Type II diabetes mellitus increases the risk of inflammatory bowel disease in a prospective cohort study.

BACKGROUND: Inflammatory bowel disease is a common digestive disorder and diabetes can lead to intestinal dysfunction. Patients with inflammatory bowel disease in combination with diabetes present a higher rate of hospitalization and consumption of medical resources, yet the association between type 2 diabetes and Inflammatory bowel disease remains unknown. METHODS: We studied 313,008 participants from the UK Biobank, including 5891 patients with type 2 diabetes at baseline. Multivariate Cox proportional risk models were constructed to examine the risks associated with type 2 diabetes and inflammatory bowel disease and its subtypes (Crohn's disease, ulcerative colitis). Potential confounders including sociodemographic, lifestyle, physical body indicators, psychological state, hypertension, and thyroid-related disorders were adjusted. Propensity score matching was also performed to analyze their sensitivity. RESULTS: Of a total of 313,008 participants included in the study, 5891 (1.88 %) were diagnosed with type 2 diabetes mellitus at baseline and 1829 (0.58 %) of the entire cohort developed inflammatory bowel disease during follow-up, with a median follow-up time of 13.72 years. Patients with type 2 diabetes had a higher cumulative risk of inflammatory bowel disease compared to the non-type 2 diabetes population (inflammatory bowel disease: 1.24% vs. 0.57%, p < 0.001; Crohn's disease: 0.46% vs. 0.15%, p < 0.001; ulcerative colitis: 0.73% vs. 0.35%, p < 0.001). Multivariate Cox regression analysis showed that type 2 diabetes was independently associated with inflammatory bowel disease (Hazard Ratio: 1.61 [95% Confidence Interval: 1.26-2.06], p < 0.001), Crohn's disease (Hazard Ratio: 2.10 [95% Confidence Interval: 1.39-3.17], p < 0.001) and ulcerative colitis (Hazard Ratio: 1.58 [95% Confidence Interval: 1.15-2.18], p = 0.005). In a propensity-matched analysis, type 2 diabetes still showed its ability to predict the risk of inflammatory bowel disease (Hazard Ratio: 2.09 [95% Confidence Interval: 1.55-2.83], p < 0.001), Crohn's disease (Hazard Ratio: 3.49 [95% Confidence Interval: 2.00 to 6.09], p < 0.001), and ulcerative colitis (Hazard Ratio: 1.76 [95% Confidence Interval: 1.20 to 2.56], p = 0.003) of robustness. CONCLUSION: In patients with type 2 diabetes mellitus, the risk of inflammatory bowel disease is higher, and the presence of gastrointestinal symptoms in patients with type 2 diabetes requires vigilance for the possibility of inflammatory bowel disease in clinical practice.

Phase 2 Study of Preoperative Tislelizumab in Combination with Low-dose Nab-Paclitaxel in Patients with Muscle-invasive Bladder Cancer.

BACKGROUND AND OBJECTIVE: Combinations of immune checkpoint inhibitors and nab-paclitaxel have achieved significant therapeutic effects in the treatment of advanced urothelial carcinoma. Our aim was to assess the efficacy and safety of tislelizumab combined with low-dose nab-paclitaxel in patients with muscle-invasive bladder cancer (MIBC). METHODS: TRUCE-01 was a single-arm phase 2 study that included 62 patients with T2-4a N0/X M0 MIBC tumors with predominant urothelial carcinoma histology. Eligible patients received three 21-d cycles of intravenous 200 mg tislelizumab on day 1 plus intravenous 200 mg nab-paclitaxel on day 2, followed by surgical assessment. The primary study endpoint was a clinical complete response (cCR). Treatment-related adverse event (TRAE) profiles were recorded according to Common Terminology Criteria for Adverse Events version 5.0. KEY FINDINGS AND LIMITATIONS: The safety analysis included all 62 patients and the efficacy analysis included 48 patients. The primary efficacy endpoint (cCR) was met by 25 patients (52%) patients. Among the 62 patients in the safety analysis, six (9.7%) had grade ≥3 TRAEs. CONCLUSIONS: Tislelizumab combined with low-dose nab-paclitaxel showed promising antitumor effectiveness and was generally well tolerated, which makes it an excellent preoperative therapy option for MIBC. PATIENT SUMMARY: We found that a combination of the drugs tislelizumab and low-dose nab-paclitaxel had satisfactory efficacy and safety for preoperative treatment of muscle-invasive bladder cancer.

Identification and validation of a platelet-related signature for predicting survival and drug sensitivity in multiple myeloma.

