Functional variation among mesenchymal stem cells derived from different tissue sources.

Background: Mesenchymal stem cells (MSCs) are increasingly recognized for their regenerative potential. However, their clinical application is hindered by their inherent variability, which is influenced by various factors, such as the tissue source, culture conditions, and passage number. Methods: MSCs were sourced from clinically relevant tissues, including adipose tissue-derived MSCs (ADMSCs, n = 2), chorionic villi-derived MSCs (CMMSCs, n = 2), amniotic membrane-derived MSCs (AMMSCs, n = 3), and umbilical cord-derived MSCs (UCMSCs, n = 3). Passages included the umbilical cord at P0 (UCMSCP0, n = 2), P3 (UCMSCP3, n = 2), and P5 (UCMSCP5, n = 2) as well as the umbilical cord at P5 cultured under low-oxygen conditions (UCMSCP5L, n = 2). Results: We observed that MSCs from different tissue origins clustered into six distinct functional subpopulations, each with varying proportions. Notably, ADMSCs exhibited a higher proportion of subpopulations associated with vascular regeneration, suggesting that they are beneficial for applications in vascular regeneration. Additionally, CMMSCs had a high proportion of subpopulations associated with reproductive processes. UCMSCP5 and UCMSCP5L had higher proportions of subpopulations related to female reproductive function than those for earlier passages. Furthermore, UCMSCP5L, cultured under low-oxygen (hypoxic) conditions, had a high proportion of subpopulations associated with pro-angiogenic characteristics, with implications for optimizing vascular regeneration. Conclusions: This study revealed variation in the distribution of MSC subpopulations among different tissue sources, passages, and culture conditions, including differences in functions related to vascular and reproductive system regeneration. These findings hold promise for personalized regenerative medicine and may lead to more effective clinical treatments across a spectrum of medical conditions.

GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.

Injectable cross-linked hyaluronic acid hydrogels with epigallocatechin gallate loading as vitreous substitutes.

Hyaluronic acid (HA) serves as a vitreous substitute owing to its ability to mimic the physical functions of native vitreous humor. However, pure HA hydrogels alone do not provide sufficient protection against potential inflammatory risks following vitrectomy. In this study, HA was crosslinked with 1,4-butanediol diglycidyl ether (BDDE) to form HA hydrogels (HB). Subsequently, the anti-inflammatory agent epigallocatechin gallate (EGCG) was added to the hydrogel (HBE) for ophthalmic applications as a vitreous substitute. The characterization results indicated the successful preparation of HB with transparency, refractive index, and osmolality similar to those of native vitreous humor, and with good injectability. The anti-inflammatory ability of HBE was also confirmed by the reduced expression of inflammatory genes in retinal pigment epithelial cells treated with HBE compared with those treated with HB. In a New Zealand white rabbit model undergoing vitreous substitution treatment, HBE 50 (EGCG 50 mM addition) exhibited positive results at 28 days post-surgery. These outcomes included restored intraocular pressure, improved electroretinogram responses, minimal increase in corneal thickness, and no inflammation during histological examination. This study demonstrated the potential of an injectable HA-BDDE cross-linked hydrogel containing EGCG as a vitreous substitute for vitrectomy applications, offering prolonged degradation time and anti-inflammatory effects postoperatively.

Clinical potential of serum prostaglandin A2 as a novel diagnostic biomarker for hepatocellular cancer.

BACKGROUND: Hepatocellular cancer (HCC) is one of the most harmful tumors to human health. Currently, there is still a lack of highly sensitive and specific HCC biomarkers in clinical practice. In this study, we aimed to explore the diagnostic performance of prostaglandin A2 (PGA2) for the early detection of HCC. METHODS: Untargeted metabolomic analyses on normal control (NC) and HCC participants in the discovery cohort were performed, and PGA2 was identified to be dysregulated in HCC. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detecting serum PGA2 was established and applied to validate the dysregulation of PGA2 in another independent validation cohort. Receiver operating characteristic (ROC), decision curve analysis (DCA) and some other statistical analyses were performed to evaluate the diagnostic performance of PGA2 for HCC. RESULTS: At first, PGA2 was found to be dysregulated in HCC in untargeted metabolomic analyses. Then a precise quantitative LC-MS/MS method for PGA2 has been established and has passed rigorous method validation. Targeted PGA2 analyses confirmed that serum PGA2 was decreased in HCC compared to normal-risk NC and high-risk cirrhosis group. Subsequently, PGA2 was identified as a novel biomarker for the diagnosis of HCC, with an area under the ROC curve (AUC) of 0.911 for differentiating HCC from the combined NC + cirrhosis groups. In addition, PGA2 exhibited high performance for differentiating small-size (AUC = 0.924), early-stage (AUC = 0.917) and AFP (-) HCC (AUC = 0.909) from the control groups. The combination of PGA2 and AFP might be useful in the surveillance of risk population for HCC and early diagnosis of HCC. CONCLUSION: This study establishes that PGA2 might be a novel diagnostic biomarker for HCC.

