Plasma immune profiling combined with machine learning contributes to diagnosis and prognosis of active pulmonary tuberculosis.

AbstractTuberculosis (TB) remains one of the deadliest chronic infectious diseases globally. Early diagnosis not only prevents the spread of TB but also ensures effective treatment. However, the absence of non-sputum-based diagnostic tests often leads to delayed TB diagnoses. Inflammation is a hallmark of TB, we aimed to identify biomarkers associated with TB based on immune profiling. We collected 222 plasma samples from healthy controls (HCs), disease controls (non-TB pneumonia; PN), patients with TB (TB), and cured TB cases (RxTB). A high-throughput protein detection technology, multiplex proximity extension assays (PEA), was applied to measure the levels of 92 immune proteins. Based on differential analysis and the correlation with TB severity, we selected 9 biomarkers (CXCL9, PDL1, CDCP1, CCL28, CCL23, CCL19, MMP1, IFNγ and TRANCE) and explored their diagnostic capabilities through 7 machine learning methods. We identified combination of these 9 biomarkers that distinguish TB cases from controls with an area under the receiver operating characteristic curve (AUROC) of 0.89 to 0.99, with a sensitivity of 82% to 93% at a specificity of 88% to 92%. Moreover, the model excels in distinguishing severe TB cases, achieving AUROC exceeding 0.95, sensitivities and specificities exceeding 93.3%. In summary, utilizing targeted proteomics and machine learning, we identified a 9 plasma proteins signature that demonstrates significant potential for accurate TB diagnosis and clinical outcome prediction.

Single-embryo transcriptomic atlas of oxygen response reveals the critical role of HIF-1α in prompting embryonic zygotic genome activation.

Adaptive response to physiological oxygen levels (physO2; 5% O2) enables embryonic survival in a low-oxygen developmental environment. However, the mechanism underlying the role of physO2 in supporting preimplantation development, remains elusive. Here, we systematically studied oxygen responses of hallmark events in preimplantation development. Focusing on impeded transcriptional upregulation under atmospheric oxygen levels (atmosO2; 20% O2) during the 2-cell stage, we functionally identified a novel role of HIF-1α in promoting major zygotic genome activation by serving as an oxygen-sensitive transcription factor. Moreover, during blastocyst formation, atmosO2 impeded H3K4me3 and H3K27me3 deposition by deregulating histone-lysine methyltransferases, thus impairing X-chromosome inactivation in blastocysts. In addition, we found atmosO2 impedes metabolic shift to glycolysis before blastocyst formation, thus resulting a low-level histone lactylation deposition. Notably, we also reported an increased sex-dimorphic oxygen response of embryos upon preimplantation development. Together, focusing on genetic and epigenetic events that are essential for embryonic survival and development, the present study advances current knowledge of embryonic adaptive responses to physO2, and provides novel insight into mechanism underlying irreversibly impaired developmental potential due to a short-term atmosO2 exposure.

Discovering novel biomarkers for diagnosis and treatment monitoring of active pulmonary tuberculosis by ion metabolism analysis.

Tuberculosis (TB) is a highly lethal infectious disease that poses a global threat. Timely and accurate biomarker for TB diagnosis and treatment monitoring remains a pressing need. Ions, the crucial trace element for humans, may be potential targets for TB diagnosis and the forecasting of TB development. To explore the potential of ions as biomarkers, we measured and compared the levels of various ions in whole blood and plasma samples from healthy control (HC), pulmonary TB patients (TB), cured pulmonary TB patients (RxTB), and other non-TB pneumonia patients (PN) by using ultra-high performance liquid chromatography-tandem mass spectrometry. Our study demonstrated that Cu (AUC = 0.670), Pb (AUC = 0.660), and Zn (AUC = 0.701) in whole blood exhibited promising diagnostic performance for TB. Then we used a neural network (NNET) for TB prediction, the AUC values used to differentiate definite TB from HC or PN in plasma were 0.867 and 0.864, respectively. The AUC values used to differentiate definite TB from HC or PN in whole blood were 0.818 and 0.660, respectively. Our correlation analysis showed that Zn (r= 0.356, p=0.001) and Cu (r= 0.361, p=0.0004) in plasma are most closely related to disease severity. Additionally, six ions (Cu, Sb, V, Mn, Fe, Sr) in plasma and whole blood were altered following anti-TB therapy. These results showed that ions could be diagnostic biomarkers for TB. Furthermore, the level of particular ions can forecast the degree of lung damage and the success of the TB treatment. In conclusion, this study highlights the possibility of using ions from blood samples to enable rapid tuberculosis diagnosis.