Background: Significant progress has been achieved in the management of multiple myeloma (MM) by implementing high-dose therapy and stem cell transplantation. Moreover, the prognosis of patients has been enhanced due to the introduction of novel immunomodulatory drugs and the emergence of new targeted therapies. However, predicting the survival rates of patients with multiple myeloma is still tricky. According to recent researches, platelets have a significant impact in affecting the biological activity of tumors and are essential parts of the tumor microenvironment. Nonetheless, it is still unclear how platelet-related genes (PRGs) connect to the prognosis of multiple myeloma. Methods: We analyzed the expression of platelet-related genes and their prognostic value in multiple myeloma patients in this study. We also created a nomogram combining clinical metrics. Furthermore, we investigated disparities in the biological characteristics, immunological microenvironment, and reaction to immunotherapy, along with analyzing the drug susceptibility within diverse risk groups. Results: By using the platelet-related risk model, we were able to predict patients' prognosis more accurately. Subjects in the high-risk cohort exhibited inferior survival outcomes, both in the training and validation datasets, as compared to those in the low-risk cohort (p < 0.05). Moreover, there were differences in the immunological microenvironments, biological processes, clinical features, and chemotherapeutic drug sensitivity between the groups at high and low risk. Using multivariable Cox regression analyses, platelet-related risk score was shown to be an independent prognostic influence in MM (p < 0.001, hazard ratio (HR) = 2.001%, 95% confidence interval (CI): 1.467-2.730). Furthermore, the capacity to predict survival was further improved when a combined nomogram was utilized. In training cohort, this outperformed the predictive value of International staging system (ISS) alone from a 5-years area under curve (AUC) = 0.668 (95% CI: 0.611-0.725) to an AUC = 0.721 (95% CI: 0.665-0.778). Conclusion: Our study revealed the potential benefits of PRGs in terms of survival prognosis of MM patients. Furthermore, we verified its potential as a drug target for MM patients. These findings open up novel possibilities for prognostic evaluation and treatment choices for MM.

Prognostic significance of ß2-microglobulin decline index in multiple myeloma.

Purpose: To assess the prognostic significance of ß2-microglobulin decline index (ß2M DI) in multiple myeloma (MM). Methods: 150 MM patients diagnosed with MM were enrolled in this study. Cox proportional hazards model was used to analyze the uni- and multivariate prognosis in training cohort (n=105). A new combined prognostic model containing ß2M DI was built up based on the data in training cohort. The validation group was used to verify the model. Results: ß2M DI showed significant correlation with prognosis in both uni- and multivariate analyses and had a good correlation with complete response (CR) rate and deep remission rate. The ROC and calibration curves in validation cohort (n=45) indicated a good predictive performance of the new model. Based on the median risk score of the training group, we classified patients into high- and low- risk groups. In both training and validation groups, patients in the low-risk group had longer overall survival (OS) time than that in the high-risk group (p<0.05). Conclusion: ß2M DI is a good predictive index for predicting treatment response and survival time in MM patients. The prognostic model added with ß2M DI showed a better correlation with OS.

[Effect of Erchen Decoction on liver mitochondrial function by inhibiting mTORC1/SREBP1/CAV1 pathway in mice with high-fat diet].

This study aims to investigate the effect of Erchen Decoction(ECD) on liver mitochondrial function in mice with a high-fat diet and its possible mechanism. A total of sixty C57BL/6J mice were randomly divided into a normal group, high-fat group, ECD group, mTORC1 activator(MHY) group, ECD+MHY group, and polyene phosphatidyl choline(PPC) group, with 10 rats in each group. The normal group was given a normal diet, and the other groups were fed a high-fat diet for 20 weeks. At the 17th week, the ECD group and ECD+MHY group were given ECD(8.7 g·kg~(-1)) daily, and the PPC group was given PPC(0.18 g·kg~(-1)) daily, while the remaining groups were given normal saline(0.01 mL·g~(-1)) daily for four weeks. In the 19th week, the MHY group and ECD+MHY group were injected intraperitoneally with MHY(5 mg·kg~(-1)) every other day for two weeks. During the experiment, the general conditions of the mice were observed. The contents of triglyceride(TG) and total cholesterol(TC) in serum were measured. Morphological changes in liver tissue were examined through HE and oil red O staining. The content of adenosine triphosphate(ATP) was determined using chemiluminescence, and mitochondrial membrane potential was assessed using a fluorescence probe(JC-1). Western blot was performed to detect the expression of rapamycin target protein complex 1(mTOR1), ribosomal protein S6 kinase B1(S6K), sterol regulatory element binding protein 1(SREBP1), and caveolin 1(CAV1). RESULTS:: revealed that compared with the normal group, the mice in the high-fat group exhibited significant increases in body weight and abdominal circumference(P<0.01). Additionally, there were significant increases in TG and TC levels(P<0.01). HE and oil red O staining showed that the boundaries of hepatic lobules were unclear; hepatocytes were enlarged, round, and irregularly arranged, with obvious lipid droplet deposition and inflammatory cell infiltration. The liver ATP content and mitochondrial membrane potential decreased significantly(P<0.01). The expression of p-mTOR, p-S6K, and n-SREBP1 increased significantly(P<0.01), while the expression of CAV1 decreased significantly(P<0.01). Compared with the high-fat group, the body weight and TG content of mice in the ECD group and PPC group decreased significantly(P<0.05). Improvements were observed in hepatocyte morphology, lipid deposition, and inflammatory cell infiltration. Furthermore, there were significant increases in ATP content and mitochondrial membrane potential(P<0.05 or P<0.01). The expression of p-mTOR, p-S6K, and n-SREBP1 decreased significantly in the ECD group(P<0.01), while CAV1 expression increased significantly(P<0.01). However, the indices mentioned above did not show improvement in the MHY group. When the ECD+MHY group was compared with the MHY group, there were significant reductions in body weight and TG contents(P<0.05). The morphological changes of hepatocytes, lipid deposition, and inflammatory cell infiltration were recovered. Moreover, there were significant increases in liver ATP content and mitochondrial membrane potential(P<0.05 or P<0.05). The expression of p-mTOR, p-S6K, and n-SREBP1 decreased significantly(P<0.01), while CAV1 expression increased significantly(P<0.01). In conclusion, ECD can improve mitochondrial function by regulating the mTORC1/SREBP1/CAV1 pathway. This mechanism may be involved in the resolution of phlegm syndrome and the regulation of lipid metabolism.