Selective ophthalmic arterial injection using a balloon catheter for retinoblastoma: a seven-year clinical evaluation.

PURPOSE: To evaluate the effectiveness and safety of selective ophthalmic arterial injection (SOAI) for retinoblastoma utilizing a microballoon catheter system with an M chamber. STUDY DESIGN: Retrospective analysis. METHODS AND PATIENTS: This study was sanctioned by theNational Cancer Center Hospital' Independent Ethics Committee. The surgeon was a general interventional radiologist. After confirming that the distal internal carotid artery was not delineated by balloon occlusion and the ophthalmic artery was visualized using digital subtraction angiography, melphalan was manually administered. Notably, in cases presenting bilateral retinoblastoma, both eyes received treatment in a singular, low-dose procedure. Between July 2015 and December 2021, 125 patients with retinoblastoma (68 boys and 57 girls) underwent SOAI at our facility. The average age at initial treatment was 19.3 months. The study covered 250 procedures, with patients undergoing an average of 3.7 procedures. RESULTS: The success rate of the procedure was 99.2%, with a mean procedure duration of 18.3 min. Two distinct technical failures were recorded: one attributed to an internal carotid artery having a wide lumen and the other due to the ophthalmic artery remaining undetected on angiography post-balloon occlusion of the internal carotid artery. Adverse events were minimal but included bronchospasm post-procedure and severe orbital inflammation in 0.8% and 0.4% of cases, respectively. CONCLUSION: SOAI using the microballoon catheter with the M chamber is a feasible and safe procedure for the treatment of retinoblastoma. The success rate was 99.2%. This system can be recommended as intra-arterial chemotherapy for retinoblastoma.

External auricle temperature enhances ear-based wearable accuracy during physiological strain monitoring in the heat.

Body core temperature (Tc) monitoring is crucial for minimizing heat injury risk. However, validated strategies are invasive and expensive. Although promising, aural canal temperature (Tac) is susceptible to environmental influences. This study investigated whether incorporation of external auricle temperature (Tea) into an ear-based Tc algorithm enhances its accuracy during multiple heat stress conditions. Twenty males (mean ± SD; age = 25 ± 3 years, BMI = 21.7 ± 1.8, body fat = 12 ± 3%, maximal aerobic capacity (VO2max) = 64 ± 7 ml/kg/min) donned an ear-based wearable and performed a passive heating (PAH), running (RUN) and brisk walking trial (WALK). PAH comprised of immersion in hot water (42.0 ± 0.3 °C). RUN (70 ± 3%VO2max) and WALK (50 ± 10%VO2max) were conducted in an environmental chamber (Tdb = 30.0 ± 0.2 °C, RH = 71 ± 2%). Several Tc models, developed using Tac, Tea and heart rate, were validated against gastrointestinal temperature. Inclusion of Tea as a model input improved the accuracy of the ear-based Tc algorithm. Our best performing model (Trf3) displayed good group prediction errors (mean bias error = - 0.02 ± 0.26 °C) but exhibited individual prediction errors (percentage target attainment ± 0.40 °C = 88%) that marginally exceeded our validity criterion. Therefore, Trf3 demonstrates potential utility for group-based Tc monitoring, with additional refinement needed to extend its applicability to personalized heat strain monitoring.

Human enteric nervous system progenitor transplantation improves functional responses in Hirschsprung disease patient-derived tissue.

