Development and validation of an early diagnosis model for bone metastasis in non-small cell lung cancer based on serological characteristics of the bone metastasis mechanism.

Background: Bone metastasis significantly impact the prognosis of non-small cell lung cancer (NSCLC) patients, reducing their quality of life and shortening their survival. Currently, there are no effective tools for the diagnosis and risk assessment of early bone metastasis in NSCLC patients. This study employed machine learning to analyze serum indicators that are closely associated with bone metastasis, aiming to construct a model for the timely detection and prognostic evaluation of bone metastasis in NSCLC patients. Methods: The derivation cohort consisted of 664 individuals with stage IV NSCLC, diagnosed between 2015 and 2018. The variables considered in this study included age, sex, and 18 specific serum indicators that have been linked to the occurrence of bone metastasis in NSCLC. Variable selection used multivariate logistic regression analysis and Lasso regression analysis. Six machine learning methods were utilized to develop a bone metastasis diagnostic model, assessed with Area Under the Curve (AUC), Decision Curve Analysis (DCA), sensitivity, specificity, and validation cohorts. External validation used 113 NSCLC patients from the Medical Alliance (2019-2020). Furthermore, a prospective validation study was conducted on a cohort of 316 patients (2019-2020) who were devoid of bone metastasis, and followed-up for at least two years to assess the predictive capabilities of this model. The model's prognostic value was evaluated using Kaplan-Meier survival curves. Findings: Through variable selection, 11 serum indictors were identified as independent predictive factors for NSCLC bone metastasis. Six machine learning models were developed using age, sex, and these serum indicators. A random forest (RF) model demonstrated strong performance during the training and internal validation cohorts, achieving an AUC of 0.98 (95% CI 0.95-0.99) for internal validation. External validation further confirmed the RF model's effectiveness, yielding an AUC of 0.97 (95% CI 0.94-0.99). The calibration curves demonstrated a high level of concordance between the anticipated risk and the observed risk of the RF model. Prospective validation revealed that the RF model could predict the occurrence of bone metastasis approximately 10.27 ± 3.58 months in advance, according to the results of the SPECT. An online computing platform (https://bonemetastasis.shinyapps.io/shiny_cls_1model/) for this RF model is publicly available and free-to-use by doctors and patients. Interpretation: This study innovatively employs age, gender, and 11 serological markers closely related to the mechanism of bone metastasis to construct an RF model, providing a reliable tool for the early screening and prognostic assessment of bone metastasis in NSCLC patients. However, as an exploratory study, the findings require further validation through large-scale, multicenter prospective studies. Funding: This work is supported by the National Natural Science Foundation of China (NO.81974315); Shanghai Municipal Science and Technology Commission Medical Innovation Research Project (NO.20Y11903300); Shanghai Municipal Health Commission Health Industry Clinical Research Youth Program (NO.20204Y034).

The safety and feasibility Assessment of Overlap Esophagojejunostomy with Self-pulling and Latter Transection Technique in Totally Laparoscopic Total Gastrectomy.

BACKGROUND: This study presents an innovative technique in totally laparoscopic total gastrectomy (TLTG) for Overlap esophagojejunostomy, termed self-pulling and latter transection (Overlap SPLT). It evaluates the effectiveness and short-term outcomes of this novel method through a comparative analysis with the established functional end-to-end esophagojejunostomy incorporating self-pulling and latter transection (FETE SPLT). METHODS: From September 2018 to September 2023, this study enrolled 68 gastric cancer patients who underwent totally laparoscopic total gastrectomy (TLTG) with Overlap SPLT anastomosis and 120 patients who underwent TLTG with FETE SPLT anastomosis. Clinicopathological characteristics, surgical and postoperative outcomes data for Overlap SPLT cases were gathered and retrospectively compared with those from FETE SPLT TLTG to evaluate the effectiveness and clinical safety. RESULTS: The duration of anastomosis for Overlap SPLT was 25.3 ± 7.4minutes, significantly longer than that for the FETE SPLT (18.1 ± 4.0minutes, P = 0.031). Perioperatively, one anastomosis-related complication occurred in each group, but this did not constitute a statistically significant difference (P = 0.682). No statistically significant differences were found between the two groups in terms of operative time, postoperative hospital stay, operative cost, surgical margins, or number of lymph nodes removed. Postoperative morbidity rates were similar between the groups (4.4% vs. 5.8%, P = 0.676). CONCLUSION: The Overlap SPLT technique is regarded as a safe and feasible method for anastomosis. There were no apparent differences in complications between Overlap SPLT and FETE SPLT, but Overlap SPLT costed one additional stapler cartridge and required a longer duration.

Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.

Osteoclasts are over-activated as we age, which results in bone loss. Src deficiency in mice leads to severe osteopetrosis due to a functional defect in osteoclasts, indicating that Src function is essential in osteoclasts. G-protein-coupled receptors (GPCRs) are the targets for ∼35% of approved drugs but it is still unclear how GPCRs regulate Src kinase activity. Here, we reveal that GPR54 activation by its natural ligand Kisspeptin-10 (Kp-10) causes Dusp18 to dephosphorylate Src at Tyr 416. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase at its proline/arginine-rich motif in its C terminus. We show that Kp-10 binding to Gpr54 leads to the up-regulation of Dusp18. Kiss1, Gpr54 and Dusp18 knockout mice all exhibit osteoclast hyperactivation and bone loss, and Kp-10 abrogated bone loss by suppressing osteoclast activity in vivo. Therefore, Kp-10/Gpr54 is a promising therapeutic target to abrogate bone resorption by Dusp18-mediated Src dephosphorylation.

N6-methyladenosine mRNA methylation positively regulated the response of poplar to salt stress.

As the most abundant form of methylation modification in messenger RNA (mRNA), the distribution of N6-methyladenosine (m6A) has been preliminarily revealed in herbaceous plants under salt stress, but its function and mechanism in woody plants were still unknown. Here, we showed that global m6A levels increased during poplar response to salt stress. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) revealed that m6A significantly enriched in the coding sequence region and 3'-untranslated regions in poplar, by recognising the conserved motifs, AGACU, GGACA and UGUAG. A large number of differential m6A transcripts have been identified, and some have been proved involving in salt response and plant growth and development. Further combined analysis of MeRIP-seq and RNA-seq revealed that the m6A hypermethylated and enrich in the CDS region preferred to positively regulate expression abundance. Writer inhibitor, 3-deazaneplanocin A treatment increased the sensitivity of poplar to salt stress by reducing mRNA stability to regulate the expression of salt-responsive transcripts PagMYB48, PagGT2, PagNAC2, PagGPX8 and PagARF2. Furthermore, we verified that the methyltransferase PagFIP37 plays a positively role in the response of poplar to salt stress, overexpressed lines have stronger salt tolerance, while RNAi lines were more sensitive to salt, which relied on regulating mRNA stability in an m6A manner of salt-responsive transcripts PagMYB48, PagGT2, PagNAC2, PagGPX8 and PagARF2. Collectively, these results revealed the regulatory role of m6A methylation in poplar response to salt stress, and revealed the importance and mechanism of m6A methylation in the response of woody plants to salt stress for the first time.

Efficacy and Safety of Oral Propranolol or Topical Timolol for the Treatment of Superficial Infantile Hemangiomas.

