The beneficial roles and mechanisms of estrogens in immune health and infection disease.

Multiple epidemiologic studies have revealed that gender is considered one of the important factors in the frequency and severity of certain infectious diseases, in which estrogens may play a vital role. There is growing evidence that estrogens as female sex hormone can modulate multiple biological functions outside of the reproductive system, such as in brain and cardiovascular system. However, it is largely unknown about the roles and mechanisms of estrogens/estrogen receptors in immune health and infection disease. Thence, by reading a lot of literature, we summarized the regulatory mechanisms of estrogens/estrogen receptors in immune cells and their roles in certain infectious diseases with gender differences. Therefore, estrogens may have therapeutic potentials to prevent and treat these infectious diseases, which needs further clinical investigation.

Fluorescence in situ hybridization reveals the evolutionary biology of minor clone of gain/amp(1q) in multiple myeloma.

Growing evidence suggests that gain or amplification [gain/amp(1q)] accumulates during disease progression of multiple myeloma (MM). Previous investigations have indicated that small gain/amp(1q) subclones present at the time of diagnosis may evolve into dominant clones upon MM relapse. However, the influence of a minor clone of gain/amp(1q) on MM survival, as well as the correlation between different clonal sizes of gain/amp(1q) and the chromosomal instability (CIN) of MM, remains poorly understood. In this study, we analyzed fluorescence in situ hybridization (FISH) results of 998 newly diagnosed MM (NDMM) patients. 513 patients were detected with gain/amp(1q) at diagnosis. Among these 513 patients, 55 had a minor clone (≤20%) of gain/amp(1q). Patients with a minor clone of gain/amp(1q) displayed similar survival outcomes compared to those without gain/amp(1q). Further analysis demonstrated patients with a minor clone of gain/amp(1q) exhibited a clonal architecture similar to those without gain/amp(1q). Lastly, our results showed a significant increase in the clonal size of the minor clone of gain/amp(1q), frequently observed in MM. These findings suggested that a minor clone of gain/amp(1q) might represent an earlier stage in the pathogenesis of gain/amp(1q) and propose a "two-step" process in the clonal size changes of gain/amp(1q) in MM.

Research progress on the roles of dopamine and dopamine receptors in digestive system diseases.

Dopamine (DA) is a neurotransmitter synthesized in the human body that acts on multiple organs throughout the body, reaching them through the blood circulation. Neurotransmitters are special molecules that act as messengers by binding to receptors at chemical synapses between neurons. As ligands, they mainly bind to corresponding receptors on central or peripheral tissue cells. Signalling through chemical synapses is involved in regulating the activities of various body systems. Lack of DA or a decrease in DA levels in the brain can lead to serious diseases such as Parkinson's disease, schizophrenia, addiction and attention deficit disorder. It is widely recognized that DA is closely related to neurological diseases. As research on the roles of brain-gut peptides in human physiology and pathology has deepened in recent years, the regulatory role of neurotransmitters in digestive system diseases has gradually attracted researchers' attention, and research on DA has expanded to the field of digestive system diseases. This review mainly elaborates on the research progress on the roles of DA and DRs related to digestive system diseases. Starting from the biochemical and pharmacological properties of DA and DRs, it discusses the therapeutic value of DA- and DR-related drugs for digestive system diseases.

MXene: A wonderful nanomaterial in antibacterial.

Increasing bacterial infections and growing resistance to available drugs pose a serious threat to human health and the environment. Although antibiotics are crucial in fighting bacterial infections, their excessive use not only weakens our immune system but also contributes to bacterial resistance. These negative effects have caused doctors to be troubled by the clinical application of antibiotics. Facing this challenge, it is urgent to explore a new antibacterial strategy. MXene has been extensively reported in tumor therapy and biosensors due to its wonderful performance. Due to its large specific surface area, remarkable chemical stability, hydrophilicity, wide interlayer spacing, and excellent adsorption and reduction ability, it has shown wonderful potential for biopharmaceutical applications. However, there are few antimicrobial evaluations on MXene. The current antimicrobial mechanisms of MXene mainly include physical damage, induced oxidative stress, and photothermal and photodynamic therapy. In this paper, we reviewed MXene-based antimicrobial composites and discussed the application of MXene in bacterial infections to guide further research in the antimicrobial field.

