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The limited success of current targeted therapies for pancreatic cancer underscores an urgent demand for novel treatment modalities. The challenge in mitigating this malignancy can be attributed to the digestive organ expansion factor (DEF), a pivotal yet underexplored factor in pancreatic tumorigenesis. The study uses a blend of in vitro and in vivo approaches, complemented by the theoretical analyses, to propose DEF as a promising anti‐tumor target. Analysis of clinical samples reveals that high expression of DEF is correlated with diminished survival in pancreatic cancer patients. Crucially, the depletion of DEF significantly impedes tumor growth. The study further discovers that DEF binds to p65, shielding it from degradation mediated by the ubiquitin‐proteasome pathway in cancer cells. Based on these findings and computational approaches, the study formulates a DEF‐mimicking peptide, peptide‐031, designed to disrupt the DEF‐p65 interaction. The effectiveness of peptide‐031 in inhibiting tumor proliferation has been demonstrated both in vitro and in vivo. This study unveils the oncogenic role of DEF while highlighting its prognostic value and therapeutic potential in pancreatic cancer. In addition, peptide‐031 is a promising therapeutic agent with potent anti‐tumor effects. [ABSTRACT FROM AUTHOR]

Di‐(2‐ethylhexyl) phthalate (DEHP), a widely used plasticizer, has been shown to cause reproductive toxicity, but the precise mechanism remains unclear. This study aimed to investigate the possible molecular mechanism of DEHP‐induced testicular damage. In vivo study, we administered different doses of DEHP (0, 250, and 500 mg/kg/day) to male C57BL/6 mice from 22 and 35 days after birth. We found that DEHP exposure induced histopathological alterations in prepubertal testes, and testicular lipidomics indicated notable alterations in lipid metabolism and significant enrichment of ferroptosis. Further tests showed that ferrous iron (Fe2+) and malondialdehyde (MDA) levels significantly increased after DEHP exposure. Western blotting revealed that DEHP exposure reduced glutathione peroxidase 4 (GPX4) expression, and elevated acyl coenzyme A synthetase long‐chain member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) expression. The in vitro results were consistent with the in vivo results. When Leydig cells and Sertoli cells were treated with ferrostatin‐1 and monoethylhexyl phthalate (MEHP), MEHP‐induced increases in Fe2+ and MDA levels, accumulation of lipid reactive oxygen species, downregulation of GPX4, and upregulation of ACSL4 and LPCAT3 were reversed. Collectively, our findings suggested that aberrant lipid metabolism and ferroptosis may be involved in prepubertal DEHP exposure‐induced testicular damage. [ABSTRACT FROM AUTHOR]

Purpose: The incidence and mortality of lung cancer are continuously rising in recent years. Mitochondrial energy metabolism malfunction is found to be crucial in cancer proliferation and bioenergetic reprogramming, especially for lung cancer. In this study, we attempted to use mitochondrial-targeted drug therapy to change the energy metabolism pattern of cancer cells to inhibit the development of lung cancer, and investigated its mechanism of action and key targets through multi-omics studies. Methods: In this study, we established the in vivo tumor mouse mode, treated mice with multiple mitochondrial-targeted drug combinations and DDP, severally. Then, we investigated the differences between the 7-drug group with the control group and the DDP treatment group by transcriptomics, proteomics and metabolomics to find the therapeutic targets. Results: We found that mitochondria-targeting drug cocktail therapy, especially the 7-drug regimen, effectively improved mitochondrial metabolism, changed energy supply patterns in lung cancer cells, significantly increased NK cells in tumor tissues, and decreased tumor markers in plasma. Multi-omics analysis informed that the combination of 7-drug could up-regulate mitochondrial oxidative phosphorylation, ATP synthesis and autophagy related genes, and down-regulate proliferation and immune-related genes compared with the control group. By further mapping the protein interaction network, we identified a key target for 7-drug therapy to reverse tumor metabolic reprogramming and validated it in metabolomics. Conclusions: Mitochondrial-targeted drug cocktail therapy can effectively inhibit the occurrence and development of tumors, through the reprogramming of energy metabolism and the increase in immune cells in tumor tissues. Thus, we provide a novel approach for the treatment of lung cancer and present evidence-based clues for the combined use of targeted mitochondrial drugs. [ABSTRACT FROM AUTHOR]