Infantile hemangiomas (IHs) are the most common benign soft tissue tumors of infancy. Oral propranolol has become a first-line treatment option since the unexpected discovery of its surprising efficacy in the treatment of IHs in 2008. However, oral propranolol causes systemic complications, including hypotension, bradycardia, and hypoglycemia. To minimize systemic adverse effects of oral propranolol, timolol maleate, a nonselective ß-blocker similar to propranolol, has been used as a topical agent to treat superficial IHs. The authors evaluated the efficacy and safety of oral propranolol or topical timolol in 60 patients with IHs. Of the 60 patients recruited, 30 patients were treated using orally administrated propranolol and an additional 30 patients received topical timolol. The efficacy rate of the oral propranolol and topical timolol was 96.7% and 93.3%, respectively. There were no significant differences between the two treatment patterns for the efficacy rate. The incidence of systemic adverse effects for patients treated with oral propranolol was significantly higher than that for cases received topically timolol treatment. Topical timolol maleate is effective and well-tolerated in the treatment of IHs. It could be considered as the first-line treatment choice, especially for superficial IHs.

mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model.

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the "superbug" MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.

ABCB1 Regulates Immune Genes in Breast Cancer.

Background: Resistance to standard chemotherapy is a critical problem for breast cancer patients. The ATP-binding cassette (ABC) superfamily transporters actively pump out drugs and play an important role in chemoresistance. ABCB1 (ABC subfamily B, member 1, also named as multidrug resistance protein 1, MDR1) and suppressive myeloid-derived suppressor cells (MDSCs) potentially involve in chemoresistance of breast cancer. The relationship between ABCB1 and immune genes in breast cancer has not been widely studied. Methods: Microarray and RNA sequencing data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma in Genomic Data Commons Data Portal and Gene Expression Omnibus database. A patient-derived xenograft (PDX) model of HER2+ breast cancer was established to investigate the association between ABCB1 and immune genes in breast cancer. Results: Expression of ABCB1 increased in doxorubicin-selected MCF-7/ADR cells. High expression of ABCB1 mRNA is correlated with lymph-node metastasis and worse overall survival in patients with breast cancer. ABCB1 is positively correlated with IL6, CSF1, CSF3, and PTGS2. In the HER2+ stage IIA breast cancer PDX model, both doxorubicin and paclitaxel suppressed growth of P2 tumors. IL6, CSF1, CSF3, and PTGS2 expression were suppressed by paclitaxel but not doxorubicin. Intrasplenic MDSCs, including CD11b+Ly6G+ and CD11b+Ly6C+ cells, were more abundant than intratumor MDSCs in PDX-carrying nude mice. Clinically, the patient developed cancer recurrence after adjuvant chemotherapy with doxorubicin-based regimen and was well controlled after paclitaxel-trastuzumab combined therapy. Conclusion: ABCB1 was a poor predictor of HER2+ LN- breast cancer. Regulation of immune genes by ABCB1 contributed to cancer recurrence and treatment effect. The PDX model was suitable for investigation the expression of target genes and expansion of immune cells.

Identification of the methotrexate resistance-related diagnostic markers in osteosarcoma via adaptive total variation netNMF and multi-omics datasets.

Osteosarcoma is one of the most common malignant bone tumors with high chemoresistance and poor prognosis, exhibiting abnormal gene regulation and epigenetic events. Methotrexate (MTX) is often used as a primary agent in neoadjuvant chemotherapy for osteosarcoma; However, the high dosage of methotrexate and strong drug resistance limit its therapeutic efficacy and application prospects. Studies have shown that abnormal expression and dysfunction of some coding or non-coding RNAs (e.g., DNA methylation and microRNA) affect key features of osteosarcoma progression, such as proliferation, migration, invasion, and drug resistance. Comprehensive multi-omics analysis is critical to understand its chemoresistant and pathogenic mechanisms. Currently, the network analysis-based non-negative matrix factorization (netNMF) method is widely used for multi-omics data fusion analysis. However, the effects of data noise and inflexible settings of regularization parameters affect its performance, while integrating and processing different types of genetic data is also a challenge. In this study, we introduced a novel adaptive total variation netNMF (ATV-netNMF) method to identify feature modules and characteristic genes by integrating methylation and gene expression data, which can adaptively choose an anisotropic smoothing scheme to denoise or preserve feature details based on the gradient information of the data by introducing an adaptive total variation constraint in netNMF. By comparing with other similar methods, the results showed that the proposed method could extract multi-omics fusion features more effectively. Furthermore, by combining the mRNA and miRNA data of methotrexate (MTX) resistance with the extracted feature genes, four genes, Carboxypeptidase E (CPE), LIM, SH3 protein 1 (LASP1), Pyruvate Dehydrogenase Kinase 1 (PDK1) and Serine beta-lactamase-like protein (LACTB) were finally identified. The results showed that the gene signature could reliably predict the prognostic status and immune status of osteosarcoma patients.