Longitudinal genetically detectable minimal residual disease by fluorescence in situ hybridization confers a poor prognosis in myeloma.

Background: Deeper depth of response (DpR) after induction therapy, especially gain of negative minimal residual disease (MRD), has been linked to prolonged survival in multiple myeloma (MM). However, flow-MRD examination focuses on the numbers but not on the biological characteristics of residual plasma cells (PCs). Objectives: To explore whether the genetic features of residual tumor cells affect the survival time of patients with MM. Design: A retrospective cohort study. Methods: We investigated the clonality of cytogenetic abnormalities (CAs) of the residual PCs using interphase fluorescence in situ hybridization (iFISH) in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Here, a longitudinal cohort of 269 patients with patient-paired diagnostic and post-induction iFISH results was analyzed. Results: Persistent CAs after induction therapy were detected in about half of the patients (118/269, 43%), and patients with undetectable CAs showed significantly improved survival compared with those with genetically detectable MRD [median progression-free survival (mPFS): 59.7 versus 35.7 months, p < 0.001; median overall survival (mOS): 97.1 versus 68.8 months, p = 0.011]. In addition, different patterns of therapy-induced clonal evolution were observed by comparing the clonal structure of residual PCs with paired baseline samples. Patients who maintained at a high risk during follow-up had the worst survival (mPFS: 30.5 months; mOS: 54.4 months), while those who returned to lower risk or had iFISH- at both time points had the best survival (mPFS: 62.0 months, mOS: not reached). Conclusion: These findings highlighted the prognostic value of genetic testing in residual tumor cells, which may provide a deep understanding of clonal evolution and guide clinical therapeutic strategies.

Study using fluorescence in situ hybridization (iFISH) to investigate the clonality of cytogenetic abnormalities of the residual plasma cells in multiple myeloma Gain of negative minimal residual disease (MRD) has been linked to prolonged survival in cancer treatment. However, in multiple myeloma (MM), detection of MRD-negativity (MRD-) using multiparameter flow cytometry (MFC) only reflects the quantitative characteristics of residual plasma cells (PCs), while the biological and genetic features of MRD are neglected. To address this gap, our study has employed interphase fluorescence in situ hybridization (iFISH) to evaluate the clonality of cytogenetic abnormalities (CAs) of the bone marrow residual PCs after induction therapy, in combined with MRD detection by MFC to predict the prognosis of MM patients. A total of 396 patients from the database of National Longitudinal Cohort of Hematological Diseases in China (ClinicalTrials.gov identifiers: NCT04645199) were enrolled. Persistent CAs after induction therapy were detected in about half of the patients (118/269, 43%), and patients with undetectable CAs showed significantly improved survival compared with those without genetically detectable MRD. In addition, different patterns of therapy-induced clonal evolution were observed by comparing the clonal structure of residual PCs with paired baseline samples. And therapy-induced clonal evolution exerted a significant impact on patient outcomes. These findings highlighted the importance of genetic testing of residual tumor cells after induction therapy, which may represent a reliable complementary technique for flow-MRD detection and provide a further understanding of clonal evolution.

Development and validation of an individualized and weighted Myeloma Prognostic Score System (MPSS) in patients with newly diagnosed multiple myeloma.

