Impact of immunotherapy on liver metastasis.

This editorial discusses the article "Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis" published in the latest edition of the World Journal of Gastrointestinal Surgery. Immunotherapy has achieved outstanding success in tumor treatment. However, the presence of liver metastasis (LM) restrains the efficacy of immunotherapy in various tumors, including lung cancer, colorectal cancer, renal cell carcinoma, melanoma, and gastric cancer. A decrease in CD8+ T cells and nature killer cells, along with an increase in macrophages and regulatory T cells, was observed in the microenvironment of LM, leading to immunotherapy resistance. More studies are necessary to determine the best strategy for enhancing the effectiveness of immunotherapy in patients with LM.

Solid pseudopapillary neoplasm of the pancreas with hepatic metastases: problems and strategies.

Background: Solid pseudopapillary neoplasms of the pancreas with hepatic metastases are infrequent and difficult to diagnose, and treatment is uncertain. Methods: A retrospective analysis of clinical data from patients with pancreatic solid pseudopapillary neoplasm (SPN) hepatic metastases who underwent surgery at the First Hospital of Jilin University from January 2005 to December 2021 was conducted. A total of 287 patients with SPN were included in the study, of which 8 (3%) developed liver metastases, all of whom were treated surgically and recovered well after surgery. The clinical presentation, imaging features, surgical treatment, histopathological examination, and postoperative follow-up data (mean 70 months; range 28-138 months) of the patients were recorded and analyzed. Clinical response strategies can be derived by reviewing previous studies on hepatic metastases of SPNs. Results: For resectable hepatic metastases from pancreatic solid pseudopapillary neoplasms, early surgery with total resection of the primary tumor and metastasis has shown great efficiency and is associated with patient good prognosis. In patients presenting unresectable hepatic metastases, aggressive tumor reduction surgery resulted in the alleviation of clinical symptoms and reduction of tumor burden while potentially achieving long-term survival. Conclusion: For hepatic metastases of SPNs, a preoperative liver tissue biopsy is beneficial for a definitive diagnosis. Surgery demonstrates excellent therapeutic efficacy and is considered the preferred curative treatment approach. This paper presents clinical experiences with SPN-related hepatic metastases at the Affiliated Hospital of Jilin University, which can be used to guide patient counseling in clinical practice.

High-sensitivity trace gas detection based on differential Helmholtz photoacoustic cell with dense spot pattern.

A high-sensitivity photoacoustic spectroscopy (PAS) sensor based on differential Helmholtz photoacoustic cell (DHPAC) with dense spot pattern is reported in this paper for the first time. A multi-pass cell based on two concave mirrors was designed to achieve a dense spot pattern, which realized 212 times excitation of incident laser. A finite element analysis was utilized to simulate the sound field distribution and frequency response of the designed DHPAC. An erbium-doped fiber amplifier (EDFA) was employed to amplify the output optical power of the laser to achieve strong excitation. In order to assess the designed sensor's performance, an acetylene (C2H2) detection system was established using a near infrared diode laser with a central wavelength 1530.3 nm. According to experimental results, the differential characteristics of DHPAC was verified. Compared to the sensor without dense spot pattern, the photoacoustic signal with dense spot pattern had a 44.73 times improvement. The minimum detection limit (MDL) of the designed C2H2-PAS sensor can be improved to 5 ppb when the average time of the sensor system is 200 s.