Comparison of the incidence of wound complications with preoperative and postoperative radiotherapy in patients with extremity soft tissue sarcoma resection: A meta-analysis.

We performed a meta-analysis to compare the effect of preoperative and postoperative radiotherapy on wound complications after resection of extremity soft tissue sarcoma (ESTS). A comprehensive computerised search of the PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang databases was conducted from their inception to August 2023 to identify studies comparing the effect of preoperative and postoperative radiotherapy on wound complications after ESTS resection. Two investigators independently screened the literature, extracted the data, and assessed the quality of the articles. The meta-analysis was performed using RevMan 5.4 software. Nine studies with 1271 patients were included, with 631 and 640 patients in the preoperative and postoperative radiotherapy groups, respectively. The results showed that the incidence of postoperative wound complications after ESTS resection was significantly higher with preoperative radiotherapy than with postoperative radiotherapy (27.26% vs. 12.03%, odds ratio [OR]: 2.88, 95% confidence interval [CI]: 2.12-3.91, p < 0.001). However, the rate of local recurrence of ESTS was significantly lower with preoperative radiotherapy than with postoperative radiotherapy (8.75% vs. 14.81%, OR: 0.57, 95% CI: 0.36-0.91, p = 0.02), and the 3-year overall survival was significantly higher in the preoperative radiotherapy group than in the postoperative radiotherapy group (82.24% vs. 70.04%, OR: 1.97, 95% CI: 1.05-3.71, p = 0.03). This pooled analysis suggests that although preoperative radiotherapy increases the rate of wound complications in ESTS compared with postoperative radiotherapy, it significantly reduces the rate of local recurrence after ESTS resection and improves the overall survival of patients. Owing to the limitations in the number and quality of the included studies, additional prospective cohort studies or randomised controlled trials are required to confirm these findings.

Knockdown of HDAC10 inhibits POLE2-mediated DNA damage repair in NSCLC cells by increasing SP1 acetylation levels.

HDAC10 has been reported to be associated with poor prognosis in patients with non-small cell lung cancer (NSCLC), however, the regulatory role and mechanisms of HDAC10 in NSCLC have not been investigated. In this study, we found that HDAC10 was increased in NSCLC patients and cell lines. And high expression of HDAC10 is linked to poor survival in NSCLC patients. The results showed that knockdown of HDAC10 triggered DNA damage, S-phase arrest, and proliferation inhibition in A549 and H1299 cells. In addition, knockdown of HDAC10 promoted cell ferroptosis by enhancing ROS, MDA and Fe2+ levels. Mechanistically, HDAC10 knockdown reduced SP1 expression and elevated the acetylation level of SP1, which inhibited the binding of SP1 to the promoter of POLE2, resulting in reduced POLE2 expression. Overexpression of SP1 or POLE2 partially reversed the effects of HDAC10 deletion on NSCLC cell proliferation and ferroptosis. In conclusion, knockdown of HDAC10 inhibited the proliferation of NSCLC cells and promoted their ferroptosis by regulating the SP1/POLE2 axis. HDAC10 might be a promising target for the treatment of NSCLC.

TINAVI robot-assisted one-stage anteroposterior surgery in lateral position for severe thoracolumbar fracture dislocation: A case report.

