Aging-related biomarker discovery in the era of immune checkpoint inhibitors for cancer patients.

Older patients with cancer, particularly those over 75 years of age, often experience poorer clinical outcomes compared to younger patients. This can be attributed to age-related comorbidities, weakened immune function, and reduced tolerance to treatment-related adverse effects. In the immune checkpoint inhibitors (ICI) era, age has emerged as an influential factor impacting the discovery of predictive biomarkers for ICI treatment. These age-linked changes in the immune system can influence the composition and functionality of tumor-infiltrating immune cells (TIICs) that play a crucial role in the cancer response. Older patients may have lower levels of TIICs infiltration due to age-related immune senescence particularly T cell function, which can limit the effectivity of cancer immunotherapies. Furthermore, age-related immune dysregulation increases the exhaustion of immune cells, characterized by the dysregulation of ICI-related biomarkers and a dampened response to ICI. Our review aims to provide a comprehensive understanding of the mechanisms that contribute to the impact of age on ICI-related biomarkers and ICI response. Understanding these mechanisms will facilitate the development of treatment approaches tailored to elderly individuals with cancer.

DR6 Augments Colorectal Cancer Cell Growth, Invasion, and Stemness by Activating AKT/NF-κB Pathway.

This study aims to elucidate the role and mechanisms of Death Receptor 6 (DR6), a member of the tumor necrosis factor receptor superfamily, in the malignant progression of colorectal cancer (CRC). The association of DR6 expression levels and CRC patient survival was examined using the CRC cohort data from GEPIA database. The functional role of DR6 in CRC cells was investigated by performing loss-of-function and gain-of-function experiments based on CCK-8 proliferation assay, transwell migration and invasion assay, and sphere-forming assays. Xenograft model of CRC cells in nude mouse was established to evaluate the impact of DR6 knockdown on CRC tumorigenesis. Elevated expression of DR6 was correlated with an unfavorable prognosis in CRC patients. In vitro functional assays demonstrated that silencing DR6 considerably suppressed the proliferation, migration, invasion, and stemness of CRC cells, whereas its overexpression showed an opposite effect. DR6 knockdown also attenuated tumor formation of CRC cells in the nude mice. Mechanistically, silencing DR6 reduced the phosphorylation of AKT and NF-κB in CRC cells, and the treatment with an AKT activator (SC79) abrogated the inhibitory effects of DR6 knockdown on the malignant features of CRC cells. Our data suggest that DR6 contributes to the malignant progression of CRC by activating AKT/NF-κB pathway, indicating its clinical potential as a prognostic marker and therapeutic target for CRC.

Biomechanical evaluation on a new type of vertebral titanium porous mini-plate and mechanical comparison between cervical open-door laminoplasty and laminectomy: a finite element analysis.

Objective: Compare the spine's stability after laminectomy (LN) and laminoplasty (LP) for two posterior surgeries. Simultaneously, design a new vertebral titanium porous mini plate (TPMP) to achieve firm fixation of the open-door vertebral LP fully. The objective is to enhance the fixation stability, effectively prevent the possibility of "re-closure," and may facilitate bone healing. Methods: TPMP was designed by incorporating a fusion body and porous structures, and a three-dimensional finite element cervical model of C2-T1 was constructed and validated. Load LN and LP finite element models, respectively, and analyze and simulate the detailed processes of the two surgeries. It was simultaneously implanting the TPMP into LP to evaluate its biomechanical properties. Results: We find that the range of motion (ROM) of C4-C5 after LN surgery was greater than that of LP implanted with different plates alone. Furthermore, flexion-extension, lateral bending, and axial rotation reflect this change. More noteworthy is that LN has a much larger ROM on C2-C3 in axial rotation. The ROM of LP implanted with two different plates is similar. There is almost no difference in facet joint stress in lateral bending. The facet joint stress of LN is smaller on C2-C3 and C4-C5, and larger more prominent on C5-C6 in the flexion-extension. Regarding intervertebral disc pressure (IDP), there is little difference between different surgeries except for the LN on C2-C3 in axial rotation. The plate displacement specificity does not significantly differ from LP with vertebral titanium mini-plate (TMP) and LP with TPMP after surgery. The stress of LP with TPMP is larger in C4-C5, C5-C6. Moreover, LP with TMP shows greater stress in the C3-C4 during flexion-extension and lateral bending. Conclusion: LP may have better postoperative stability when posterior approach surgery is used to treat CSM; at the same time, the new type of vertebral titanium mini-plate can achieve almost the same effect as the traditional titanium mini-plate after surgery for LP. In addition, it has specific potential due to the porous structure promoting bone fusion.

