Maternal-fetal immunity and recurrent spontaneous abortion.

Recurrent Spontaneous Abortion (RSA) is a common pregnancy complication, that has multifactorial causes, and currently, 40%-50% of cases remain unexplained, referred to as Unexplained RSA (URSA). Due to the elusive etiology and mechanisms, clinical management is exceedingly challenging. In recent years, with the progress in reproductive immunology, a growing body of evidence suggests a relationship between URSA and maternal-fetal immunology, offering hope for the development of tailored treatment strategies. This article provides an immunological perspective on the pathogenesis, diagnosis, and treatment of RSA. On one hand, it comprehensively reviews the immunological mechanisms underlying RSA, including abnormalities in maternal-fetal interface immune tolerance, maternal-fetal interface immune cell function, gut microbiota-mediated immune dysregulation, and vaginal microbiota-mediated immune anomalies. On the other hand, it presents the diagnosis and existing treatment modalities for RSA. This article offers a clear knowledge framework for understanding RSA from an immunological standpoint. In conclusion, while the "layers of the veil" regarding immunological factors in RSA are gradually being unveiled, our current research may only scratch the surface. In terms of immunological etiology, effective diagnostic tools for RSA are currently lacking, and the efficacy and safety of immunotherapies, primarily based on lymphocyte immunotherapy and intravenous immunoglobulin, remain contentious.

Chemotherapy regimen for recurrent uterine leiomyosarcoma.

INTRODUCTION: Uterine leiomyosarcoma is a rare gynecological malignancy, the limited literature indicated that doxorubicin alone or gemcitabine/docetaxel combination is the preferred chemotherapy regimen. Given the rarity of the disease and the lack of high-level clinical evidence, there is no consensus on the best treatment. CASE REPORT: We report a case of a patient with uterine leiomyosarcoma who recurred after adjustment treatment with doxorubicin, gemcitabine, docetaxel, and anlotinib; and required a new chemotherapy regimen. MANAGEMENT AND OUTCOMES: The follow-up chemotherapy regimen was doxorubicin-liposome 40 mg/m2 on one day in combination with dacarbazine 250 mg/m2 on one to five days of intravenous infusion every 21 days. We monitored adverse effects during chemotherapy and the process was smooth. DISCUSSION: It is important to comprehensively consider the patient's condition, and fully consider the efficacy, dosage, and adverse reactions of the chemotherapy regimen to determine the appropriate plan, in order to achieve the best therapeutic benefits for patients.

Glycolithocholic acid increases the frequency of circulating Tregs through constitutive androstane receptor to alleviate postmenopausal osteoporosis.

BACKGROUND AND PURPOSE: Gut microbiota and their metabolic activity are important regulators of host immunity. However, the role of gut microbiota and their metabolic activity-mediated osteoimmunity in postmenopausal osteoporosis (PMO) remains unknown. This study aimed to explore the role of gut microbiota and their metabolic activity in PMO. EXPERIMENTAL APPROACH: 16S rDNA sequencing was used for analyzing the gut microbiota diversity of patients with PMO and rat models, and a targeted metabolism study was performed for analyzing metabolite levels. Flow cytometry was used for analyzing the frequency of immune cells. Micro-CT was used for analyzing bone damage in rat models. Fecal microbiota transplantation was performed for exploring the therapeutic effect of the gut microbiota on PMO. CD4+ T cells were co-cultured with bone marrow mesenchymal stem cells for evaluating their molecular mechanisms. KEY RESULTS: Patients with PMO exhibited reduced gut microbiota diversity, and fecal glycolithocholic acid (GLCA) levels correlated with the degree of osteoporosis. GLCA levels in the gut were positively correlated with the frequency of circulating Tregs in ovariectomized rats. Restoration of the gut microbiota alleviated osteoporosis in ovariectomized rats. Circulating GLCA augmented CD4+ T cell differentiation into Tregs via constitutive androstane receptors. The increased frequency of Tregs further promoted the osteogenic differentiation of bone marrow mesenchymal stem cells to alleviate osteoporosis. CONCLUSION AND IMPLICATIONS: GLCA alleviated PMO by increasing the frequency of circulating Tregs, acting via the constitutive androstane receptor. This study reveals a new strategy for the treatment of PMO, with GLCA as a potential drug candidate.

Confocal microscopy based on dual blur depth measurement.

In this paper, we propose a confocal microscopy based on dual blur depth measurement (DBCM). The first blur is defocus blur, and the second blur is artificial convolutional blur. First, the DBCM blurs the defocus image using a known Gaussian kernel and calculates the edge gradient ratio between it and the re-blurred image. Then, the axial measurement of edge positions is based on a calibration measurement curve. Finally, depth information is inferred from the edges using the original image. Experiments show that the DBCM can achieve depth measurement in a single image. In a 10×/0.25 objective, the error measured for a step sample of 4.7397 µm is 0.23 µm. The relative error rate is 4.8%.

Confocal microscopy multi-focus image fusion method based on axial information guidance.

Aiming at the problems of poor anti-interference of existing pixel-level fusion rules and low efficiency of transform domain fusion rules, this study proposes a confocal microscopic multi-focus image fusion method (IGCM) based on differential confocal axial information guidance. Unlike traditional multi-focus image fusion (MFIF) methods, IGCM uses height information rather than grayscale or frequency to determine clear areas. First, the differential confocal axial measurement curve is calibrated to determine the suitable scan step u. Second, the image set required for fusion is constructed by performing a hierarchical scan of the measurement samples. Then, multiple differential image pairs are constructed using the step size u and the set of images, and the extraction area of the current reference image is decided based on the height obtained from the differential image. Finally, the regions determined by each reference image are extracted and the duplicated pixels are averaged to obtain the MFIF image. The results were that IGCM improves the interference immunity based on pixel-level image fusion compared to the maximum peak fusion method. Compared with other MFIFs, IGCM has excellent fusion efficiency while ensuring fusion clarity, which can meet the application scenario of real-time fusion and offers a new approach to panoramic depth images for confocal devices.

Combat Against Gynecological Cancers with Blood Vessels as Entry Point: Anti-Angiogenic Drugs, Clinical Trials and Pre-Clinical Nano-Delivery Platforms.

Angiogenesis is an essential mechanism for the progression of gynecological cancers. Although approved anti-angiogenic drugs have demonstrated clinical efficacy in treating gynecological cancers, the full potential of therapeutic strategies based on tumor blood vessels has not yet been realized. This review summarizes the latest angiogenesis mechanisms involved in the progression of gynecological cancers and discusses the current clinical practice of approved anti-angiogenic drugs and related clinical trials. Given the close relationship between gynecological cancers and blood vessels, we highlight more delicate strategies for regulating tumor vessels, including wise drug combinations and smart nano-delivery platforms to achieve highly efficient drug delivery and overall vessel microenvironment regulation. We also address current challenges and future opportunities in this field. We aim to generate interest in therapeutic strategies that target blood vessels as a key entry point and offer new potential and inspiration for combating gynecological cancers.

Differential confocal over-range determination method based on an information theory.

The existing differential confocal axial three-dimensional (3D) measurement method cannot determine whether the surface height of the sample in the field of view is within its effective measurement range. Therefore, in this paper, we propose a differential confocal over-range determination method (IT-ORDM) based on an information theory to determine whether the surface height information of the sample to be examined is within the effective measurement range of the differential confocal axial measurement. First, the IT-ORDM finds the boundary position of the axial effective measurement range by the differential confocal axial light intensity response curve. Then the effective intensity measurement ranges of the pre-focus axial response curve (ARC) and the post-focus ARC are determined by the correspondence between the boundary position and the ARC. Finally, the intersection operation of the pre-focus image of effective measurement and the post-focus image of effective measurement is used to realize the extraction of the effective measurement area of the differential confocal image. The experimental results show that the IT-ORDM can effectively determine and restore the 3D shape of the measured sample surface at the reference plane position in the multi-stage sample experiments.

Nanotechnology-integrated ferroptosis inducers: a sharp sword against tumor drug resistance.

Presently, the biggest hurdle to cancer therapy is the inevitable emergence of drug resistance. Since conventional therapeutic schedules fall short of the expectations in curbing drug resistance, the development of novel drug resistance management strategies is critical. Extensive research over the last decade has revealed that the process of ferroptosis is correlated with cancer resistance; moreover, it has been demonstrated that ferroptosis inducers reverse drug resistance. To elucidate the development and promote the clinical transformation of ferroptosis strategies in cancer therapy, we first analyzed the roles of key ferroptosis-regulating molecules in the progression of drug resistance in-depth and then reviewed the design of ferroptosis-inducing strategies based on nanotechnology for overcoming drug resistance, including glutathione depletion, reactive oxygen species generation, iron donation, lipid peroxidation aggregation, and multiple-drug resistance-associated tumor cell destruction. Finally, the prospects and challenges of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance were evaluated. This review aimed to provide a comprehensive understanding for researchers to develop ferroptosis-inducing nanoplatforms that can overcome drug resistance.

Short-chain fatty acids regulate B cells differentiation via the FFA2 receptor to alleviate rheumatoid arthritis.

BACKGROUND AND PURPOSE: Short-chain fatty acids (SCFAs) are metabolites from gut microbes involved in the host's inflammatory response and immunity. The aim of this study was to investigate the role of SCFAs in rheumatoid arthritis (RA) and possible mechanisms. EXPERIMENTAL APPROACH: Gut microbiota diversity in mice was analysed by 16S rDNA sequencing. SCFAs levels were analysed by gas chromatography mass spectrometry. T and B cells were analysed by flow cytometry. Bone damage was analysed by micro-CT and X-ray. Histopathological status was analysed by HE staining. Proteins in tissues were analysed by immunohistochemistry and PCR. Mice with CD19+ B cells deficient in FFA2 receptors were used to explore the molecular mechanisms involved. KEY RESULTS: Levels of acetate, propionate, butyrate, and valerate were decreased in RA patients, and the first three correlated positively with the frequency of Bregs but not Tregs in peripheral blood. Administration of the three SCFAs prior to the onset of collagen-induced arthritis in mice improved arthritic symptoms, increased the Bregs frequency, and decreased transitional B and follicular B cell frequency. However, the preceding phenomena could not be observed in mice with CD19+ B cells deficient in FFA2 receptors. The effects of the three SCFAs in RA were dependent on FFA2 receptors but were independent of the other five B cell receptors (FFA3 receptor, HCA2 receptor, PPARγ, Olfr-78, and AhR). CONCLUSIONS AND IMPLICATIONS: SCFAs regulate B cells differentiation via FFA2 receptors to alleviate RA. This provides new insights into the treatment of RA from an immunological and microbiological perspective.

The role of short-chain fatty acids in immunity, inflammation and metabolism.

Short-chain fatty acids (SCFAs) are carboxylic acids with carbon atom numbers less than 6, which are important metabolites of gut microbiome. Existing research shows that SCFAs play a vital role in the health and disease of the host. First, SCFAs are the key energy source for colon and ileum cells, and affect the intestinal epithelial barrier and defense functions by regulating related gene expression. Second, SCFAs regulate the function of innate immune cells to participate in the immune system, such as macrophages, neutrophils and dendritic cells. Third, SCFAs can also regulate the differentiation of T cells and B cells and the antigen-specific adaptive immunity mediated by them. Besides, SCFAs are raw materials for sugar and lipid synthesis, which provides a theoretical basis for studying the potential role of SCFAs in regulating energy homeostasis and metabolism. There are also studies showing that SCFAs inhibit tumor cell proliferation and promote apoptosis. In this article, we summarized in detail the role of SCFAs in immunity, inflammation and metabolism, and briefly introduced the role of SCFAs in tumor cell survival. It provides a systematic theoretical basis for the study of SCFAs as potential drugs to promote human health.

The Role of Microbiota in Infant Health: From Early Life to Adulthood.

From early life to adulthood, the microbiota play a crucial role in the health of the infant. The microbiota in early life are not only a key regulator of infant health but also associated with long-term health. Pregnancy to early life is the golden time for the establishment of the infant microbiota, which is affected by both environmental and genetic factors. Recently, there is an explosion of the studies on the role of microbiota in human diseases, but the application to disease or health is relatively limited because many aspects of human microbiota remain controversial, especially about the infant microbiota. Therefore, a critical and conclusive review is necessary to understand fully the relationship between the microbiota and the health of infant. In this article, we introduce in detail the role of microbiota in the infant from pregnancy to early life to long-term health. The main contents of this article include the relationship between the maternal microbiota and adverse pregnancy outcomes, the establishment of the neonatal microbiota during perinatal period and early life, the composition of the infant gut microbiota, the prediction of the microbiota for long-term health, and the future study directions of microbiota.

Engineering of bioactive metal sulfide nanomaterials for cancer therapy.

Metal sulfide nanomaterials (MeSNs) are a novel class of metal-containing nanomaterials composed of metal ions and sulfur compounds. During the past decade, scientists found that the MeSNs engineered by specific approaches not only had high biocompatibility but also exhibited unique physicochemical properties for cancer therapy, such as Fenton catalysis, light conversion, radiation enhancement, and immune activation. To clarify the development and promote the clinical transformation of MeSNs, the first section of this paper describes the appropriate fabrication approaches of MeSNs for medical science and analyzes the features and limitations of each approach. Secondly, we sort out the mechanisms of functional MeSNs in cancer therapy, including drug delivery, phototherapy, radiotherapy, chemodynamic therapy, gas therapy, and immunotherapy. It is worth noting that the intact MeSNs and the degradation products of MeSNs can exert different types of anti-tumor activities. Thus, MeSNs usually exhibit synergistic antitumor properties. Finally, future expectations and challenges of MeSNs in the research of translational medicine are spotlighted.

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases.

Osteoimmunity is involved in regulating the balance of bone remodeling and resorption, and is essential for maintaining normal bone morphology. The interaction between immune cells and osteoclasts in the bone marrow or joint cavity is the basis of osteoimmunity, in which the macrophage-osteoclast axis plays a vital role. Monocytes or tissue-specific macrophages (macrophages resident in tissues) are an important origin of osteoclasts in inflammatory and immune environment. Although there are many reports on macrophages and osteoclasts, there is still a lack of systematic reviews on the macrophage-osteoclast axis in osteoimmunity. Elucidating the role of the macrophage-osteoclast axis in osteoimmunity is of great significance for the research or treatment of bone damage caused by inflammation and immune diseases. In this article, we introduced in detail the concept of osteoimmunity and the mechanism and regulators of the differentiation of macrophages into osteoclasts. Furthermore, we described the role of the macrophage-osteoclast axis in typical bone damage caused by inflammation and immune diseases. These provide a clear knowledge framework for studying macrophages and osteoclasts in inflammatory and immune environments. And targeting the macrophage-osteoclast axis may be an effective strategy to treat bone damage caused by inflammation and immune diseases.

Bioactive metal-containing nanomaterials for ferroptotic cancer therapy.

The clinical performance of the current cancer therapies is still far from satisfactory. The emerging ferroptosis-driven therapy strategies reignite the hope of chemotherapy in tumor treatment due to their incredible tumor suppression. Among ferroptosis-based cancer therapies, metal elements have attracted remarkable attention due to their inherent physicochemical properties in inducing ferroptosis of tumor cells quickly and strongly without complex cellular signal transduction. Although the discovery and applications of ferroptosis for tumor treatment have been discussed in many reviews, the unique advantages of metal-containing nanomaterials interfering ferroptotic cancer therapies (MIFCT) have seldom been mentioned. Here, we outline the latest advances of MIFCT comprehensively. Firstly, the functions of different kinds of metal elements or their ions are introduced to illustrate their advantages in MIFCT. Secondly, the emerging metal-containing nanomaterials that are designed to achieve ferroptosis-driven therapy are overviewed, including their ability to boost the Fenton or Fenton-like reaction for reactive oxygen species generation, act as hydrogen peroxide self-providers, damage the reducing system, and disturb cellular communication. Moreover, metal-containing nanomaterials with external energy conversion features for MIFCT are discussed. Finally, the future expectations and challenges of MIFCT for clinical cancer therapy are spotlighted.

Construction of arsenic-metal complexes loaded nanodrugs for solid tumor therapy: A mini review.

Arsenic trioxide (As2O3), a front-line therapeutic agent against acute promyelocytic leukemia, has a broad spectrum against malignancies. Unfortunately, the clinical application of As2O3 in treating hematological cancers has not been transformed to solid tumors, for its dose-limited toxicity and undesirable pharmacokinetics. The ordinary As2O3 loaded nanodrugs (such as liposomes, polymer micelles, albumin-based nanodrugs, and silica-based nanodrugs, etc.) still could not fuel up pharmaceuticals and eradicate toxicity for low delivery efficiency caused by the instability and severe drug leakage of formulations during circulation. Recently, the approach of forming and delivering arsenic-metal complexes which will dissociate in the tumoral environment caught our mind. This is the most effective strategy to reduce drug leakage in circulation and accumulate arsenite ions in tumor sites, therefore promote the anti-tumor effect and lighten the toxicity of the drug. This review aims to explain the formation mechanism of arsenic-metal nanocomposites and summarize the constructing strategies of the arsenic-metal nanocomplexes (arsenic-nickel, arsenic-manganese, arsenic-platinum, arsenic-gadolinium, arsenic-zinc, and arsenic-iron nanobins) loaded nanodrugs for solid tumor therapy. Furthermore, the expectations and challenges of arsenic-metal complexes containing nanodrugs for cancer therapy in the future were discussed.

Efficient delivery of Notch1 siRNA to SKOV3 cells by cationic cholesterol derivative-based liposome.

A novel cationic cholesterol derivative-based small interfering RNA (siRNA) interference strategy was suggested to inhibit Notch1 activation in SKOV3 cells for the gene therapy of ovarian cancer. The cationic cholesterol derivative, N-(cholesterylhemisuccinoyl-amino-3-propyl)-N, N-dimethylamine (DMAPA-chems) liposome, was incubated with siRNA at different nitrogen-to-phosphate ratios to form stabilized, near-spherical siRNA/DMAPA-chems nanoparticles with sizes of 100-200 nm and zeta potentials of 40-50 mV. The siRNA/DMAPA-chems nanoparticles protected siRNA from nuclease degradation in 25% fetal bovine serum. The nanoparticles exhibited high cell uptake and Notch1 gene knockdown efficiency in SKOV3 cells at an nitrogen-to-phosphate ratio of 100 and an siRNA concentration of 50 nM. They also inhibited the growth and promoted the apoptosis of SKOV3 cells. These results may provide the potential for using cationic cholesterol derivatives as efficient nonviral siRNA carriers for the suppression of Notch1 activation in ovarian cancer cells.

Antitumor effects of cecropin B-LHRH' on drug-resistant ovarian and endometrial cancer cells.

BACKGROUND: Luteinizing hormone-releasing hormone receptor (LHRHr) represents a promising therapeutic target for treating sex hormone-dependent tumors. We coupled cecropin B, an antimicrobial peptide, to LHRH', a form of LHRH modified at carboxyl-terminal residues 4-10, which binds to LHRHr without interfering with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. This study aimed to assess the antitumor effects of cecropin B-LHRH' (CB-LHRH') in drug-resistant ovarian and endometrial cancers. METHODS: To evaluate the antitumor effects of CB-LHRH', three drug resistant ovarian cancer cell lines (SKOV-3, ES-2, NIH:OVCAR-3) and an endometrial cancer cell line (HEC-1A) were treated with CB-LHRH'. Cell morphology changes were assessed using inverted and electron microscopes. In addition, cell growth and cell cytotoxicity were measured by MTT assay and LDH release, respectively. In addition, hemolysis was measured. Furthermore, radioligand receptor binding, hypersensitization and minimal inhibitory concentrations (against Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, and Acinetobacter baumannii) were determined. Finally, the impact on tumor growth in BALB/c-nu mice was assessed in an ES-2 xenograft model. RESULTS: CB-LHRH' bound LHRHr with high-affinity (dissociation constant, Kd = 0.252 ± 0.061 nM). Interestingly, CB-LHRH' significantly inhibited the cell viability of SKOV-3, ES-2, NIH:OVCAR-3 and HEC-1A, but not that of normal eukaryotic cells. CB-LHRH' was active against bacteria at micromolar concentrations, and caused no hypersensitivity in guinea pigs. Furthermore, CB-LHRH' inhibited tumor growth with a 23.8 and 20.4 % reduction in tumor weight at 50 and 25 mg/kg.d, respectively. CONCLUSIONS: CB-LHRH' is a candidate for targeted chemotherapy against ovarian and endometrial cancers.

Specific targeting of A54 homing peptide-functionalized dextran-g-poly(lactic-co-glycolic acid) micelles to tumor cells.

The delivery of chemotherapeutics into tumor cells is a fundamental knot for tumor-target therapy to improve the curative effect and avoid side effects. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA self-assembled to form micelles with a low critical micelle concentration of 16.79 µg·mL(-1) and diameter of about 50 nm. With doxorubicin (DOX) base as a model antitumor drug, the drug-encapsulation efficiency of DOX-loaded A54-Dex-PLGA micelles (A54-Dex-PLGA/DOX) reached up to 75%. In vitro DOX release from the A54-Dex-PLGA/DOX was prolonged to 72 hours. The A54-Dex-PLGA micelles presented excellent internalization ability into hepatoma cells (BEL-7402 cell line and HepG2 cell line) in vitro, and the cellular uptake of the micelles by the BEL-7402 cell line was specific, which was demonstrated by the blocking experiment. In vitro antitumor activity studies confirmed that A54-Dex-PLGA/DOX micelles suppressed tumor-cell (BEL-7402 cell) growth more effectively than Dex-PLGA micelles. Furthermore, in vivo biodistribution testing demonstrated that the A54-Dex-PLGA micelles had a higher distribution ability to BEL-7402 tumors than that to HepG2 tumors.

Knockdown of STAT3 expression in SKOV3 cells by biodegradable siRNA-PLGA/CSO conjugate micelles.

Biodegradable and biocompatible poly(d,l-lactic-co-glycolic acid) (PLGA)was conjugated to the 5'-thiol end of signal transducer and activator of transcription 3 (STAT3) small interfering RNA (STAT3-siRNA) via a disulfide bond. In aqueous environments, these siRNA-PLGA conjugates can spontaneously form core/shell type spherical micelles with a particle size of about 200 nm. A biodegradable, low molecular weight cationic polymer, chitosan oligosaccharide (CSO), was added to the siRNA-PLGA micelles at different nitrogen to phosphate (N/P) ratios to form stable, spherical siRNA-PLGA/CSO micelles with sizes of 150-180 nm. The siRNA-PLGA/CSO micelles were produced via ionic complexation between negatively charged siRNA and positively charged CSO on the outer shell of the micelles. The siRNA-PLGA/CSO micelles exhibited superior cellular uptake and STAT3 gene silencing efficiency in SKOV3 ovarian cancer cells when compared with siRNA/CSO complexes at the same N/P ratios with no significant differences with lipofectamine 2000. Furthermore, the siRNA-PLGA/CSO micelles showed that the efficiencies of cellular uptake and STAT3 gene silencing gradually increased with increasing N/P ratios. The siRNA-PLGA/CSO micelles also inhibited the growth of SKOV3 cells, as well as, promoted apoptosis of the cells. These results indicate that siRNA-PLGA/CSO micelles can be utilized as a novel and efficient siRNA carrier to treat a variety of diseases.

A critical analysis of the concepts and measurement of awareness and equanimity in Goenka's Vipassana meditation.

Goenka's Vipassana meditation (GVM), a widely applied mindfulness training system rooted in Buddhism, is currently widely used. Although the two abilities cultivated in GVM, awareness and equanimity, exhibit certain similarities with the mindfulness cultivated in mindfulness-based psychotherapies (MBTs), they are not major concerns in MBTs. While many mindfulness scales have been created to measure different aspects of mindfulness constructs and certain scales and items can indeed reflect the basic abilities of awareness and equanimity, none of them can adequately capture the way in which those abilities and related ideas are applied in GVM. This paper presents a critical examination of the problems associated with the concepts and measurement of awareness and equanimity and presents potential solutions for achieving better measurement of these concepts in the future.