BACKGROUND: The combined anterior/posterior approach appears to be capable of reconstructing spinal stability, correcting thoracolumbar deformity, and promoting neural recovery in severe thoracolumbar fracture dislocation. However, this type of operation requires changing the body position during the procedure, resulting in a lengthy operation time. As a universal surgical robot, TINAVI robot has achieved good surgical results in clinical surgery. But to our knowledge, no reports describing TINAVI robot-assisted single lateral position anteroposterior surgery for thoracolumbar fracture dislocation. CASE SUMMARY: We describe a case of a 16-year-old female patient with severe thoracolumbar fracture and dislocation underwent surgery assisted by the TINAVI robot. A one-stage combined anterior and posterior operation was performed on a severe thoracolumbar fracture dislocation using the TINAVI robot, and the operation was completed in right lateral position. CONCLUSION: The TINAVI robot-assisted one-stage anterior and posterior surgery in right lateral position for severe thoracolumbar fracture and dislocation is both safe and effective.

Target-independent hybridization chain reaction-fluorescence resonance energy transfer for sensitive assay of ctDNA based on Cas12a.

Circulating tumor DNA (ctDNA) is a noninvasive biomarker which offer valuable information for cancer diagnosis and prognosis. In this study, a target-independent fluorescent signal system, Hybridization chain reaction-Fluorescence resonance energy transfer (HCR-FRET) system, is designed and optimized. Combined with CRISPR/Cas12a system, a fluorescent biosensing protocol was developed for sensing assay of T790 M. When the target is absent, the initiator remains intact, opens the fuel hairpins and triggers the following HCR-FRET. At presence of the target, the Cas12a/crRNA binary complex specifically recognizes the target, and the Cas12a trans-cleavage activity is activated. As a result, the initiator is cleaved and subsequent HCR responses and FRET processes are attenuated. This method showed detection range from 1 pM to 400 pM with a detection limit of 316 fM. The target independent property of the HCR-FRET system endows this protocol a promising potential to transplant to the assay of other DNA target in parallel.

Src-FAK Signaling Mediates Interleukin 6-Induced HCT116 Colorectal Cancer Epithelial-Mesenchymal Transition.

Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial-mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators-twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPß. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPß toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPß and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression.

Optimal postoperative surveillance strategies for cancer survivors with gastric neuroendocrine carcinoma based on individual risk: a multicenter real-world cohort study.

BACKGROUND: The best follow-up strategy for cancer survivors after treatment should balance the effectiveness and cost of disease detection while detecting recurrence as early as possible. Due to the low incidence of gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma [G-(MA)NEC], high-level evidence-based follow-up strategies is limited. Currently, there is a lack of consensus among clinical practice guidelines regarding the appropriate follow-up strategies for patients with resectable G-(MA)NEC. MATERIALS AND METHODS: The study included patients diagnosed with G-(MA)NEC from 21 centers in China. The random forest survival model simulated the monthly probability of recurrence to establish an optimal surveillance schedule maximizing the power of detecting recurrence at each follow-up. The power and cost-effectiveness were compared with the National Comprehensive Cancer Network, European Neuroendocrine Tumor Society, and European Society for Medical Oncology Guidelines. RESULTS: A total of 801 patients with G-(MA)NEC were included. The patients were stratified into four distinct risk groups utilizing the modified TNM staging system. The study cohort comprised 106 (13.2%), 120 (15.0%), 379 (47.3%), and 196 cases (24.5%) for modified groups IIA, IIB, IIIA, and IIIB, respectively. Based on the monthly probability of disease recurrence, the authors established four distinct follow-up strategies for each risk group. The total number of follow-ups 5 years after surgery in the four groups was 12, 12, 13, and 13 times, respectively. The risk-based follow-up strategies demonstrated improved detection efficiency compared to existing clinical guidelines. Further Markov decision-analytic models verified that the risk-based follow-up strategies were better and more cost-effective than the control strategy recommended by the guidelines. CONCLUSIONS: This study developed four different monitoring strategies based on individualized risks for patients with G-(MA)NEC, which may improve the detection power at each visit and were more economical, effective. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending follow-up strategies for G-(MA)NEC.

