Associations of blood pressure in the third trimester and risk of venous thromboembolism postpartum.

Studies on the associations of blood pressure (BP) and the risk of venous thromboembolism (VTE) had been performed neither among pregnant women nor in Chinese population. This study included participants of pregnant women from a retrospective multicenter cohort, between May 2020 and April 2023. Systolic BP (SBP) and diastolic BP (DBP) of the participants were measured in the third trimester. The incidences of VTE (including deep venous thrombosis and/or pulmonary embolism) at 42 days postpartum were followed. With regards to SBP, pregnant women in the Q1 (≤114 mmHg), Q2 (115-122 mmHg), and Q4 group (≥131 mmHg) had increased risk of VTE than those in Q3 group (123-130 mmHg), with ORs 4.48 [1.69, 11.85], 3.52 [1.30, 9.59], and 3.17 [1.12, 8.99], respectively. Compared with pregnant women with the Q4 of DBP (≥85 mmHg), women of Q1 (≤71 mmHg) were found to have elevated risk of VTE (OR 2.73 [1.25, 5.96]). A one standard deviation decrease of DBP (9 mmHg) was related with 37% elevated risk of VTE (OR 1.37 [1.05, 1.79]). This study demonstrated a U-shaped association of SBP in the third trimester and VTE postpartum and inverse association of DBP in the third trimester and VTE postpartum.

Advances in nano-immunotherapy for hematological malignancies.

Hematological malignancies (HMs) encompass a diverse group of blood neoplasms with significant morbidity and mortality. Immunotherapy has emerged as a validated and crucial treatment modality for patients with HMs. Despite notable advancements having been made in understanding and implementing immunotherapy for HMs over the past decade, several challenges persist. These challenges include immune-related adverse effects, the precise biodistribution and elimination of therapeutic antigens in vivo, immune tolerance of tumors, and immune evasion by tumor cells within the tumor microenvironment (TME). Nanotechnology, with its capacity to manipulate material properties at the nanometer scale, has the potential to tackle these obstacles and revolutionize treatment outcomes by improving various aspects such as drug targeting and stability. The convergence of nanotechnology and immunotherapy has given rise to nano-immunotherapy, a specialized branch of anti-tumor therapy. Nanotechnology has found applications in chimeric antigen receptor T cell (CAR-T) therapy, cancer vaccines, immune checkpoint inhibitors, and other immunotherapeutic strategies for HMs. In this review, we delineate recent developments and discuss current challenges in the field of nano-immunotherapy for HMs, offering novel insights into the potential of nanotechnology-based therapeutic approaches for these diseases.

Platelet RNA sequencing reveals profile of caffeic acid affecting hemostasis in mice.

Background: Caffeic acid (CA) is a naturally occurring phenolic compound with diverse pharmacologic properties. CA plays a crucial role in hemostasis by increasing platelet count. However, the mechanism by which CA regulates platelets to promote hemostasis remains unclear. Objectives: We aim to identify the potential target pathways and genes by which CA regulates platelets to promote hemostasis. Methods: We performed RNA sequencing (RNA-seq) analysis of mouse platelet pools in both the CA-gavaged group and phosphate-buffered saline-gavaged group. Results: The 12,934 expressed transcripts had been annotated after platelet RNA-seq. Compared with the phosphate-buffered saline group, 987 differentially expressed genes (DEGs) were identified, of which 466 were downregulated and 521 were upregulated in CA group. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome gene set enrichment analysis demonstrated that upregulated DEGs were enriched in the pathways of hemostasis, platelet activation, signaling, aggregation, and degranulation. Moreover, Kyoto Encyclopedia of Genes and Genomes and Reactome gene set enrichment analysis revealed that 5 of the 25 cosignificantly upregulated DEGs were essential in CA-mediated platelet regulation to promote hemostasis. Conclusion: Our findings of platelet RNA-seq analysis demonstrate that CA regulates the gene expression of hemostasis and platelet activation-related pathways to increase platelet count and promote hemostasis. It will also provide reference molecular resources for future research on the function and mechanism by which CA regulates platelets to promote hemostasis.

Construction of Bi2WO6/g-C3N4 Z-Scheme Heterojunction and Its Enhanced Photocatalytic Degradation of Tetracycline with Persulfate under Solar Light.