OBJECTIVE: Hirschsprung disease (HSCR) is a severe congenital disorder affecting 1:5000 live births. HSCR results from the failure of enteric nervous system (ENS) progenitors to fully colonise the gastrointestinal tract during embryonic development. This leads to aganglionosis in the distal bowel, resulting in disrupted motor activity and impaired peristalsis. Currently, the only viable treatment option is surgical resection of the aganglionic bowel. However, patients frequently suffer debilitating, lifelong symptoms, with multiple surgical procedures often necessary. Hence, alternative treatment options are crucial. An attractive strategy involves the transplantation of ENS progenitors generated from human pluripotent stem cells (hPSCs). DESIGN: ENS progenitors were generated from hPSCs using an accelerated protocol and characterised, in detail, through a combination of single-cell RNA sequencing, protein expression analysis and calcium imaging. We tested ENS progenitors' capacity to integrate and affect functional responses in HSCR colon, after ex vivo transplantation to organotypically cultured patient-derived colonic tissue, using organ bath contractility. RESULTS: We found that our protocol consistently gives rise to high yields of a cell population exhibiting transcriptional and functional hallmarks of early ENS progenitors. Following transplantation, hPSC-derived ENS progenitors integrate, migrate and form neurons/glia within explanted human HSCR colon samples. Importantly, the transplanted HSCR tissue displayed significantly increased basal contractile activity and increased responses to electrical stimulation compared with control tissue. CONCLUSION: Our findings demonstrate, for the first time, the potential of hPSC-derived ENS progenitors to repopulate and increase functional responses in human HSCR patient colonic tissue.

A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

Dual mode of DDX3X as an ATP-dependent RNA helicase and ATP-independent nucleic acid chaperone.

Human DDX3X, an important member of the DEAD-box family RNA helicases, plays a crucial role in RNA metabolism and is involved in cancer development, viral infection, and neurodegenerative disease. Although there have been many studies on the physiological functions of human DDX3X, issues regarding its exact targets and mechanisms of action remain unclear. In this study, we systematically characterized the biochemical activities and substrate specificity of DDX3X. The results demonstrate that DDX3X is a bidirectional RNA helicase to unwind RNA duplex and RNA-DNA hybrid driven by ATP. DDX3X also has nucleic acid annealing activity, especially for DNA. More importantly, it can function as a typical nucleic acid chaperone which destabilizes highly structured DNA and RNA in an ATP-independent manner and promotes their annealing to form a more stable structure. Further truncation mutations confirmed that the highly disordered N-tail and C-tail are critical for the biochemical activities of DDX3X. They are functionally complementary, with the N-tail being crucial. These results will shed new light on our understanding of the molecular mechanism of DDX3X in RNA metabolism and DNA repair, and have potential significance for the development of antiviral/anticancer drugs targeting DDX3X.

In situ/Operando Synchrotron Radiation Analytical Techniques for CO2/CO Reduction Reaction: From Atomic Scales to Mesoscales.

Electrocatalytic carbon dioxide/carbon monoxide reduction reaction (CO(2)RR) has emerged as a prospective and appealing strategy to realize carbon neutrality for manufacturing sustainable chemical products. Developing highly active electrocatalysts and stable devices has been demonstrated as effective approach to enhance the conversion efficiency of CO(2)RR. In order to rationally design electrocatalysts and devices, a comprehensive understanding of the intrinsic structure evolution within catalysts and micro-environment change around electrode interface, particularly under operation conditions, is indispensable. Synchrotron radiation has been recognized as a versatile characterization platform, garnering widespread attention owing to its high brightness, elevated flux, excellent directivity, strong polarization and exceptional stability. This review systematically introduces the applications of synchrotron radiation technologies classified by radiation sources with varying wavelengths in CO(2)RR. By virtue of in situ/operando synchrotron radiationanalytical techniques, we also summarize relevant dynamic evolution processes from electronic structure, atomic configuration, molecular adsorption, crystal lattice and devices, spanning scales from the angstrom to the micrometer. The merits and limitations of diverse synchrotron characterization techniques are summarized, and their applicable scenarios in CO(2)RR are further presented. On the basis of the state-of-the-art fourth-generation synchrotron facilities, a perspective for further deeper understanding of the CO(2)RR process using synchrotron radiation analytical techniques is proposed.

Appendiceal intussusception complicated by adenocarcinoma of the cecum: A case report.