In-situ-formed immunotherapeutic and hemostatic dual drug-loaded nanohydrogel for preventing postoperative recurrence of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by an exceedingly high recurrence rate post-surgery, significantly impairing the prognosis of HCC patients. However, a standard in-care strategy for postoperative therapy is still lacking. Although encouraging results have been obtained in a newly published clinical trial for postoperative therapy by targeting the vascular endothelial growth factor (VEGF) and programmed death ligand 1 (anti-PD-L1), its efficacy remains constrained. Combining a hemostatic hydrogel with a nanoparticle-based drug delivery system presents an opportunity to optimize the antitumor effect. Herein, we developed a nanoplatform, termed HMSN@Sor/aP@Gel, comprising a hemostatic fibrin hydrogel and functionalized hollow mesoporous silica nanoparticles (HMSNs) loaded with sorafenib and anti-PD-L1 for locally administered targeted-immunotherapy to prevent the postoperative recurrence and metastasis of HCC. The antitumor mechanism is grounded in dual inhibition of Ras/Raf/MEK/ERK (MAPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways, synergistically complemented by PD-L1 blockade. HMSN@Sor/aP@Gel facilitates dendritic cell maturation, enhances cytotoxic T-lymphocyte infiltration, promotes the polarization of tumor-associated macrophages to M1 phenotype, induces tumor immunogenic cell death, reverses immunosuppression, and establishes immune memory to counter postoperative recurrence. Animal studies corroborate that HMSN@Sor/aP@Gel-mediated targeted immunotherapy significantly impedes primary and metastatic tumor growth and establishes immune memory to prevent recurrence post-surgery. This investigation presents a promising strategy for postoperative therapy with considerable potential for clinical translation.

Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes.

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

Analysis of the Short-Term Complications of Laparoscopic Pancreaticoduodenectomy in Patients with Metabolic Syndrome.

Objective: To investigate the impact of metabolic syndrome (MetS) on short-term complications of laparoscopic pancreaticoduodenectomy (LPD). Materials and Methods: We retrospectively analyzed perioperative data of patients who underwent LPD in our department from January 2020 to January 2022. The patients were divided into the MetS group and non-MetS group based on whether they had MetS. The incidence of postoperative complications and mortality rate was compared between the two groups. Results: The study involved 279 patients, with 30 having MetS and 249 without. However, the MetS and non-MetS groups differed significantly in terms of postoperative pancreatic fistula rate (26.6% versus 8.4%), abdominal infection rate (33.3% versus 10.0%), pulmonary complications rate (16.7% versus 6.42%), Clavien-Dindo ≥3 rate (20% versus 8.0%), multiple complications rate (23.3% versus 9.6%), percutaneous drainage rate (33.3% versus 10.0%), 90-day mortality rate (6.7% versus 1.2%), and length of postoperative hospital stay (15.00 ± 12.78 versus 10.63 ± 5.23 days). However, the two groups differed no significantly with respect to age, gender, American Society of Anesthesiologists score, preoperative CA125/CA199 levels, surgery time, specimen removal time, and intraoperative blood loss. Conclusion: MetS increases the incidence of postoperative complications and perioperative mortality rate in LPD.

Coordinated activation of DNMT3a and TET2 in cancer stem cell-like cells initiates and sustains drug resistance in hepatocellular carcinoma.

BACKGROUND: Resistance to targeted therapies represents a significant hurdle to successfully treating hepatocellular carcinoma (HCC). While epigenetic abnormalities are critical determinants of HCC relapse and therapeutic resistance, the underlying mechanisms are poorly understood. We aimed to address whether and how dysregulated epigenetic regulators have regulatory and functional communications in establishing and maintaining drug resistance. METHODS: HCC-resistant cells were characterized by CCK-8, IncuCyte Live-Cell analysis, flow cytometry and wound-healing assays. Target expression was assessed by qPCR and Western blotting. Global and promoter DNA methylation was measured by dotblotting, methylated-DNA immunoprecipitation and enzymatic digestion. Protein interaction and promoter binding of DNMT3a-TET2 were investigated by co-immunoprecipitation, ChIP-qPCR. The regulatory and functional roles of DNMT3a and TET2 were studied by lentivirus infection and puromycin selection. The association of DNMT and TET expression with drug response and survival of HCC patients was assessed by public datasets, spearman correlation coefficients and online tools. RESULTS: We identified the coordination of DNMT3a and TET2 as an actionable mechanism of drug resistance in HCC. The faster growth and migration of resistant HCC cells were attributed to DNMT3a and TET2 upregulation followed by increased 5mC and 5hmC production. HCC patients with higher DNMT3a and TET2 had a shorter survival time with a less favorable response to sorafenib therapy than those with lower expression. Cancer stem cell-like cells (CSCs) displayed DNMT3a and TET2 overexpression, which were insensitive to sorafenib. Either genetic or pharmacological suppression of DNMT3a or/and TET2 impaired resistant cell growth and oncosphere formation, and restored sorafenib sensitivity. Mechanistically, DNMT3a did not establish a regulatory circuit with TET2, but formed a complex with TET2 and HDAC2. This complex bound the promoters of oncogenes (i.e., CDK1, CCNA2, RASEF), and upregulated them without involving promoter DNA methylation. In contrast, DNMT3a-TET2 crosstalk silences tumor suppressors (i.e., P15, SOCS2) through a corepressor complex with HDAC2 along with increased promoter DNA methylation. CONCLUSIONS: We demonstrate that DNMT3a and TET2 act coordinately to regulate HCC cell fate in DNA methylation-dependent and -independent manners, representing strong predictors for drug resistance and poor prognosis, and thus are promising therapeutic targets for refractory HCC.