Individualized treatment decision model for inoperable elderly esophageal squamous cell carcinoma based on multi-modal data fusion.

BACKGROUND: This research aimed to develop a model for individualized treatment decision-making in inoperable elderly patients with esophageal squamous cell carcinoma (ESCC) using machine learning methods and multi-modal data. METHODS: A total of 189 inoperable elderly ESCC patients aged 65 or older who underwent concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) were included. Multi-task learning models were created using machine learning techniques to analyze multi-modal data, including pre-treatment CT images, clinical information, and blood test results. Nomograms were constructed to predict the objective response rate (ORR) and progression-free survival (PFS) for different treatment strategies. Optimal treatment plans were recommended based on the nomograms. Patients were stratified into high-risk and low-risk groups using the nomograms, and survival analysis was performed using Kaplan-Meier curves. RESULTS: The identified risk factors influencing ORR were histologic grade (HG), T stage and three radiomic features including original shape elongation, first-order skewness and original shape flatness, while risk factors influencing PFS included BMI, HG and three radiomic features including high gray-level run emphasis, first-order minimum and first-order skewness. These risk factors were incorporated into the nomograms as independent predictive factors. PFS was substantially different between the low-risk group (total score ≤ 110) and the high-risk group (total score > 110) according to Kaplan-Meier curves (P < 0.05). CONCLUSIONS: The developed predictive models for ORR and PFS in inoperable elderly ESCC patients provide valuable insights for predicting treatment efficacy and prognosis. The nomograms enable personalized treatment decision-making and can guide optimal treatment plans for inoperable elderly ESCC patients.

Effect of adjuvant radiotherapy after breast-conserving surgery in elder women with early-stage breast cancer: a propensity-score matching analysis.

Purpose: The study aimed to explore the role of adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) in elder women with early-stage breast cancer (BC). Methods: BC patients with 70-79 years of age, stage T1-2N0-1M0, undergoing BCS were screened in the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2015. The clinicopathological characteristics were balanced with propensity-score matching (PSM) method. Kaplan-Meier curves and Cox regression analyses were performed to determine the impact of adjuvant RT on BC patients. Results: Ultimately, 12,310 patients treated with adjuvant RT and 4837 patients treated with no RT, were involved in the analysis. Overall, patients treated with adjuvant RT was associated with a better breast cancer-specific survival (BCSS) (HR: 1.980 [1.596- 2.456], P < 0.001) and overall survival (OS) (HR: 2.214 [1.966- 2.494], P < 0.001) than those who did not undergo RT. After 1:1 PSM, adjuvant RT still performed advantage in both BCSS (HR: 1.918 [1.439- 2.557], P < 0.001) and OS (HR: 2.235 [1.904- 2.624], P < 0.001). In the multivariate COX analysis of BCSS, widowed, divorced and separated patients, tumor grade III, T2 stage, N1 stage, no RT, molecular subtypes with luminal B and triple negative were associated with a shorter BCSS (P < 0.05). In the multivariate COX analysis of OS, age ≥74 years, widowed, divorced and separated patients, tumor grade II/III, T2 stage, no RT, no chemotherapy, molecular subtypes with triple negative were associated with a shorter OS (P < 0.05). Furthermore, the advantages of adjuvant RT were observed in all subgroup analysis. Conclusion: Adjuvant RT after BCS can improve both BCSS and OS in elderly patients with early-stage BC. Additionally, all subgroups analysis-derived BCSS and OS were in support of RT.

Autonomous metal-organic framework nanorobots for active mitochondria-targeted cancer therapy.