Most children with a neurogenic bladder (NB) have bladder fibrosis, which causes irreversible bladder dysfunction and damage to the upper urinary tract. However, the mechanism of bladder fibrosis remains unclear. This study aimed to investigate the underlying causes of bladder fibrosis. Here, the lumbar 6 (L6) and sacral 1 (S1) spinal nerves of Sprague Dawley rats were severed bilaterally to establish NB models. Using RNA-seq, we discovered that the NF-κB signaling pathway and inflammation were upregulated in spinal cord injury (SCI)-induced bladder fibrosis. Subsequent Western blotting, enzyme-linked immunosorbent assays, immunohistochemical staining, and immunofluorescence staining verified the RNA-seq findings. To further clarify whether the NF-κB signaling pathway and pyroptosis were involved in bladder fibrosis, a TGF-β1-treated urinary epithelial cell line (SV-HUC-1 cells) was used as an in vitro model. Based on the results of RNA-seq, we consistently found that the NF-κB signaling pathway and pyroptosis might play important roles in TGF-β1-treated cells. Further experiments also confirmed the RNA-seq findings in vitro. Moreover, using the NLRP3 inhibitor MCC950 rescued TGF-β1-induced fibrosis, and the NF-κB signaling pathway inhibitor BAY 11-7082 effectively rescued TGF-β1-induced pyroptosis and the deposition of extracellular matrix by SV-HUC-1 cells. In summary, our research demonstrated for the first time that the NF-κB signaling pathway inhibition rescued bladder epithelial cells pyroptosis and fibrosis in neurogenic bladders. [ABSTRACT FROM AUTHOR]

Background: Minimally invasive liver resection of the posterosuperior region is considered a challenging procedure due to poor exposure and difficult bleeding control. A robotic approach is supposed to be advantageous in posterosuperior segmentectomy. Its benefits over laparoscopic liver resection (LLR) remain undetermined. This study compared robotic liver resection (RLR) and LLR in the posterosuperior region performed by a single surgeon. Materials and methods: We retrospectively analyzed consecutive RLR and LLR performed by a single surgeon between December 2020 and March 2022. Patient characteristics and perioperative variables were compared. A 1:1 propensity score matched (PSM) analysis was performed between both groups. Results: The analysis included 48 RLR and 57 LLR procedures in the posterosuperior region. After PSM analysis, 41 cases of both groups were retained. In pre-PSM cohort, the operative time in the RLR group was significantly shorter than in the LLR group (160 vs. 208 min, P = 0.001), especially in radical resection of malignant tumors (176 vs. 231 min, P = 0.004). The total Pringle maneuver duration was also markedly shorter (40 vs. 51 min, P = 0.047), and the estimated blood loss in the RLR group was lower (92 vs. 150 mL, P = 0.005). The postoperative hospital stay (POHS) in the RLR group was significantly shorter (5.4 vs. 7.5 days, P = 0.048). In PSM cohort, operative time in the RLR group was also significantly shorter (163 vs. 193 min, P = 0.036), and the estimated blood loss was lower (92 vs. 144 mL, P = 0.024). However, the total Pringle maneuver duration and POHS showed no significant difference. The complications were similar between two groups in both pre-PSM and PSM cohorts. Conclusion: RLR in the posterosuperior region was as safe and feasible as LLR. RLR was associated with reduced operative time and blood loss than LLR. [ABSTRACT FROM AUTHOR]

Difenoconazole (DFZ) is a broad-spectrum triazole fungicide that is widely utilized in agriculture. Although DFZ has been demonstrated to induce reproductive toxicity in aquatic species, its toxic effects on the mammalian reproductive system have yet to be fully elucidated. In vivo, male mice were administered 0, 20 or 40 mg/kg/d of DFZ via oral gavage for 35 days. Consequently, DFZ significantly decreased testicular organ coefficient, sperm count and testosterone levels, augmented sperm malformation rates, and elicited histopathological alterations in testes. TUNEL assay showed increased apoptosis in testis. Western blotting results suggested abnormally high expression of the sperm meiosis-associated proteins STRA8 and SCP3. The concentrations of retinoic acid (RA), retinaldehyde (RE), and retinol (ROL) were increased in the testicular tissues of DFZ-treated groups. The mRNA expression level of genes implicated in RA synthesis significantly increased while genes involved in RA catabolism significantly decreased. In vitro, DFZ reduced cell viability and increased RA, RE, and ROL levels in GC-2 cells. Transcriptome analysis revealed a significant enrichment of numerous terms associated with the RA pathway and apoptosis. The qPCR experiment verified the transcriptome results. In conclusion, our results indicate that DFZ exposure can disrupt RA signaling pathway homeostasis, and induce testicular injury in mice testes. [ABSTRACT FROM AUTHOR]

A modified two-axis surface encoder is proposed to separately measure both the in-plane displacement and the Z-directional out-of-plane displacement with minor crosstalk errors. The surface encoder is composed of a scale grating and a small-sized sensor head. In the modified surface encoder, the measurement laser beam from the sensor head is designed to be projected onto the scale grating at a right angle. For measurement of the X- and Y-directional in-plane scale displacement, the positive and negative first-order diffracted beams from the scale grating are superimposed on each other in the sensor head, producing interference signals. On the other hand, the Z-directional out-of-plane scale displacement is measured based on the principle of a Michelson-type interferometer. To avoid the influence of reflection from the middle area of the transparent grating, which causes periodic crosstalk errors in the previous research, a specially fabricated transparent grating with a hole in the middle is employed in the newly designed optical system. A prototype sensor head is constructed, and basic performances of the modified surface encoder are tested by experiments. [ABSTRACT FROM AUTHOR]