BACKGROUND: Appendiceal intussusception is a pathological condition in which the appendix is inverted into the cecum, which may cause symptoms that resemble those of other gastrointestinal disorders and may induce intestinal obstruction. The rarity of this case presentation is the co-occurrence of appendiceal intussusception and cecal adenocarcinoma, a combination that to our knowledge has not previously been reported in the medical literature. This case provides new insights into the complexities of diagnosing and managing overlapping pathologies. CASE SUMMARY: A 25-year-old woman presented with persistent periumbilical pain and bloody stools. An initial biopsy showed cecal cancer; however, subsequent colonoscopy and computed tomography findings raised the suspicion of appendiceal intussusception, which was later confirmed postoperatively. This unique case was characterized by a combination of intussusception and adenocarcinoma of the cecum. The intervention included a laparoscopic right hemicolectomy, which led to the histopathological diagnosis of mucinous adenocarcinoma with appendiceal intussusception. The patient recovered well postoperatively and was advised to initiate adjuvant chemotherapy. This case highlights not only the importance of considering appendiceal intussusception in the differential diagnosis, but also the possibility of appendicitis and the atypical presentation of neoplastic lesions. CONCLUSIONS: Physicians should consider the possibility of appendiceal intussusception in cases of atypical appendicitis, particularly when associated with neoplastic presentation.

C-type lectin 4 of Toxocara canis activates NF-ĸB and MAPK pathways by modulating NOD1/2 and RIP2 in murine macrophages in vitro.

Toxocara canis is a parasitic zoonose that is distributed worldwide and is one of the two pathogens causing toxocariasis. After infection, it causes serious public health and safety problems, which pose significant veterinary and medical challenges. To better understand the regulatory effects of T. canis infection on the host immune cells, murine macrophages (RAW264.7) were incubated with recombinant T. canis C-type lectin 4 (rTc-CTL-4) protein in vitro. The quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to analyze the nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2), receptor-interacting protein 2 (RIP2), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and mitogen-activated protein kinase (MAPK) on mRNA level and protein expression level in macrophages. Our results indicated that 10 µg/mL rTc-CTL-4 protein could modulate the expression of NOD1, NOD2, and RIP2 at both the transcriptional and translational levels. The protein translation levels of NF-κB, P-p65, p38, and P-p38 in macrophages were also modulated by rTc-CTL-4 protein. Macrophages were co-incubated with rTc-CTL-4 protein after siRNA silencing of NOD1, NOD2, and RIP2. The expression levels of NF-κB, P-p65, p38, and P-p38 were significantly changed compared with the negative control groups (Neg. Ctrl.). Taken together, rTc-CTL-4 protein seemed to act on NOD1/2-RIP2-NF-κB and MAPK signaling pathways in macrophages and might activate MAPK and NF-κB signaling pathways by regulating NOD1, NOD2, and RIP2. The insights from the above studies could contribute to our understanding of immune recognition and regulatory mechanisms of T. canis infection in the host animals.

Effect of vertical central plication on vertical deviations.

PURPOSE: To evaluate the surgical effect of the Wright central plication on vertical rectus muscles to correct vertical strabismus. METHODS: In this multicenter, retrospective, observational outcomes study, data were collected from two surgeons in different practice settings (2017-22). All patients who underwent vertical rectus central plication were included; those undergoing any concurrent strabismus surgery for vertical strabismus were excluded. Primary outcome was amount of strabismus correction in prism diopters per vertical rectus central plication. Secondary outcome was to determine factors associated with better or worse surgical outcomes and patient and patient responses. Data were analyzed using descriptive and bivariate statistics. RESULTS: A total of 36 patients were included. Mean age was 60 years. Mean follow-up was 8.4 months. Of the 36 patients, 11 (31%) had idiopathic strabismus, and 7 (19%) had congenital superior oblique palsy. The remainder had a history that included prior ocular surgery, trauma, and Brown syndrome; 16 (44 %) had prior strabismus surgery. Of 31 patients with preoperative diplopia, 23 (74%) had postoperative resolution of diplopia, and 10 of 16 patients with preoperative prisms (63%) no longer required prisms postoperatively. Mean vertical deviation change was 4.7Δ. Subgroup analysis removing patients with congenital superior oblique palsy showed a larger response of 5.5Δ. 78% of patients had a final deviation <5Δ. No complications or induced postoperative diplopia was reported. CONCLUSIONS: In our study cohort, vertical rectus central plication corrected approximately 5Δ (range, 4.5Δ-5.5Δ) of vertical strabismus due to a variety of causes.

