Opportunities and perspectives of small molecular phosphodiesterase inhibitors in neurodegenerative diseases.

Phosphodiesterase (PDE) is a superfamily of enzymes that are responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE inhibition promotes the gene transcription by activating cAMP-response element binding protein (CREB), initiating gene transcription of brain-derived neurotrophic factor (BDNF). The procedure exerts neuroprotective profile, and motor and cognitive improving efficacy. From this point of view, PDE inhibition will provide a promising therapeutic strategy for treating neurodegenerative disorders. Herein, we summarized the PDE inhibitors that have entered the clinical trials or been discovered in recent five years. Well-designed clinical or preclinical investigations have confirmed the effectiveness of PDE inhibitors, such as decreasing Aß oligomerization and tau phosphorylation, alleviating neuro-inflammation and oxidative stress, modulating neuronal plasticity and improving long-term cognitive impairment.

SLC27A2 is a potential immune biomarker for hematological tumors and significantly regulates the cell cycle progression of diffuse large B-cell lymphoma.

BACKGROUND: Research on the fatty acid metabolism related gene SLC27A2 is currently mainly focused on solid tumors, and its mechanism of action in hematological tumors has not been reported. METHOD: This study aims to explore the pathological and immune mechanisms of the fatty acid metabolism related gene SLC27A2 in hematological tumors and verify its functional role in hematological tumors through cell experiments to improve treatment decisions and clinical outcomes of hematological tumors. RESULT: This study identified the fatty acid metabolism related gene SLC27A2 as a common differentially expressed gene between DLBCL and AML. Immune microenvironment analysis showed that SLC27A2 was significantly positively correlated with T cell CD4 + , T cell CD8 + , endothelial cells, macrophages, and NK cells in DLBCL. In AML, there is a significant negative correlation between SLC27A2 and B cells, T cell CD8 + , and macrophages. SLC27A2 participates in the immune process of hematological tumors through T cell CD8 + and macrophages. The GESA results indicate that high expression of SLC27A2 is mainly involved in the fatty acid pathway, immune pathway, and cell cycle pathway of DLBCL. The low expression of SLC27A2 is mainly involved in the immune pathway of AML. Therefore, SLC27A2 is mainly involved in the pathological mechanisms of hematological tumors through immune pathways, and cell experiments have also confirmed that SLC27A2 is involved in the regulation of DLBCL cells. CONCLUSION: In summary, our research results comprehensively report for the first time the mechanism of action of SLC27A2 in the immune microenvironment of DLBCL and AML, and for the first time verify the cycle and apoptotic effects of the fatty acid related gene SLC27A2 in DLBCL cells through cell experiments. Research can help improve the treatment of AML and DLBCL patients.

Optimization of Bear Oil Extraction Process and Hair Growth Activity.

According to ancient Chinese books, bear grease has the effects of strengthening muscles and bones, which is beneficial for weakness, but there is relatively little research on it. Thus, the extraction of it is beneficial for compensating for research in this area. In this study, a uniform experimental design method was used to optimize the extraction process of bear grease by enzymatic hydrolysis extraction, and the extraction rate can reach 81.89% under optimized extraction conditions. Furthermore, the components of bear grease obtained by this study were analyzed by GC-MS, and the results showed that ursolic oil was rich in unsaturated fatty acids (67.51%), which was higher than that of the traditional method (66.92%). The composition of bear grease extracted by the enzymatic method was also better than that extracted by the traditional method. In addition, bear grease obtained in this study had the obvious activity of promoting hair growth. The length, weight, and number of hair follicles in the depilation area of mice in the high-dose group were significantly different from those in the blank group (p < 0.01). This study optimized the extraction process of bear grease and conducted a preliminary analysis of its fatty acid composition, which is expected to provide some reference for the development of the medicinal value of bear grease.

Super-enhancer mediated upregulation of MYEOV suppresses ferroptosis in lung adenocarcinoma.