Glutathione safeguards TET-dependent DNA demethylation and is critical for the acquisition of totipotency and pluripotency during preimplantation development.

During early development, both genome-wide epigenetic reprogramming and metabolic remodeling are hallmark changes of normal embryogenesis. However, little is known about their relationship and developmental functions during the preimplantation window, which is essential for the acquisition of totipotency and pluripotency. Herein, we reported that glutathione (GSH), a ubiquitous intracellular protective antioxidant that maintains mitochondrial function and redox homeostasis, plays a critical role in safeguarding postfertilization DNA demethylation and is essential for establishing developmental potential in preimplantation embryos. By profiling mitochondria-related transcriptome that coupled with different pluripotency, we found GSH is a potential marker that is tightly correlated with full pluripotency, and its beneficial effect on prompting developmental potential was functionally conformed using in vitro fertilized mouse and bovine embryos as the model. Mechanistic study based on preimplantation embryos and embryonic stem cells further revealed that GSH prompts the acquisition of totipotency and pluripotency by facilitating ten-eleven-translocation (TET)-dependent DNA demethylation, and ascorbic acid (AsA)-GSH cycle is implicated in the process. In addition, we also reported that GSH serves as an oviductal paracrine factor that supports development potential of preimplantation embryos. Thus, our results not only advance the current knowledge of functional links between epigenetic reprogramming and metabolic remodeling during preimplantation development but also provided a promising approach for improving current in vitro culture system for assisted reproductive technology.

Doxorubicin-loaded PEG-CdTe QDs conjugated with anti-CXCR4 mAbs: a novel delivery system for extramedullary multiple myeloma treatment.

Extramedullary multiple myeloma (EMM) is defined as the presence of plasma cells outside the bone marrow of multiple myeloma patients, and its prognosis is poor. High-dose chemotherapy with autologous stem cell transplantation, as a good option on early lines of therapy, has retained the survival benefit of youny EMM patients, but is intolerant for the majority of old patients because of drug cytotoxicity. To essentially address the intolerance above, we designed a CXCR4-PEG-CdTe-DOX (where CXCR4: chemokine receptor 4; PEG-CdTe: polyethylene glycol-modified cadmium telluride; DOX:doxorubicin) nanoplatform. First, CXCR4 is highly expressed in extramedullary plasma cells. Second, PEG-CdTe a drug carrier that controls drug release, can reduce adverse reactions, prolong drug (e.g, DOX) circulation time in the body, and form a targeting carrier after connecting antibodies. In vitro experiments showed CXCR4-PEG-CdTe-DOX facilitated intracellular drug accumulation through active CXCR4 targeting and released DOX into the microenvironment in a pH-controlled manner, enhancing the therapeutic efficacy and apoptosis rate of myeloma cells (U266). Therefore, targeted chemotherapy mediated by CXCR4-PEG-CdTe-DOX is a promising option for EMM treatment.

WNT Co-Receptor LRP6 Is Critical for Zygotic Genome Activation and Embryonic Developmental Potential by Interacting with Oviductal Paracrine Ligand WNT2.

Mammalian preimplantation development depends on the interaction between embryonic autocrine and maternal paracrine signaling. Despite the robust independence of preimplantation embryos, oviductal factors are thought to be critical to pregnancy success. However, how oviductal factors regulate embryonic development and the underlying mechanism remain unknown. In the present study, focusing on WNT signaling, which has been reported to be essential for developmental reprogramming after fertilization, we analyzed the receptor-ligand repertoire of preimplantation embryonic WNT signaling, and identified that the WNT co-receptor LRP6 is necessary for early cleavage and has a prolonged effect on preimplantation development. LRP6 inhibition significantly impeded zygotic genome activation and disrupted relevant epigenetic reprogramming. Focusing on the potential oviductal WNT ligands, we found WNT2 as the candidate interacting with embryonic LRP6. More importantly, we found that WNT2 supplementation in culture medium significantly promoted zygotic genome activation (ZGA) and improved blastocyst formation and quality following in vitro fertilization (IVF). In addition, WNT2 supplementation significantly improved implantation rate and pregnancy outcomes following embryo transfer. Collectively, our findings not only provide novel insight into how maternal factors regulate preimplantation development through maternal-embryonic communication, but they also propose a promising strategy for improving current IVF systems.