Individualized small bowel preparation for computed tomography enterography: A prospective randomized controlled trial.

BACKGROUND AND AIM: The study aims to evaluate the feasibility of body mass index (BMI)-based individualized small bowel preparation for computed tomography enterography (CTE). METHODS: In this prospective randomized controlled study, patients undergoing CTE were randomly assigned to the individualized group or standardized group. Those in individualized group were given different volumes of mannitol solution based on BMI (1000 mL for patients with BMI < 18.5 kg/m2, 1500 mL for patients with 18.5 kg/m2 ≤ BMI < 25 kg/m2 and 2000 mL for patients with BMI ≥ 25 kg/m2) while patients in the standardized group were all asked to consume 1500-mL mannitol solution. CTE images were reviewed by two experienced radiologists blindly. Each segment of the small bowel was assessed for small bowel image quality and disease detection rates. Patients were invited to record a diary regarding adverse events and acceptance. RESULTS: A total of 203 patients were enrolled and randomly divided into two groups. For patients with BMI < 18.5 kg/m2, 1000-mL mannitol solution permitted a significantly lower rate of flatulence (P = 0.045) and defecating frequency (P = 0.011) as well as higher acceptance score (P = 0.015), but did not affect bowel image quality and diseases detection compared with conventional dosage. For patients with BMI ≥ 25 kg/m2, 2000-mL mannitol solution provided better overall image quality (P = 0.033) but comparable rates of adverse events and patients' acceptance compared with conventional dosage. CONCLUSIONS: Individualized bowel preparation could achieve both satisfactory image quality and patients' acceptance thus might be an acceptable alternative in CTE.

Joint association of physical activity and diet quality with dyslipidemia: a cross-sectional study in Western China.

OBJECTIVE: This study aims to investigate the prevalence of dyslipidemia and assess the joint association of physical activity (PA) and diet quality on dyslipidemia risk in urban areas of Xinjiang. METHODS: Conducted from July 2019 to September 2021 in Xinjiang, China, this cross-sectional study involved 11,855 participants (mean age 47.1 ± 9.4 years, 53.1% male). Standard methods were used to measure plasma cholesterol levels, and validated questionnaires were employed to evaluate dietary habits and PA. The definition of dyslipidemia is based on 2023 Chinese guidelines for lipid management. PA was divided into guideline-recommended moderate-to-vigorous physical activity (MVPA) and non-MVPA, following World Health Organization guidelines. The Food Frequency Questionnaire was used to obtain the intake frequency of each dietary term. Each item was scored based on consumption frequency and divided into three groups (good, intermediate, and poor) based on total dietary score. Multivariate logistic regression analysis was performed to identify dyslipidemia risk factors, as well as the joint association of PA and diet quality. RESULTS: Dyslipidemia prevalence among urban adults in Xinjiang was 39.3%, with notable sex disparities (52.6% in males vs. 24.3% in females, P < 0.001). Among participants with dyslipidemia, the awareness, treatment and control rates were 6.9%, 3.1%, and 1.9%, respectively. A significant multiplicative interaction between PA and diet quality is associated with dyslipidemia (P for interaction < 0.05). Less PA and poor diet quality were associated with an increased odds of dyslipidemia. Even individuals with poor (OR = 1.464, 95% CI: 1.106-1.939) or intermediate (OR = 1.229, 95% CI: 1.003-1.505) diet quality but adhering to recommended MVPA had lower odds of dyslipidemia compared to those with good diet quality but inadequate MVPA (OR = 1.510, 95% CI: 1.252-1.821). CONCLUSIONS: Dyslipidemia prevalence was 39.3% in urban adults in Xinjiang, with limited awareness, treatment, and control. Following guideline-recommended MVPA and maintaining good diet quality were protective against dyslipidemia. Low levels of PA associated with a higher prevalence of dyslipidemia, even in individuals with good diet quality.

Digital protractor as an intraoperative guide to cup anteversion in total hip arthroplasty.

