Research progress of the Fanconi anemia pathway and premature ovarian insufficiency†.

The Fanconi anemia pathway is a key pathway involved in the repair of deoxyribonucleic acidinterstrand crosslinking damage, which chiefly includes the following four modules: lesion recognition, Fanconi anemia core complex recruitment, FANCD2-FANCI complex monoubiquitination, and downstream events (nucleolytic incision, translesion synthesis, and homologous recombination). Mutations or deletions of multiple Fanconi anemia genes in this pathway can damage the interstrand crosslinking repair pathway and disrupt primordial germ cell development and oocyte meiosis, thereby leading to abnormal follicular development. Premature ovarian insufficiency is a gynecological clinical syndrome characterized by amenorrhea and decreased fertility due to decreased oocyte pool, accelerated follicle atresia, and loss of ovarian function in women <40 years old. Furthermore, in recent years, several studies have detected mutations in the Fanconi anemia gene in patients with premature ovarian insufficiency. In addition, some patients with Fanconi anemia exhibit symptoms of premature ovarian insufficiency and infertility. The Fanconi anemia pathway and premature ovarian insufficiency are closely associated.

Induction of filopodia formation by α-Actinin-2 via RelA with a feedforward activation loop promoting overt bone marrow metastasis of gastric cancer.

BACKGROUND: Bone marrow metastasis (BMM) is underestimated in gastric cancer (GC). GC with BMM frequently complicate critical hematological abnormalities like diffused intravascular coagulation and microangiopathic hemolytic anemia, which constitute a highly aggressive GC (HAGC) subtype. HAGC present a very poor prognosis with peculiar clinical and pathological features when compared with not otherwise specified advanced GC (NAGC). But the molecular mechanisms underlying BMM from GC remain rudimentary. METHODS: The transcriptomic difference between HAGC and NAGC were analyzed. Genes that were specifically upregulated in HAGC were identified, and their effect on cell migration and invasion was studied. The function of ACTN2 gene were confirmed by GC cell lines, bone-metastatic animal model and patients' tissues. Furthermore, the molecular mechanism of ACTN2 derived-BMM was explored by multiple immunofluorescence staining, western blot, chromatin immunoprecipitation, and luciferase reporter assays. RESULTS: We elucidated the key mechanisms of BMM depending on the transcriptomic difference between HAGC and NAGC. Five genes specifically upregulated in HAGC were assessed their effect on cell migration and invasion. The ACTN2 gene encoding protein α-Actinin-2 was detected enhanced the metastatic capability and induced BMM of GC cells in mouse models. Mechanically, α-Actinin-2 was involved in filopodia formation where it promoted the Actin filament cross-linking by replacing α-Actinin-1 to form α-Actinin-2:α-Actinin-4 complexes in GC cells. Moreover, NF-κB subunit RelA and α-Actinin-2 formed heterotrimers in the nuclei of GC cells. As a direct target of RelA:α-Actinin-2 heterotrimers, the ACTN2 gene was a positive auto-regulatory loop for α-Actinin-2 expression. CONCLUSIONS: We demonstrated a link between filopodia, BMM and ACTN2 activation, where a feedforward activation loop between ACTN2 and RelA is established via actin in response to distant metastasis. Given the novel filopodia formation function and the new mechanism of BMM in GC, we propose ACTN2 as a druggable molecular vulnerability that may provide potential therapeutic benefit against BMM of GC.

Elderly patients with stage II gastric cancer do not benefit from adjuvant chemotherapy.