Local Corrosion Behaviors in the Coarse-Grained Heat-Affected Zone in a Newly Developed Zr-Ti-Al-RE Deoxidized High-Strength Low-Alloy Steel.

Oxide metallurgy technology can improve the microstructure of a coarse-grained heat-affected zone (CGHAZ) but introduces extra inclusions. Local corrosion behavior of the CGHAZ of a Zr-Ti-Al-RE deoxidized steel was investigated in this work using theoretical calculations and experimental verification. The modified inclusions have a (Zr-Mg-Al-Ca-RE)Ox core claded by a CaS and TiN shell. CaS dissolves first, followed by the oxide core, leaving TiN parts. This confirms that the addition of rare earth can reduce lattice distortion and prevent a galvanic couple between the inclusions and the matrix, while the chemical dissolution of CaS causes localized acidification, resulting in the pitting corrosion initiation.

Lewis x-carrying O-glycans are candidate modulators for conceptus attachment in pigs†.

Successful attachment of conceptus to the uterine luminal epithelium (LE) is crucial for establishing a functional placenta in pigs. However, the underlying mechanisms are yet to be elucidated. The uterine LE-conceptus interface is enriched in various glycoconjugates essential to implantation. Using MALDI-MS profiling, we identified for the first time the O-glycan repertoire of pig endometrium during the conceptus attachment stage. The expression pattern of blood group A, O(H), Lewis x, y, a, b (Lex, Ley, Lea, and Leb), the sialylated and sulfated Lex antigens in the uterine LE-conceptus interface was assessed using immunofluorescence assays. Notably, the Lex-carrying O-glycans exhibited a temporal-spatial expression pattern. They were absent in the endometrium on estrous cycle days but strongly and spatially presented in the conceptus and uterine LE to which the conceptus apposes during the early conceptus attachment stage. In addition, Lex-carrying O-glycans were co-localized with secreted phosphoprotein 1 (SPP1), a well-characterized factor that plays a role in promoting conceptus attachment through interacting with integrin αVß3 and integrin αVß6. Meanwhile, the immunoprecipitation assays revealed an interaction between the Lex-carrying O-glycans and SPP1, integrin αV, and integrin ß6. Furthermore, we provided evidence that the ß1,4-galactosyltransferase 1 (B4GALT1) gene is a potential regulator for Lex antigen expression in the uterine LE-conceptus interface during the early conceptus attachment stage. In conclusion, our findings show that Lex-carrying O-glycans, presumably dependent on B4GALT1 gene expression, might modulate conceptus attachment by interacting with the SPP1-integrin receptor complex in pigs.

Freehand transperineal prostate biopsy with a coaxial needle under local anesthesia: Experience from a single institution in Malaysia.

Background: Freehand transperineal prostate biopsy (TPPBx) using a coaxial needle technique offers an alternative to probe-mounted freehand or template-guided techniques in the diagnosis of prostate cancer (PCa). It only requires the same equipment used for transrectal ultrasound-guided (TRUS) biopsy. Our study is the first in Malaysia to report this experience and its outcomes. We aim to determine PCa detection rate and pain tolerability of freehand TPPBx utilizing a coaxial needle under local anesthesia (LA). Methods: Institutional review board approval was obtained from National Medical Research Register (NMRR ID-21-02052-VIL). We retrospectively reviewed the medical records of patients who underwent TPPBx between August 2020 and April 2022. Records were reviewed for patients' characteristics, prostate volume, prostate-specific antigen (PSA) results, biopsy results and pain tolerability. Data was analyzed to determine PCa and clinically significant prostate cancer (csPCa) detection rate. LA was achieved using perineal skin infiltration and a periprostatic nerve block. The commonly used standard side-firing transrectal ultrasound with its Prostate Biplane Transducer was used as an imaging guide. The principles of the Ginsburg protocol were followed. Pain tolerability was assessed using a visual analog scale. Results: A total of 55 patients with elevated PSA levels underwent freehand TPPBx under LA. The mean age was 67.3 years, the median PSA was 14.2 ng/mL, and the median PSA density (PSAD) was 0.33 ng/mL/cc. The optimal PSAD cutoff for predicting csPCa was 0.35 ng/mL/cc (area under the curve [AUC], 0.792; sensitivity, 87.5%; specificity, 69.2%). PCa was detected in 24 patients (43.6%), of whom 16 (29.1%) had csPCa. The median pain scores during LA infiltration and biopsy were four and two, respectively, which were significant different (P < 0.05). TPPBx exhibited an infection rate of zero. Conclusion: The PCa detection rate and patient tolerability of freehand TPPBx using a coaxial needle are similar to those of a contemporary published series. The use of existing equipment that is used for TRUS biopsy allows for widespread use and transition from TRUS biopsy.