Current standard predictive models of disease risk do not adequately account for the heterogeneity of survival outcomes in patients with new-diagnosed multiple myeloma (NDMM). In this retrospective, multicohort study, we collected clinical and genetic data from 1792 NDMM patients and identified the prognostic impact of all features. Using the top-ranked predictive features, a weighted Myeloma Prognostic Score System (MPSS) risk model was formulated and validated to predict overall survival (OS). In the training cohort, elevated lactate dehydrogenase level (LDH), International Staging System (ISS) Stage III, thrombocytopenia, and cumulative high-risk cytogenetic aberration (HRA) numbers were found to have independent prognostic significance. Each risk factor was defined as its weighted value respectively according to their hazard ratio for OS (thrombocytopenia 2, elevated LDH 1, ISS III 2, one HRA 1, and ≥2 HRA 2, points). Patients were further stratified into four risk groups: MPSS I (22.5%, 0 points), II (17.6%, 1 points), III (38.6%, 2-3 points), and IV (21.3%, 4-7 points). MPSS risk stratification showed optimal discrimination, as well as calibration, of four risk groups with median OS of 91.0, 69.8, 45.0, and 28.0 months, for patients in MPSS I to IV groups (p < .001), respectively. Importantly, the MPSS model retained its prognostic value in the internal validation cohort and an independent external validation cohort, and exhibited significant risk distribution compared with conventional prognostic models (R-ISS, R2-ISS, and MASS). Utilization of the MPSS model in clinical practice could improve risk estimation in NDMM patients, thus prompting individualized treatment strategies.

Monitoring Minimal Residual Disease in Patients with Multiple Myeloma by Targeted Tracking Serum M-Protein Using Mass Spectrometry (EasyM).

PURPOSE: We investigated both the clinical utilities and the prognostic impacts of the clonotypic peptide mass spectrometry (MS)-EasyM, a blood-based minimal residual disease (MRD) monitoring protocol in multiple myeloma. EXPERIMENTAL DESIGN: A total of 447 sequential serum samples from 56 patients with multiple myeloma were analyzed using EasyM. Patient-specific M-protein peptides were sequenced from diagnostic samples; sequential samples were quantified by EasyM to monitor the M-protein. The performance of EasyM was compared with serum immunofixation electrophoresis (IFE), bone marrow multiparameter flow cytometry (MFC), and next-generation flow cytometry (NGF) detection. The optimal balance of EasyM sensitivity/specificity versus NGF (10-5 sensitivity) was determined and the prognostic impact of MS-MRD status was investigated. RESULTS: Of the 447 serum samples detected and measured by EasyM, 397, 126, and 92 had time-matching results for comparison with serum IFE, MFC-MRD, and NGF-MRD, respectively. Using a dotp >0.9 as the MS-MRD positive, sensitivity was 99.6% versus IFE and 100.0% versus MFC and NGF. Using an MS negative cutoff informed by ROC analysis (<1.86% of that at diagnosis), EasyM sensitivity remained high versus IFE (88.3%), MFC (85.1%), and NGF (93.2%), whereas specificity increased to 90.4%, 55.8%, and 93.2%, respectively. In the multivariate analysis, older diagnostic age was an independent predictor for progression-free survival [PFS; high risk (HR), 3.15; 1.26-7.86], the best MS-MRD status (MS-MRD negative) was independent predictor for both PFS (HR, 0.25; 0.12-0.52) and overall survival (HR, 0.16; 0.06-0.40). CONCLUSIONS: EasyM is a highly sensitive and minimal invasive method of MRD monitoring in multiple myeloma; MS-MRD had significant predictive ability for survival outcomes.

Immunophenotypic profile defines cytogenetic stability and unveils distinct prognoses in patients with newly-diagnosed multiple myeloma (NDMM).