Single and mixed effects of multiple volatile organic compounds exposure on hematological parameters in the U.S. adult population.

BACKGROUND: Most research exploring the correlation between volatile organic compounds (VOCs) and hematological parameters have focused on single VOCs. Our study aimed to explore the single and combined effects of VOCs on hematological parameters through three statistical models. METHODS: Data from 4 cycles of the National Health and Nutrition Examination Survey (NHANES) were used in this study. The correlations between single exposure to 16 VOCs and hematological parameters in the general population were assessed by weighted multiple linear regression. Weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were used to explore the relationship between the combined important VOCs selected by the least absolute shrinkage and selection operator (LASSO) and hematological parameters, as well as the effects of smoking status on them. RESULTS: A total of 4089 adults were included in the study. We found that a variety of VOCs were significantly associated with hematological parameters. Among them, N-acetyl-S-(benzyl)-l-cysteine (BMA) was significantly negatively correlated with white blood cell (WBC), red blood cell (RBC), lymphocyte, and neutrophil counts. N-acetyl-S-(3-hydroxypropyl-1-methyl)-l-cysteine (HPMMA) was significantly positively correlated with WBC, monocyte, lymphocyte, and neutrophil counts. In the WQS analysis, the WQS index of the VOCs mixtures was positively correlated with WBC (ß: 0.031; P < 0.001), monocyte (0.023; P = 0.021), and neutrophil (0.040; P = 0.001) counts, while negatively associated with RBC (-0.013; P < 0.001) counts. The BKMR model revealed that combined exposure to VOCs levels ≥70th percentile was significantly associated with lower RBC counts, and BMA was identified as the dominant contributor. Smoking significantly influenced the relationship between VOCs and hematological parameters. CONCLUSIONS: Our study indicated the effects of single and overall VOCs exposure on hematological parameters and suggested the hematotoxicity as well as pro-inflammatory effects of VOCs, which had strong public health implications for reducing the potential health hazards of VOCs exposure to the hematologic system.

Pentraxin 3 exacerbates psoriasiform dermatitis through regulation of macrophage polarization.

OBJECTIVE: To elucidate the mechanism of Pentraxin 3 (PTX3) in the pathogenesis of psoriasiform dermatitis using Ptx3-knockout (Ptx3-KO) background mice. METHODS: An Imiquimod (IMQ)-induced murine psoriatic model was created using Ptx3-KO (Ptx3-/-) and wild-type (Ptx3+/+) mice. Skin lesion severity and expression of inflammatory mediators (IL-6 and TNFα) were assessed using PASI score and ELISA, respectively. Cutaneous tissues from the two mice groups were subjected to histological analyses, including HE staining, Masson staining, and Immunohistochemistry (IHC). The PTX3, iNOS, COX2, and Arg1 expressions were quantified and compared between the two groups. We used RNA-seq to clarify the underlying mechanisms of the disease. Flow cytometry was used to analyze systemic Th17 cell differentiation and macrophage polarization. RESULT: The psoriatic region exhibited a higher PTX3 expression than the normal cutaneous area. Moreover, PTX3 was upregulated in HaCaT cells post-TNFα stimulation. Upon IMQ stimulation, Ptx3-/- mice displayed a lower degree of the psoriasiform dermatitis phenotype compared to Ptx3+/+ mice. Consistent with the RNA-seq results, further experiments confirmed that compared to the wild-type group, the PTX3-KO group exhibited a generally lower IL-6, TNFα, iNOS, and COX2 expression and a contrasting trend in macrophage polarization. However, no significant difference in Th17 cell activation was observed between the two groups. CONCLUSIONS: This study revealed that PTX3 was upregulated in psoriatic skin tissues and TNFα-stimulated HaCaT cells. We also discovered that PTX3 deficiency in mice ameliorated the psoriasiform dermatitis phenotype upon IMQ stimulation. Mechanistically, PTX3 exacerbates psoriasiform dermatitis by regulating macrophage polarization rather than Th17 cell differentiation.