Super-enhancers (SEs) exerted a crucial role in regulating the transcription of oncogenes across various malignancies while the roles of SEs driven genes and the core regulatory elements remain elusive in LUAD. In this study, cancer-specific-SE-genes of lung adenocarcinoma (LUAD) were profiled through H3K27ac ChIP-seq data of cancer cell lines and normal lung tissues, which enriched in in biological processes and pathways integral to the pathophysiology of LUAD. Based on this study, LUAD cells were susceptible to SEs inhibitors, with a reduction of cell proliferation as well as an elevation of apoptosis upon JQ1 or THZ1 intervention. Moreover, the integration of SEs landscapes, CRISPRi, ChIP-PCR, Hi-C data analysis and dual-luciferase reporter assays revealed that myeloma overexpressed gene (MYEOV) was aberrantly overexpressed in LUAD via transcriptional activation by the core SE elements. Functionally, the knockdown of MYEOV undermined cell proliferation in vitro and tumor growth in vivo. In addition, the knockdown of MYEOV generated a prominent ferroptotic phenotype, characterized by elevation of intracellular ferrous iron, reactive oxygen species and lipid peroxidation, together with alteration in marker proteins (SLC7A11, GPX4, FTH1, and ACSL4). Instead, the overexpression of MYEOV accelerated cell proliferation and abrogated ferroptosis. Clinically, the overexpression of MYEOV was observed in LUAD tissues indicating a poor prognosis in patients with LUAD. Mechanistically, SMPD1-induced autophagic degradation of GPX4 assumed a crucial role in the process of ferroptosis triggered by MYEOV knockdown. Serving as an oncogene repressing ferroptosis, promoting proliferation as well as shortening survival in LUAD, SEs-mediated activation of MYEOV might distinguish as a promising therapeutic target.

Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma.

Background: Recent research has shown that lysosomes play a critical role in the onset and progression of malignancy by regulating tumor cell death through several mechanisms. Nevertheless, the involvement of lysosome-associated genes (LSAGs) in lung adenocarcinoma (LUAD) is still not well understood. Methods: LSAGs were identified in malignant lung epithelial cells, as well as biologically and functionally annotated by the comprehensive integration of single-cell and bulk RNA-sequencing data. Prognostic characterization of LSAGs was established, of which the accuracy and reliability were assessed by one-way Cox and LASSO regression. Correlations between LSAG properties and immune cell infiltration, chemotherapy, and immunotherapy were analyzed by integrated omics data. Finally, we characterized the expression of three LSAGs (KCNE1, NPC2, and SFTPD) in malignant lung epithelium and assessed their impact on tumor malignancy related phenotypes. Results: We identified 18 LSAGs associated with prognosis, of which 3 LSAGs were used to construct prognostic models. High-risk patients had worse survival and the model predicted it better than other clinical indicators. Based on the functional enrichment analyses, LSAGs were associated with binding and molecular activity functions, inhibition of DNA damage repair and tumor growth, IL7 signaling pathway, and glycolysis. M0 macrophages and M1 macrophages were substantially enriched in high-risk patients. Conversely, there was a considerable enrichment of resting dendritic cells and M2 macrophages in patients at low risk. We also found that risk scores predicted the outcome of immunotherapy. In vitro, we found that KCNE1, NPC2, and SFTPD were lowly expressed in malignant epithelial cells and patients with low expression of KCNE1, NPC2, and SFTPD had a higher percentage of M2 macrophage infiltration. Overexpression of KCNE1, NPC2, and SFTPD suppressed the proliferation and invasion of malignant cells, and M0 macrophages remarkably reduced M2 macrophage polarization and cellular secretion of pro-tumor cytokines. Conclusions: We used three LASGs-KCNE1, NPC2, and SFTPD-to develop and validate a predictive signature for LUAD patients. Furthermore, we found that low expression of KCNE1, NPC2, and SFTPD promotes lung cancer cell proliferation and invasion and M2 macrophage polarization. Our study may provide fresh perspectives for customized immunotherapy.

Tim4 deficiency reduces CD301b+ macrophage and aggravates periodontitis bone loss.

