delivery platform, may provide a sustained IOP-lowering treatment for patients with ocular hypertension or glaucoma, without the need for invasive procedures.

Ca2+-nano starch-lutein endowed 3D printed surimi with antioxidation and mutual reinforcing transmembrane transport mechanisms via hepg2 and caco-2 cells model.

To better enhance printing effects meanwhile casting functionality, antioxidation and absorption of bioactive component in printed Ca2+-nano starch (NS)-lutein (L)-surimi were investigated. Results shown that Ca2+-NS-L promoted surimi printability due to enhanced gel strength and denser structure. Mixing Ca2+-NS-L endowed printed surimi with antioxidation (DPPH, ABTS, hydroxyl radical, Fe2+ reduction were 42 %, 79 %, 65 %, 0.104 mg·mL-1, respectively) due to the ability of lutein with more -OH groups and conjugate bonds to capture free radicals. It also manifested in cellular antioxidation that Ca2+-NS-L-surimi regulated the level of Nrf2 to protect gene expression of antioxidases (SOD, CAT, GSH-Px increased by 30-180 %, compared to damaged cells) through keap1-Nrf2-ARE pathway. Additionally, lutein absorption and transportation of Ca2+-NS-L-surimi increased by 20 %, compared to NS-L. Possibly, combination of samples and membrane was facilitated by surface hydrophobic, promoting endocytosis. Meanwhile, digestive surimi (peptides) with acidic-alkaline amino acids and negative charges made samples be attracted and moved in bypass parts under electrostatic traction and repulsion (electrostatic domain) to promote transport process. Also, Ca2+ facilitated CaM expression in membrane and formed Ca2+ channel by combining with CaM to accelerate entry of samples into cells. Conclusively, Ca2+-NS-L both strengthened printability of surimi and antioxidation, promoting application of printed functional surimi.

Correlations between plasma markers and brain Aß deposition across the AD continuum: Evidence from SILCODE.

BACKGROUND: Previous studies have found that Alzheimer's disease (AD)-related plasma markers are associated with amyloid beta (Aß) deposition, but the change of this association in different Aß pathological stages remains unclear. METHODS: Data were obtained from the SILCODE. According to the standardized uptake value ratio (SUVR) and Aß stage classification, correlation analysis was performed among plasma biomarkers, and voxel/SUVR values in the regions of interest (ROI) and clinical scale information, respectively. Mediation analysis was used to study the possible pathways. RESULTS: The proportion of cognitively normal (CN) and subjective cognitive decline (SCD) was the highest in stages A0 to 1, while in stages A2 to 4, the proportion of mild cognitive impairment (MCI) and AD increased. Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) levels were significantly lower in stage A0 compared to the later phases. Two pathways demonstrated fully mediated effects: positron emission tomography (PET) SUVR-plasma p-tau181-Mini-Mental State Examination (MMSE) and PET SUVR-plasma GFAP-MMSE. DISCUSSION: This study demonstrated the role of plasma biomarkers in the early stage of AD, especially in SCD, from both the clinical diagnosis and Aß stage dimensions. HIGHLIGHTS: Plasma ptau181 and GFAP level serve as indicators of early Alzheimer's disease and the pathologic Aß staging classification. A possible ceiling effect of GFAP was observed in the mid-to-late stages of the AD course. This study confirms the role of AD plasma markers in promoting Aß deposition at an early stage, particularly in females with subjective cognitive decline(SCD). The overlapping brain regions of plasma p-tau181, GFAP, and neurofilament light for Aß deposition in the brain in early AD were distributed across various regions, including the posterior cingulate gyrus, rectus gyrus, and inferior temporal gyrus.

Trafficking circuit of CD8+ T cells between the intestine and bone marrow governs antitumour immunity.

Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44-CD62L- T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin ß7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4-vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy.

Nanomaterial-Based Repurposing of Macrophage Metabolism and Its Applications.

Macrophage immunotherapy represents an emerging therapeutic approach aimed at modulating the immune response to alleviate disease symptoms. Nanomaterials (NMs) have been engineered to monitor macrophage metabolism, enabling the evaluation of disease progression and the replication of intricate physiological signal patterns. They achieve this either directly or by delivering regulatory signals, thereby mapping phenotype to effector functions through metabolic repurposing to customize macrophage fate for therapy. However, a comprehensive summary regarding NM-mediated macrophage visualization and coordinated metabolic rewiring to maintain phenotypic equilibrium is currently lacking. This review aims to address this gap by outlining recent advancements in NM-based metabolic immunotherapy. We initially explore the relationship between metabolism, polarization, and disease, before delving into recent NM innovations that visualize macrophage activity to elucidate disease onset and fine-tune its fate through metabolic remodeling for macrophage-centered immunotherapy. Finally, we discuss the prospects and challenges of NM-mediated metabolic immunotherapy, aiming to accelerate clinical translation. We anticipate that this review will serve as a valuable reference for researchers seeking to leverage novel metabolic intervention-matched immunomodulators in macrophages or other fields of immune engineering.