Construction and In Vitro Evaluation of a Tumor Acidic pH-Targeting Drug Delivery System Based on Escherichia coli Nissle 1917 Bacterial Ghosts.

Synthetic nanocarriers are a promising therapeutic delivery strategy. However, these systems are often hampered by inherent disadvantages such as strong biotoxicity and poor biocompatibility. To overcome these issues, biological carriers with commonly used chemotherapy drugs have been developed. In this work, engineered bacterial ghosts (BGs) originated from probiotic Escherichia coli Nissle 1917 (EcN) were devised to specifically target acidic extracellular environments of tumor tissue. To improve the production efficiency and safety, a novel lysis protein E from phage α3 was applied to produce EcN BGs under high growth densities in high quality. In addition, the acidity-triggered rational membrane (ATRAM) peptides were displayed in EcN BGs to facilitate specific cancer cell internalization within the acidic tumor microenvironment before drug release. In conclusion, the engineered EcN BGs offer a promising means for bionic bacteria construction for hepatocellular carcinoma therapy.

C/EBP-ß contributes to pig endometrial LE receptivity by targeting cell remodeling genes during implantation.

In brief: Transforming the endometrial luminal epithelium (LE) into a receptive state is a requisite event for successful embryo implantation. This study suggests the role of a transcription factor in regulating endometrial LE receptivity. Abstract: The endometrial luminal epithelium (LE) undergoes extensive remodeling during implantation to establish receptivity of the uterus in response to the conceptus signals, such as interleukin 1ß (IL1B). But the mechanisms remain to be fully understood. This study investigated the role of CCAAT/enhancer-binding protein ß (C/EBP-ß) in regulating pig endometrial LE receptivity. Our results showed that C/EBP-ß was expressed and activated only in the endometrial LE in an implantation-dependent manner. In addition, C/EBP-ß was highly activated at the pre-attachment stage compared to the attachment stage, and its activation was correlated with the expression of IL1B-dependent extracellular signal-regulated kinases1/2-p90 ribosomal S6 kinase signaling axis. Subsequent chromatin immunoprecipitation (ChIP)-sequencing analysis revealed that the binding of C/EBP-ß within the promoter was positively associated with the transcription of genes related to cell remodeling. One such gene is matrix metalloproteinase 8 (MMP8), which is responsible for extracellular matrix degradation. The expression of MMP8 was abundant at the pre-attachment stage but dramatically declined at the attachment stage in the endometrial LE. Consistent with C/EBP-ß, the expression and activation of MMP8 were limited to the endometrial LE in an implantation-dependent manner. Using ChIP-qPCR and electrophoresis mobility shift assay approaches, we demonstrated that C/EBP-ß regulated the expression of the MMP8 gene during implantation. Furthermore, we detected that MMP8 and one of its substrates, type II collagen, showed a mutually exclusive expression pattern in pig endometrial LE during implantation. Our findings indicate that C/EBP-ß plays a role in pig endometrial LE receptivity by regulating cell remodeling-related genes, such as MMP8, in response to conceptus signals during implantation.