Periodontitis is a common chronic inflammatory disease that causes the periodontal bone destruction and may ultimately result in tooth loss. With the progression of periodontitis, the osteoimmunology microenvironment in periodontitis is damaged and leads to the formation of pathological alveolar bone resorption. CD301b+ macrophages are specific to the osteoimmunology microenvironment, and are emerging as vital booster for conducting bone regeneration. However, the key upstream targets of CD301b+ macrophages and their potential mechanism in periodontitis remain elusive. In this study, we concentrated on the role of Tim4, a latent upstream regulator of CD301b+ macrophages. We first demonstrated that the transcription level of Timd4 (gene name of Tim4) in CD301b+ macrophages was significantly upregulated compared to CD301b- macrophages via high-throughput RNA sequencing. Moreover, several Tim4-related functions such as apoptotic cell clearance, phagocytosis and engulfment were positively regulated by CD301b+ macrophages. The single-cell RNA sequencing analysis subsequently discovered that Cd301b and Timd4 were specifically co-expressed in macrophages. The following flow cytometric analysis indicated that Tim4 positive expression rates in total macrophages shared highly synchronized dynamic changes with the proportions of CD301b+ macrophages as periodontitis progressed. Furthermore, the deficiency of Tim4 in mice decreased CD301b+ macrophages and eventually magnified alveolar bone resorption in periodontitis. Additionally, Tim4 controlled the p38 MAPK signaling pathway to ultimately mediate CD301b+ macrophages phenotype. In a word, Tim4 might regulate CD301b+ macrophages through p38 MAPK signaling pathway in periodontitis, which provided new insights into periodontitis immunoregulation as well as help to develop innovative therapeutic targets and treatment strategies for periodontitis.

A contact-electro-catalysis process for producing reactive oxygen species by ball milling of triboelectric materials.

Ball milling is a representative mechanochemical strategy that uses the mechanical agitation-induced effects, defects, or extreme conditions to activate substrates. Here, we demonstrate that ball grinding could bring about contact-electro-catalysis (CEC) by using inert and conventional triboelectric materials. Exemplified by a liquid-assisted-grinding setup involving polytetrafluoroethylene (PTFE), reactive oxygen species (ROS) are produced, despite PTFE being generally considered as catalytically inert. The formation of ROS occurs with various polymers, such as polydimethylsiloxane (PDMS) and polypropylene (PP), and the amount of generated ROS aligns well with the polymers' contact-electrification abilities. It is suggested that mechanical collision not only maximizes the overlap in electron wave functions across the interface, but also excites phonons that provide the energy for electron transition. We expect the utilization of triboelectric materials and their derived CEC could lead to a field of ball milling-assisted mechanochemistry using any universal triboelectric materials under mild conditions.

Glycyrrhizin alleviates radiation-induced lung injury by regulating the NLRP3 inflammasome through endoplasmic reticulum stress.

Objective: Radiation pneumonitis (RP) is the major adverse response of radiation therapy for thoracic malignant tumors, and there is a lack of effective interventions. The aim of this study was to investigate the radioprotective effect of Glycyrrhizin (GL) on RP and its potential mechanism. Method: The body weight and lung weight of mice were monitored. HE staining was used to observe lung injury, and the expression of endoplasmic reticulum (ER) stress biomarkers and the activation of NLRP3 inflammasome were determined by Western blotting and immunohistochemistry. Flow cytometry was performed to check MLE-12 apoptosis. ER stress activator, Tunicamycin (Tuni), was used to verify the potential mechanism of GL. A systemic pharmacology explored the potential targets and pathways of GL. Results: In this study, the lungs of irradiated mice showed significant pneumonic changes. In vivo and in vitro assay, NLRP3 inflammasome was significantly activated, the expression of ER stress biomarkers was elevated, flow cytometry confirms increased apoptosis in irradiated MLE-12 cells. GL inhibits the activation of NLRP3 inflammasome and ER stress pathways. Furthermore, systemic pharmacology revealed that the radioprotective effect of GL may be related to the MAPK signaling pathway. Conclusion: In the present study, the results indicated that GL may regulate NLRP3 inflammasome through ER stress, thus exerting irradiation-protective effects on RP, and the ER stress pathway may be a potential target for RP treatment.

Analysis of Risk Factors for Recurrence after Transurethral Resection of Bladder Tumor in Patients with Non-Muscle Invasive Bladder Cancer: 2-Year Follow-Up Outcomes.