Nanorobotic manipulation to access subcellular organelles remains unmet due to the challenge in achieving intracellular controlled propulsion. Intracellular organelles, such as mitochondria, are an emerging therapeutic target with selective targeting and curative efficacy. We report an autonomous nanorobot capable of active mitochondria-targeted drug delivery, prepared by facilely encapsulating mitochondriotropic doxorubicin-triphenylphosphonium (DOX-TPP) inside zeolitic imidazolate framework-67 (ZIF-67) nanoparticles. The catalytic ZIF-67 body can decompose bioavailable hydrogen peroxide overexpressed inside tumor cells to generate effective intracellular mitochondriotropic movement in the presence of TPP cation. This nanorobot-enhanced targeted drug delivery induces mitochondria-mediated apoptosis and mitochondrial dysregulation to improve the in vitro anticancer effect and suppression of cancer cell metastasis, further verified by in vivo evaluations in the subcutaneous tumor model and orthotopic breast tumor model. This nanorobot unlocks a fresh field of nanorobot operation with intracellular organelle access, thereby introducing the next generation of robotic medical devices with organelle-level resolution for precision therapy.

Recent Progress and Perspectives of Direct Ink Writing Applications for Mass Transfer Enhancement in Gas-Phase Adsorption and Catalysis.

Conventional adsorbents and catalysts shaped by granulation or extrusion have high pressure drop and poor flexibility for chemical, energy, and environmental processes. Direct ink writing (DIW), a kind of 3D printing, has evolved into a crucial technique for manufacturing scalable configurations of adsorbents and catalysts with satisfactory programmable automation, highly optional materials, and reliable construction. Particularly, DIW can generate specific morphologies required for excellent mass transfer kinetics, which is essential in gas-phase adsorption and catalysis. Here, DIW methodologies for mass transfer enhancement in gas-phase adsorption and catalysis, covering the raw materials, fabrication process, auxiliary optimization methods, and practical applications are comprehensively summarized. The prospects and challenges of DIW methodology in realizing good mass transfer kinetics are discussed. Ideal components with a gradient porosity, multi-material structure, and hierarchical morphology are proposed for future investigations.

Immune Checkpoint Inhibitor (ICI) Genes and Aging in Clear Cell Renal Cell Carcinoma (ccRCC): Clinical and Genomic Study.

Background: It is anticipated that there will be a large rise in the number of tumor diagnoses and mortality in those aged 65 and older over the course of upcoming decades. Immune checkpoint inhibitors, often known as ICIs, boost immune system activity by selectively targeting ICI genes. On the other hand, old age may be connected with unfavorable results. Methods: The Cancer Genome Atlas (TCGA) provided gene expression data from ccRCC tissue and key clinical variables. ICI gene databases were applied and verified using the GEO database. Results: We identified 14 ICI genes as risk gene signatures among 528 ccRCC patients using univariate and multivariable cox hazard models, and the elderly group was linked with poor survival. Then, by utilizing a new nomogram method, the TNFSF15 gene and age predicting values were estimated at one, three, and five years (85%, 81%, and 81%), respectively, and our age-related risk score was significant even after multivariable analysis (HR = 1.518, p = 0.009, CI = 1.1102.076). TNFSF15 gene expression was lower in elderly ccRCC patients (p = 0.0001). A negative connection between age and the TNFSF15 gene expression was discovered by correlation analysis (p = 0.0001). The verification of the gene by utilizing GEO (GSE167093) with 604 patients was obtained as external validation that showed significant differences in the TNFSF15 gene between young and elderly patients (p = 0.007). Additionally, the protein-protein interactions of the TNFSF15 gene with other ICI genes and aging-related genes was determined. In addition, the TNFSF15 expression was significantly correlated with pathological stages (p = 0.018). Furthermore, it was discovered that the biological processes of senescence, cellular senescence, the immune system, and many immune cell infiltration and immune function types are all closely tied. Conclusions: Along with the risk score evaluation, the ICI gene TNFSF15 was identified as a tumor suppressor gene related to inequalities in age survival and is associated with pathological stages and different immunity statuses. The aging responses of ccRCC patients and related gene expression need further investigation in order to identify potential therapeutic targets.

ARID1A promotes chemosensitivity to gemcitabine in pancreatic cancer through epigenetic silencing of RRM2.