Identification of candidate genomic regions for egg yolk moisture content based on a genome-wide association study.

BACKGROUND: Eggs represent important sources of protein and are widely loved by consumers. Egg yolk taste is an important index for egg selection, and the moisture content of the egg yolk affects the taste. To understand the molecular mechanism underlying egg yolk moisture content, this study determined the phenotype and heritability of egg yolk water content and conducted a genome-wide association study (GWAS) using a mixed linear model. RESULTS: We determined the phenotype and heritability of thermogelled egg yolk water content (TWC) and found that the average TWC was 47.73%. Moreover, significant variations occurred (41.06-57.12%), and the heritability was 0.11, which indicates medium-low heritability. Through the GWAS, 48 single nucleotide polymorphisms (SNPs) related to TWC (20 significantly, 28 suggestively) were obtained, and they were mainly located on chromosomes 10 and 13. We identified 36 candidate genes based on gene function and found that they were mainly involved in regulating fat, protein, and water content and embryonic development. FGF9, PIAS1, FEM1B, NOX5, GLCE, VDAC1, IGFBP7, and THOC5 were involved in lipid formation and regulation; AP3S2, GNPDA1, HSPA4, AP1B1, CABP7, EEF1D, SYTL3, PPP2CA, SKP1, and UBE2B were involved in protein folding and hydrolysis; and CSF2, SOWAHA, GDF9, FSTL4, RAPGEF6, PAQR5, and ZMAT5 were related to embryonic development and egg production. Moreover, MICU2, ITGA11, WDR76, BLM, ANPEP, TECRL, EWSR1, and P4HA2 were related to yolk quality, while ITGA11, WDR76, BLM, and ANPEP were potentially significantly involved in egg yolk water content and thus deserve further attention and research. In addition, this study identified a 19.31-19.92 Mb genome region on GGA10, and a linkage disequilibrium analysis identified strong correlations within this region. Thus, GGA10 may represent a candidate region for TWC traits. CONCLUSION: The molecular genetic mechanism involved in TWC was revealed through heritability measurements and GWAS, which identified a series of SNPs, candidate genes, and candidate regions related to TWC. These results provide insights on the molecular mechanism of egg yolk moisture content and may aid in the development of new egg traits.

Characterization of four thermogelled egg yolk varieties based on moisture and protein content.

There are obvious differences between egg yolks of different varieties. Additionally, boiled eggs, which are widely liked and consumed globally, are nutrient rich. However, they absorb water in the esophagus during swallowing, and this result in an uncomfortable sensation. Here, we determined the moisture content and distribution as well as the protein contents and properties of 4 varieties of thermogelled egg yolks. Among the varieties, Green Shelled thermogelled egg yolk showed the highest protein content and solubility. Additionally, the ionic, hydrogen, and disulfide bonds corresponding to Rhode Island Red thermogelled egg yolk samples were the weakest, while the hydrophobic interaction force corresponding to the Hetian Dahei (HD) egg yolk samples was the weakest. Further, the distribution of the moisture contents of the 4 varieties was significantly different (P < 0.05). HD egg yolk showed the highest moisture content, and its bound and immobile moisture contents were significantly higher than those of the other 3 varieties. Egg yolk moisture content also affected free amino acid content, which was the highest for HD egg yolk. Therefore, owing to its high moisture content, HD egg yolk was conducive for chewing and swallowing and given its high free amino acid content, it also had a more suitable taste and flavor. The results of this study provide a theoretical basis for the application of egg yolks in food processing.

Pan-Cancer Analysis Reveals the Relation between TRMT112 and Tumor Microenvironment.