[Mechanism about LMP1 of EB Virus Promoting Plasma Blast Differentiation of DLBCL Cell via mTORC1].

OBJECTIVE: To investigate possible mechanism on protien LMP1 expressed by EBV inducing plasmablast differentiation of DLBCL cell via the mTORC1 pathway. METHODS: The expression levels of LMP1 protein, CD38 and the phosphorylation levels of p70S6K in EBV+ and EBV- DLBCL cell lines were detected by Western blot. Cell lines overexpressing LMP1 gene stablely were constructed and LMP1 gene was silenced by RNAi. The expression of LMP1 gene was verified by RT-qPCR. The expression levels of LMP1 and CD38 and the phosphorylation levels of p70S6K in each group were detected by Western blot. RESULTS: Compared with EBV-DLBCL cells, the expression of LMP1 was detected on EBV +DLBCL cells (P =0.0008), EBV +DLBCL cells had higher phosphorylation levels of p70S6K (P =0.0072) and expression levels of CD38(P =0.0091). Compared with vector group, the cells of LMP1OE group had higher expression levels of LMP1 and CD38 (P =0.0353; P <0.0001), meanwhile molecular p70S6K was phosphorylated much more(P =0.0065); expression of LMP1 mRNA was verified(P <0.0001). Compared with si-NC group, expression level of LMP1 protein(P =0.0129) was not detected and phosphorylated p70S6K disappeared of LMP1KO group (P =0.0228); meanwhile, expression of CD38 decreased,although there was no significant difference (P =0.2377). CONCLUSION: LMP1 promotes DLBCL cells plasmablast differentiation via activating mTORC1 signal pathway.

Self-assembly of maltose-albumin nanoparticles for efficient targeting delivery and therapy in liver cancer.

The effective delivery and targeted release of drugs within tumor cells are critical factors in determining the therapeutic efficacy of nanomedicine. To achieve this objective, a conjugate of maltose (Mal) and bovine serum albumin (BSA) was synthesized by the Maillard reaction and self-assembled into nanoparticles with active-targeting capabilities upon pH/heating induction. This nanoparticle could be effectively loaded with doxorubicin (DOX) to form stable nanodrugs (Mal-BSA/DOX) that were sensitive to low pH or high glutathione (GSH), thereby achieving a rapid drug release (96.82 % within 24 h). In vitro cell experiments indicated that maltose-modified BSA particles efficiently enhance cellular internalization via glucose transporters (GLUT)-mediated endocytosis, resulting in increased intracellular DOX levels and heightened expression of γ-H2AX. Consequently, these results ultimately lead to selective tumor cells death, as evidenced by an IC50 value of 3.83 µg/mL in HepG2 cells compared to 5.87 µg/mL in 293t cells. The efficacy of Mal-BSA/DOX in tumor targeting therapy has been further confirmed by in vivo studies, as it effectively delivered a higher concentration of DOX to tumor tissue. This targeted delivery approach not only reduces the systemic toxicity of DOX but also effectively inhibits tumor growth (TGI, 75.95 %). These findings contribute valuable insights into the advancement of targeting-albumin nanomedicine and further support its potential in tumor treatment.

Activation and characterization of G protein-coupled receptors for CHHs in the mud crab, Scylla paramamosain.