Prognostic significance of multiple immune antigens in multiple myeloma has been well established. However, a level of uncertainty remains regarding the intrinsic relationship between immunophenotypes and cytogenetic stability and precise risk stratification. To address these unresolved issues, we conducted a study involving 1389 patients enrolled in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Our results revealed that the correlation between antigen expression and cytogenetics is more prominent than cytopenia or organ dysfunction. Most immune antigens, apart from CD38, CD138, and CD81, exhibit significant associations with the incidence of at least one cytogenetic abnormality. In turn, we identified CD138-low/CD27-neg as specific adverse immunophenotypic profile, which remaining independent impact on progression-free survival (HR, 1.49; P = 0.007) and overall survival (HR, 1.77; P < 0.001) even in the context of cytogenetics. Importantly, CD138-low/CD27-neg profile was also associated with inferior survival after first relapse (P < 0.001). Moreover, the antigen expression profiles were not strictly similar when comparing diagnosis and relapse; in particular, the CD138-low/CD27-neg pattern was notably increased after disease progression (19.1 to 29.1%; P = 0.005). Overall, our study demonstrates that diverse immune profiles are strongly associated with cytogenetic stability, and a specific immunophenotype (CD138-low/CD27-neg) could effectively predict prognoses across different disease stages.

Early relapse within 18 months is a powerful dynamic predictor for prognosis and could revise static risk distribution in multiple myeloma.

BACKGROUND: The duration of response to treatment is a major prognostic factor, and early relapse (ER) strongly predicts inferior survival in multiple myeloma (MM). However, the definitions of ER in MM vary from study to study and how to dynamically integrate risk distribution is still unsolved. METHODS: This study evaluated these ER definitions and further investigated the underlying relationship with static risk distribution in 629 newly diagnosed MM (NDMM) patients from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). RESULTS: These data indicated that early relapse within 18 months (ER18) after initial treatment was the best time point for identifying early progression and dynamic high-risk in MM. The ER18 population (114 of 587, 19.4%) presented with more aggressive biologic features and the inferior response to treatment compared to a reference cohort (p < .001), with a significantly short median overall survival (OS) of 28.9 months. Multivariate analyses confirmed the most significant prognostic value of ER18 on OS in the context of International Staging System stage, elevated lactate dehydrogenase, thrombocytopenia, cytogenetic abnormalities, and treatment (hazard ratio, 4.467; p < .001). The authors also described the specific transitions from static risk profile to dynamic risk distribution and then constructed a mixed-risk-pattern to identify four novel populations with distinct survival (p < .001). Additionally, the authors proposed a second-state model that predicts dynamic risk changes, enabling a complementary role to the Revised International Staging System model in facilitating individualized systematic treatment. CONCLUSIONS: Collectively, this study concludes that ER18 is a simple and dynamic prognostic predictor in MM. In addition to static risk assessment, dynamic risk plays an important role in survival prediction.

Minor clone of del(17p) provides a reservoir for relapse in multiple myeloma.

The deletion of chromosome 17p (del(17p)) is considered a crucial prognostic factor at the time of diagnosis in patients with multiple myeloma (MM). However, the impact of del(17p) on survival at different clonal sizes at relapse, as well as the patterns of clonal evolution between diagnosis and relapse and their prognostic value, has not been well described. To address these issues, we analyzed the interphase fluorescence in situ hybridization (iFISH) results of 995 newly diagnosed MM (NDMM) patients and 293 patients with MM at their first relapse. Among these patients, 197 had paired iFISH data at diagnosis and first relapse. Our analysis of paired iFISH revealed that a minor clone of del(17p) at relapse but not at diagnosis was associated with poor prognosis in MM (hazard ratio for median overall survival 1.64 vs. 1.44). Fifty-six and 12 patients developed one or more new cytogenetic abnormalities at relapse, mainly del(17p) and gain/amp(1q), respectively. We classified the patients into six groups based on the change patterns in the clonal size of del(17p) between the two time points. Patients who did not have del(17p) during follow-up showed the best outcomes, whereas those who acquired del(17p) during their disease course, experienced compromised survival (median overall survival: 61.3 vs. 49.4 months; hazard ratio =1.64; 95% confidence interval: 1.06-2.56; P<0.05). In conclusion, our data confirmed the adverse impact of a minor clone of del(17p) at relapse and highlighted the importance of designing optimal therapeutic strategies to eliminate high-risk cytogenetic abnormalities (clinicaltrials gov. identifier: NCT04645199).