Dysregulated epigenetic modifications play a critical role in cancer development where TRMT112 is a member of the transfer RNA (tRNA) methyltransferase family. Till now, no studies have revealed the linkage between TRMT112 expression and diverse types of tumors. Based on TCGA data, we first probed into the relation between TRMT112 and prognosis and the potential role of TRMT112 in tumor microenvironment across 33 types of tumor. TRMT112 presented with increased expression in most cancers, which was significantly prognostic. Furthermore, TRMT112 was associated with tumor-associated fibroblasts in a variety of cancers. Additionally, a positive relationship was identified between TRMT112 expression and multiple tumor-related immune infiltrations, such as dendritic cells, CD8+ T cells, macrophages, CD4+ T cells, neutrophils, and B cells in lung adenocarcinoma and breast invasive carcinoma. In summary, our results suggest that TRMT112 might be a potential prognostic predictor of cancers and involved in regulating multiple cancer-related immune responses to some extent.

Effect of Maternal Sildenafil Supplementation During Gestation on the Reproductive Performance of Sows/Gilts and Growth Performance of Neonatal Piglets.

Sildenafil, a phosphodiesterase 5 (PDE-5) inhibitor, provides an alternative and effective strategy to increase uterine blood flow and vascular development, thus improving fetal development. Previous studies have shown that sildenafil attenuates fetal growth restriction in rodents, sheep, and humans. However, the effect of sildenafil intervention on fetal growth in pigs remains unclear. This study aims to evaluate the effect of dietary supplementation with sildenafil on the reproductive performance of sows and gilts. Over 700 Landrace × Large White crossbred sows in the 3rd or 4th parity were randomly assigned to the control group and the sildenafil treatment groups. In brief, sows in the treatment groups were given a basic diet supplemented with sildenafil (0.32 g/day) during different stages of gestation: (1) gestation day (GD) 0-110; (2) GD 0-30; (3) GD 30-80; (4) GD 80-110; and (5) GD 30-110. At parturition, the total number of piglets born per litter, the number of piglets born alive or dead, the average birth weight, the number of weaned piglets, and the average weaning weights were recorded and analyzed. Sildenafil supplementation throughout gestation (GD 0-110) increased both the litter size and the average birth weight. To reduce the cost of extended sildenafil supplementation, time-phased strategies were further tested. Sildenafil supplementation during early gestation (GD 0-30), mid-gestation (GD 30-80), and late gestation (GD 80-110) partially improved litter performance. Notably, sows fed sildenafil supplementation from the mid-to-late gestation period (GD 30-110) showed significantly improved litter performance, approaching the levels in the sows supplemented with sildenafil throughout the whole gestation period. Taken together, our results showed that maternal sildenafil supplementation during gestation can effectively improve the reproductive performance of sows and gilts, and enhance the growth performance of neonatal piglets, thus providing a promising and practical intervention strategy to improve reproductive management in pig farming.

Reduced CXCR4 expression in associated with extramedullary and predicts poor survival in newly diagnosed multiple myeloma.

BACKGROUND: Multiple myeloma (MM), a bone marrow-resident hematological malignancy of plasma cells, has remained largely incurable despite the recent advancement in novel therapies. The heterogeneity of myeloma cells makes risk stratification of MM important for therapeutic regimen planning. RESEARCH DESIGN AND METHODS: No immunohistochemical (IHC) predictive and prognostic marker of MM has been constructed yet. Herein, the prognostic value of chemokine (C-X-C motif) receptor 4 (CXCR4) expression in 48 newly diagnosed MM patients was explored using IHC. Correlations between CXCR4 expression and clinical features of MM were analyzed. RESULTS: CXCR4-positive patients significantly outperformed CXCR4-negative patients in both 3-year estimated overall survival (93.8% vs 45.8%, P = 0.0392) and progression-free survival (57.1% vs 40.9%, P = 0.0436). CONCLUSIONS: The incidence of extramedullary lesions in CXCR4-negative patients increased significantly compared with CXCR4-positive patients. Plasma cells that reduce CXCR4 expression have poor prognosis and increase the incidence of extramedullary lesions.

Analysis of Pan-Cancer Revealed the Immunological and Prognostic Potential of CBX3 in Human Tumors.