Background: Neurogenic bladder (NB) patients exhibit varying degrees of bladder fibrosis, and the thickening and hardening of the bladder wall induced by fibrosis will further affect bladder function and cause renal failure. Our study aimed to investigate the mechanism of bladder fibrosis caused by a spinal cord injury (SCI). Methods: NB rat models were created by cutting the bilateral lumbar 6 (L6) and sacral 1 (S1) spinal nerves. RNA-seq, Western blotting, immunofluorescence, cell viability and ELISA were performed to assess the inflammation and fibrosis levels. Results: The rats showed bladder dysfunction, upper urinary tract damage and bladder fibrosis after SCI. RNA-seq results indicated that hypoxia, EMT and pyroptosis might be involved in bladder fibrosis induced by SCI. Subsequent Western blot, ELISA and cell viability assays and immunofluorescence of bladder tissue confirmed the RNA-seq findings. Hypoxic exposure increased the expression of HIF-1α and induced EMT and pyroptosis in bladder epithelial cells. Furthermore, HIF-1α knockdown rescued hypoxia-induced pyroptosis, EMT and fibrosis. Conclusion: EMT and pyroptosis were involved in the development of SCI-induced bladder fibrosis via the HIF-1α pathway. Inhibition of the HIF-1α pathway may serve as a potential target to alleviate bladder fibrosis caused by SCI. [ABSTRACT FROM AUTHOR]

In a lidar system, replacing moving components with solid-state devices is highly anticipated to make a reliable and compact lidar system, provided that a substantially large beam area with a large angular extent as well as high angular resolution is assured for the lidar transmitter and receiver. A new quasi-solid-state lidar optical architecture employs a transmitter with a two-dimensional MEMS mirror for fine beam steering at a fraction of the degree of the angular resolution and is combined with a digital micromirror device for wide FOV scanning over 37 degree while sustaining a large aperture area of 140 mm squared. In the receiver, a second digital micromirror device is synchronized to the transmitter DMD, which enables a large FOV receiver. An angular resolution of 0.57 ° (H)   by 0.23 °   (V) was achieved with 0.588 fps for scanning 1344 points within the field of view. [ABSTRACT FROM AUTHOR]

Bismuth drugs have long been used against gastrointestinal diseases, especially the gastric infection of Helicobacter pylori. Cisplatin is a widely used anticancer drug that tends to accumulate at renal proximal tubules and causes severe nephrotoxicity. It was found that bismuth pretreatment reduces cisplatin-induced nephrotoxicity, but the mechanism of action remains unclear. To understand bismuth's effect on renal tubules, we profiled the proteomic changes in human proximal tubular cells (HK-2) upon bismuth treatment. We found that bismuth induced massive glutathione biosynthesis, glutathione S-transferase activity, and vesicular transportation, which compartmentalizes bismuth to the vesicles and forms bismuth–sulfur nanoparticles. The timing of glutathione induction concurs that of bismuth-induced cisplatin toxicity mitigation in HK-2, and bismuth enhanced cisplatin sequestration to vesicles and incorporation into bismuth–sulfur nanoparticles. Finally, we found that bismuth mitigates the toxicity of general soft metal compounds but not hard metal compounds or oxidants. It suggests that instead of through oxidative stress reduction, bismuth reduces cisplatin-induced toxicity by direct sequestration. [ABSTRACT FROM AUTHOR]

Background: A link between body temperature and stroke outcomes has been established but not for acute basilar artery occlusion. We aimed to determine the association between body temperature and clinical outcomes in patients with acute basilar artery occlusion and temperature management range. Methods: We included patients from the Endovascular Treatment for Acute Basilar Artery Occlusion Study (BASILAR) database with records of both admission body temperature (ABT) and peak body temperature (PBT). ABT was defined as the body temperature first measured at the hospital visit, PBT was defined as the highest temperature within 24 h of treatment, and minus body temperature (MBT) was defined as PBT-ABT. The primary clinical outcome was favorable functional outcome, defined as the proportion of patients with a modified Rankin Scale score of 0–3 at 3 months. Secondary outcomes included 3-month mortality, in-hospital mortality, and symptomatic cerebral hemorrhage. Results: A total of 664 patients were enrolled in the study; 74.7% were men, with a median age of 65 (interquartile range, 57.25–74) years. In all patients, multivariate analysis indicated that PBT and MBT were independent predictors of favorable functional outcome [odds ratio (OR), 0.57 (95% CI, 0.43–0.77); OR, 0.68 (95% CI, 0.52–0.88), respectively], and higher ABT, PBT, and MBT were associated with an increased 3-month mortality [OR, 1.47 (95% CI, 1.03–2.10), OR, 1.58 (95% CI, 1.28–1.96), OR, 1.35 (95% CI, 1.11–1.65), respectively]. Proportional odds models demonstrated that when ABT, PBT, MBT were in the range of <37.5, <38.9, and −0.6–2.7°C, respectively, the benefit of the endovascular treatment is clearly greater than that of standard medical treatment in terms of favorable functional outcome. Conclusions: Body temperature is an independent predictor of clinical outcome in patients with acute basilar artery occlusion. It is necessary to control the patient body temperature within the appropriate range in clinical settings. Trial Registration: Chinese Clinical Trial Registry ChiCTR1800014759. Registered 03 February 2018. Retrospectively registered. [ABSTRACT FROM AUTHOR]