Crustacean hyperglycemic hormone (CHH) superfamily peptides constitute a group of neurohormones, including the crustacean hyperglycemic hormone (CHH), molt-inhibiting hormone (MIH), and gonad-inhibiting hormone (GIH) or vitellogenesis-inhibiting hormone (VIH), which reportedly play an essential role in regulating various biological activities by binding to their receptors in crustaceans. Although bioinformatics analyses have identified G protein-coupled receptors (GPCRs) as potential CHH receptors, no validation through binding experiments has been carried out. This study employed a eukaryotic expression system, HEK293T cell transient transfection, and ligand-receptor interaction tests to identify the GPCRs of CHHs in the mud crab Scylla paramamosain. We found that four GPCRs (Sp-GPCR-A34-A37) were activated by their corresponding CHHs (Sp-CHH1-v1, Sp-MIH, Sp-VIH) in a dose-dependent manner. Of these, Sp-GPCR-A34 was exclusively activated by Sp-VIH; Sp-GPCR-A35 was activated by Sp-CHH1-v1 and Sp-VIH, respectively; Sp-GPCR-A36 was activated by Sp-CHH1-v1 and Sp-MIH; Sp-GPCR-A37 was exclusively activated by Sp-MIH. The half-maximal effective concentration (EC50) values for all CHHs/GPCRs pairs (both Ca2+ and cAMP signaling) were in the nanomolar range. Overall, our study provided hitherto undocumented evidence of the presence of G protein-coupled receptors of CHH in crustaceans, providing the foothold for further studies on the signaling pathways of CHHs and their corresponding GPCRs.

Acute pancreatitis in intraductal papillary mucinous neoplasm: a single-center retrospective cohort study with systematic review and meta-analysis.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is a cystic tumor of the pancreas arising from abnormal papillary proliferation of ductal epithelial cells, and is a precancerous lesion of pancreatic malignancy. This study aimed to evaluate associations between acute pancreatitis (AP) and histologic subtypes of IPMN. METHODS: In the clinical study, patients with IPMN confirmed by surgical resection specimens at our institute between 2009 and 2021 were eligible for inclusion. Associations and predictive accuracy of AP on the presence of HGD were determined by logistic regressions. In addition, a systematic review and meta-analysis was conducted through literatures upon search in PubMed, Embase, CENTRAL, China National Knowledge Infrastructure (CKNI), and Wanfang database, up to June, 2023. Pooled effects of the associations between AP and HGD and intestinal epithelial subtype subtype, shown as odds ratios (ORs) with 95% confidence intervals (CIs), were calculated using random effects model. RESULTS: The retrospective cohort study included 47 patients (32 males, 15 females) diagnosed with IPMN at our center between 2009 and 2021, including 11 cases with AP (median 62 years) and 36 cases (median 64.5 years) without. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of AP in predicting HGD were 78.7%, 57.1%, 82.5%, 36.4%, and 91.7%, respectively. Univariate logistic regression analysis showed that AP group had greater odds of presence of HGD (OR: 6.29,95% CI: 1.14-34.57) than non-AP group. Meta-analysis of five case-control studies in the literature included 930 patients and showed that AP-IPMN patients had higher odds for HGD (OR: 2.13, 95% CI 1.38-3.29) and intestinal epithelial subtype (OR: 5.38, 95% CI: 3.50-8.27) compared to non-AP IPMN. CONCLUSIONS: AP is predictive of malignancy in patients with IPMN.

Effect of O-arm on reduction quality and functional recovery of acetabular dome impaction fractures: a retrospective clinical study.

BACKGROUND: Acetabular dome impaction fractures (ADIF) are difficult to reduce and have a high failure rate. Consistency between the acetabulum and the femoral head is usually assessed using intraoperative X-ray fluoroscopy to evaluate the quality of fracture reduction. This study examines the effects of intraoperative mobile 2D/3DX imaging system (O-arm) on the reduction quality and functional recovery of ADIF. METHODS: We retrospectively analysed the data of 48 patients with ADIF treated at Honghui Hospital between October 2018 and October 2021.The patients were divided into the X-ray and O-arm groups. The residual step-off and gap displacements in the acetabular dome region were measured, and fracture reduction quality was evaluated. Hip function was evaluated using the modified Merle d'Aubigné and Postel scoring systems. RESULTS: There were no significant intergroup differences in the preoperative general data (p > 0.05). The mean residual average step displacement in the acetabular dome region was 3.48 ± 2.43 mm and 1.61 ± 1.16 mm (p < 0.05), while the mean gap displacement was 6.72 ± 3.69 mm and 3.83 ± 1.67 mm (p < 0.05) in the X-ray and the O-arm groups, respectively. In the X-ray group, according to the fracture reduction criteria described by Verbeek and Moed et al., one case was excellent, 13 cases were good, 11 cases were poor; 56% were excellent or good. In the O-arm group, seven cases were excellent, 12 cases were good, and four cases were poor; overall in this group, 82.6% were excellent or good (p < 0.05). A total of 46 patients achieved fracture healing at the last follow-up. In the X-ray group, according to the modified Merle d'Aubigné and Postel function score, three cases were excellent,12 cases were good, six cases were middle, three cases were poor; 62.5% were excellent or good, In the O-arm group, 15 cases were excellent, four cases were good, two cases were middle, one case was poor; 86.4% were excellent or good (p < 0.05). CONCLUSIONS: The application of O-arm in ADIF can improve fracture reduction quality and functional recovery.