Chromobox protein homolog 3 (CBX3) has been recognized as a member of the heterochromatin protein 1 family and participate in transcriptional activation or inhibition, cell differentiation and growth. Despite more and more evidence shows that CBX3 has a critical function in the development of some tumors, no systematic extensive analysis of CBX3 has been reported. Thus, we intended to examine the prognostic significance of CBX3 in 33 tumors and investigate its potential immune function. We employed several bioinformatics methods to explore the potential carcinogenic impact of CBX3 premised on the data sets collected from tumor genome maps, human protein maps, cBioPortal, and genotype tissue expression. The approaches include assessing the link between CBX3 and prognosis of different tumors, immune cell infiltration, micro-satellite instability (MSI), DNA methylation, and tumor mutational burden (TMB). The outcomes illustrated that CBX3 was increasingly expressed in 29 tumors. Moreover, CBX3 exhibited a negative correlation with the prognosis of many tumors. The expression of CBX3 was linked to MSI in 12 tumors and TMB in 16 tumors. In 24 tumors, the expression of CBX3 was linked to DNA methylation. Moreover, the CBX3 expression exhibited a negative relationship with the infiltration level of the majority of immune cells, but showed a positive link to T gamma delta cells, central memory T cells, and T helper cells, especially when invading breast carcinoma, thymic carcinoma, colon carcinoma, cutaneous melanoma, endometrial carcinoma, and lung squamous carcinoma. Our research indicates that CBX3 might be used as a prognostic indicator for different malignant tumors due to its function in tumor genesis as well as tumor immunity.

Vitamin C Rescues in vitro Embryonic Development by Correcting Impaired Active DNA Demethylation.

During preimplantation development, a wave of genome-wide DNA demethylation occurs to acquire a hypomethylated genome of the blastocyst. As an essential epigenomic event, postfertilization DNA demethylation is critical to establish full developmental potential. Despite its importance, this process is prone to be disrupted due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF), and thus leading to epigenetic errors. However, since the first case of aberrant DNA demethylation reported in IVF embryos, its underlying mechanism remains unclear and the strategy for correcting this error remains unavailable in the past decade. Thus, understanding the mechanism responsible for DNA demethylation defects, may provide a potential approach for preventing or correcting IVF-associated complications. Herein, using mouse and bovine IVF embryos as the model, we reported that ten-eleven translocation (TET)-mediated active DNA demethylation, an important contributor to the postfertilization epigenome reprogramming, was impaired throughout preimplantation development. Focusing on modulation of TET dioxygenases, we found vitamin C and α-ketoglutarate, the well-established important co-factors for stimulating TET enzymatic activity, were synthesized in both embryos and the oviduct during preimplantation development. Accordingly, impaired active DNA demethylation can be corrected by incubation of IVF embryos with vitamin C, and thus improving their lineage differentiation and developmental potential. Together, our data not only provides a promising approach for preventing or correcting IVF-associated epigenetic errors, but also highlights the critical role of small molecules or metabolites from maternal paracrine in finetuning embryonic epigenomic reprogramming during early development.

The mRNA-destabilizing protein Tristetraprolin targets "meiosis arrester" Nppc mRNA in mammalian preovulatory follicles.

C-natriuretic peptide (CNP) and its receptor guanylyl cyclase, natriuretic peptide receptor 2 (NPR2), are key regulators of cyclic guanosine monophosphate (cGMP) homeostasis. The CNP-NPR2-cGMP signaling cascade plays an important role in the progression of oocyte meiosis, which is essential for fertility in female mammals. In preovulatory ovarian follicles, the luteinizing hormone (LH)-induced decrease in CNP and its encoding messenger RNA (mRNA) natriuretic peptide precursor C (Nppc) are a prerequisite for oocyte meiotic resumption. However, it has never been determined how LH decreases CNP/Nppc In the present study, we identified that tristetraprolin (TTP), also known as zinc finger protein 36 (ZFP36), a ubiquitously expressed mRNA-destabilizing protein, is the critical mechanism that underlies the LH-induced decrease in Nppc mRNA. Zfp36 mRNA was transiently up-regulated in mural granulosa cells (MGCs) in response to the LH surge. Loss- and gain-of-function analyses indicated that TTP is required for Nppc mRNA degradation in preovulatory MGCs by targeting the rare noncanonical AU-rich element harbored in the Nppc 3' UTR. Moreover, MGC-specific knockout of Zfp36, as well as lentivirus-mediated knockdown in vivo, impaired the LH/hCG-induced Nppc mRNA decline and oocyte meiotic resumption. Furthermore, we found that LH/hCG activates Zfp36/TTP expression through the EGFR-ERK1/2-dependent pathway. Our findings reveal a functional role of TTP-induced mRNA degradation, a global posttranscriptional regulation mechanism, in orchestrating the progression of oocyte meiosis. We also provided a mechanism for understanding CNP-dependent cGMP homeostasis in diverse cellular processes.