INTRODUCTION: To explore if digital protractor could guide the anteversion of acetabular cup during primary THA and make it consistent with preoperative. METHODS: We retrospectively reviewed 172 cases of primary THA with direct anterior approach (DAA) over 2 years. The anteversion of acetabular cup were measured from computed tomography (CT) scan preoperative and de-identified plain radiographs postoperative by two blinded investigators who were not involved in the surgery. The effect of the digital protractor on the anteversion was determined using regression analysis. RESULTS: The mean anteversion for the THAs in digital protractor group was 15.5°and 21.4°in control group (P < 0.01). The mean anteversion bias for the THAs in digital protractor group was 1.59° and 6.63° in control group (P < 0.01).Regression analysis identified a 10.7% difference in anteversion due to the use of digital protractor (P < 0.01), and THAs performed without digital protractor were six times more likely to result in anteversion of > 25°. The correlation coefficient for the interobserver reliability of the measurement of the two investigators was 0.94. CONCLUSION: The digital protractor is a practical tool in the DAA for THA to determine the anteversion of the acetabular prosthesis.

Macro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma.

Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB+ and CD8 proliferating proportions and a low Macro CD5L+ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB+ and CD8 proliferating proportions are increased, but the CD8 GZMK+ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB+ to CD8 GZMK+ facilitates good response to the therapy, while Macro CD5L+-CD8 GZMB+ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB+. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8+T-cell status conversion and exhaustion induced by Macro CD5L+ in influencing the response, suggesting future avenues for cancer treatment optimization.

Berberine modulates the immunometabolism and differentiation of CD4+ T cells alleviating experimental arthritis by suppression of M1-exo-miR155.

BACKGROUND: The inflammatory cascade mediated by macrophages and T cells is considered to be an important factor in promoting the progression of rheumatoid arthritis (RA). Our previous study found that berberine (BBR) can therapeutically impact adjuvant arthritis (AA) in rats through the regulation of macrophage polarization and the balance of Th17/Treg. However, whether BBR's effects on CD4+T cells response are related to its suppression of M1 macrophage still unclear. PURPOSE: The study aimed to estimate the mechanism of BBR in regulating the immunometabolism and differentiation of CD4+T cells are related to exosome derived from M1-macrophage (M1-exo). STUDY-DESIGN/METHODS: Mice model of collagen-induced arthritis (CIA) was established to investigate the antiarthritic effect of BBR was related with regulation of M1-exo to balance T cell subsets. Bioinformatics analysis using the GEO database and meta-analysis. In vitro, we established the co-culture system involving M1-exo and CD4+ T cells to examine whether BBR inhibits CD4+T cell activation and differentiation by influencing M1-exo-miR155. Exosome was characterized using transmission electron microscopy and western blot analysis, macrophage and CD4+T cell subpopulation were detected by flow cytometry. Further, the metabolic profiles of CD4+T cells were assessed by ECAR, OCR, and the level of glucose, lactate, intracellular ATP. RESULT: BBR reinstates CD4+ T cell homeostasis and reduces miR155 levels in both M1-exo and CD4+ T cells obtained from mice with CIA. In vitro, we found exosomes are indispensable for M1-CM on T lymphocyte activation and differentiation. BBR reversed M1-exo facilitating the activation and differentiation of CD4+T cells. Furthermore, BBR reversed glycolysis reprogramming of CD4+T cells induced by M1-exo, while these regulation effects were significantly weakened by miR155 mimic. CONCLUSION: The delivery of miR-155 by M1-exo contributes to CD4+ T cell immunometabolism dysfunction, a process implicated in the development of RA. The anti-arthritic effect of BBR is associated with the suppression of glycolysis and the disruption of CD4+ T cell subsets balance, achieved by reducing the transfer of M1-exo-miR155 into T cells.

Construction of 1,3,4-oxadiazolines bearing CF3-quaternary centers via amino-assisted [3 + 2] cycloadditions.

An amino-assisted [3 + 2] cycloaddition strategy of nitrile imines with o-aminotrifluoroacetophenones has been explored, thus providing functionalized 1,3,4-oxadiazolines bearing CF3-quaternary centers in good to excellent yields in the presence of K2CO3 under mild conditions. The amino groups located at the ortho-position of trifluoroacetophenone might play a crucial role in the present cyclization. The MTT assay shows that the 1,3,4-oxadiazoline derivatives could be potential candidates for the treatment of head and neck cancers.