2S-BUSGAN: A Novel Generative Adversarial Network for Realistic Breast Ultrasound Image with Corresponding Tumor Contour Based on Small Datasets.

Deep learning (DL) models in breast ultrasound (BUS) image analysis face challenges with data imbalance and limited atypical tumor samples. Generative Adversarial Networks (GAN) address these challenges by providing efficient data augmentation for small datasets. However, current GAN approaches fail to capture the structural features of BUS and generated images lack structural legitimacy and are unrealistic. Furthermore, generated images require manual annotation for different downstream tasks before they can be used. Therefore, we propose a two-stage GAN framework, 2s-BUSGAN, for generating annotated BUS images. It consists of the Mask Generation Stage (MGS) and the Image Generation Stage (IGS), generating benign and malignant BUS images using corresponding tumor contours. Moreover, we employ a Feature-Matching Loss (FML) to enhance the quality of generated images and utilize a Differential Augmentation Module (DAM) to improve GAN performance on small datasets. We conduct experiments on two datasets, BUSI and Collected. Moreover, results indicate that the quality of generated images is improved compared with traditional GAN methods. Additionally, our generated images underwent evaluation by ultrasound experts, demonstrating the possibility of deceiving doctors. A comparative evaluation showed that our method also outperforms traditional GAN methods when applied to training segmentation and classification models. Our method achieved a classification accuracy of 69% and 85.7% on two datasets, respectively, which is about 3% and 2% higher than that of the traditional augmentation model. The segmentation model trained using the 2s-BUSGAN augmented datasets achieved DICE scores of 75% and 73% on the two datasets, respectively, which were higher than the traditional augmentation methods. Our research tackles imbalanced and limited BUS image data challenges. Our 2s-BUSGAN augmentation method holds potential for enhancing deep learning model performance in the field.

Multi-omics investigation of the resistance mechanisms of pomalidomide in multiple myeloma.

Background: Despite significant therapeutic advances over the last decade, multiple myeloma remains an incurable disease. Pomalidomide is the third Immunomodulatory drug that is commonly used to treat patients with relapsed/refractory multiple myeloma. However, approximately half of the patients exhibit resistance to pomalidomide treatment. While previous studies have identified Cereblon as a primary target of Immunomodulatory drugs' anti-myeloma activity, it is crucial to explore additional mechanisms that are currently less understood. Methods: To comprehensively investigate the mechanisms of drug resistance, we conducted integrated proteomic and metabonomic analyses of 12 plasma samples from multiple myeloma patients who had varying responses to pomalidomide. Differentially expressed proteins and metabolites were screened, and were further analyzed using pathway analysis and functional correlation analysis. Also, we estimated the cellular proportions based on ssGSEA algorithm. To investigate the potential role of glycine in modulating the response of MM cells to pomalidomide, cell viability and apoptosis were analyzed. Results: Our findings revealed a consistent decrease in the levels of complement components in the pomalidomide-resistant group. Additionally, there were significant differences in the proportion of T follicular helper cell and B cells in the resistant group. Furthermore, glycine levels were significantly decreased in pomalidomide-resistant patients, and exogenous glycine administration increased the sensitivity of MM cell lines to pomalidomide. Conclusion: These results demonstrate distinct molecular changes in the plasma of resistant patients that could be used as potential biomarkers for identifying resistance mechanisms for pomalidomide in multiple myeloma and developing immune-related therapeutic strategies.

Enhancing Efficacy of Albumin-Bound Paclitaxel for Human Lung and Colorectal Cancers through Autophagy Receptor Sequestosome 1 (SQSTM1)/p62-Mediated Nanodrug Delivery and Cancer therapy.

Selective autophagy is a defense mechanism by which foreign pathogens and abnormal substances are processed to maintain cellular homeostasis. Sequestosome 1 (SQSTM1)/p62, a vital selective autophagy receptor, recruits ubiquitinated cargo to form autophagosomes for lysosomal degradation. Nab-PTX is an albumin-bound paclitaxel nanoparticle used in clinical cancer therapy. However, the role of SQSTM1 in regulating the delivery and efficacy of nanodrugs remains unclear. Here we showed that SQSTM1 plays a crucial role in Nab-PTX drug delivery and efficacy in human lung and colorectal cancers. Nab-PTX induces SQSTM1 phosphorylation at Ser403, which facilitates its incorporation into the selective autophagy of nanoparticles, known as nanoparticulophagy. Nab-PTX increased LC3-II protein expression, which triggered autophagosome formation. SQSTM1 enhanced Nab-PTX recognition to form autophagosomes, which were delivered to lysosomes for albumin degradation, thereby releasing PTX to induce mitotic catastrophe and apoptosis. Knockout of SQSTM1 downregulated Nab-PTX-induced mitotic catastrophe, apoptosis, and tumor inhibition in vitro and in vivo and inhibited Nab-PTX-induced caspase 3 activation via a p53-independent pathway. Ectopic expression of SQSTM1 by transfection of an SQSTM1-GFP vector restored the drug efficacy of Nab-PTX. Importantly, SQSTM1 is highly expressed in advanced lung and colorectal tumors and is associated with poor overall survival in clinical patients. Targeting SQSTM1 may provide an important strategy to improve nanodrug efficacy in clinical cancer therapy. This study demonstrates the enhanced efficacy of Nab-PTX for human lung and colorectal cancers via SQSTM1-mediated nanodrug delivery.