Development of an insulin-like growth factor-1 certified reference material by SI-traceable isotope-dilution mass spectrometry.

In this study, an insulin-like growth factor-1 (IGF-1) certified reference material (CRM) was developed by the National Institute of Metrology (NIM), and two different principles for evaluating the IGF-1 CRM were established. After optimisation of the acid hydrolysis conditions (110 °C, 36 h), quantitative determination of peptide purity, and chromatographic separation and mass spectrometric detection, amino acid analysis-based high-performance liquid chromatography combined with isotope-dilution tandem mass spectrometry (AAA-HPLC-IDMS/MS) and peptide analysis-based HPLC-IDMS/MS (Peptide-HPLC-IDMS/MS) were used for certified value assignment; the results obtained were 136.28 and 135.01 µg/g, respectively, which were in good agreement. These results were subjected to the normal distribution test, outlier test, and method consistency test. The homogeneity and stability of the reference materials were also examined, and the uncertainty introduced in the experimental process was calculated. The final certified value was (136 ± 15) µg g-1 (k = 2). The CRM was found to be stable for at least six months when stored at -70 °C and for 7 d when stored at higher temperatures (-20 °C, 4 °C, 25 °C, or 40 °C). The CRM is expected to be used as a primary calibrator for quality control in biopharmaceutical production and clinical diagnostics.

A transcriptome based molecular classification scheme for cholangiocarcinoma and subtype-derived prognostic biomarker.

Previous studies on the molecular classification of cholangiocarcinoma (CCA) focused on certain anatomical sites, and disregarded tissue contamination biases in transcriptomic profiles. We aim to provide universal molecular classification scheme and prognostic biomarker of CCAs across anatomical locations. Comprehensive bioinformatics analysis is performed on transcriptomic data from 438 CCA cases across various anatomical locations. After excluding CCA tumors showing normal tissue expression patterns, we identify two universal molecular subtypes across anatomical subtypes, explore the molecular, clinical, and microenvironmental features of each class. Subsequently, a 30-gene classifier and a biomarker (called "CORE-37") are developed to predict the molecular subtype of CCA and prognosis, respectively. Two subtypes display distinct molecular characteristics and survival outcomes. Key findings are validated in external cohorts regardless of the stage and anatomical location. Our study provides a CCA classification scheme that complements the conventional anatomy-based classification and presents a promising prognostic biomarker for clinical application.

Laparoscopic Duodenum-Preserving Pancreatic Head Resection: A Technique for the Treatment of Benign or Low-Grade Malignant Tumors (10 Cases Report).

Background: Laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) is a surgical procedure that involves the removal of the pancreatic head while aiming to preserve the integrity of the digestive and biliary tracts. With advancements in laparoscopic techniques, the utilization of LDPPHR has been increasing. Methods: We retrospectively analyzed the clinical data of 10 patients who underwent laparoscopic duodenum-preserving total pancreatic head resection (LDPPHR-t) at our center from June 2019 to October 2021. Additionally, we analyzed the use of indocyanine green (ICG) in the initial stage of LDPPHR, based on current reports. Results: LDPPHR-t was successfully performed in all patients. After surgery, 3 patients experienced pancreatic fistula (Grade B), 2 patients experienced bile leakage, and 2 patients experienced postoperative hemorrhage. However, no patient exhibited recurrence or required secondary surgery. Conclusion: LDPPHR-t is a new method for treating benign and low-grade malignant tumors in the pancreatic head. However, it is associated with a high incidence of postoperative complications. In the initial stage, the use of ICG can assist surgeons in identifying the biliary duct and pancreaticoduodenal artery arcade.