Estrogen regulates duodenal glucose absorption by affecting estrogen receptor-α on glucose transporters.

The mechanisms of estrogen in glucose metabolism are well established; however, its role in glucose absorption remains unclear. In this study, we investigated the effects of estrogen on glucose absorption in humans, mice, and SCBN intestinal epithelial cells. We first observed a correlation between estrogen and blood glucose in young women and found that glucose tolerance was significantly less in the premenstrual phase than in the preovulatory phase. Similarly, with decreased serum estradiol levels in ovariectomized mice, estrogen receptors alpha (ERα) and beta (ERß) in the duodenum were reduced, and weight and abdominal fat increased significantly. The expression of sodium/glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) and glucose absorption in the duodenum decreased significantly. Estrogen significantly upregulated SGLT1 and GLUT2 expression in SCBN cells. Silencing of ERα, but not ERß, reversed this trend, suggesting that ERα may be key to estrogen-regulating glucose transporters. A mechanistic study revealed that downstream, estrogen regulates the protein kinase C (PKC) pathway. Overall, our findings indicate that estrogen promotes glucose absorption, and estrogen and ERα deficiency can inhibit SGLT1 and GLUT2 expression through the PKC signaling pathway, thereby reducing glucose absorption.

Impact of residual tumor cells in the stem cell collection on multiple myeloma patients receiving autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) is the standard therapy for patients with transplant-eligible multiple myeloma (TEMM). However, the ideal depth of response required before ASCT and the impact of residual tumor cells in the stem cell collection (SCC) on survival remains unclear. Here we collected data of 89 patients with TEMM undergoing ASCT and analyzed the minimal residual disease of SCC (cMRD) and bone marrow (BM) (mMRD) before transplantation. Before ASCT, 31.5% and 76.4% of patients achieved MRD negativity in BM and SCC, respectively. Tumor cells were less in SCC samples than that in BM samples. Neoplastic cells in SCC could be observed in patients with different responses after induction therapy, and there were no significant differences in the percentage and level of cMRD among these subgroups (P > 0.05). No correlation was found between the cMRD status and the response patients achieved after ASCT (P > 0.05). The median follow-up was 26.8 months. mMRD negativity before ASCT was associated with longer PFS (55.9 vs. 27.1 months; P = 0.009) but not OS (not reached vs. 58.9 months; P = 0.115). Patients with different cMRD statuses before ASCT experienced similar PFS (40.5 vs. 76.4 months for negativity vs. positivity; P = 0.685) and OS (not reached vs. 58.8 months for negativity vs. positivity; P = 0.889). These results suggested that detectable cMRD does not significantly predict the inferior post-ASCT response or shorter survival, and patients are eligible to undergo ASCT upon achieving partial response.

Clinical Benefit of Autologous Stem Cell Transplantation for Patients with Multiple Myeloma Achieving Undetectable Minimal Residual Disease after Induction Treatment.

Attaining undetectable minimal residual disease (MRD) is the current therapeutic goal for multiple myeloma. But there is a current lack of data regarding the clinical benefit of autologous stem cell transplantation (ASCT) for patients with myeloma achieving early MRD-negative status after induction treatment, in addition to the interaction of longitudinal MRD status with ASCT. The current study included 407 patients with transplant-eligible multiple myeloma with available MRD status from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199), of whom 147 (34.4%) achieved early undetectable MRD and 182 (44.7%) received ASCT. Early MRD-negative status was associated with a lower risk of disease progression [HR = 0.447; 95% confidence interval (CI), 0.333-0.600; P < 0.001] and death (HR = 0.473; 95% CI, 0.320-0.700; P < 0.001). Of note, patients who achieved undetectable MRD early still benefitted from ASCT, with a remarkable improvement in the median MRD-negative duration (33.5-58.0 months, P < 0.001), progression-free survival (PFS; 46.0-88.3 months, P < 0.001), and overall survival (OS; 76.4 months to not reached, P = 0.003). These clinical benefits were more pronounced in patients with aggressive features (high-risk cytogenetic abnormalities or high tumor burden) compared with standard-risk patients. Similar results were observed in patients with detectable MRD after induction treatment. In addition, we identified four MRD-status transformation patterns following ASCT, which were strongly correlated with diverse survival outcomes (P < 0.001). Our study revealed the enhanced clinical significance of ASCT in patients with transplant-eligible myeloma, regardless of early MRD status, particularly for high-risk patients. Subsequent prospective trials are essential to validate these observations. Significance: Achieving and maintaining undetectable MRD is the current treatment goal for multiple myeloma. Our results emphasized the remarkable clinical benefit of ASCT on MRD-negative duration, PFS, and OS in patients with multiple myeloma regardless of early MRD status. These favorable impacts were more evident in patients with aggressive features. Importantly, dynamic MRD monitoring among ASCT could facilitate personalized stratification of therapeutic approaches.