Pancreatic cancer is one of the most common malignancies with very poor prognosis due to its broad resistance to chemotherapy. ARID1A, a subunit of SWI/SNF complex, is involved in pancreatic carcinogenesis through epigenetic silencing of oncogenes. In this study, we aimed to explore whether ARID1A was implicated in the gemcitabine resistance in pancreatic cancer patients via regulating RRM2. We examined the effect of ARID1A depletion on the gemcitabine sensitivity in pancreatic cancer cells and explored the role of RRM2 in ARID1A-mediated pancreatic cancer cells chemosensitivity to gemcitabine. We found that Knockout of ARID1A led to gemcitabine resistance in pancreatic cancer cells, effect of which could be reversed by RRM2, a gemcitabine resistance related gene. ARID1A decreased the transcription of RRM2, and directly bound to the promoter of RRM2. Moreover, expression of RRM2 was negatively correlated with ARID1A in pancreatic cancer tissues. Thus, ARID1A-mediated RRM2 epigenetic suppression is crucial for enhancement of pancreatic cancer chemosensitivity to gemcitabine, and ARID1A could be used as a biomarker to guide the gemcitabine chemotherapy of pancreatic cancer.

Artificial Intelligence Meets Whole Slide Images: Deep Learning Model Shapes an Immune-Hot Tumor and Guides Precision Therapy in Bladder Cancer.

Background: To construct and validate a deep learning cluster from whole slide images (WSI) for depicting the immunophenotypes and functional heterogeneity of the tumor microenvironment (TME) in patients with bladder cancer (BLCA) and to explore an artificial intelligence (AI) score to explore the underlying biological pathways in the developed WSI cluster. Methods: In this study, the WSI cluster was constructed based on a deep learning procedure. Further rerecognition of TME features in pathological images was applied based on a neural network. Then, we integrated the TCGA cohort and several external testing cohorts to explore and validate this novel WSI cluster and a corresponding quantitative indicator, the AI score. Finally, correlations between the AI cluster (AI score) and classical BLCA molecular subtypes, immunophenotypes, functional heterogeneity, and potential therapeutic method in BLCA were assessed. Results: The WSI cluster was identified associated with clinical survival (P < 0.001) and was proved as an independent predictor (P = 0.031), which could also predict the immunology and the clinical significance of BLCA. Rerecognition of pathological images established a robust 3-year survival prediction model (with an average classification accuracy of 86%, AUC of 0.95) for BLCA patients combining TME features and clinical features. In addition, an AI score was constructed to quantify the underlying logic of the WSI cluster (AUC = 0.838). Finally, we hypothesized that high AI score shapes an immune-hot TME in BLCA. Thus, treatment options including immune checkpoint blockade (ICB), chemotherapy, and ERBB therapy can be used for the treatment of BLCA patients in WSI cluster1 (high AI score subtype). Conclusions: In general, we showed that deep learning can predict prognosis and may aid in the precision medicine for BLCA directly from H&E histology, which is more economical and efficient.

Clinical value and molecular mechanism of AQGPs in different tumors.

Aquaglyceroporins (AQGPs), including AQP3, AQP7, AQP9, and AQP10, are transmembrane channels that allow small solutes across biological membranes, such as water, glycerol, H2O2, and so on. Increasing evidence suggests that they play critical roles in cancer. Overexpression or knockdown of AQGPs can promote or inhibit cancer cell proliferation, migration, invasion, apoptosis, epithelial-mesenchymal transition and metastasis, and the expression levels of AQGPs are closely linked to the prognosis of cancer patients. Here, we provide a comprehensive and detailed review to discuss the expression patterns of AQGPs in different cancers as well as the relationship between the expression patterns and prognosis. Then, we elaborate the relevance between AQGPs and malignant behaviors in cancer as well as the latent upstream regulators and downstream targets or signaling pathways of AQGPs. Finally, we summarize the potential clinical value in cancer treatment. This review will provide us with new ideas and thoughts for subsequent cancer therapy specifically targeting AQGPs.

Magnetic-Powered Janus Cell Robots Loaded with Oncolytic Adenovirus for Active and Targeted Virotherapy of Bladder Cancer.

A unique robotic medical platform is designed by utilizing cell robots as the active "Trojan horse" of oncolytic adenovirus (OA), capable of tumor-selective binding and killing. The OA-loaded cell robots are fabricated by entirely modifying OA-infected 293T cells with cyclic arginine-glycine-aspartic acid tripeptide (cRGD) to specifically bind with bladder cancer cells, followed by asymmetric immobilization of Fe3 O4 nanoparticles (NPs) on the cell surface. OA can replicate in host cells and induce cytolysis to release the virus progeny to the surrounding tumor sites for sustainable infection and oncolysis. The asymmetric coating of magnetic NPs bestows the cell robots with effective movement in various media and wireless manipulation with directional migration in a microfluidic device and bladder mold under magnetic control, further enabling steerable movement and prolonged retention of cell robots in the mouse bladder. The biorecognition of cRGD and robust, controllable propulsion of cell robots work synergistically to greatly enhance their tissue penetration and anticancer efficacy in the 3D cancer spheroid and orthotopic mouse bladder tumor model. Overall, this study integrates cell-based microrobots with virotherapy to generate an attractive robotic system with tumor specificity, expanding the operation scope of cell robots in biomedical community.