Z-scheme heterojunction Bi2WO6/g-C3N4 was obtained by a novel hydrothermal process; its photocatalysis-persulfate (PDS) activation for tetracycline (TC) removal was explored under solar light (SL). The structure and photoelectrochemistry behavior of fabricated samples were well characterized by FT-IR, XRD, XPS, SEM-EDS, UV-vis DRS, Mott-Schottky, PL, photocurrent response, EIS and BET. The critical experimental factors in TC decomposition were investigated, including the Bi2WO6 doping ratio, catalyst dosage, TC concentration, PDS dose, pH, co-existing ion and humic acid (HA). The optimum test conditions were as follows: 0.4 g/L Bi2WO6/g-C3N4 (BC-3), 20 mg/L TC, 20 mg/L PDS and pH = 6.49, and the maximum removal efficiency of TC was 98.0% in 60 min. The decomposition rate in BC-3/SL/PDS system (0.0446 min-1) was 3.05 times higher than that of the g-C3N4/SL/PDS system (0.0146 min-1), which might be caused by the high-efficiency electron transfer inside the Z-scheme Bi2WO6/g-C3N4 heterojunction. Furthermore, the photogenerated hole (h+), superoxide (O2•-), sulfate radical (SO4•-) and singlet oxygen (1O2) were confirmed as the key oxidation factors in the BC-3/SL/PDS system for TC degradation by a free radical quenching experiment. Particularly, BC-3 possessed a wide application potential in actual antibiotic wastewater treatment for its superior catalytic performance that emerged in the experiment of co-existing components.

ACSL4: a double-edged sword target in multiple myeloma, promotes cell proliferation and sensitizes cell to ferroptosis.

Overactive fatty acid metabolism is usually found in hematological malignancies including multiple myeloma (MM), but the underlying mechanisms remain unclear. Here, we reveal that acyl-CoA synthetase long-chain family member 4 (ACSL4) is abnormally overexpressed in MM cell lines and MM patients compared to healthy donors. Knockdown of ACSL4 inhibited MM cell proliferation and reduced fatty acid levels possibly by regulating lipid metabolism genes including c-Myc and sterol regulatory element binding proteins (SREBPs). As a propellent in ferroptosis, ACSL4 also determines the sensitivity of MM cells to ferroptosis inducer RSL3. Knockdown of ACSL4 rendered MM cells resistance to ferroptosis. Our findings suggest that ACSL4 is a double-edged sword target in MM. Based on the high expression of ACSL4, ferroptosis induction represents a promising therapeutic strategy for MM.

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.

TEMPI Syndrome: Update on Clinical Features, Management, and Pathogenesis.

TEMPI (telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting) syndrome is a rare and newly defined multisystemic disease, which belongs to "monoclonal gammopathy of clinical significances". Due to its rarity, the etiology, pathogenesis, and clinical features of this disease remain largely unknown. Owing to its hidden and diverse clinical manifestations, missed diagnosis and misdiagnosis are common. In recent years, as more patients (including three fatal cases) were identified, some special clinical manifestations other than the typical pentad of TEMPI syndrome have been reported. Meanwhile, several studies attempting to identify the pathogenesis of TEMPI syndrome were conducted. In this review, we summarize the reported clinical characteristics of TEMPI syndrome and discuss the current and potential treatment options for patients with TEMPI syndrome, including those with relapsed/refractory disease. Furthermore, we provide an overview of current knowledge on the pathophysiology of TEMPI syndrome.

Cardiovascular-specific mortality among multiple myeloma patients: a population-based study.

Introduction: Multiple myeloma (MM) survival has greatly improved in recent decades. MM is usually diagnosed at a median age of 66-70 years. MM patients do not necessarily die from primary cancer, so cardiovascular health may be a key factor threatening long-term survival. This study was designed to explore the cardiovascular disease mortality (CVM) trends in MM patients and compare them with those in the general population. Methods: In total, 88,328 MM patients from the Surveillance, Epidemiology, and End Results (SEER) database (1975-2016) were included. Standardized mortality ratios (SMRs) were used to assess CVM risk. Results: The CVM risk was significantly higher in MM patients than in the general population (SMR, 1.84 (95% CI, 1.78-1.89)). MM patients had the highest CVM SMR, at 2.62 (95% CI, 2.49-2.75), in the first year after diagnosis, and it decreased over the follow-up period. Over the study period, the incidence of CVM continued to decrease in MM patients diagnosed at age 65-74 (APC, -1.2% (95% CI, -1.9% to -0.4%)) and ⩾75 years (APC, -1.9% (95% CI, -2.6% to -1.2%)) but not younger. CVM was the second-most common cause of death in patients ⩾75 years. In only MM case analyses, male sex, Black race, older age at diagnosis, and earlier year of diagnosis were poor prognostic factors for heart-specific mortality. Conclusion: The CVM risk in MM patients was significantly higher than that in the general population. To improve survival, cardiovascular health should receive attention upon diagnosis.

Terbutaline attenuates LPS-induced injury of pulmonary microvascular endothelial cells by cAMP/Epac signaling.