A randomized phase II, open-label and multicenter study of combination regimens of bortezomib at two doses by subcutaneous injection for newly diagnosed multiple myeloma patients.

PURPOSE: Combinations of bortezomib (Velcade), cyclophosphamide and dexamethasone have shown significant efficacy and safety for patients of newly diagnosed multiple myeloma (NDMM). In this study, we compared the efficacy and safety of modified VCD regimens with novel changes in bortezomib dose and schedule for NDMM. METHODS: Eighty-five NDMM patients from multiple centers were randomly assigned to a high-dose (1.6 mg/m2) (group A) or a low-dose (1.3 mg/m2) (group B) bortezomib, administrated on days 1, 6, 11, and 16 subcutaneously in a 4-week cycle for nine cycles, combined with 40 mg dexamethasone on bortezomib days and cyclophosphamide 300 mg/m2 on days 1-3 intravenously. RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During induction, for patients with R-ISS stage III, the CR or better rate in group A was superior to that in group B (P = 0.01). Of patients < 65, the CR or better rate of group A was superior to that of group B (P = 0.004). Rapid onset of CR occurred in group A (P < 0.01). Meanwhile, rate of 3-4 diarrhea was higher in group A (P = 0.03), which caused higher rate of dose reduction for patients ≥ 65 (P = 0.041). No significant difference between the two groups in PFS and OS. CONCLUSIONS: The studied high-dose VCD as induction regimen had an improved CR rate, especially in patients < 65 or with R-ISS stage III, and is feasible for young and high-risk patients. Trial registration ClinicalTrials.gov: NCT02086942.

CD5-negative chronic lymphocytic leukemia/small lymphocytic lymphoma in a patient with gastrointestinal mantle cell lymphoma: an unusual case report.

Richter's syndrome, the development of high-grade non-Hodgkin lymphoma in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), may be triggered by viral infections (eg, Epstein-Barr virus infection). Herein, we report an unusual case of CD5-negative CLL/SLL patient with gastrointestinal mantle cell lymphoma (MCL) and hepatitis B virus infection. CLL/SLL was diagnosed based on lymph node immunohistochemistry and bone marrow pathology. This patient was treated with seven cycles of multi-agent chemotherapy. During treatment, the hepatitis B viruses were activated. Then, after 20 months of antiviral treatment with entecavir, he developed abdominal discomfort and abdominal lymphadenopathy and was diagnosed with MCL based on intestinal biopsy. This work indicates that the hepatitis B virus in patients with CLL/SLL may accelerate the progress or transformation to MCL.

Primary testicular lymphoma: A SEER analysis of 1,169 cases.

Primary testicular lymphoma (PTL) is a rare lymphoid malignancy. The present retrospective study aimed to investigate the demographic characteristics and survival of patients with PTL, as well as the associated prognostic factors, using a population-based database. All adults diagnosed with PTL in the Surveillance, Epidemiology, and End Results database were identified between 1973 and 2013. The Kaplan-Meier method was used to estimate cause-specific survival (CSS). Log-rank test or multivariate Cox regression model was used to assess the influence of demographic and clinical parameters on CSS. A total of 1,169 patients with PTL were identified from the database, and the median age was 70 years. The predominant histological subtype was diffuse large B-cell lymphoma, which affected 82.9% (970/1,169) of patients, and 68.6% (802/1,169) of patients had early stage disease (stages I-II). Patients >70 years, those diagnosed at the earlier time period, or those who had advanced-stage symptoms had the worst 5-year CSS rates; however, treatment with rituximab significantly improved the 5-year CSS. In conclusion, this retrospective study presented data from the largest cohort of patients with PTL and described the effects of rituximab on the CSS of patients with PTL.