BACKGROUND: With the aging of the population, the burden of elderly gastric cancer (EGC) increases worldwide. However, there is no consensus on the definition of EGC and the efficacy of adjuvant chemotherapy in patients with stage II EGC. Here, we investigated the effectiveness of adjuvant chemotherapy in defined EGC patients. METHODS: We enrolled 5762 gastric cancer patients of three independent cohorts from the Sixth Affiliated Hospital of Sun Yat-sen University (local), the Surveillance, Epidemiology, and End Results (SEER), and the Asian Cancer Research Group (ACRG). The optimal age cutoff for EGC was determined using the K-adaptive partitioning algorithm. The defined EGC group and the efficacy of adjuvant chemotherapy for them were confirmed by Cox regression and Kaplan-Meier survival analyses. Furthermore, gene set variation analyses (GSVA) were performed to reveal pathway enrichment between groups. RESULTS: The optimal age partition value for EGC patients was 75. In the local, SEER, and ACRG cohorts, the EGC group exhibited significantly worse overall survival and cancer-specific survival than the non-EGC group (P < 0.05) and was an independent risk factor. Stratified analyses based on chemotherapy showed that EGC patients derived little benefit from adjuvant chemotherapy. Furthermore, GSVA analysis revealed the activation of DNA repair-related pathways and downregulation of the p53 pathway, which may partially contribute to the observed findings. CONCLUSION: In this retrospective, international multi-center study, 75 years old was identified as the optimal age cutoff for EGC definition, and adjuvant chemotherapy proved to be unbeneficial for stage II EGC patients.

Combined tumor-associated macrophages biomarker predicting extremely poor outcome of patients with primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive and rare malignancy with poor prognosis. However, there are no reliable prognostic biomarkers for PCNSL in clinical practice. Here, we aimed to identify a reliable prognostic biomarker for predicting the survival of PCNSL patients. In this study, multiplex immunofluorescence and digital imaging analysis were used to characterize tumor-associated macrophages (TAMs) immunophenotypes and the expression of programmed cell death ligand 1 on TAMs, with regard to prognosis from diagnostic tumor tissue samples of 59 PCNSL patients. We found that the M2-to-M1 ratio was a more reliable prognostic biomarker for PCNSL than M1-like or M2-like macrophage infiltration. In addition, the combination of programmed death-ligand 1 (PD-L1) expression on TAMs and the M2-to-M1 ratio in PCNSL demonstrated improved performance in prognostic discrimination than PD-L1-positive TAMs or M2-to-M1 ratio. To validate the prognostic significance of the combined TAMs associated biomarkers, they were integrated into the International Extranodal Lymphoma Study Group (IELSG) index and termed as IELSG-M index. Kaplan-Meier plots showed that the IELSG-M index could discriminate patients into low-, intermediate- or high-risk subgroups, better than IELSG, in terms of prognosis. The areas under the receiver operating characteristic curves of IELSG-M was 0.844 for overall survival; superior to the IELSG model (0.580). Taken together, this study's findings showed that the combination of PD-L1 on TAMs and the M2-to-M1 ratio could be strong prognostic predictive biomarkers for PCNSL and the IELSG-M index had improved prognostic significance than the IELSG index.

Elevated expression of HMGB1 is prognostic of poor survival in patients with relapsed/refractory T/NK-CL.

Despite the clinical value of HMGB1 in non-Hodgkin lymphoma (NHL), the impact of HMGB1 protein expression on survival of patients with mature T-cell and NK-cell lymphoma (T/NK-CL) is unknown. Here, we evaluated correlations of HMGB1 expression in tumor tissues with pathophysiological characteristics of disease and determined the prognostic value of HMGB1 expression in relapsed/refractory T/NK-CL. HMGB1 expression was detected by immunohistochemistry (IHC) in 66 cases of relapsed/refractory T/NK-CL, and specimens were classified as high or low HMGB1 expression. Univariate and multivariate Cox regression analyses identified prognostic factors associated with progression-free survival (PFS) and overall survival (OS). High HMGB1 expression was significantly correlated with increased Ki67 levels and progressive lymphoma subtypes. Univariate Cox regression analysis showed that high HMGB1 expression was associated with unfavorable PFS (P = 0.006) and poorer OS (P < 0.001). Prognostic factors identified by univariate analysis were prognostic index for peripheral T-cell lymphoma non-specified (PIT) score ≥ 2, bone marrow involvement, Ki67 ≥ 70%, and high HMGB1 expression. Multivariate Cox regression analysis revealed that high HMGB1 expression was an independent prognostic factor for poorer PFS [hazard ratio (HR) 3.593; 95% confidence interval (CI) 1.171-11.027; P = 0.025] and OS [HR 7.663; 95% CI 2.367-24.803; P = 0.001]. A proposal prognostic model combining HMGB1 and Ki67 expression showed improved prognostic capacity and may help guide treatment planning. High HMGB1 expression may be a promising prognostic predictor and a potential therapeutic target for relapsed/refractory T/NK-CL. Furthermore, to apply HMGB1 as one of the best bio-maker, an external independent control cohort is needed.