Effect of Laparoscopic and Open Pancreaticoduodenectomy for Pancreatic or Periampullary Tumors: Three-year Follow-up of a Randomized Clinical Trial.

OBJECTIVE: This study aimed to estimate whether the potential short-term advantages of laparoscopic pancreaticoduodenectomy (LPD) could allow patients to recover in a more timely manner and achieve better long-term survival than with open pancreaticoduodenectomy (OPD) in patients with pancreatic or periampullary tumors. BACKGROUND: LPD has been demonstrated to be feasible and may have several potential advantages over OPD in terms of shorter hospital stay and accelerated recovery than OPD. METHODS: This noninferiority, open-label, randomized clinical trial was conducted in 14 centers in China. The initial trial included 656 eligible patients with pancreatic or periampullary tumors enrolled from May 18, 2018, to December 19, 2019. The participants were randomized preoperatively in a 1:1 ratio to undergo either LPD (n=328) or OPD (n=328). The 3-year overall survival (OS), quality of life, which was assessed using the 3-level version of the European Quality of Life-5 Dimensions, depression, and other outcomes were evaluated. RESULTS: Data from 656 patients [328 men (69.9%); mean (SD) age: 56.2 (10.7) years] who underwent pancreaticoduodenectomy were analyzed. For malignancies, the 3-year OS rates were 59.1% and 54.3% in the LPD and OPD groups, respectively ( P =0.33, hazard ratio: 1.16, 95% CI: 0.86-1.56). The 3-year OS rates for others were 81.3% and 85.6% in the LPD and OPD groups, respectively ( P =0.40, hazard ratio: 0.70, 95% CI: 0.30-1.63). No significant differences were observed in quality of life, depression and other outcomes between the 2 groups. CONCLUSION: In patients with pancreatic or periampullary tumors, LPD performed by experienced surgeons resulted in a similar 3-year OS compared with OPD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03138213.

CDC-NET: a cell detection and confirmation network of bone marrow aspirate images for the aided diagnosis of AML.

Standardized morphological evaluation in pathology is usually qualitative. Classifying and qualitatively analyzing the nucleated cells in the bone marrow aspirate images based on morphology is crucial for the diagnosis of acute myoid leukemia (AML), acute lymphoblastic leukemia (ALL), and Myelodysplastic syndrome (MDS), etc. However, it is time-consuming and difficult to accurately identify nucleated cells and calculate the percentage of the cells because of the complexity of bone marrow aspirate images. This paper proposed a deep learning analysis model of bone marrow aspirate images, termed Cell Detection and Confirmation Network (CDC-NET), for the aided diagnosis of AML by improving the accuracy of cell detection and recognition. Specifically, we take the nucleated cells in the bone marrow aspirate images as the detection objects to establish the model. Since some cells from different categories have similar morphology, classification error is inevitable. We design a confirmation network in which multiple trained classifiers work as pathologists to confirm the cell category by a voting method. To demonstrate the effectiveness of the proposed approach, experiments on clinical microscopic datasets are conducted. The Recall and Precision of CDC-NET are 78.54% and 91.74% respectively, and the missed rate of our method is lower than those of the other popular methods. The experimental results demonstrated that the proposed model has the potential for the pathological analysis of aspirate smears and the aided diagnosis of AML.

Interaction and binding mechanism of ovalbumin with cereal phenolic acids: improved structure, antioxidant activity, emulsifying and digestion properties for potential targeted delivery systems.