A Highly Sensitive and Selective Fluorescent Sensor for Folic Acid Detection Based on D-penicillamine Stabilized Ag/Cu Alloy Nanoclusters.

In this work, a highly sensitive and selective method for detecting folic acid (FA) was developed using D-penicillamine (DPA) stabilized Ag/Cu alloy nanoclusters (DPA@Ag/Cu NCs). The yellow emission of DPA@Ag/Cu NCs was found to be quenched upon the addition of FA to the system. The fluorescence intensity quenching value demonstrated a linear relationship with FA concentrations ranging from 0.01 to 1200 µM, with a limit of detection (LOD) of 5.3 nM. Furthermore, the detection mechanism was investigated through various characterization analyses, including high resolution transmission electron microscopy, fluorescence spectra, ultraviolet-visible absorption spectra, and fluorescence lifetime. The results indicated that the fluorescence quenching induced by FA was a result of electron transfer from FA to the ligands of DPA@Ag/Cu NCs. The selectivity of the FA sensor was also evaluated, showing that common amino acids and inorganic ions had minimal impact on the detection of FA. Moreover, the standard addition method was successfully applied to detect FA in human serum, chewable tablets and FA tablets with promising results. The use of DPA@Ag/Cu NCs demonstrates significant potential for detecting FA in complex biological samples.

Targeting STAT3 potentiates CDK4/6 inhibitors therapy in head and neck squamous cell carcinoma.

Anti-CDK4/6 therapy has been employed for the treatment for head and neck squamous cell carcinoma (HNSCC) with CDK4/6 hyperactivation, but the response rate is relatively low. In this study, we first showed that CDK4 and CDK6 was over-expressed and conferred poor prognosis in HNSCC. Moreover, in RB-positive HNSCC, STAT3 signaling was activated induced by CDK4/6 inhibition and STAT3 promotes RB deficiency by upregulation of MYC. Thirdly, the combination of Stattic and CDK4/6 inhibitor results in striking anti-tumor effect in vitro and in Cal27 derived animal models. Additionally, phospho-STAT3 level negatively correlates with RB expression and predicts poor prognosis in patients with HNSCC. Taken together, our findings suggest an unrecognized function of STAT3 confers to CDK4/6 inhibitors resistance and presenting a promising combination strategy for patients with HNSCC.

Changes in the Biomechanical Properties of Corneal Stromal Lens after Collagen Crosslinking Induced by EDC-NHS.

Introduction: To evaluate the changes of lens antidilatation, antiedema, and antienzymolysis ability after different concentrations of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide (EDC-NHS)-induced collagen cross-linking. Methods: Corneal stromal lenticules (n = 100) obtained from small incision lenticule extraction (SMILE) procedures were divided into 5 groups: no treatment (control); EDC/NHS (5%/2.5%); EDC/NHS(5%/5%); EDC/NHS (10%/5%); riboflavin and ultraviolet-A light (UVA). Collagen crosslinking was induced using EDC-NHS and UVA. Biomechanical assessments including inflation test, enzymatic degradation resistance, and light transmittance were evaluated posttreatment. Results: (1) Lenticule apex displacement ranked: control Group > UVA Group > Group (5%/5%) > Group (5%/2.5%) > Group (10%/5%) (Friedman test, p < 0.0001). (2) Light transmittance was significantly higher in the crosslinked groups versus control, with EDC/NHS superior to UVA riboflavin. After 15 minutes in PBS, light transmittance decreased due to swelling; however, crosslinked groups maintained significantly higher transmittance versus control. (3) Following crosslinking, enzymatic resistance improved significantly, with the EDC-NHS crosslinking group was significantly better than the UVA cross-linking group. Conclusions: EDC/NHS crosslinking enhanced lenticule stiffness, antiedema, and enzymatic resistance and without compromising the transparency of the lens. Moreover, EDC/NHS crosslinking efficacy exceeded UVA riboflavin crosslinking in improving lenticule biomechanical properties.