Unbalanced expression of membrane-bound and soluble inducible costimulator and programmed cell death 1 in patients with myasthenia gravis.

This study aimed to investigate the possible functions and mechanisms of positive and negative costimulatory molecules in the pathological process of myasthenia gravis (MG). The expression levels of membrane-bound inducible costimulator (ICOS) and programmed cell death 1 (PD-1) in peripheral blood T cells, their corresponding ligands ICOSL and PDL-1 on B cells, and their soluble forms (sICOS, sPD-1, sICOSL, and sPDL-1) in plasma were detected in patients with untreated-stage MG (USMG) and remission-stage MG (RSMG). The results showed that the expression levels of membrane-bound ICOS and PD-1 in the peripheral blood T cells of the USMG group and their corresponding ligands ICOSL and PD-L1 on B cells were significantly increased compared to those in the RSMG group and healthy controls (HCs). The levels of sICOSL and sPD-1 were significantly upregulated in USMG patients compared to those in the RSMG and HC groups, while the levels of sICOS and sPD-L1 were not different. The expression of PD-L1 on CD19+ B cells was positively correlated with the concentrations of AchR Ab in the USMG group. The expression of ICOS and PD-1 in CD4+ T cells and the expression of ICOSL and PD-L1 on CD19+ B cells were positively correlated with the quantitative myasthenia gravis (QMG) scores in the USMG group. Also, in the USMG group, the plasma levels of sICOSL and sPD-1 were positively correlated with the QMG scores. In addition, the percentage of peripheral blood follicular helper T (Tfh) cells in the USMG group was positively correlated with ICOS and PD-1 expression on CD4+ T cells and ICOSL and PD-L1 expression on CD19+ B cells. There were positive correlations between sICOSL and sPD-1 levels and the percentage of peripheral blood Tfh cells and plasma interleukin-21 (IL-21) levels in the USMG group. The results suggest that the positive ICOS/ICOSL and negative PD-1/PD-L1 costimulatory molecule pairs participate in the pathological process of MG. Abnormal sICOSL and sPD-1 expression might interfere with the normal signal transduction of ICOS and PD-1 on Tfh cells, causing excessive activation of Tfh cells and promotion of disease progression. sICOSL and sPD-1 have potential value in monitoring MG disease states.

A short-term stimulation of ethanol enhances the effect of magnetite on anaerobic digestion.

Conductive iron oxides (CIO) have been proved recently to facilitate the anaerobic microbial syntrophy based on the direct interspecies electron transfer (DIET) in batch experiments. However, the effect of CIO was always insignificant in anaerobic digestion (AD) reactor especially when the DIET-based syntrophic partners were absent. In this study, the effect of magnetite on performance of AD system with sucrose as a sole carbon source was investigated, but limited enhancement was achieved during the first 36-day operation. The short-term effect of ethanol addition was further studied in the magnetite-amended AD reactor, and results showed that the AD reactor with 10gFe/L micro-sized magnetite (R3) achieved higher performance of COD removal and methane proportion compared with the other reactors (R1 without magnetite; R2 with 2gFe/L micro-sized magnetite; R4 with 2gFe/L nano-sized magnetite). Meanwhile, the pyridoxine in extracellular polymeric substances (EPS) and conductivity of anaerobic sludge from R3 increased more significantly than those of the others. Analysis of high-throughput sequencing indicated that the abundance of archaea increased in sludge from R3 and Methanosarcina responsible for DIET was dominant (63.64%). Additionally, the abundance of potential electroactive bacteria Chloroflexi in R3 was 7.57-fold, 3.61-fold and 7.37-fold as that of R1, R2 and R4, respectively. These results demonstrated that the electroactive microbes and methanogens could be enriched efficiently in anaerobic sludge via synergetic effect of magnetite addition and ethanol short-term stimulation.