Ovalbumin (OVA) has been considered as a nutrient carrier for bioactive, which has high nutrition value and multiple properties. Recently, proteins-phenolic acids composite delivery systems have received widespread attention. Therefore, this research aimed to investigate the interaction between OVA and cereal phenolic acids (CPA) to establish delivery systems for bioactive. Spectroscopy results have found that CPA generated complexes with OVA, causing the microenvironment changes of OVA. Ferulic acid (FA), p-coumaric acid (CA), vanillic acid (VA), syringic acid (SY), sinapic acid (SI), and protocatechuic acid (PA) not only quenched the intrinsic fluorescence of OVA, but also altered protein microenvironment. Further investigation showed these complexes were formed by static quenching mode, while hydrogen bond and hydrophobic interaction were dominant binding forces. Meanwhile, the interaction decreased α-helix contents and increased ß-sheet contents, leading to conformational changes in OVA. Besides, OVA/CPA complexes displayed an increase in hydrophobicity with a reduce in free-SH. After combination with FA, SY, CA, VA, SI, PA, it was found that all formed complexes had superior solubility, emulsifying and antioxidant activities than native OVA. Among them, OVA-PA exhibited the highest emulsifying activity index and emulsion stability index values (36.4 ± 0.39 m2/g and 60.4 ± 0.94 min) and stronger antioxidant activities. Finally, the combination with phenolic acids further improved the digestion efficiency in vitro of OVA. The OVA-CPA complexes showed improved properties for excellent delivery systems. Overall, OVA-CPA complexes could be a good carrier for bioactive, which provided valuable avenues in target delivery system application.

Overexpression of FNDC4 constrains ovarian cancer progression by promoting cell apoptosis and inhibiting cell growth.

Hepatocellular carcinoma is one of the most common malignant tumors in the world. It has been reported that fibronection type III domain containing family plays an important role in the formation and development of a variety of tumors, but the role of FNDC4 is still unclear. In our study, we found that FNDC4 was highly expressed in normal liver tissues but abnormally expressed at low levels in liver cancer tissues. Enhanced apoptosis and decreased proliferation were shown in the FNDC4 overexpression model in HepG2 cells. In addition, FNDC4 was negatively correlated with AFP, a tumor marker of HCC, and other cancer-related genes such as AHSA1, GDF1, GPC3 and MDK. In addition, we found that FNDC4 was associated with the abundance of several tumor-infiltrating lymphocytes and the expression of chemokines and immunostimulators, and FNDC4 was enriched in response to transforming growth factor ß. These results indicated that FNDC4 plays a key role in hepatocellular carcinoma progression and might be a promising biomarker for cancer diagnosis.

Machine learning-based models for the prediction of breast cancer recurrence risk.

Breast cancer is the most common malignancy diagnosed in women worldwide. The prevalence and incidence of breast cancer is increasing every year; therefore, early diagnosis along with suitable relapse detection is an important strategy for prognosis improvement. This study aimed to compare different machine algorithms to select the best model for predicting breast cancer recurrence. The prediction model was developed by using eleven different machine learning (ML) algorithms, including logistic regression (LR), random forest (RF), support vector classification (SVC), extreme gradient boosting (XGBoost), gradient boosting decision tree (GBDT), decision tree, multilayer perceptron (MLP), linear discriminant analysis (LDA), adaptive boosting (AdaBoost), Gaussian naive Bayes (GaussianNB), and light gradient boosting machine (LightGBM), to predict breast cancer recurrence. The area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and F1 score were used to evaluate the performance of the prognostic model. Based on performance, the optimal ML was selected, and feature importance was ranked by Shapley Additive Explanation (SHAP) values. Compared to the other 10 algorithms, the results showed that the AdaBoost algorithm had the best prediction performance for successfully predicting breast cancer recurrence and was adopted in the establishment of the prediction model. Moreover, CA125, CEA, Fbg, and tumor diameter were found to be the most important features in our dataset to predict breast cancer recurrence. More importantly, our study is the first to use the SHAP method to improve the interpretability of clinicians to predict the recurrence model of breast cancer based on the AdaBoost algorithm. The AdaBoost algorithm offers a clinical decision support model and successfully identifies the recurrence of breast cancer.

The m6A reader YTHDC1-mediated lncRNA CTBP1-AS2 m6A modification accelerates cholangiocarcinoma progression.