Acute lung injury (ALI), characterized by an acute onset of severe hypoxemia, is a common and devastating syndrome usually triggered by lipopolysaccharide (LPS) infection from bacteria. This study is intended to explore whether terbutaline can alleviate LPS-induced human pulmonary microvascular endothelial cell (HPMVEC) injury through cAMP/Epac signaling. LPS was utilized to induce ALI in HPMVECs, and after exposure of LPS-induced HPMVECs to terbutaline, the cellular functions including cell viability and apoptosis were measured by cell counting kit-8 and terminal deoxynucleotidyl transferase dUTP nick-end labeling. The protein expression related to cAMP/Epac signaling, apoptosis, and that of tight junction and inflammatory factors were evaluated at the same time. The effects of terbutaline on cellular functions were confirmed again after the addition of antagonists of cAMP and Epac, respectively. The levels of both cAMP and Epac reduced by LPS was concentration-dependently increased by terbutaline. The apoptosis and endothelial cell permeability damage of LPS-induced HPMVECs were enhanced after the addition of KT-5720 and ESI-09. The beneficial effects of terbutaline on alleviating the inflammation and apoptosis in HPMVECs injured by LPS are mediated by cAMP/Epac signaling, and this evidence would demonstrate the potential of terbutaline in the treatment of ALI.

FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner.

N6-methyladenosine (m6A), as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased m6A methylation in plasma cells (PCs) from MM patients and showed that the abnormal m6A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined m6A and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated m6A modification. FTO significantly promotes MM cell proliferation, migration, and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib (BTZ) treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcem26Cd52il2rgem26Cd22/Nju (NCG) mice. We demonstrated the functional importance of m6A demethylase FTO in MM progression, especially in promoting extramedullary myeloma (EMM) formation, and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.

International Prognostic Index-Based Immune Prognostic Model for Diffuse Large B-Cell Lymphoma.

Background: The International Prognostic Index (IPI) is widely used to discriminate the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). However, there is a significant need to identify novel valuable biomarkers in the context of targeted therapy, such as immune checkpoint blockade (ICB). Methods: Gene expression data and clinical DLBCL information were obtained from The Cancer Genome Atlas and Gene Expression Omnibus datasets. A total of 371 immune-related genes in DLBCL patients associated with different IPI risk groups were identified by weighted gene co-expression network analysis, and eight genes were selected to construct an IPI-based immune prognostic model (IPI-IPM). Subsequently, we analyzed the somatic mutation and transcription profiles of the IPI-IPM subgroups as well as the potential clinical response to immune checkpoint blockade (ICB) in IPI-IPM subgroups. Results: The IPI-IPM was constructed based on the expression of CMBL, TLCD3B, SYNDIG1, ESM1, EPHA3, HUNK, PTX3, and IL12A, where high-risk patients had worse overall survival than low-risk patients, consistent with the results in the independent validation cohorts. The comprehensive results showed that high IPI-IPM risk scores were correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, and upregulation of inhibitory immune checkpoints, including PD-L1, BTLA, and SIGLEC7, indicating a greater potential response to ICB therapy. Conclusion: The IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms of tumor progression and sheds light on the development of immunotherapy for DLBCL.

The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology.

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products.

The relationship among primary anatomic subsite and risk and distribution of second malignant neoplasms in patients with stage I/II diffuse large B-cell lymphoma: An analysis of the surveillance, epidemiology, and end results database.

BACKGROUND: Recent studies have reported that diffuse large B-cell lymphoma (DLBCL) involving different primary extranodal sites have distinct clinicopathological characteristics and prognosis. However, the risk of secondary malignant neoplasms (SMNs) in DLBCL survivors with different primary extranodal sites are unknown. METHODS: A total of 40,714 patients diagnosed with stage I/II DLBCL were included from the Surveillance, Epidemiology, and End Results (SEER) database from 1983 to 2015.The standardized incidence ratio (SIR) and absolute excess risk (AER) were used to assess the risk of SMNs. RESULTS: The results show that the risk of SMN was significantly higher in extranodal DLBCL than in the US general population (SIR, 1.18; 95% CI, 1.11-1.26), and the risk of developing SMN remains significantly elevated with increased latency. Moreover, there were multiple site-specific risk patterns. There was a 22%, 44%, 66%, 123% and 151% increased risk of SMN 10 years after primary gastrointestinal tract, head/neck, skeletal, lung and liver/pancreas DLBCL diagnosis, respectively. There was a significant decrease risk of SMN with increasing age at diagnosis for primary gastrointestinal tract and skeletal DLBCL. In addition, DLBCL patients with primary sites in the gastrointestinal tract, thyroid and liver/pancreas had the highest incidences of secondary stomach cancer, second thyroid cancer, and second hepatobiliary cancer, respectively, which indicated that the initial site of DLBCL may predict the type of SMN. CONCLUSIONS: The strategies for cancer surveillance after extranodal DLBCL diagnosis may need to be individualized according to the subsite of extranodal DLBCL.