Function of TRP channels in monocytes/macrophages.

The transient receptor potential channel (TRP channel) family is a kind of non- specific cation channel widely distributed in various tissues and organs of the human body, including the respiratory system, cardiovascular system, immune system, etc. It has been reported that various TRP channels are expressed in mammalian macrophages. TRP channels may be involved in various signaling pathways in the development of various systemic diseases through changes in intracellular concentrations of cations such as calcium and magnesium. These TRP channels may also intermingle with macrophage activation signals to jointly regulate the occurrence and development of diseases. Here, we summarize recent findings on the expression and function of TRP channels in macrophages and discuss their role as modulators of macrophage activation and function. As research on TRP channels in health and disease progresses, it is anticipated that positive or negative modulators of TRP channels for treating specific diseases may be promising therapeutic options for the prevention and/or treatment of disease.

A universal approach for producing lignin-based monocomponent fiber by one-step ethanol fractionation.

To achieve sustainable whole process of carbon-fiber production and high-value utilization of lignin, one-step ethanol fractionation followed by coaxial electrospinning was applied to produce lignin-based monocomponent carbon-fiber. To elucidate the mechanism, hydrothermal extracted poplar lignin (HPL) were obtained to be divide into two parts through ethanol fractionation, in which the ethanol-soluble lignin (ESL) was eletrcospun into fiber precursors. Then, to verify the universality of this method, four more lignin were extracted to produce fiber precursors, after which five kinds of carbon fibers were prepared by carbonization of the corresponding precursors. Structural analysis showed that ESL of HPL is a small and highly branched three-dimensional stereomolecules. Combined with the SEM results of fiber precursors, the mechanism which hydrogen bonding promotes fiber formation was elucidated. Among all five samples, carbon-fiber prepared from HPL possesses the minimum fiber diameter of 557 nm, the smallest interplanar spacing of 0.3909 nm, ID/IG value of 0.6345 and the largest specific surface area of 408.15 m2/g. This work proposes a universal method to prepare lignin-based monocomponent carbon-fiber, in which carbon-fibers prepared from HPL exhibits the best comprehensive performance and can be applied to capture radioactive iodine.

Roles of inflammasomes in viral myocarditis.

Viral myocarditis (VMC), characterized by viral infection-induced inflammation, is a life-threatening disease associated with dilated cardiomyopathy or heart failure. Innate immunity plays a crucial role in the progression of inflammation, in which inflammasomes provide a platform for the secretion of cytokines and mediate pyroptosis. Inflammasomes are rising stars gaining increasing attention. The nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, the caspase recruitment domain-containing protein 8 (CARD8) inflammasome, and the caspase-11 inflammasome are three inflammasomes that were reported to affect the process and prognosis of VMC. These inflammasomes can be activated by a wide range of cellular events. Accumulating evidence has suggested that inflammasomes are involved in different stages of VMC, including the trigger and progression of myocardial injury and remodeling after infection. In this review, we summarized the pathways involving inflammasomes in VMC and discussed the potential therapies targeting inflammasomes and related pathways.