Background: Cholangiocarcinoma (CCA) is a serious malignancy originating from the bile ducts and the second most common primary liver cancer. Long non-coding RNA (lncRNA) is a functional lncRNA that plays an important role in human cancers. However, the role and underlying mechanisms of CTBP1-AS2 in CCA remain unknown. Purpose: In this study, we investigated the functional role and mechanism of long-stranded non-coding RNA (lncRNA) C-terminal binding protein 1 antisense RNA 2 (CTBP1-AS2) in CCA progression. Result: In the present study, the bioinformatics analysis revealed that YTHDC1 and CTBP1-AS2 were significantly upregulated, and it was confirmed in cholangiocarcinoma tissues from CCA patients. Meanwhile, we demonstrated that knockdown of YTHDC1 or lncRNA CTBP1-AS2 inhibited CCA cell proliferation, migration and invasion, blocked the cell cycle in G2/M phase and promoted apoptosis of CCA cells. In addition, lncRNA CTBP1-AS2-mediated N6-methyladenosine (m6A) methylation levels were significantly elevated in cholangiocarcinoma tissues, whereas knockdown of YTHDC1 resulted in a significant down-regulation of m6A methylation levels by lncRNA CTBP1-AS2. Conclusion: Our results suggest that YTHDC1 affects cholangiocarcinoma progression by modifying the lncRNA CTBP1-AS2 m6A, and CTBP1-AS2 may be a promising therapeutic target for CCA.

Short-Term Outcomes Following Laparoscopic vs Open Pancreaticoduodenectomy in Patients With Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial.

Importance: The safety and efficacy of laparoscopic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma remain controversial. Objective: To compare laparoscopic and open pancreaticoduodenectomy performed by experienced surgeons in patients with pancreatic ductal adenocarcinoma. Design, Setting, and Participants: This was a noninferiority, open-label randomized clinical trial between September 20, 2019 and March 20, 2022, at 10 hospitals in China. A total of 412 adult patients were assessed for eligibility; 200 patients with histologically confirmed or clinically diagnosed pancreatic ductal adenocarcinoma who were eligible to undergo pancreaticoduodenectomy were enrolled. Study recruitment is complete, and follow-up is ongoing. This article reports prespecified early safety results from the trial. Interventions: Participants were randomized in a 1:1 ratio to undergo either laparoscopic or open pancreaticoduodenectomy, to be performed by experienced surgeons who had already performed at least 104 laparoscopic pancreaticoduodenectomy operations. Main Outcomes and Measures: The primary end point is 5-year overall survival, but the data for this end point are not yet mature; thus, secondary short-term outcomes, including operative findings, complications, mortality, and oncological results are reported here. The outcomes were analyzed according to a modified intention-to-treat and per-protocol principle. Results: Among 412 patients for eligibility, 200 patients were enrolled and randomly assigned 1:1 to have laparoscopic pancreaticoduodenectomy or open pancreaticoduodenectomy. The mean (SD) age was 61.3 (9.3) years, and 78 participants (39%) were female. Laparoscopic procedures had longer operative times (median [IQR], 330.0 [287.5-405.0] minutes vs 297.0 [245.0-340.0] minutes; P < .001). Patients in the laparoscopic group lost less blood than those in the open group (median [IQR], 145.0 [100.0-200.0] mL vs 200.0 [100.0-425.0] mL; P = .02). Ninety-day mortality occurred in 2 of 100 patients in the laparoscopic group and 0 of 100 patients in the open group. There was no difference in the rates of complications of the Clavien-Dindo grades III-IV (n = 17 [17.0%] vs n = 23 [23.0%]; P = .29), comprehensive complication index (median [IQR], 0.0 [0.0-22.6] vs 8.7 [0.0-26.2]; P = .79) or median (IQR) postoperative length of stay (14.0 [11.0-17.0] days vs 14.0 [12.0-18.5] days; P = .37) between the 2 groups. Conclusions and Relevance: Laparoscopic pancreaticoduodenectomy performed by experienced surgeons in high-volume specialized institutions resulted in similar short-term outcomes compared with open pancreaticoduodenectomy among patients with pancreatic ductal adenocarcinoma. Trial Registration: ClinicalTrials.gov Identifier: NCT03785743.

