miR-34a promotes the immunosuppressive function of multiple myeloma-associated macrophages by dampening the TLR-9 signaling.

BACKGROUND: Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR-T) cell therapy. However, a portion of MM patients do not respond to CAR-T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR-34a on the immunosuppressive polarization of macrophages obtained from MM patients. METHODS: The levels of miR-34a and TLR9 (Toll-like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co-culture experiments were conducted to evaluate the immunomodulatory impact of MM-associated macrophages on CAR-T cells. RESULTS: There was an observed suppressed activation of macrophages and CD4+ T lymphocytes in the blood samples of MM patients. Overexpression of miR-34a in MM-associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co-culture system and an animal model, MM-associated macrophages suppressed the activity and tumoricidal effect of CAR-T cells in a miR-34a-dependent manner. CONCLUSION: The findings imply that targeting the macrophage miR-34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR-T therapy in MM patients.

Development of a predictive nomogram for intermediate-risk differentiated thyroid cancer patients after fixed 3.7GBq (100mCi) radioiodine remnant ablation.

Objectives: The objective of this study was to develop a predictive nomogram for intermediate-risk differentiated thyroid cancer (DTC) patients after fixed 3.7GBq (100mCi) radioiodine remnant ablation (RRA). Methods: Data from 265 patients who underwent total thyroidectomy with central lymph node dissection (CND) and received RRA treatment at a single institution between January 2018 and March 2023 were analyzed. Patients with certain exclusion criteria were excluded. Univariate and multivariate logistic regression analyses were performed to identify risk factors for a non-excellent response (non-ER) to RRA. A nomogram was developed based on the risk factors, and its performance was validated using the Bootstrap method with 1,000 resamplings. A web-based dynamic calculator was developed for convenient application of the nomogram. Results: The study included 265 patients with intermediate-risk DTC. Significant differences were found between the ER group and the non-ER group in terms of CLNM>5, Hashimoto's thyroiditis, sTg level, TgAb level (P < 0.05). CLNM>5 and sTg level were identified as independent risk factors for non-ER in multivariate analysis. The nomogram showed high accuracy, with an area under the curve (AUC) of 0.833 (95% CI = 0.770-0.895). The nomogram's predicted probabilities aligned closely with actual clinical outcomes. Conclusions: This study developed a predictive nomogram for intermediate-risk DTC patients after fixed 3.7GBq (100mCi) RRA. The nomogram incorporates CLNM>5 and sTg levels as risk factors for a non-ER response to RRA. The nomogram and web-based calculator can assist in treatment decision-making and improve the precision of prognosis information. Further research and validation are needed.

Treg-derived TGF-ß1 dampens cGAS-STING signaling to downregulate the expression of class I MHC complex in multiple myeloma.

Multiple myeloma (MM) progression involves diminished tumor antigen presentation and an immunosuppressive microenvironment, characterized by diminished expression of major histocompatibility complexes (MHC) class I molecule and elevated programmed death ligand 1 (PDL1) in MM cells, along with an enriched population of regulatory T cells (Tregs). To investigate Treg's influence on MM cells, we established a co-culture system using Tregs from MM patients and the MM cell lines (MM.1S and SK-MM-1) in vitro and assessed the effects of intervening in the relevant pathways connecting Tregs and MM cells in vivo. In vitro, Tregs induced transforming growth factor beta-1 (TGF-ß1) production, downregulated MHC I members, and increased PDL1 expression in MM cells. Treg-derived TGF-ß1 suppressed the cGAS-STING pathway, contributing to the loss of MHC I molecule expression and PDL1 upregulation. Correspondingly, neutralizing TGF-ß1 or activating the cGAS-STING pathway restored MHC I and PDL1 expression, effectively countering the pro-tumorigenic effect of Tregs on MM cells in vivo. These data elucidated how Tregs influence tumor antigen presentation and immunosuppressive signal in MM cells, potentially providing therapeutic strategies, such as neutralizing TGF-ß1 or activating the cGAS-STING pathway, to address the immune escape and immunosuppressive dynamics in MM.

Natural alkaloids from Dicranostigma leptopodum (Maxim.) Fedde and their G5. NHAc-PBA dendrimer-alkaloid complexes for targeting chemotherapy in breast cancer MCF-7 cells.