JunB is a key regulator of multiple myeloma bone marrow angiogenesis.

Bone marrow (BM) angiogenesis significantly influences disease progression in multiple myeloma (MM) patients and correlates with adverse prognosis. The present study shows a statistically significant correlation of the AP-1 family member JunB with VEGF, VEGFB, and IGF1 expression levels in MM. In contrast to the angiogenic master regulator Hif-1α, JunB protein levels were independent of hypoxia. Results in tumor-cell models that allow the induction of JunB knockdown or JunB activation, respectively, corroborated the functional role of JunB in the production and secretion of these angiogenic factors (AFs). Consequently, conditioned media derived from MM cells after JunB knockdown or JunB activation either inhibited or stimulated in vitro angiogenesis. The impact of JunB on MM BM angiogenesis was finally confirmed in a dynamic 3D model of the BM microenvironment, a xenograft mouse model as well as in patient-derived BM sections. In summary, in continuation of our previous study (Fan et al., 2017), the present report reveals for the first time that JunB is not only a mediator of MM cell survival, proliferation, and drug resistance, but also a promoter of AF transcription and consequently of MM BM angiogenesis. Our results thereby underscore worldwide efforts to target AP-1 transcription factors such as JunB as a promising strategy in MM therapy.

Epidemiological features of primary breast lymphoma patients and development of a nomogram to predict survival.

BACKGROUND: Studies on the epidemiology and prognosis of primary breast lymphoma (PBL) are lack for low incidence. Therefore, we aimed to investigate the epidemiological characteristics of PBL and develop nomograms to predict patient survival. METHODS: Data of patients who were diagnosed with PBL from 1975 to 2011 and incidence rate of PBL from 1975 to 2017 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Time-varying multivariable Cox regression analysis was performed to identify independent prognostic factors for overall survival (OS) and disease-specific survival (DSS). Nomograms were constructed based on the independent prognostic factors identified in multivariate Cox regression analysis. RESULTS: A total of 1427 patients diagnosed with PBL were identified with the average age of 67.1 years. The overall incidence of PBL is 1.35/1,000,000 (adjusted to the United States standard population in 2000) from 1975 to 2017, with a significant upward trend by an annual percentage change (APC) of 2.91 (95%CI 2.29-3.94, P < 0.05). Age, sex, race, year of diagnosis, marital status, histological subtype, Ann Arbor Stage, and treatment modality were assessed as independent prognostic factors for OS and DSS by multivariable Cox regression (P < 0.05). Nomograms were constructed to predict the 1-, 3-, 5-, and 10- year OS and DSS. The concordance index (C-index) and calibration plots showed robustness and accuracy of the nomogram. CONCLUSION: The overall incidence of PBL was steadily increasing over the past four decades. Nomograms constructed can predicting 1-, 3-, 5-, and 10-year OS and identify patients with high-risk PBL.

Corrigendum: Trends in Incidence and Mortality of Waldenström Macroglobulinemia: A Population-Based Study.

[This corrects the article DOI: 10.3389/fonc.2020.01712.].

Trends in Incidence and Mortality of Waldenström Macroglobulinemia: A Population-Based Study.

Background: The incidence of Waldenström macroglobulinemia (WM) has increased in certain groups over several decades in the United States. It is unclear whether the increasing incidence is associated with mortality trends. Methods: The incidence and incidence-based mortality (IBM) rates were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (1980-2016) with SEER*Stat software. The secular trends stratified by demographic characteristics were analyzed by joinpoint regression. Results: The incidence of WM showed an initial rapid increase from 1980 to 1993 {annual percentage change (APC), 14.1% [95% confidence interval (CI), 10 to 18.4%]}, whereas it began to stabilize from 1993 to 2016 [APC, 0.5% (95% CI, -0.3 to 1.3%)]. The WM IBM trend followed a similar pattern, with a decrease occurring around 1994. The trends in the incidence and mortality significantly differed according to geographic location, race, age, sex, primary site of involvement and subtype, which could help in further investigations into the specific etiology. Moreover, a dramatic increase in the 5-year survival rate from the 1980s to 2010s was observed (47.84 vs. 69.41%). Conclusions: Although both the incidence and IBM of WM continued to increase during the study period, a reduction in the rate of increase occurred around 1993. We believe that further advances in healthcare delivery and research can ensure a low mortality rate. Future studies can use the findings of this paper to monitor the results of WM therapy.