This paper proposes a new optical configuration for a two-axis surface encoder that can measure the in-plane (X-axis) and out-of-plane (Z-axis) displacements of a positioning stage. The two-axis surface encoder is composed of a scale grating and a sensor head. A transparent grating is employed in the sensor head for measurement of the Z-directional displacement of the scale grating based on the Fizeau-type measurement method; a reference beam reflected from the transparent grating and the zeroth-order diffracted beam from the scale grating are superimposed to generate an interference signal. A pair of prisms and a beam splitter are also employed in the sensor head, so that the positive and negative first-order diffracted beams can be superimposed over a long working distance to generate an interference signal for measurement of the X-directional displacement of the scale grating. Focusing on the new, extended Z-directional measurement mechanism, proof-of-principle experiments were carried out to verify the feasibility of the proposed optical configuration for the surface encoder that can measure the uni-directional displacements of a scale grating along the X- and Z-axis. Experimental results from the developed optical configuration demonstrated the achievement of a Z-directional measuring range of ±1.5 mm. [ABSTRACT FROM AUTHOR]

Tacrolimus (FK506) and rapamycin (RAPA) are widely used to maintain long‐term immunosuppression after organ transplantation. However, the impact of accumulative drug administration on the recipients' immune systems remains unclear. We investigated the impact of 3‐year FK506 or RAPA treatment after renal transplantation on the human immune systems. A discovery cohort of 30 patients was first recruited, and we discovered two distinctive T lineage suppressive regulatory patterns induced by chronic treatment of FK506 and RAPA. The increased percentage of senescent CD8+CD57+ T lineages and less responsive T cell receptor (TCR) pathway in the FK506 group indicate better graft acceptance. Meanwhile, percentages of regulatory T cells (Tregs) and expression of CTLA‐4 were both up to two‐fold higher in the RAPA group, suggesting the inconsistent reactivation potential of the FK506 and RAPA groups when an anti‐tumour or anti‐infection immune response is concerned. Additionally, up‐regulation of phosphorylated signaling proteins in T lineages after in vitro CD3/CD28 stimulation suggested more sensitive TCR‐signaling pathways reserved in the RAPA group. An independent validation cohort of 100 renal transplantation patients was further investigated for the hypothesis that long‐term RAPA administration mitigates the development of tumours and infections during long‐term intake of immunosuppressants. Our results indicate that RAPA administration indeed results in less clinical oncogenesis and infection. The deep phenotyping of T‐cell lineages, as educated by the long‐term treatment of different immunosuppressants, provides new evidence for personalized precision medicine after renal transplantations. [ABSTRACT FROM AUTHOR]

The blood–testis barrier (BTB) and apical ectoplasmic specialization (ES), which are synchronized through the crosstalk of Sertoli cells and Sertoli germ cells, are required for spermatogenesis and sperm release. Here, we show that Wnt5a, a noncanonical Wnt signaling pathway ligand, is predominately expressed in both the BTB and apical ES and has a specific expression pattern during the seminiferous epithelium cycle. We employed siRNA to knockdown Wnt5a expression in testis and Sertoli cells, and then identified elongated spermatids that lost their polarity and were embedded in the seminiferous epithelium. Moreover, phagosomes were found near the tubule lumen. These defects were due to BTB and apical ES disruption. We also verified that the expression level and/or location of BTB-associated proteins, actin binding proteins (ABPs), and F-actin was changed after Wnt5a knockdown in vivo and in vitro. Additionally, we demonstrated that Wnt5a regulated actin dynamics through Ror2-mediated mTORC1 and mTORC2. This study clarified the molecular mechanism of Wnt5a in Sertoli cell junctions through the planar cell polarity (PCP) signaling pathway. Our findings could provide an experimental basis for the clinical diagnosis and treatment of male infertility caused by Sertoli cell junction impairment. [ABSTRACT FROM AUTHOR]