Assessment of intestinal status in MPLW515L mutant myeloproliferative neoplasms mice model.

The MPLW515L mutation is a prevalent genetic mutation in patients with myeloproliferative neoplasms (MPN), and utilizing this mutation in mice model can provide important insights into the disease. However, the relationship between intestinal homeostasis and MPN mice model remains elusive. In this study, we utilized a retroviral vector to transfect hematopoietic stem cells with the MPLW515L mutation, creating mutated MPN mice model to investigate their intestinal status. Our results revealed that the MPLW515L in MPN mice model aggravated inflammation in the intestines, decreased the levels of tight junction proteins and receptors for bacteria metabolites. Additionally, there was increased activation of the caspase1/IL-1ß signaling pathway and a significant reduction in phos-p38 levels in the intestinal tissue in MPN mice. The MPLW515L mutation also led to up-expression of anti-microbial genes in the intestinal tract. Though the mutation had no impact on the alpha diversity and dominant bacterial taxa, it did influence the rare bacterial taxa/sub-communities and consequently impacted intestinal homeostasis. Our findings demonstrate the significance of MPLW515L mice model for studying MPN disease and highlight the mutation's influence on intestinal homeostasis, including inflammation, activation of the IL-1ß signaling pathway, and the composition of gut microbial communities.

Clodronate liposomes may biases MSC differentiation toward adipogenesis through activation of NLRP3.

Introduction: Clodronate-Liposomes (Clod-Lipo) injection after hematopoietic stem cell transplantation (HSCT) has been shown to be detrimental to hematopoietic reconstitution after transplantation, and our previous study showed that Clod-Lipo injection after HSCT increased adipocytes in the bone marrow cavity of mice after HSCT, but the reason for the large increase in adipocytes has not been clearly explained. The aim of this study was to investigate the source and mechanism of bone marrow cavity adipocytes after HSCT injection of Clod-Lipo. Methods: BALB/c mice received 7.5 Gy of total body irradiation followed by infusion of 5x106 bone marrow mononuclear cells from C57BL/6 via the tail vein. Clod-Lipo were injected through the tail vein on the first day after HSCT and every 5 days for the rest of the day. BALB/c mice were then divided into three groups: BMT, BMT + Clodronate-Liposomes (BMT + Clod-Lipo), and BMT + PBS-Liposomes (BMT + PBS-Lipo). Bone marrow pathological changes were detected by H&E staining, Western blot was used to detect the expression of NLRP3 and Caspase-1 in mouse bone marrow cells, and RT-qPCR was used to detect the expression levels of the key transcription factors peroxisome proliferator-activated receptor γ (PPAR-γ) and CCAAT/enhancer binding protein (C/EBPα) mRNA in bone marrow cells. Mouse mesenchymal stem cells (MSC) cultured in vitro were identified by flow cytometry, and adipocyte induction assays were performed using Clod-Lipo action for 24 h, Oil red staining was used to identify adipogenesis. Western blot was performed to detect NLRP3 and caspase-1 expression in MSC after Clod-Lipo action. Caspase-1 was blocked with Ac-YVAD-cmk (Ac-YV), followed by adipogenesis assay after 24 h of Clod-Lipo action to observe the change in the amount of adipogenesis. Results: Compared with the other two groups, a significant increase in adipocytes was found in the Clod-Lipo group by HE staining, and increased expression of NLRP3 and Caspase-1 in mouse bone marrow cells was found by western Blot. By culturing MSC in vitro and performing adipogenesis assay after 24 h of Clod-Lipo action, it was found that adipogenesis was increased in the Clod-Lipo group, while the expression of NLRP3 and Caspase-1 was increased in MSCs, and adipogenesis assay was performed after 2 h of action using Caspase-1 inhibitor, and it was found that adipocytes was reduced. Conclusions: The results of this study suggest that MSC are biased towards adipocyte generation in response to Clod-Lipo, a process that may be associated with activation of the NLRP3/caspase-1 pathway.