[Application of body temperature rinse in percutaneous transforaminal endoscopic lumbar discectomy through intervertebral approach].

OBJECTIVE: To investigate the effects of two types of temperature rinses on body temperature, inflammatory cytokine levels, and bleeding volume in percutaneous endoscopic lumbar discectomy. METHODS: Eighty patients underwent percutaneous endoscopic lumbar discectomy from January 2018 to December 2020 were selected and divided into experimental group (40 cases) and control group(40 cases). In experimental group, there were 19 males and 21 females, aged (38.8±9.8) years old;7patients on L4,5 and 33 patients on L5S1;Body msss index(BMI) was (27.8±7.2) kg·m-2. In contral group, there were 18 males and 22 females, aged (41.5±10.9) years old, 5 patients on L4,5 and 35 patients on L5S1;BMI was (26.4±6.2) kg·m-2. The patients in the control group were received normal saline rinse at room temperature, and the patients in the experimental group were received normal saline rinse heated to 37 ℃. Body temperature, chills, nausea, vomiting, and other adverse reactions were recorded. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) in two groups were recorded before and 2 hours after operation. Visual analogue scale (VAS) was used to evaluate the degree of lumbar pain in two groups before and 2 hours after surgery. Fibrinolytic-coagulation indexes with preoperative and 2 hours after surgery, including the D-dimer (DD), fibrinogen degradation products (FDP), activated partial thrombin time (APTT) and prothrombin time (PT) were recorder. Operation time and blood loss in two groups were recorded. RESULTS: The body temperature of both groups showed a downward trend, while the body temperature of the control group was lower than that of the experimental group. The levels of TNF-α, IL-6 and IL-10 in two groups were increased 2 hours after surgery compared with those before surgery(P<0.05), while the levels in experimental group were lower than those in control group(P<0.05). Postoperative VAS in experimental group 2.19±1.13 was significantly lower than that in the control group 3.38±1.35(P<0.05). The levels of DD and FDP at 2 hours after surgery in both groups were higher than those before surgery (P<0.05), while the levels of DD and FDP in the experimental group were higher than those in the control group (P<0.05). There was no significant difference in APTT and PT levels between two groups after operation (P>0.05). The blood loss in the experimental group of (45.2±14.1) ml was lower than that in the control group of (59.52±15.6) ml. The operation time of experimental group (46.7±13.8) min was less than that of control group (58.3±15.2) min(P<0.05). CONCLUSION: Body temperature rinse can reduce the incidence of adverse reactions, alleviate local inflammatory reactions, reduce intraoperative blood loss and shorten the operation time.

Comprehensive analysis of ferroptosis-related genes in immune infiltration and prognosis in multiple myeloma.

Background: One particular type of cellular death that is known as ferroptosis is caused by the excessive lipid peroxidation. It is a regulated form of cell death that can affect the response of the tumor cells. Currently, it is not known if the presence of this condition can affect the prognosis of patients with multiple myeloma (MM). Methods: In this study, we studied the expression differences and prognostic value of ferroptosis-related genes (FRGs) in MM, and established a ferroptosis risk scoring model. In order to improve the prediction accuracy and clinical applicability, a nomogram was also established. Through gene enrichment analysis, pathways closely related to high-risk groups were identified. We then explored the differences in risk stratification in drug sensitivity and immune patterns, and evaluated their value in prognostic prediction and treatment response. Lastly, we gathered MM cell lines and samples from patients to confirm the expression of marker FRGs using quantitative real-time PCR (qRT-PCR). Results: The ability to predict the survival of MM patients is a challenging issue. Through the use of a risk model derived from ferroptosis, we were able to develop a more accurate prediction of the disease's prognosis. They were then validated by a statistical analysis, which showed that the model is an independent factor in the prognosis of MM. Patients of high ferroptosis risk scores had a much worse chance of survival than those in the low-risk groups. The calibration and power of the nomogram were also strong. We noted that the link between the ferroptosis risk score and the clinical treatment was suggested by the FRG's significant correlation with the immune checkpoint genes and the medication sensitivity. We validated the predictive model using qRT-PCR. Conclusion: We demonstrated the association between FRGs and MM, and developed a new risk model for prognosis in MM patients. Our study sheds light on the potential clinical relevance of ferroptosis in MM and highlights its potential as a therapeutic target for patients with this disease.