INTRODUCTION: The aim was to investigate the risk factors for recurrence after transurethral resection of bladder tumor (TURBT) in patients with non-muscle invasive bladder cancer (NMIBC) and to provide a basis for clinical prevention of recurrence of NMIBC. METHODS: From January 2012 to December 2020, 592 patients with NMIBC who underwent TURBT attending the Second Affiliated Hospital of Xi'an Jiaotong University were retrospectively included in this study. Patients were divided into relapse and relapse-free groups according to whether relapse occurred within 2 years. Ultimately, 72 patients were included in the relapse group and 350 patients were included in the relapse-free group. Observation indicators included age, sex, smoking, underlying disease (hypertension, diabetes, coronary heart disease), two or more lesions, tumor size, hematuria, pathology grading (low, medium, high), staging (Ta, T1), muscular invasion in initial pathology, tumor base (sessile, pedunculated), use of intravesical drug (pirarubicin, bacillus Calmette-Guerin [BCG], mitomycin, hydroxycamptothecin, gemcitabine). RESULTS: In this study, the 2-year recurrence rate of NMIBC patients after TURBT was 17.06%. There were significant differences in comparison of pirarubicin, BCG, and mitomycin treatment between the two groups (p < 0.05). To avoid missing risk factors for recurrence, factors with p < 0.1 were analyzed. The results of univariate logistic regression analysis showed that NMIBC patients with BCG treatment (OR = 5.088, 95% CI = 1.444-17.73, p = 0.012), high pathology grading (OR = 0.415, 95% CI = 0.197-0.880, p = 0.023), T1 stage (OR = 2.097, 95% CI = 0.996-4.618, p = 0.059), mitomycin treatment (OR = 5.029, 95% CI = 1.149-21.77, p = 0.031), and pirarubicin treatment (OR = 1.794, 95% CI = 1.079-3.030, p = 0.024) had significantly higher risk of recurrence within 2 years after TURBT. The results of multivariate logistic regression analysis showed that NMIBC patients with high pathology grading (OR = 0.4030, 95% CI = 0.1702-0.8426, p = 0.0241), pirarubicin treatment (OR = 1.961, 95% CI = 1.159-3.348, p = 0.0125), and BCG treatment (OR = 6.201, 95% CI = 1.275-29.73, p = 0.0190) had significantly higher risk of recurrence within 2 years after TURBT. CONCLUSION: Our study highlights the importance of postoperative surveillance and individualized treatment for patients with NMIBC. Our findings show that high pathology grading, pirarubicin treatment, and BCG treatment are independent risk factors for recurrence after TURBT in patients with NMIBC. However, caution is warranted when interpreting our findings due to the small sample size and the need for further research to confirm the negative impact of mitomycin and BCG on recurrence rates.

Characteristics and mechanism of lower limb injury induced by landmine blast: A research in a rabbit model.

BACKGROUND: Limb injuries caused by landmine explosions are tricky to treat and difficult to protect. It is necessary to establish an animal model for studying lower limb injury and to investigate the characteristics and mechanisms of lower limb injury induced by landmine blasts. METHODS: Twenty-six mature white rabbits were randomly divided into sham group (n=10) and injury group (n=16). Landmine blast was simulated by electric detonators under the right lower limb in upright state by a special modified fixation frame. High-speed photography was used to observe the body movements. Vital signs, vascular injury (determining by digital subtraction angiography), pathological characteristics, and ATP concentration of the tibialis anterior muscle and triceps surae of shank were recorded for com-parison. RESULTS: Generally, middle and lower segment of the injured legs of the rabbits was seriously damaged. The limb stump presents a distribution of three areas, tissue free zone, contusion hematoma, and edema contusion. Sneak wound track, myofascial destruction, and periosteum stripping were typical characteristics of landmine blast injury. ATP concentration and pathological analysis showed that the tibialis anterior muscle was the most seriously injured, followed by the gastrocnemius and soleus. ATP concentration of affected muscle of both the contusion and commotio area declined remarkably over time, but the muscle in the avulsion area stayed at a low activity level with no change over the time. Small vascular injury in the contusion area was evident. The site of the sciatic nerve lesion was higher than the muscle. Injured site of sciatic nerve injury was higher than serious contusion muscle. High-speed photography demonstrated that the joints of the injured limb extremely flexed followed by a rapid stretch under the blast shock wave. CONCLUSION: The established experimental model presents typical effect of lower limbs wounded by the mine blast in war field. Landmine blast can cause typical damage on lower limbs including nerve lesion, knee injury, and microcirculation damage that is pro-gressive over time. The limb stump is divided into three zones based on gross pathology and micropathology, which can provide an important reference for clinical treatments and prognosis.