Herein, we isolated five natural alkaloids, iso-corydine (iso-CORY), corydine (CORY), sanguinarine (SAN), chelerythrine (CHE) and magnoflorine (MAG), from traditional medicinal herb Dicranostigma leptopodum (Maxim.) Fedde (whole herb) and elucidated their structures. Then we synthesised G5. NHAc-PBA as targeting dendrimer platform to encapsulate the alkaloids into G5. NHAc-PBA-alkaloid complexes, which demonstrated alkaloid-dependent positive zeta potential and hydrodynamic particle size. G5. NHAc-PBA-alkaloid complexes demonstrated obvious breast cancer MCF-7 cell targeting effect. Among the G5. NHAc-PBA-alkaloid complexes, G5.NHAc-PBA-CHE (IC50=13.66 µM) demonstrated the highest MCF-7 cell inhibition capability and G5.NHAc-PBA-MAG (IC50=24.63 µM) had equivalent inhibitory effects on cell proliferation that comparable to the level of free MAG (IC50=23.74 µM), which made them the potential breast cancer targeting formulation for chemotherapeutic application. This work successfully demonstrated a pharmaceutical research model of 'natural bioactive product isolation-drug formulation preparation-breast cancer cell targeting inhibition'.

Association between a family history of cancer and multiple primary lung cancer risks: a population-based analysis from China.

OBJECTIVES: The incidence of multiple primary lung cancer (MPLC) has increased in recent years. The risk factors of MPLC are not well studied, especially in the Asian population. This case-control study investigated the association between a family history of cancer and MPLC risk. METHODS: We used data from people who surgically confirmed MPLC with at least 2 nodes of Fujian Medical University Union Hospital and matched 1:2 normal individuals as controls between 2016 and 2017. Information on age, sex, lifestyle, personal history, and family history of cancer was collected using a self-administered questionnaire, and odds ratios (OR) were estimated using unconditional logistic regression. RESULTS: We included 2 104 patients. In total, 321 patients with histologically confirmed MPLC and 642 healthy controls were studied. The significantly higher ratio of current smokers was observed for the cases than the controls (54.1% vs. 30.0%). A family history of LC in first-degree relatives of the cases reported a significantly higher proportion than in the controls (15.3% vs. 8.6%). Family history of all cancers and LC significantly increased the risk of MPLC (OR = 1.64, P = 0.009 and OR = 2.59, P = 0.000, respectively). The multivariate analysis identified a significantly increased risk of MPLC (OR = 2.45, P = 0.000) associated with parents and siblings influenced by LC history. The younger age (aged < 55 years) of LC cases at diagnosis exhibited a significantly increased risk of MPLC (OR = 2.39, P = 0.000). A significant association with a family history of LC was found for male squamous carcinoma and male adenocarcinoma (OR = 1.59, p = 0.037 and OR = 1.64, p = 0.032, respectively). A positive association with LC history was only observed for female adenocarcinoma (OR = 2.23, p = 0.028). The risk of MPLC was not significantly associated with A family history of cancers in non-smokers (OR = 0.91, P = 0.236). Ever-smokers with a positive family history of cancer or LC had a significantly elevated risk of MPLC (OR = 4.01, P = 0.000 and OR = 6.49, P = 0.000, respectively). We also observed a very elevated risk for smokers with no family history (OR = 3.49, P = 0.000). Such a positive association was also observed in ever-smokers with no family history of LC (OR = 3.55, P = 0.000). Adenocarcinoma in females was prevalent and significantly associated with a family history of LC in risk of MPLC compared with other histologic subtypes. CONCLUSIONS: Our findings suggest an association between a family history of LC and MPLC risk among an Asian population. Smoking status and family history of LC have a synergistic effect on MPLC. These findings indicate that MPLC exhibits familiar aggregation and that inherited genetic susceptibility may contribute to the development of MPLC.

A Comprehensive Evaluation Framework of Water-Energy-Food System Coupling Coordination in the Yellow River Basin, China.

For mankind's survival and development, water, energy, and food (WEF) are essential material guarantees. In China, however, the spatial distribution of WEF is seriously unbalanced and mismatched. Here, a collaborative governance mechanism that aims at nexus security needs to be urgently established. In this paper, the Yellow River Basin in China with a representative WEF system, was selected as a case. Firstly, a comprehensive framework for WEF coupling coordination was constructed, and the relationship and mechanism between them were analyzed theoretically. Then, we investigated the spatiotemporal characteristics and driving mechanisms of the coupling coordination degree (CCD) with a composite evaluation method, coupling coordination degree model, spatial statistical analysis, and multiscale geographic weighted regression. Finally, policy implications were discussed to promote the coordinated development of the WEF system. The results showed that: 1) WEF subsystems showed a significant imbalance of spatial pattern and diversity in temporal changes; 2) the CCD for the WEF system varied little and remained at moderate coordination. Areas with moderate coordination have increased, while areas with superior coordination and mild disorder have decreased. In addition, the spatial clustering phenomenon of the CCD was significant and showed obvious characteristics of polarization; and 3) the action of each factor is self-differentiated and regionally variable. For different factors, GDP per capita was of particular importance, which contributed most to the regional development's coupling coordination. For different regions, GDP per capita, average yearly precipitation, population density, and urbanization rate exhibited differences in geographical gradients in an east-west direction. The conclusion can provide references for regional resource allocation and sustainable development by enhancing WEF system utilization efficiency.