The relationship between dietary patterns derived from inflammation and cognitive impairment in patients undergoing hemodialysis.

Introduction: Dietary patterns were shown to be closely related to inflammation, which was independently associated with cognitive impairment (CI) in patients undergoing hemodialysis (HD). However, it remains unclear the influence of dietary patterns derived from inflammation on CI in this population. This study aimed to examine the association between dietary patterns derived from C-reactive protein (CRP) and interleukin-6 (IL-6) and CI in patients undergoing HD. Methods: Dietary intake was obtained from the simplified quantitative food frequency questionnaire. Reduced rank regression (RRR) was used to extract two dietary patterns, with IL-6 and CRP as response variables. Cognitive function was examined by the Montreal Cognitive Assessment (Beijing version). Venous blood was drawn for measuring IL-6 and CRP levels. Multivariable logistic regression was used to investigate the association between dietary patterns and CI. Results: Dietary pattern derived from IL-6 was not significantly associated with CI. The third quartile of dietary pattern, which used CRP as the response variable, significantly contributed to the increased risk of CI (AOR 8.62, 95% CI 1.47-50.67) after controlling age, sex, education level, marital status, and residential pattern (p-for-trend = 0.028). After considering hypertension and diabetes, physical activity level, anxiety and depression, smoking and drinking status, social support, energy intake, and the dietary pattern derived from IL-6 (p-for-trend = 0.026), the relationship between the dietary pattern derived from CRP and CI remained significant (AOR 14.54, 95% CI 1.40-151.13). Conclusion: Dietary pattern associated with high CRP level, including high intake of rice, liquor, fruit, tea and coffee and low intake of dark vegetables and juice, contributed to the increased risk of CI. The association between the consumption of seafood, sweet beverages, and alcohol and CI is yet to be established. However, they may be dietary contributing factors to inflammation in patients undergoing HD.

The mechanism investigation of mutation genes in liver and lung metastasis of colorectal cancer by using NGS technique.

BACKGROUND: We analyzed the somatic mutation distributions as well as pathways associated with liver/lung metastasis of CRC using next-generation sequencing panel. METHODS: We detected the somatic SNV/indel mutations of 1126 tumor-related genes in CRC, liver/lung metastasis of CRC and liver /lung cancer. We combined the MSK and GEO datasets to identified the genes and pathways related to the metastasis of CRC. RESULTS: We identified 174 genes related to liver metastasis of CRC, 78 genes related to lung metastasis of CRC, and 57 genes related to both liver and lung metastasis in two datasets. The genes related to liver and lung metastasis were collectively enriched in various pathways. Finally we found that IRS1, BRCA2, EphA5, PTPRD, BRAF, and PTEN could be prognosis-related genes in CRC metastasis. CONCLUSION: Our finding may help clarify the pathogenesis of CRC metastasis more clearly and provide new perspectives for the diagnosis and treatment of CRC metastasis.

A novel glycolysis-related gene signature for predicting the prognosis of multiple myeloma.

Background: Metabolic reprogramming is an important hallmark of cancer. Glycolysis provides the conditions on which multiple myeloma (MM) thrives. Due to MM's great heterogeneity and incurability, risk assessment and treatment choices are still difficult. Method: We constructed a glycolysis-related prognostic model by Least absolute shrinkage and selection operator (LASSO) Cox regression analysis. It was validated in two independent external cohorts, cell lines, and our clinical specimens. The model was also explored for its biological properties, immune microenvironment, and therapeutic response including immunotherapy. Finally, multiple metrics were combined to construct a nomogram to assist in personalized prediction of survival outcomes. Results: A wide range of variants and heterogeneous expression profiles of glycolysis-related genes were observed in MM. The prognostic model behaved well in differentiating between populations with various prognoses and proved to be an independent prognostic factor. This prognostic signature closely coordinated with multiple malignant features such as high-risk clinical features, immune dysfunction, stem cell-like features, cancer-related pathways, which was associated with the survival outcomes of MM. In terms of treatment, the high-risk group showed resistance to conventional drugs such as bortezomib, doxorubicin and immunotherapy. The joint scores generated by the nomogram showed higher clinical benefit than other clinical indicators. The in vitro experiments with cell lines and clinical subjects further provided convincing evidence for our study. Conclusion: We developed and validated the utility of the MM glycolysis-related prognostic model, which provides a new direction for prognosis assessment, treatment options for MM patients.