Adsorption film with sub-milli-interface morphologies via direct ink writing for indoor formaldehyde removal.

In-situ thermally regenerated flexible adsorption films are superior for long-term purification of indoor low-concentration volatile organic compounds (VOCs). To further improve the adsorption kinetics of the films, the surface morphology of adsorption films was suggested in hierarchical channel structure. However, such structure is far from practical applications because of its complicated fabrication method and limited flexibility. In this study, we proposed a convenient and fast method named direct ink writing (DIW) based 3D printing to fabricate flexible adsorption films. Inks were prepared to have appropriate rheological properties and good printability. Three types of adsorption film (flat, straight finned, and trough-like finned) were constructed on flexible polyimide circuit substrates by DIW. We utilized the printed adsorption films for indoor level (1 ppm) formaldehyde removal. The trough-like finned film achieved the best performance among the three printed films, showing a 275% longer penetration time and 252% larger effective adsorption capacity than the flat film. By conducting a 7-cycle adsorption-desorption experiment (more than 12 h), we verified that the films' adsorption performance could effectively recover via in-situ heating. This work could dance around the complicated coating process, increase the structural flexibility and reduce the adsorbent interfacial modification cost.

The effect of mechanical force in genitourinary malignancies.

INTRODUCTION: Mechanical force is attributed to the formation of tumor blood vessels, influences cancer cell invasion and metastasis, and promotes reprogramming of the energy metabolism. Currently, therapy strategies for the tumor microenvironment are being developed progressively. The purpose of this article is to discuss the molecular mechanism, diagnosis, and treatment of mechanical force in urinary tract cancers and outline the medications used in the mechanical microenvironment. AREAS COVERED: This review covers the complex mechanical elements in the microenvironment of urinary system malignancies, focusing on mechanical molecular mechanisms for diagnosis and treatment. EXPERT OPINION: The classification of various mechanical forces, such as matrix stiffness, shear force, and other forces, is relatively straightforward. However, little is known about the molecular process of mechanical forces in urinary tract malignancies. Because mechanical therapy is still controversial, it is critical to understand the molecular basis of mechanical force before adding mechanical therapy solutions.

Higher intakes of dietary caffeine are associated with 25-hydroxyvitamin D deficiency.

Low serum 25-hydroxyvitamin D [25(OH)D] levels remain a challenge worldwide. While some in vitro studies show a caffeine-induced decrease in vitamin D receptor expression, there is a paucity of research to define the extent of caffeine intake and effects on 25(OH)D levels. Therefore, we aimed to associate dietary caffeine intake with 25(OH)D deficiency through a recognized dataset. Using data collected from the 2005-2006 National Health and Nutrition Examination Survey (NHANES), 25(OH)D levels and dietary caffeine intake were extracted from 13134 individuals (30-47 years, interquartile range). We used one-way ANOVA and chi-square tests for quantitative and qualitative variables, respectively, and performed multivariate logistic regression for four models to assess the odds ratio (OR) of 25(OH)D deficiency (<20 ng/ml or <50 nmol/L) based on quartiles of dietary caffeine intake. Both crude and multivariable models detected higher OR for 25(OH)D deficiency according to the highest intakes of caffeine (15.8±9.5, 51.9±11.9, and 177±156 mg/d) when compared to the reference category (2.19±1.04 mg/d), in which the OR in the highest category of caffeine intake was 1.24 (95% CI: 1.12 to 1.37) and 1.48 (95% CI: 1.16 to 1.78) for the crude model and the most complete multivariable analysis (adjustment for age, sex, race, body mass index, smoking, physical activity, occupation, energy intake, protein intake, and fat intake), respectively. In conclusion, higher dietary intakes of caffeine were associated with 25(OH)D deficiency in a representative sample of the American population, but further investigation is warranted to determine causation.

Identification of Immune-Related Genes and Small-Molecule Drugs in Interstitial Cystitis/Bladder Pain Syndrome Based on the Integrative Machine Learning Algorithms and Molecular Docking.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, severely distressing clinical syndrome characterized by bladder pain and pressure perceptions. The origin and pathophysiology of IC/BPS are currently unclear, making it difficult to diagnose and formulate successful treatments. Our study is aimed at investigating the role of immune-related genes in the diagnosis, progression, and therapy of IC/BPS. Method: The gene expression datasets GSE11783, GSE11839, GSE28242, and GSE57560 were retrieved from the GEO database for further analysis. Immune-related IC/BPS differentially expressed genes (DEGs) were identified by limma. Three distinct machine learning approaches, least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forest (RF), were used to find the immune-related IC characteristic genes. Nomogram and receiving operator curves (ROC) were plotted to measure characteristic effectiveness. Using the CMap database and the molecular docking approach, potential small-molecule medicines were found and verified. Consensus cluster analysis was also performed to separate the IC/BPS samples into immunological subtypes. Results: A total of 24 immune-related IC/BPS-DEGs were identified. When compared to the normal control group, the IC/BPS cohort had significantly more immune cell infiltration. Integrative machine learning methods discovered 5 IC/BPS characteristic genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) that may predict IC/BPS diagnosis and immune cell infiltration. Furthermore, two immunological subgroups with substantial variations in immune cell infiltration across IC/BPS samples were identified, which were named cluster1 and cluster2, with the hallmark genes having greater expression in cluster2. Finally, bumetanide was shown to have the potential to be a medication for the treatment of IC/BPS, and it performed well in terms of its molecular binding with RASGRP1. Conclusion: We found and validated 5 immune-related IC/BPS genes (RASGRP1, PPBP, RBP4, CR2, and PROS2) and 2 IC/BPS immune subtypes. In addition, bumetanide was discovered to be a potential drug for treating IC/BPS, which may provide new insight into the diagnosis and immune therapy of IC/BPS patients.

Multifunctional Metal-Organic Framework Exoskeletons Protect Biohybrid Sperm Microrobots for Active Drug Delivery from the Surrounding Threats.

Utilizing spermatozoa as the engine unit of robotic systems at a microscale has brought revolutionized inspirations and strategies to the biomedical community. However, the motility of sperms is impaired by the surrounding threats. For example, the antisperm antibody (AsA) can specifically bind with surface antigens on the sperm membrane and adversely affect their propulsion, hindering the operation of sperm-based microrobots in practical environments. In the present work, we report a biohybrid sperm microrobot by encapsulating sperm cells within metal-organic frameworks (MOFs) and zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) (ZIFSpermbot), capable of active drug delivery and cytoprotection from the biological threats of AsA. ZIF-8 NPs can be facilely coated on the sperm membrane through complexation with tannic acid. Such cell surface engineering has a negligible impact on sperm motility under optimized conditions. The selective permeability of the resulting porous ZIF-8 wrappings protects ZIFSpermbots from the specific binding of AsA, enabling the preservation of intrinsic propulsion of the sperm engine. Besides, ZIF-8 wrappings sustainably release zinc ions and attenuate the oxidative damage generated in sperm cells, allowing the maintenance of sperm movement. Combining the effective protection of sperm propulsion with the drug-loading capacity of ZIF-8 NPs provides new applicability to ZIFSpermbots in risky surroundings with AsA, exhibiting rapid migration in a microfluidic device for active drug delivery with enhanced therapeutic efficacy due to their retained effective propulsion. Imparting bioengine-based microrobots with multifunctional wrappings holds great promise for designing adaptive cell robots that endure harsh environments toward locally extended and diverse operations, facilitating their use in practical and clinical applications.

miR-125a-5p increases cellular DNA damage of aging males and perturbs stage-specific embryo development via Rbm38-p53 signaling.

An increasing number of men are fathering children at an older age than in the past. While advanced maternal age has long been recognized as a risk factor for adverse reproductive outcomes, the influence of paternal age on reproduction is incompletely comprehended. Herein, we found that miR-125a-5p was upregulated in the sperm of aging males and was related to inferior sperm DNA integrity as an adverse predictor. Moreover, we demonstrated that miR-125a-5p suppressed mitochondrial function and increased cellular DNA damage in GC2 cells. We also found that miR-125a-5p perturbed embryo development at specific morula/blastocyst stages. Mechanistically, we confirmed that miR-125a-5p disturbed the mitochondrial function by targeting Rbm38 and activating the p53 damage response pathway, and induced a developmental delay in a p21-dependent manner. Our study revealed an important role of miR-125a-5p in sperm function and early embryo development of aging males, and provided a fresh view to comprehend the aging process in sperm.