Telomeric repeat-containing RNA (TERRA) related to polycystic ovary syndrome (PCOS).

CONTEXT: Telomeric repeat-containing RNA (TERRA) participates in the regulation of telomere length, and leucocyte telomere length (LTL) plays an important role in the pathophysiology of polycystic ovary syndrome (PCOS), but little is known about the role of TERRA in PCOS. OBJECTIVE: To evaluate the role of TERRA and peripheral blood LTL in PCOS. DESIGN AND PARTICIPANTS: Forty women with PCOS and 35 healthy women without PCOS were recruited. A prospective case-control study was performed. MEASUREMENTS: RNA fluorescence in situ hybridization (FISH) was used to detect TERRA expression in peripheral blood leucocyte. Quantitative PCR was used to measure TERRA expression and the mean LTL in the PCOS and control groups. We analysed the association between related clinical parameters and the age-adjusted ratio of the telomere repeat length (T/S ratio) or TERRA. RESULTS: Telomeric repeat-containing RNA was expressed in human peripheral blood leucocytes, and the signal was abolished after culture with RNase A. The age-adjusted LTLs were significantly longer in the PCOS group than in the control group (P < 0·01). The age-adjusted TERRA level was significantly lower in the PCOS group than in the control group (P < 0·01). Testosterone (TTE) was related positively to LTL and negatively to TERRA in the PCOS group (r = 0·532, P = 0·002; r = -0·477, P = 0·017). CONCLUSION: We found TERRA expression in human peripheral blood leucocytes, and LTLs were positively associated with PCOS. TERRA and testosterone play an important role in the LTL regulation in PCOS.

Plasmonic and photo-electrochemical enhancements of the AuAg@Au/RGO-C3N4 nanocomposite for the detection of DA.

Plasmonic photocatalyst has attracted significant attention due to its valuable theoretical study and promising practical applications in solar cells, functional composites, and sensors. Herein, an interesting RGO-C3N4-supported AuAg core-Au shell (AuAg@Au) nanocomposite has been reported. Due to the surface plasmon resonance (SPR) of AuAg@Au and the accelarated electron transfer and separation of charge carriers induced by the fascinating RGO-C3N4 substrate, the newly-generated AuAg@Au/RGO-C3N4 nanomaterials show a strong photo-electrochemical response under visible-light irradiation. The AuAg@Au/RGO-C3N4 photocatalyst demonstrated an excellent photo-electrochemical performance with a broad concentration linear range of 0.064-780.904 µM and a low detection limit of 0.022 µM, high stability, and good selectivity when applied in the determination of dopamine (DA) under visible-light irradiation.

Expression of Clonorchis sinensis GIIIsPLA2 protein in baculovirus-infected insect cells and its overexpression facilitating epithelial-mesenchymal transition in Huh7 cells via AKT pathway.