Clinical efficacy of ultrasound doppler-guided hemorrhoidal artery ligation combined with procedure for prolapse and hemorrhoids in treatment of severe hemorrhoids.

Hemorrhoids are a prevalent anorectal condition that affects a wide range of adult populations. The severity of this condition was graded using a validated hemorrhoidal grading system, specifically focusing on grade III and IV cases. This retrospective study aimed to compare the clinical efficacy of a standard Procedure for Prolapse and Hemorrhoids (PPH) with a combined Doppler-guided Hemorrhoidal Artery Ligation (DG-HAL) and a PPH approach in patients with severe hemorrhoids. Conducted from May 2021 to January 2023, the study included patients aged 18-65 with confirmed diagnosis of Grade III or Grade IV hemorrhoids. Patients with a history of anorectal surgery and significant comorbidities were excluded. The control group underwent standard PPH, whereas the observation group received DG-HAL followed by PPH. Clinical outcomes were measured using variables such as the operative duration, intraoperative blood loss, postoperative wound healing time, and length of hospital stay. Efficacy was evaluated using a hierarchical scale and a visual analog scale (VAS) for postoperative pain. The complication rates were also assessed. baseline characteristics were homogeneous between the 2 groups. The observation group demonstrated significantly faster postoperative wound healing and shorter hospital stay (P < .01). The overall therapeutic efficacy in the observation group was 90.0%, which was higher than that of the control group (75.0%; P = .025). The VAS pain scores were also significantly lower in the observation group (P = .002). A marked decrease in complication rates was observed in the observation group (3.3%) compared with that in the control group (17.9%) (P < .05). The combined DG-HAL and PPH surgical approach exhibited superior clinical efficacy in treating severe hemorrhoids. This technique offers high effectiveness, reduced postoperative VAS pain scores, and lower complication rates. The long-term efficacy requires further observation.

Progress in the treatment of neonatal hypoxic-ischemic encephalopathy with umbilical cord blood mononuclear cells.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a common disease among newborns, which is a leading cause of neonatal death and permanent neurological sequelae. Therapeutic hypothermia (TH) is the only method for the treatment of HIE that has been recognized effective clinically at home and abroad, but the efficacy is limited. Recent research suggests that the cord blood-derived mononuclear cells (CB-MNCs), which the refer to blood cells containing one nucleus in the cord blood, exert anti-oxidative, anti-inflammatory, anti-apoptotic effects and play a neuroprotective role in HIE. This review focuses on safety and efficacy, the route of administration, dose, timing and combination treatment of CB-MNCs in HIE.

Complication Rates and Survival of Nonagenarians after Hip Hemiarthroplasty versus Proximal Femoral Nail Antirotation for Intertrochanteric Fractures: A 15-Year Retrospective Cohort Study of 113 Cases.

OBJECTIVE: Intertrochanteric fracture is a very common but serious type of hip fracture in nonagenarians. The surgical treatment remains a significant challenge for orthopedists. The objective of this study was to investigate postoperative complications and survival outcomes compared between bipolar hemiarthroplasty (HA) and proximal femoral nail anti-rotation (PFNA) in nonagenarians with intertrochanteric fractures, and to evaluate the efficacy and safety of the two surgical procedures in this patient population. METHODS: A total of 113 consecutive nonagenarians who underwent bipolar HA or PFNA for the treatment of intertrochanteric fractures from January 2006 to August 2021 were retrospectively studied in the current paper. There were 34 males and 79 females, with a mean age of 92.2 years (range 90-101 years) at the time of operation. The average duration of follow-up was 29.7 months (range 1-120 months). The full cohort was divided into bipolar HA (77 cases) and PFNA (36 cases) groups. Damage control orthopedics was used to determine the optimal surgery time and assist in perioperative management. A restrictive blood transfusion strategy was employed, along with appropriate adjustments under multidisciplinary assessment, throughout the perioperative period. Perioperative clinical information and prognostic data were analyzed. Kaplan-Meier survival curves were used for survival analysis, and landmark analysis divided the entire follow-up period into 1-12 months (short-term), 13-42 months (medium-term) and 43-120 months (long-term) according to the configurations of Kaplan-Meier survival curves. RESULTS: Both groups had similar general variables except for the proportion of high adjusted Charlson comorbidity index (aCCI) (≥6 points) (6.5% in bipolar HA group and 22.2% in PFNA group, p = 0.024). Intraoperative blood loss and transfusion requirements were greater, and the intraoperative transfusion rates were higher in the bipolar HA group compared to the PFNA group (all p < 0.05). The complications rates, 1- to 60-month cumulative all-cause mortality, postoperative optimal Harris hip score (HHS), and Barthel index (BI) presented no significant difference between the two groups (all p > 0.05). Both groups had similar overall survival curves (p = 0.37). However, landmark analysis revealed that bipolar HA group exhibited higher survival rates in medium-term (p = 0.01), while similar survival rates were observed in the short- and long-term post-operation periods (both p > 0.05). Cox regression with survival-time-dependent covariate calculated the hazard ratio (HR) of bipolar HA was 0.41 in medium-term (p = 0.039). CONCLUSION: Bipolar HA is equally effective and reliable as PFNA for treating intertrochanteric fractures in nonagenarians. Despite resulting in more intraoperative blood loss and transfusions, bipolar HA therapy is associated with a higher medium-term survival rate compared to PFNA treatment. The application of damage control orthopedics and precise perioperative patient blood management could contribute to the positive clinical outcomes observed in this patient population.

Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis.

Increasing evidence indicates that circular RNAs (circRNAs) accumulate in aging tissues and nonproliferating cells due to their high stability. However, whether upregulation of circRNA expression mediates stem cell senescence and whether circRNAs can be targeted to alleviate aging-related disorders remain unclear. Here, RNA sequencing analysis of differentially expressed circRNAs in long-term-cultured mesenchymal stem cells (MSCs) revealed that circSERPINE2 expression was significantly increased in late passages. CircSERPINE2 small interfering RNA delayed MSC senescence and rejuvenated MSCs, while circSERPINE2 overexpression had the opposite effect. RNA pulldown followed by mass spectrometry revealed an interaction between circSERPINE2 and YBX3. CircSERPINE2 increased the affinity of YBX3 for ZO-1 through the CCAUC motif, resulting in the sequestration of YBX3 in the cytoplasm, inhibiting the association of YBX3 with the PCNA promoter and eventually affecting p21 ubiquitin-mediated degradation. In addition, our results demonstrated that senescence-related downregulation of EIF4A3 gave rise to circSERPINE2. In vivo, intra-articular injection of si-circSerpine2 restrained native joint-resident MSC senescence and cartilage degeneration in mice with aging-related osteoarthritis. Taken together, our findings provide strong evidence for a regulatory role for the circSERPINE2/YBX3/PCNA/p21 axis in MSC senescence and the therapeutic potential of si-circSERPINE2 in alleviating aging-associated syndromes, such as osteoarthritis.

The active phthalate metabolite, DHEP, induces proliferation and metastasis of prostate cancer cells via upregulation of ß-catenin and downregulation of KLF7.

Phthalates such as DHEP are among the widely used compounds in industry. It has been shown that DHEP can convey various biological consequences in mammalian cells, among them, the carcinogenic effects of DHEP are emphasized. The present study aimed to assess the impact of DHEP exposure on the proliferation and invasiveness of DU145 prostate cancer cells through in vitro and in vivo models. The DU145 cells were treated with increasing concentrations of DHEP and the tumorigenic parameters were analyzed. KLF7 as a probable mediator of the effect of DHEP was either overexpressed or knocked down in DU145 to evaluate the probable impact of KLF7 on the biological effects of DHEP. The effect of DHEP was also studied in a DU145 xenograft tumor model. The moderate doses of DHEP increased the proliferation and migration of DU145 cells. In the case of gene expression patterns, DHEP reduced the levels of p53 and KLF7 while elevated the expression of ß-catenin. The knock-down of KLF7 conveyed comparable effects to that of DHEP to some degree and increased the proliferation of DU145 cells, while the transduction of KLF7 increased the expressions of p53 and p21 along with controlling the tumor size. The present study demonstrated the potential of DHEP in increasing the tumorigenic properties of DU145 cells along with a focus on the underlying mechanisms. Sustained exposure to DHEP can cause a dysregulation in balance between oncogenes and tumor suppressor genes which is the hallmark of malignant transformation. Thus, special considerations seem necessary for the safe exploitation of phthalates.

Efficacy and safety of immune checkpoint inhibitors in Proficient Mismatch Repair (pMMR)/ Non-Microsatellite Instability-High (non-MSI-H) metastatic colorectal cancer: a study based on 39 cohorts incorporating 1723 patients.

PURPOSE: This study was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs)-based therapy in proficient mismatch repair (pMMR)/non-microsatellite instability-high (non-MSI-H) metastatic colorectal cancer (mCRC). METHODS: Electronic databases were screened to identify relevant trials. The primary endpoints were pooled objective response rate (ORR) and disease control rate (DCR). Stratified analysis was accomplished on ICIs-based regimens, treatment lines and RAS status. RESULTS: Totally, 1723 mCRC patients from 39 cohorts were included. The pooled ORR, DCR, 12-month overall survival (OS) rate and 6-month progression-free survival (PFS) rate of ICIs-based therapy in pMMR/non-MSI-H mCRC were 8.5% (95% CI: 4.4%-13.5%), 48.2% (95% CI: 37.8%-58.6%), 52.3% (95% CI: 46.4%-58.1%) and 32.8% (95% CI: 23.5%-42.7%) respectively. As a whole, no significantly differences were shown between ICIs-based and non-ICIs-based therapy for pMMR/non-MSI-H mCRC in terms of both PFS (HR = 1.0, 95% CI: 0.9-1.1, P = 0.91) and OS (HR = 1.0, 95% CI: 0.9-1.2, P = 0.51). It was worth noting that the addition of ICIs to anti-vascular endothelial growth factor (VEGF) agent plus chemotherapy displayed excellent efficacy in pMMR/non-MSI-H mCRC (ORR = 42.4%, 95% CI: 10.0%-78.6%; DCR = 92.0%, 95% CI: 68.3%-100.0%; 12-month OS rate = 71.4%, 95% CI: 50.0%-89.1%; 6-month PFS rate = 55.2%, 95% CI: 24.8%-83.8%; and PFS (compared with non-ICIs-based therapy): HR = 0.9, 95% CI: 0.8-1.0, P = 0.02), especially served as first-line therapy (ORR = 74.2%, 95% CI: 61.4%-85.4%; DCR = 98.7%, 95% CI: 92.0%-100.0%); and without additional treatment related adverse events (TRAEs) were observed. CONCLUSIONS: ICIs-based combination therapy, especially the addition of ICIs to first-line anti-VEGF agent plus chemotherapy, is promising in pMMR/non-MSI-H mCRC with good efficacy and controllable toxicity.

Extracellular vesicles as a novel mediator of interkingdom communication.

Extracellular vesicles (EVs) are nanosized lipid bilayer-delimited particles secreted from almost all types of cells including bacteria, mammals and plants, and are presumed to be mediators of intercellular communication. Bacterial extracellular vesicles (BEVs) are nanoparticles with diverse diameters, ranging from 20 to 400 nm. BEVs are composed of soluble microbial metabolites, including nucleic acid, proteins, lipoglycans, and short-chain fatty acids (SCFAs). In addition, EVs may contain quorum sensing peptides that are endowed with the ability to protect bacteria against bacteriophages, form and maintain bacterial communities, and modulate the host immune system. BEVs are potentially promising therapeutic modalities for use in vaccine development, cancer immunotherapy regimens, and drug delivery cargos. Plant-derived EVs (PEVs), such as EVs derived from herbal medicines, can be absorbed by the gut microbiota and influence the composition and homeostasis of gut microbiota. This review highlights the roles of BEVs and PEVs in bacterial and plant physiology and discusses crosstalk among gut bacteria, host metabolism and herbal medicine. In summary, EVs represent crucial communication messengers in the gut microbiota, with potential therapeutic value in the delivery of herbal medicines.

MEN1 is a regulator of alternative splicing and prevents R-loop-induced genome instability through suppression of RNA polymerase II elongation.

The fidelity of alternative splicing (AS) patterns is essential for growth development and cell fate determination. However, the scope of the molecular switches that regulate AS remains largely unexplored. Here we show that MEN1 is a previously unknown splicing regulatory factor. MEN1 deletion resulted in reprogramming of AS patterns in mouse lung tissue and human lung cancer cells, suggesting that MEN1 has a general function in regulating alternative precursor mRNA splicing. MEN1 altered exon skipping and the abundance of mRNA splicing isoforms of certain genes with suboptimal splice sites. Chromatin immunoprecipitation and chromosome walking assays revealed that MEN1 favored the accumulation of RNA polymerase II (Pol II) in regions encoding variant exons. Our data suggest that MEN1 regulates AS by slowing the Pol II elongation rate and that defects in these processes trigger R-loop formation, DNA damage accumulation and genome instability. Furthermore, we identified 28 MEN1-regulated exon-skipping events in lung cancer cells that were closely correlated with survival in patients with lung adenocarcinoma, and MEN1 deficiency sensitized lung cancer cells to splicing inhibitors. Collectively, these findings led to the identification of a novel biological role for menin in maintaining AS homeostasis and link this role to the regulation of cancer cell behavior.

Accuracy of Femoral Tunnel Localization With Mixed Reality Technology-Assisted Single-Bundle ACL Reconstruction.

Background: It is clinically challenging to accurately drill femoral and tibial tunnels to reconstruct the anterior cruciate ligament (ACL). Mixed reality (MR) technology, a further development of virtual reality technology, presents virtual scene information in real time and establishes an interactive feedback information loop among the real world, the virtual world, and the user. Purpose/Hypothesis: The purpose of this study was to investigate the structural and early clinical outcomes of ACL reconstruction assisted by MR technology. It was hypothesized that MR technology would improve the accuracy of tunnel localization. Study Design: Cohort study; Level of evidence, 3. Methods: Included were 44 patients at a single institution who underwent arthroscopic single-bundle ACL reconstruction between June 2020 and March 2022. Reconstruction with the aid of MR technology was performed in 21 patients (MR group), and conventional arthroscopic reconstruction was performed in 23 patients. Postoperatively, the parameters related to the bone tunnel positioning were compared by computed tomography imaging with 3-dimensional (3D) reconstruction, and 12-month postoperative clinical outcomes were assessed with the Lysholm and International Knee Documentation Committee scores. Results: There was no statistically significant difference in projection angles in the coronal, axial, or sagittal plane between the preoperative virtually created tunnel guide pin and the actual tunnel (P > .05 for all). In the MR group, the center of the femoral tunnel exit was closer to the apex of the lateral femoral condyle along the proximal-distal axis (14.07 ± 4.12 vs 17.49 ± 6.24 mm for the conventional group; P < .05) and the graft bending angle was lower (117.71° ± 8.08° vs 127.81° ± 11.91° for the conventional group; P < .05). The scatterplot of the femoral tunnel location distribution showed that the entrance and exit points in the MR group were more concentrated and closer to the ideal location of the preoperative design than in the conventional group. Patients in both groups had significant preoperative-to-postoperative improvement based on outcome scores (P < .001 for all), with no significant difference between groups. Conclusion: ACL reconstruction with the aid of MR technology allowed for more accurate positioning and orientation of the femoral tunnel during surgery when compared with conventional reconstruction.