C-type natriuretic peptide enhances mouse preantral follicle growth.

Compared to ovarian antral follicle development, the mechanism underlying preantral follicle growth has not been well documented. Although C-type natriuretic peptide (CNP) involvement in preantral folliculogenesis has been explored, its detailed role has not been fully defined. Here, we used mouse preantral follicles and granulosa cells (GCs) as a model for investigating the dynamic expression of CNP and natriuretic peptide receptor 2 (NPR2) during preantral folliculogenesis, the regulatory role of oocyte-derived growth factors (ODGFs) in natriuretic peptide type C (Nppc) and Npr2 expression, and the effect of CNP on preantral GC viability. Both mRNA and protein levels of Nppc and Npr2 were gradually activated during preantral folliculogenesis. CNP supplementation in culture medium significantly promoted the growth of in vitro-cultured preantral follicles and enhanced the viability of cultured GCs in a follicle-stimulating hormone (FSH)-independent manner. Using adult and prepubertal mice as an in vivo model, CNP pre-treatment via intraperitoneal injection before conventional superovulation also had a beneficial effect on promoting the ovulation rate. Furthermore, ODGFs enhanced Nppc and Npr2 expression in the in vitro-cultured preantral follicles and GCs. Mechanistic study demonstrated that the regulation of WNT signaling and estrogen synthesis may be implicated in the promoting role of CNP in preantral folliculogenesis. This study not only proves that CNP is a critical regulator of preantral follicle growth, but also provides new insight in understanding the crosstalk between oocytes and somatic cells during early folliculogenesis.

Doxorubicin-Loaded PEG-CdTe Quantum Dots as a Smart Drug Delivery System for Extramedullary Multiple Myeloma Treatment.

New drug treatments still do not improve the prognosis of extramedullary multiple myeloma (EMM) patients. Luckily, high-dose chemotherapy can raise the prognosis, but is intolerant to most patients because of drug cytotoxicity. Nanoparticles (NPs) are used as drug carriers to prolong drug circulation time, control drug release, reduce drug toxicity and bioavailability, and target specific sites. In this work, doxorubicin (DOX) was loaded in polyethylene glycol-modified cadmium telluride quantum dots (PEG-CdTe QDs). PEG-CdTe-DOX facilitated intracellular drug accumulation through polyethylene organizational compatibility and released DOX into the microenvironment in a pH-controlled manner, which enhanced the therapeutic efficacy and the apoptosis rate of myeloma cells (PRMI8226). PEG-CdTe-DOX improved the anti-tumor activity of DOX by regulating the protein expressions of apoptosis-associated genes. In summary, PEG-CdTe-DOX provides a specific and effective clinical treatment for EMM patients.

Microarray-Based Gene Expression Analysis Identifies Potential Diagnostic and Prognostic Biomarkers for Waldenström Macroglobulinemia.

Waldenström macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is rare but a clinicopathologically distinct B-cell malignancy. This study assessed differentially expressed genes (DEGs) to identify potential WM biomarkers and uncover the underlying the molecular mechanisms of WM progression using gene expression profiles from the Gene Expression Omnibus database. DEGs were identified using the LIMMA package and their potential functions were then analyzed by using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and the protein-protein interaction (PPI) network analysis by using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Data showed that among 1,756 DEGs, 926 were upregulated and 830 were downregulated by comparing WM BM CD19+ with normal PB CD19+ B cell samples, whereas 241 DEGs (95 upregulated and 146 downregulated) were identified by comparing WM BM CD138+ with normal BM CD138+ plasma cell samples. The DEGs were enriched in different GO terms and pathways, including the apoptotic process, cell cycle arrest, immune response, cell adhesion, mitogen-activated protein kinase signaling pathway, toll-like receptor signaling pathway, and the gonadotropin-releasing hormone signaling pathway. Hub nodes in the PPI network included CDK1, JUN, CREBBP, EP300, CAD, CDK2, and MAPK14. Bioinformatics analysis of the GSE9656 dataset identified 7 hub genes that might play an important role in WM development and progression. Some of the candidate genes and pathways may serve as promising therapeutic targets for WM.