Although prior studies confirmed that group III secretory phospholipase A2 of Clonorchis sinensis (CsGIIIsPLA2) had stimulating effect on liver fibrosis by binding to LX-2 cells, large-scale expression of recombinant protein and its function in the progression of hepatoma are worth exploring. Because of high productivity and low lipopolysaccharides (LPS) in the Sf9-baculovirus expression system, we firstly used this system to express the coding region of CsGIIIsPLA2. The molecular weight of recombinant CsGIIIsPLA2 protein was about 34 kDa. Further investigation showed that most of the recombinant protein presented intracellular expression in Sf9 insect cell nucleus and could be detected only into cell debris, which made the protein purification and further functional study difficult. Therefore, to study the role of CsGIIIsPLA2 in hepatocellular carcinoma (HCC) progression, CsGIIIsPLA2 overexpression Huh7 cell model was applied. Cell proliferation, migration, and the expression level of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, N-cadherin, α-catenin, Vimentin, p300, Snail, and Slug) along with possible mechanism were measured. The results indicated that CsGIIIsPLA2 overexpression not only inhibited cell proliferation and promoted migration and EMT but also enhanced the phosphorylation of AKT in HCC cells. In conclusion, this study supported that CsGIIIsPLA2 overexpression suppressed cell proliferation and induced EMT through the AKT pathway.

Design of PdAg Hollow Nanoflowers through Galvanic Replacement and Their Application for Ethanol Electrooxidation.

In this study, galvanic replacement provides a simple route for the synthesis of PdAg hollow nanoflower structures by using the Ag-seeds as sacrificial templates in the presence of l-ascorbic acid (reductant) and CTAC (capping agent). Transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and EDS mapping were used to characterize the as-prepared PdAg hollow nanoflower catalysts, where they were alloyed nanoflower structures with hollow interiors. By maneuvering the Pd/Ag ratio, we found that the as-prepared Pd1 Ag3 hollow nanoflower catalysts had the optimized performance for catalytic activity toward ethanol oxidation reaction. Moreover, these as-prepared PdAg hollow nanoflower catalysts exhibited noticeably higher electrocatalytic activity as compared to pure Pd and commercial Pd/C catalysts due to the alloyed Ag-Pd composition as well as the hollow nanoflower structures. It is anticipated that this work provides a rational design of other architecturally controlled bimetallic nanocrystals for application in fuel cells.

A facile fabrication of copper particle-decorated novel graphene flower composites for enhanced detecting of nitrite.

We describe a simple electrochemical preparation method of a novel three dimensional (3D) graphene material, porous flower-like reduced graphene oxide (f-RGO) nanosheets, which was explored as the support for Cu particles on a glassy carbon electrode (Cu/f-RGO/GCE) for detecting nitrite. In morphology studies, scanning electron microscopy (SEM) demonstrates the 3D porous structure of f-RGO enlarges the surface area of the electrode and promotes more Cu particles depositing on the surface of f-RGO with homogeneous dispersion. In cyclic voltammetry (CV), a well-defined voltammetric peak along with the remarkable reduction current indicates excellent electrocatalytic activity of the Cu/f-RGO/GCE for NaNO2 reduction compared with other corresponding electrodes. The effects of pH value and detection potential on the current responses of Cu/f-RGO/GCE towards nitrite were optimized to obtain the maximal sensitivity. In the optimal experimental conditions, Cu/f-RGO/GCE displays the wide detection range from 0.15 µM to 10,500 µM and the low limit of detection of 0.06 µM (S/N = 3) with fast response time 2 s for detecting NaNO2 through an amperometric method. Furthermore, the presence of K(+), Na(+), Cl(-), NH4(+), NO3(-), SO4(2-) and ascorbic acid show a negligible effect on the current response of nitrite determination suggesting Cu/f-RGO/GCE have the high selectivity for detecting nitrite even in the presence of high concentration of interferents. Moreover, the real sample determination experiment indicated practical feasibility of the obtained sensor. The prepared sensor for determination of NaNO2 exhibited wide liner range, low detection limit, good reproducibility, nice stability and remarkable anti-interference ability. In this paper, not only did the Cu/f-RGO/GCE show high performance for determination of nitrite, but also it was simple to prepare, user-friendly and cost-effective.