Preparation and investigation of a novel iodine-based visible polyvinyl alcohol embolization material.

Polyvinyl alcohol (PVA) embolization particles, currently used in clinical practice, have good expansibility and are capable of permanent embolization. However, the lack of adhesion of embolization particles contributes to facilitated recanalization after embolization, while the lack of visualization facilitates misembolization. At present, embolization materials with good expansion, adhesion, and visualization potential are urgently required in clinical practice. Here, we report the development of PVA/gelatin/iohexol (I) fiber blocks as a novel embolization material for liver embolization in rats. In our work, electrospun PVA/gelatin/I nanofibrous mats were first prepared, homogenized, centrifuged in a gradient manner, and freeze-dried to obtain fiber blocks (fiber diameter â€‹= â€‹296.2 â€‹± â€‹74.23 â€‹nm, length 99.6 â€‹± â€‹17.0 â€‹µm â€‹× â€‹width 46.9 â€‹± â€‹13.3 â€‹µm). The fiber blocks exhibited excellent cytocompatibility and hemocompatibility. Fiber blocks with a PVA/gelatin/I mass ratio of 8:2:10 were selected due to their excellent expansibility and adhesive properties. The PVA/gelatin/I fiber blocks display excellent liver embolic effects and computed tomography (CT) imaging potential due to a combination of the following characteristics: expansibility of PVA and gelatin, adhesive property of gelatin, and CT imaging potential of I. The developed fiber block material is an embolic material that may potentially be used in interventional medicine.

CD192 gene variant and susceptibility to cervical cancer: a meta analysis.

BACKGROUND: Several molecular epidemiological studies have explored the association between G46295A variant of CD192 gene and cervical cancer susceptibility in distinct populations. However, the results are contradictory. To provide convincing evidence for the association, we performed the present meta-analysis incorporating all case-control studies. METHODS AND FINDINGS: The Cochrane, Google Scholar and PubMed databases were systematically searched to identify the potentially relevant studies. Statistical analyses were performed using R software. Crude odds ratio (OR) was calculated to estimate the risk of cervical cancer. Five case-control studies were considered in the final analysis. Using the homozygous, heterogeneous, allele, dominant, and recessive model, we found the association between CD192 G46295A variant and cervical cancer was not statistically significant. CONCLUSIONS: This meta-analysis shows that the CD192 G46295A variant may not confer genetic susceptibility towards cervical cancer.

Sulfur-nitrogen co-doped three-dimensional carbon foams with hierarchical pore structures as efficient metal-free electrocatalysts for oxygen reduction reactions.

Despite the good progress in developing doped carbon catalysts for oxygen-reduction reaction (ORR), the current metal-free carbon catalysts are still far from satisfactory for large-scale applications of fuel cell. Developing new metal free doped carbon materials with abundance active sites as well as excellent electron transfer and reactant transport rate towards ORR may be a potential solution. Herein, we develop a novel three-dimensional (3D) sulfur-nitrogen co-doped carbon foams (S-N-CF) with hierarchical pore structures, using a convenient, economical, and scalable method. The experimental results have demonstrated that the obtained 3D S-N-CF exhibited better catalytic activity, longer-term stability and higher methanol tolerance than a commercial Pt/C catalyst. Such excellent performances may be attributed to the synergistic effect, which includes high catalytic sites for ORR provided by high S-N heteroatom loading, excellent reactant transport caused by hierarchical pore structures and high electron transfer rate provided by 3D continuous networks. Our results not only develop a new type of catalysts with excellent electrocatalytic performance by a commercially valid route, but also provide useful information for further clarification of the relationship between the microstructures of metal-free carbon materials and catalyst properties for ORR. More importantly, the idea to design hierarchical pore structures could be applied to other catalytic materials and serve as a general strategy for improving the activity of various ORR catalysts.

[Identification of new markers for childhood acute lymphoblastic leukemia by MALDI-TOF-MS].

The aim of this study was to identify new biomarkers for early diagnosis of childhood acute lymphoblastic leukemia (ALL). The total protein samples of ALL cells and normal peripheral lymphocytic cells were extracted respectively. The two-dimensional gel electrophoresis (2-DE), matrix-assisted laser desorption ionization time-of-flight-mass spectrometer (MALDI-TOF-MS) and database searching were used to identified differentially upregulated proteins, the S-P immunohistochemical method was performed for confirming and validating these proteins. The results indicated that two differentially upregulated proteins were preliminarily identified as glutathione S-transferase P (GST-P) and prohibitin (PHB) in ALL group. The immunohistochemistry detection revealed that the positive ratio of GST-P/PHB in ALL group was statistically higher than that in control group. It is concluded that GST-P and PHB may become the promising diagnostic biomarkers and drug targets for childhood patients with ALL.