Laparoscopic specimen extraction in vitro: preliminary experience.

BACKGROUND: The last procedure performed by the surgeon in laparoscopic surgery is to extract the specimen through the smallest incision possible. This experiment aimed to explore the maximum diameter of specimens that can be extracted through auxiliary incisions of different lengths and shapes by in vitro physical experiments. MATERIALS AND METHODS: We used the abdominal wall with the muscle layer, fixed on a square wooden frame, to simulate the human abdominal wall. Then, specimen extraction ports were made with circular, inverted Y-shaped and straight-line incisions of different sizes and lengths, and specimens of different sizes were made from tissues of different species. These specimens were extracted from different incisions with a force gauge. The tension value (N) was measured, and records were made of the length or diameter of the smallest auxiliary incision through which a given specimen could pass, as well as the largest specimen diameter that could pass through an incision of a given size. This experiment provides us with preliminary experience-based knowledge of how to choose the appropriate auxiliary incision for surgical specimen extraction according to the diameter of the specimen. RESULTS: The maximum diameters of specimens that could be extracted with circular ostomy diameters of 2.4, 2.7 and 3.3 cm were 4.0, 4.5 and 6.0 cm, respectively. Specimens with diameters of 6.0, 8.0 and 10.0 cm could be extracted through inverted Y-shaped incisions with a length around the umbilicus of 1 cm and an extension length of 1.0, 3.0, and 4.0 cm, respectively. Moreover, these same specimens could be extracted through inverted Y-shaped incisions with a length around the umbilicus of 2 cm and extension lengths of 0.0, 1.0 and 2.0 cm. Tough tissue specimens (made from chicken gizzards) with diameters of 1.0, 2.0, 4.0 and 6.0 cm, respectively, could be removed through straight-line incisions measuring 1.0, 2.0, 3.0 and 4.0 cm in length. CONCLUSION: Along with preoperative imaging, surgical planning and trocar position, the shape and length of auxiliary incisions can be used to improve the extraction of specimens via laparoscopic surgery.

Development of dominant epitope-based vaccines encoding Gp63, Kmp-11 and Amastin against visceral leishmaniasis.

The most dangerous form of leishmaniasis is Visceral leishmaniasis (VL). The elimination of VL depends not only on agent treatments but also on effective vaccines against Leishmania parasites. Epitope-based vaccines composed of alternative short antigenic epitopes have the advantages of MHC epitope easy designing, which has broad application prospects. In a previous study, we analyzed Leishmania Gp63, Kmp-11 and Amastin protein sequence in silico, and found that the amino acid fragments of Gp63 (138-360aa), Kmp-11 (1-91aa) and Amastin (1-72aa) were rich in dominant epitopes. In this study, we used the three amino acid fragments as multi-epitope vaccine candidates to construct DNA and protein vaccines. BALB/c mice were vaccinated with the DNA and protein vaccines by DNA prime-protein boost strategy and challenged with Leishmania promastigotes. To evaluate vaccine immunogenicity and immunoprotection, serum specific antibody titers and cytokines were detected using ELISA, splenic CD3+, CD4+ and CD8+ cells were analyzed by flow cytometry, livers were made into pathological sections to observe pathological changes, and splenic parasitic loads were quantified using qPCR. The results showed that the increased specific IgG titers from vaccinated mice supported the vaccine immunogenicity. The increased cytokines (IFN-γ, IL-12 and TNF-α), splenic CD3+, CD4+ and CD8+ T cells and hepatic granulomas, and the decreased splenic parasitic loads (parasite reduction rates of Gp63, Kmp-11 and Amatin groups were 89%, 86% and 79%, respectively) from immunized mice post-infection were suggested the good immunoprotection of the vaccines. Our study demonstrated that vaccines based on the dominant epitopes of Gp63, Kmp-11 and Amastin with DNA prime-protein boost vaccination strategy showed significant immune effects against Leishmania, especially the Gp63 group showed a nearly 90% parasites reduction rate. This study will provide references for visceral leishmaniasis epitope vaccine design and immune strategy selection.