Reduced graphene oxide modified highly ordered TiO2 nanotube arrays photoelectrode with enhanced photoelectrocatalytic performance under visible-light irradiation.

In this paper, reduced graphene oxide modified highly ordered TiO2 nanotube arrays (RGO-TNTs) have been fabricated and used for photoelectrocatalytic (PEC) degradation of organic pollutants under visible light irradiation. Firstly, the RGO-TNT electrode was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Raman, FT-IR, X-ray photoelectron spectroscopy (XPS) and UV-vis diffuse reflectance spectroscopy. The responsive photocurrent and electrochemical impedance spectroscopy (EIS) results indicated that our present RGO-TNTs displayed superior photoresponsive and electron transfer performances compared with bare TNTs. Moreover, by comparison with bare TNT electrode, the RGO-TNT arrays showed stable and evidently improved PEC activity for degradation of methyl orange (MO) under visible light illumination. This might be attributed to the introduction of RGO, which extended the absorption edge and promoted electron-hole separation in the PEC process. Furthermore, owing to the synergetic effect of photocatalysis and electrocatalysis in the PEC process, the efficiency of PEC process (3.0 × 10(-3) min(-1)) is ca. 7.9 and 2.5 times faster than that of the electrochemical process (3.8 × 10(-4) min(-1)) and photocatalytic process (1.2 × 10(-3) min(-1)), respectively. Our investigation likely provides new opportunities for developing stable and efficient one-dimensional graphene modified TNT-based catalysts for PEC degradation of organic pollutants under visible light illumination.

Nanoscale exopolymer reassembly-trap mechanism determines contrasting PFOS exposure patterns in aquatic animals with different feeding habitats: A nano-visualization study.

The behavior and fate of PFOS (perfluorooctanesulfonate) in the aquatic environment have received great attention due to its high toxicity and persistence. The nanoscale supramolecular mechanisms of interaction between PFOS and ubiquitous EPS (exopolymers) remain unclear though EPS have been widely-known to influence the bioavailability of PFOS. Typically, the exposure patterns of PFOS in aquatic animals changed with the EPS-PFOS interaction are not fully understood. This study hypothesized that PFOS exposure and accumulation pathways depended on the PFOS-EPS interactive assembly behavior and animal species. Two model animals, zebrafish and chironomid larvae, with different feeding habitats were chosen for the exposure and accumulation tests at the environmental concentrations of PFOS in the absence and presence of EPS. It was found that PFOS triggered the self-assembly of EPS to form large aggregates which significantly trapped PFOS. PFOS accumulation was significantly promoted in zebrafish but drastically reduced in chironomid larvae because of the nanoscale interactive assembly between EPS and PFOS. The decreased dermal uptake but increased oral uptake of PFOS by zebrafish with large mouthpart size could be ascribed to the increased ingestion of PFOS-enriched EPS aggregates as food. For the chironomid larvae with small mouthpart size, the PFOS-EPS assemblies reduced the dermal, oral and intestinal uptake of PFOS. The nano-visualization evidences confirmed that the PFOS-enriched EPS-PFOS assemblies blocked PFOS penetration through skin of both animals. These findings provide novel knowledge about the ecological risk of PFOS in aquatic environments.

Effect of Composition Characteristics on Mechanical Properties of UHPMC Based on Response Surface Methodology and Acoustic Emission Monitoring.

Manufactured sand (MS) is a promising alternative aggregate to quartz sand (QS) in ultra-high-performance concrete (UHPC) in the preparation of ultra-high-performance manufactured sand concrete (UHPMC), which possesses the characteristics of high strength, low cost, and environmental friendliness. In this study, the effects of variable compositional characteristics including the water-binder ratio, the stone powder (SP) content, and the MS replacement ratio on the mechanical and flexural strength of UHPMC were compared and analyzed based on response surface methodology (RSM). Meanwhile, the damage characteristics of UHPMC during compressive and flexural stress were monitored and evaluated using acoustic emission (AE) technology. The results reveal that the compressive and flexural strengths of UHPMC are both negatively correlated with the water-binder ratio, while they are positively correlated with the MS replacement rate. They tend to firstly increase and subsequently decrease with the increase in the stone powder content. In the load-displacement curve of concrete with a high MS replacement ratio and a low water-binder ratio, the slope in the elastic stage is steeper, the stiffness is higher, and the bending toughness and ductility are also better. The specimens with a 10% to 0% stone powder content present a steeper elastic phase slope, a slightly higher stiffness, and superior ductility. The specimens with a low MS replacement ratio and a high water-binder ratio display earlier cracking and weaker resistance, and the destruction process is complex and very unstable. The damage mode analysis based on RA-AF shows that an increase in the MS replacement ratio and a decrease in the water-binder ratio can both reduce the tensile cracking of UHPMC specimens under a four-point bending test. Although 10% stone powder can marginally slow down crack growth, the failure mode is not significantly affected.

Research progress of extracellular vesicles in the treatment of ovarian diseases (Review).

The ovary is an essential reproductive organ in the female organism and its development seriously affects the physical and mental health of female patients. Ovarian diseases include ovarian cancer, premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS). Women should pay attention to the most effective treatments for this condition because it is one of the most prevalent gynecological illnesses at present. Extracellular vesicles (EVs), which are smaller vesicles that mediate the exchange of cellular information, include the three categories of exosomes, microvesicles and apoptotic bodies. They are able to transport proteins, RNA and other substances to adjacent or distal cells, thus allowing cellular and tissue homeostasis to be maintained. Numerous previous studies have revealed that EVs are crucial for the treatment of ovarian diseases. They are known to transport its contents to ovarian cancer cells as well as other ovarian cells such as granulosa cells, affecting the development of ovarian disease processes. Therefore, this extracellular vesicle may be involved as a target in the therapeutic process of ovarian disease and may have great potential in the treatment of ovarian disease. In the present review, the role of EVs in the development of three ovarian diseases, including ovarian cancer, POI and PCOS, was mainly summarizes. It is expected that this will provide some theoretical support for the treatment of ovarian disease.

Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance.

INTRODUCTION: Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature. OBJECTIVES: To elucidate the role of LAMs in mediating ibrutinib resistance in MCL. METHODS: We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 inhibitor, could reverse ibrutinib resistance through CCK-8 and caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line. RESULTS: In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone. CONCLUSION: Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.

The patients with multiple myeloma were infected with COVID-19 during autologous stem cell transplantation: case report and literature review.

This paper introduces two cases of multiple myeloma, COVID-19 infection during autologous stem cell transplantation, the treatment process, and different results of the two patients, which provides a reference for how to carry out ASCT safely during the COVID-19 normalization stage.

Research progress on the fanconi anemia signaling pathway in non-obstructive azoospermia.

Non-obstructive azoospermia (NOA) is a disease characterized by spermatogenesis failure and comprises phenotypes such as hypospermatogenesis, mature arrest, and Sertoli cell-only syndrome. Studies have shown that FA cross-linked anemia (FA) pathway is closely related to the occurrence of NOA. There are FA gene mutations in male NOA patients, which cause significant damage to male germ cells. The FA pathway is activated in the presence of DNA interstrand cross-links; the key step in activating this pathway is the mono-ubiquitination of the FANCD2-FANCI complex, and the activation of the FA pathway can repair DNA damage such as DNA double-strand breaks. Therefore, we believe that the FA pathway affects germ cells during DNA damage repair, resulting in minimal or even disappearance of mature sperm in males. This review summarizes the regulatory mechanisms of FA-related genes in male azoospermia, with the aim of providing a theoretical reference for clinical research and exploration of related genes.

Increased coexpression of PD-L1 and IDO1 is associated with poor overall survival in patients with NK/T-cell lymphoma.

Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma.