Effect and mechanism of Hashimoto thyroiditis on female infertility: A clinical trial, bioinformatics analysis, and experiments-based study.

Diagnosing Hashimoto thyroiditis (HT) relies on thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) titers. The influence of these antibodies on female infertility remains a subject of debate. This study aims to explore the effect and mechanism of HT on female infertility. First, a single-center cross-sectional study was conducted to investigate whether TgAb and TPOAb are the key factors leading to female infertility. Second, bioinformatic analysis was performed to investigate the potential target molecules and pathways. Third, in vivo experiments were performed to explore the effects of elevated TgAb levels on embryo implantation in a mouse model of autoimmune thyroiditis (AIT). Four hundred and five infertile women and 155 healthy controls were enrolled in the cross-sectional study. Results indicated that the TPOAb titer was associated with female infertility, while the TgAb titer showed no significant association. The increased levels of TgAb and TPOAb are not significantly correlated with anti-Mullerian hormone. Bioinformatic analysis indicated that the common target molecules for HT and female infertility include interleukin (IL)-6, IL-10, matrix metalloproteinase 9, and tumor necrosis factor, suggesting potential regulation through multiple signaling pathways such as HIF-1, VEGF, MAPK, and Th17 cell differentiation. A certain dose of porcine thyroglobulin can successfully establish a mouse model of AIT. In this mouse model, embryo implantation and ovarian reserve remain unaffected by elevated TgAb levels. In conclusion, the serum TPOAb titer was associated with infertility due to female factors but the TgAb titer showed no significant association. A simple increase in serum TgAb titer does not affect embryo implantation and ovarian reserve in the AIT model.

Significant response to pembrolizumab plus lenvatinib in Epstein-Barr-virus-associated intrahepatic cholangiocarcinoma: a case report.

BACKGROUND: The prognosis for advanced intrahepatic cholangiocarcinoma (iCCA) is poor, and there remains an urgent need to develop efficient systemic therapy. The efficacy of Pembrolizumab immunotherapy combined with lenvatinibin in iCCA is still unclear. The role of Epstein-Barr-virus (EBV) as a biomarker in iCCA for response to immunotherapy needs further exploration. CASE PRESENTATION: We report a case of a 60-year-old female with EBV-associated advanced iCCA (EBVaiCCA) who progressed after first-line therapy. She accomplished an available response to the combination therapy of pembrolizumab with lenvatinib, with overall survival of 20 months. CONCLUSIONS: As far as we know, this is the first case report about the application of Pembrolizumab with lenvatinib for EBVaiCCA patients. This case indicates that the combination of immunotherapy and antiangiogenic therapy provides a glimmer of hope for advanced EBVaiCCA patients.

Yishen Huatan Huoxue decoction and quercetin ameliorate decidualization dysfunction in polycystic ovary syndrome: A comprehensive investigation combining clinical trial and experimental studies.

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder characterized by a complex pathogenesis and limited treatment options. Yishen Huatan and Huoxue decoction (YHHD), as a traditional Chinese Medicine formula, has shown effectiveness in treating PCOS. However, the specific mechanisms by which YHHD exerts its therapeutic effects remain unclear. In this study, we performed to investigate the therapeutic effects of YHHD and quercetin on dehydroepiandrosterone-induced PCOS mice, and examine the effect of quercetin on the decidualization of T-HESCs under hyperinsulinemic conditions. The results showed that YHHD could reduce early miscarriage rates in PCOS patients and significantly improved glucose metabolism disorders, sex hormone levels, and the estrous cycles in PCOS mice. Quercetin could alleviate effect of high insulin levels and restore the low expression of insulin receptor substrate1/2 (IRS1/2) and glucose transporte 4 (GLUT4) in T-HESCs, demonstrating its potential to mitigate hyperinsulin-induced decidualization dysfunction via the GLUT4 signaling pathway mediated by IRS1/2. This study provides valuable molecular insights of YHHD and highlight the therapeutic potential of quercetin in treating decidualization dysfunction in PCOS.

Changes and Significance of Central Carbon Metabolism before and after Metformin Treatment of Type 2 Diabetes Based on Mass Spectrometry.

BACKGROUND: An imbalance in energy metabolism serves as a causal factor for type 2 diabetes (T2D). Although metformin has been known to ameliorate the overall energy metabolism imbalance, but the direct correlation between metformin and central carbon metabolism (CCM) has not been thoroughly investigated. In this study, we employed a high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) technique to examine the alterations and significance of CCM both before and after metformin treatment for T2D. METHODS: We recruited 29 participants, comprising 10 individuals recently diagnosed with T2D (T2D group). Among these, 10 patients underwent a 4-6-week treatment with metformin (MET group). Additionally, we included 9 healthy subjects (CON group). Employing HPIC-MS/MS, we quantitatively analyzed 56 metabolites across 18 biologically relevant metabolic pathways associated with CCM. Univariate and multivariate statistical analyses were utilized to identify differential metabolites. Subsequently, correlation analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted on the identified differential metabolites. RESULTS: We identified seven distinct metabolites in individuals with T2D (p < 0.05). Notably, cyclic 3',5'-Adenosine MonoPhosphate (AMP), Glucose 6-phosphate, L-lactic acid, Maleic acid, and Malic acid exhibited a reversal to normal levels following metformin treatment. Furthermore, Malic acid demonstrated a positive correlation with L-lactic acid (r = 0.94, p < 0.05), as did succinic acid with malic acid (r = 0.81, p < 0.05), L-lactic acid with succinic acid (r = 0.78, p < 0.05), and L-lactic acid with glucose-6-phosphate (r = 0.72, p < 0.05). These metabolites were notably enriched in pyruvate metabolism (p = 0.005), tricarboxylic acid cycle (TCA) (p = 0.007), propanoate metabolism (p = 0.007), and glycolysis or gluconeogenesis (p = 0.009), respectively. CONCLUSIONS: We employed HPIC-MS/MS to uncover alterations in CCM among individuals recently diagnosed with T2D before and after metformin treatment. The findings suggest that metformin may ameliorate the energy metabolism imbalance in T2D by reducing intermediates within the CCM pathway.

Bu-Shen-Ning-Xin decoction inhibits macrophage activation to ameliorate premature ovarian insufficiency-related osteoimmune disorder via FSH/FSHR pathway.

Limited studies are associated with premature ovarian insufficiency (POI)-related osteoimmune disorder currently. Bu-Shen-Ning-Xin decoction (BSNXD) displayed a favorable role in treating postmenopausal osteoporosis. However, its impact on the POI-related osteoimmune disorder remains unclear. The study primarily utilized animal experiments and network pharmacology to investigate the effects and underlying mechanisms of BSNXD on the POI-related osteoimmune disorder. First, a 4-vinylcyclohexene dioxide (VCD)-induced POI murine model was conducted to explore the therapeutical action of BSNXD. Second, we analyzed the active compounds of BSNXD and predicted their potential mechanisms for POI-related osteoimmune disorder via network pharmacology, further confirmed by molecular biology experiments. The results demonstrated that VCD exposure led to elevated follicle-stimulating hormone (FSH) levels, a 50% reduction in the primordial follicles, bone microstructure changes, and macrophage activation, indicating an osteoimmune disorder. BSNXD inhibited macrophage activation and osteoclast differentiation but did not affect serum FSH and estradiol levels in the VCD-induced POI model. Network pharmacology predicted the potential mechanisms of BSNXD against the POI-related osteoimmune disorder involving tumor necrosis factor α and MAPK signaling pathways, highlighting BSNXD regulated inflammation, hormone, and osteoclast differentiation. Further experiments identified BSNXD treatment suppressed macrophage activation via downregulating FSH receptor (FSHR) expression and inhibiting the phosphorylation of ERK and CCAAT enhancer binding proteins ß. In conclusion, BSNXD regulated POI-related osteoimmune disorder by suppressing the FSH/FSHR pathway to reduce macrophage activation and further inhibiting osteoclastogenesis.

Evodiamine inhibits growth of vemurafenib drug-resistant melanoma via suppressing IRS4/PI3K/AKT signaling pathway.

Evodiamine, a novel alkaloid, was isolated from the fruit of tetradium. It exerts a diversity of pharmacological effects and has been used to treat gastropathy, hypertension, and eczema. Several studies reported that evodiamine has various biological effects, including anti-nociceptive, anti-bacterial, anti-obesity, and anti-cancer activities. However, there is no research regarding its effects on drug-resistant cancer. This study aimed to investigate the effect of evodiamine on human vemurafenib-resistant melanoma cells (A375/R cells) proliferation ability and its mechanism. Cell activity was assessed using the cell counting kit-8 (CCK-8) method. Flow cytometry assay was used to assess cell apoptosis and cell cycle. A xenograft model was used to analyze the inhibitory effects of evodiamine on tumor growth. Bioinformatics analyses, network pharmacology, and molecular docking were used to explore the potential mechanism of evodiamine in vemurafenib-resistant melanoma. RT-qPCR and Western blotting were performed to reveal the molecular mechanism. The alkaloid extract of the fruit of tetradium, evodiamine showed the strongest tumor inhibitory effect on vemurafenib-resistant melanoma cells compared to treatment with vemurafenib alone. Evodiamine inhibited vemurafenib-resistant melanoma cell growth, proliferation, and induced apoptosis, conforming to a dose-effect relationship and time-effect relationship. Results from network pharmacology and molecular docking suggested that evodiamine might interact with IRS4 to suppress growth of human vemurafenib-resistant melanoma cells. Interestingly, evodiamine suppressed IRS4 expression and then inhibited PI3K/AKT signaling pathway, and thus had the therapeutic action on vemurafenib-resistant melanoma.

Quantitative parameters of contrast-enhanced ultrasound effectively promote the prediction of cervical lymph node metastasis in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC), the most common endocrine tumor, often spreads to cervical lymph nodes metastasis (CLNM). Preoperative diagnosis of CLNM is important when selecting surgical strategies. Therefore, we aimed to explore the effectiveness of quantitative parameters of contrast-enhanced ultrasound (CEUS) in predicting CLNM in PTC. We retrospectively analyzed 193 patients with PTC undergoing conventional ultrasound (CUS) and CEUS. The CUS features and quantitative parameters of CEUS were evaluated according to PTC size ≤ 10 or > 10 mm, using pathology as the gold standard. For the PTC ≤ 10 mm, microcalcification and multifocality were significantly different between the CLNM (+) and CLNM (-) groups (both P < 0.05). For the PTC > 10 mm, statistical significance was noted between the two groups with respect to the margin, capsule contact, and multifocality (all P < 0.05). For PTC ≤ 10 mm, there was no significant difference between the CLNM (+) and CLNM (-) groups in all quantitative parameters of CEUS (all P > 0.05). However, for PTC > 10 mm, the peak intensity (PI), mean transit time, and slope were significantly associated with CLNM (all P < 0.05). Multivariate analysis showed that PI > 5.8 dB was an independent risk factor for predicting CLNM in patients with PTC > 10 mm (P < 0.05). The area under the curve of PI combined with CUS (0.831) was significantly higher than that of CUS (0.707) or PI (0.703) alone in the receiver operator characteristic curve analysis (P < 0.05). In conclusion, PI has significance in predicting CLNM for PTC > 10 mm; however, it is not helpful for PTC ≤ 10 mm.

Targeting tumor-associated macrophages: Novel insights into immunotherapy of skin cancer.

BACKGROUND: The incidence of skin cancer is currently increasing, and conventional treatment options inadequately address the demands of disease management. Fortunately, the recent rapid advancement of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has ushered in a new era for numerous cancer patients. However, the efficacy of immunotherapy remains suboptimal due to the impact of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), a major component of the TME, play crucial roles in tumor invasion, metastasis, angiogenesis, and immune evasion, significantly impacting tumor development. Consequently, TAMs have gained considerable attention in recent years, and their roles have been extensively studied in various tumors. However, the specific roles of TAMs and their regulatory mechanisms in skin cancer remain unclear. AIM OF REVIEW: This paper aims to elucidate the origin and classification of TAMs, investigate the interactions between TAMs and various immune cells, comprehensively understand the precise mechanisms by which TAMs contribute to the pathogenesis of different types of skin cancer, and finally discuss current strategies for targeting TAMs in the treatment of skin cancer. KEY SCIENTIFIC CONCEPTS OF OVERVIEW: With a specific emphasis on the interrelationship between TAMs and skin cancer, this paper posits that therapeutic modalities centered on TAMs hold promise in augmenting and harmonizing with prevailing clinical interventions for skin cancer, thereby charting a novel trajectory for advancing the landscape of immunotherapeutic approaches for skin cancer.

TPX2 influences the regulation of macrophage polarization via the NF-κB pathway in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer. Xklp2 targeting protein (TPX2), a crucial oncogene exhibits high expression levels in various cancers including LUAD, may serve as a potential target for clinical intervention. Additionally, the growth of lung cancer is significantly influenced by the tumor microenvironment (TME). However, there have been no reports on experiments investigating TPX2 in tumor-infiltrating immune cells (TIICs) in LUAD. Therefore, we verified the effect of TPX2 on macrophage polarization both in vitro and in vivo. METHODS: We silenced TPX2 the gene in A549 cells and collected supernatants for macrophage culture. We then used flow cytometry and Western blot analysis to assess macrophage polarization. Additionally, we verified the expression of macrophage colony-stimulating factor (M-CSF), and CD163 by immunohistochemistry (IHC) in tissue specimens from LUAD patients. Finally, pathways related to TPX2's regulatory function in macrophage polarization were analyzed through whole genome sequencing, Western blotting, and immunofluorescence (IF). RESULTS: Silencing TPX2 can affect the ratio of CD80+ M1/CD163+ M2 and reduce the polarization of M0 macrophages to CD163+ M2 macrophages mainly by inhibiting the expression of M-CSF. In human LUAD tissues, the expression levels of TPX2, M-CSF and CD163 increased with the degree of differentiation. Silencing TPX2 inhibits the NF-κB signaling pathway, thereby reducing the expression of M-CSF, and affecting macrophage polarization. CONCLUSION: Silencing TPX2 can inhibit the expression of M-CSF by blocking the NF-κB signal, thereby reducing CD163+ M2 macrophage polarization. The TPX2/NF-κB/M-CSF signaling axis may be involved in regulating macrophage polarization.

Quercetin antagonized advanced glycated end products induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament.

The altered behaviors and functions of pelvic floor fibroblasts are pathophysiological changes of pelvic organ prolapse (POP). Our previous study showed that advanced glycated end products (AGEs) accumulated in the pelvic tissues of POP and induced fibroblast apoptosis. The study was designed to investigate whether quercetin antagonize AGEs-induced apoptosis and functional inhibition of fibroblasts. The uptake of 5-ethynyl-2'-deoxyuridine (EdU) was evaluated for cell proliferation. Flow cytometric analysis was applied for cell apoptosis. Intracellular reactive oxygen species (ROS) content was determined by the fluorescence of dichlorofluorescein (DCF). The contractility of fibroblasts was measured by collagen gel contraction assay. The expressions of extracellular matrix (ECM) related genes and the expression of miR-4429 and caspase-3 were quantified by qPCR. The expressions of phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), serine-threonine kinase (Akt), and phosphorylated Akt (p-Akt) were analyzed by Western Blot. The down-regulation of miR-4429 was achieved by cell transfection. Quercetin antagonized AGEs-induced apoptosis, proliferation inhibition, and ROS increase in fibroblasts. Quercetin did not alleviate AGEs-induced contractile impairment of fibroblasts. Quercetin reduced the gene expressions of lysyl oxidase like protein 1 (LOXL1)and matrix metallopeptidase 1 (MMP1), and increased the gene expressions of lysyl oxidase (LOX) and fibrillin 2 (FBN2) in fibroblasts. Quercetin reversed AGEs-induced upregulation of PTEN and downregulation of PI3K, P-Akt, and miR-4429 in fibroblasts. The inhibitory effect of quercetin on AGEs-induced fibroblast apoptosis was inhibited by downregulating the expression of miR-4429. In conclusion, quercetin antagonized AGEs-induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament. And inhibiting AGEs-induced down-regulation of miR-4429/PTEN/PI3K/Akt pathway was the mechanism underlying the antagonistic effect of quercetin on AGEs-induced apoptosis.

Polycystic ovary syndrome and adverse pregnancy outcomes: potential role of decidual function.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting fertility and mental health among women of reproductive age. In addition to anovulation and hyperandrogenism, patients also experience metabolic issues, such as insulin resistance, obesity, and dyslipidemia, as well as chronic low-grade inflammation throughout the body. Recent studies have shown that even with assisted reproductive technology to treat anovulatory issues, patients with PCOS still have higher rates of adverse pregnancy outcomes and abortion compared to normal pregnancies. These findings suggest that PCOS may impair the endometrium and disrupt the onset and maintenance of healthy pregnancies. Decidualization is a crucial step in the process of healthy pregnancy, during which endometrial stromal cells (ESCs) differentiate into secretory decidual stromal cells (DSCs) regulated by hormones and local metabolism. This article comprehensively reviews the pathological processes of PCOS and the mechanisms involved in its impaired decidualization. In addition, we explore how PCOS increases the incidence of adverse pregnancy outcomes (APO). By gaining a better understanding of the adverse effects of PCOS on pregnancy and its specific mechanisms, we hope to provide a theoretical basis for reducing APO and improving the live birth rate among women with PCOS.

The effect of the female genital tract and gut microbiome on reproductive dysfunction.

Microorganisms are ubiquitous in the human body; they are present in various areas including the gut, mouth, skin, respiratory tract, and reproductive tract. The interaction between the microbiome and reproductive health has become an increasingly compelling area of study. Disruption of the female genital tract microbiome can significantly impact the metabolism of amino acids, carbohydrates, and lipids, increasing susceptibility to reproductive tract diseases such as vaginitis, chronic endometritis, endometrial polyps, endometriosis, and polycystic ovary syndrome. The gut microbiome, considered an endocrine organ, plays a crucial role in the reproductive endocrine system by interacting with hormones like estrogen and androgens. Imbalances in the gut microbiome composition can lead to various diseases and conditions, including polycystic ovary syndrome, endometriosis, and cancer, although research on their mechanisms remains limited. This review highlights the latest advancements in understanding the female genital tract and gut microbiomes in gynecological diseases. It also explores the potential of microbial communities in the treatment of reproductive diseases. Future research should focus on identifying the molecular mechanisms underlying the association between the microbiome and reproductive diseases to develop new and effective strategies for disease prevention, diagnosis, and treatment related to female reproductive organs.

Risk model-guided identification of MTDH expression as a marker for ferroptosis induction therapy in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) are a prevalent malignancy with high mortality and morbidity rates. Therefore, in this study, we aimed to develop a novel risk score model by using a DNA methylation signature associated with ferroptosis to enhance the prognosis prediction of HNSCC. The transcriptome, methylome, and clinical data of HNSCC patients were collected from The Cancer Genome Atlas (TCGA) database. Additionally, data from a methylation dataset in the Gene Expression Omnibus (GEO) database were used for validation. The ferroptosis score (FS) in each patient was calculated using the transcriptome data, and the single-sample gene set enrichment analysis (ssGSEA) was performed to assess ferroptosis activity. Furthermore, a series of biochemical experiments including CCK8, colony formation, wound healing, and ROS detection were carried out to evaluate the influence of MTDH on the malignancy of HNSCC. Our results revealed that the FS was associated with patient prognosis, as the patients with high FS had a poor prognosis. The receiver operating characteristic (ROC) curve established based on the ferroptosis-associated DNA methylation signature, demonstrated the excellent predictive power of FS for the 1-, 3-, and 5-year survival of HNSCC. Importantly, this predictive model was successfully validated in the GEO dataset. The nomogram also demonstrated excellent accuracy and reliability, as determined by the calibration curves and the decision curve analysis (DCA) plot. Interestingly, the risk score model was found to be correlated with immune cell infiltration and immunotherapy-related biomarkers, suggesting its potential in predicting the immunotherapy response in HNSCC treatment. Moreover, we found that the expression of two risk score model component genes, SETD1B and MTDH, was significantly different between tumor and the adjacent tissues in patients with LSCC, which was also significantly correlated with patient prognosis. Further experimental validation showed that the upregulated expression of MTDH significantly inhibited ferroptosis through regulating GPX4 expression and enhanced the cytotoxicity of ferroptosis inducers in HNSCC cells. In conclusion, we have developed a risk score model by using a ferroptosis-related DNA methylation signature, which can be used as an alternative tool to predict the prognosis of patients with HNSCC. SETD1B and MTDH were identified as the pivotal genes in this model and might play important role in the progression of HNSCC.

Nanocarrier-Mediated Immunogenic Cell Death for Melanoma Treatment.

Melanoma, a highly aggressive skin tumor, exhibits notable features including heterogeneity, a high mutational load, and innate immune escape. Despite advancements in melanoma treatment, current immunotherapies fail to fully exploit the immune system's maximum potential. Activating immunogenic cell death (ICD) holds promise in enhancing tumor cell immunogenicity, stimulating immune amplification response, improving drug sensitivity, and eliminating tumors. Nanotechnology-enabled ICD has emerged as a compelling therapeutic strategy for augmenting cancer immunotherapy. Nanoparticles possess versatile attributes, such as prolonged blood circulation, stability, and tumor-targeting capabilities, rendering them ideal for drug delivery. In this review, we elucidate the mechanisms underlying ICD induction and associated therapeutic strategies. Additionally, we provide a concise overview of the immune stress response associated with ICD and explore the potential synergistic benefits of combining ICD induction methods with the utilization of nanocarriers.

Efficacy and safety of radiotherapy combined with anti-angiogenic therapy and immune checkpoint inhibitors in MSS/pMMR metastatic colorectal cancer.

PURPOSE: Several studies have demonstrated the effectiveness of anti-angiogenic drugs in combination with immune checkpoint inhibitors (ICIs) in patients with microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC). However, whether combination radiotherapy (RT) can further improve the prognosis of mCRC patients after second-line treatment remains to be explored. METHODS: Retrospective analysis of data from mCRC patients who received anti-angiogenic targeted therapy (TT) and immunotherapy (IT) with or without RT after the failure of standard therapy. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated. RESULTS: A total of 82 patients who received TT + IT were analyzed. For RT group (n = 42) versus NRT group (n = 40), ORR was 21.4% (9/42) versus 5.0% (2/40); DCR was 83.8% (35/42) versus 65.0% (26/40). Compared with NRT group, RT improved PFS (median: 5.0 vs. 3.6 months; p = 0.04) and OS (median: 15.2 vs. 7.2 months; p = 0.01). In addition, in the population receiving RT, the PFS of RT sequential/simultaneous TT + IT was superior to TT + IT sequential RT (median: 7.1 vs. 6.2 vs. 3.5 months, p = 0.004). Multivariate analysis suggested RT was an independent prognostic factor for PFS and OS. No treatment-related deaths were reported. CONCLUSIONS: Compared with TT + IT, RT combined with TT + IT improved survival outcomes in MSS/pMMR mCRC patients, with manageable toxicity. RT sequential/simultaneous TT + IT treatment is expected to be the optimal strategy for MSS/PMMR mCRC.

Nanomedicine-induced programmed cell death enhances tumor immunotherapy.

BACKGROUND: There has been widespread concern about the high cancer mortality rate and the shortcomings of conventional cancer treatments. Immunotherapy is a novel oncology therapy with high efficiency and low side effects, which is a revolutionary direction for clinical oncology treatment. However, its clinical effectiveness is uneven. Based on the redefinition and reclassification of programmed cell death (PCD) (divided into necroptosis, ferroptosis, pyroptosis, and autophagy), the role of nanomedicine-induced PCD in cancer therapy has also received significant attention. Clinical and preclinical studies have begun to combine PCD with immunotherapy. AIM OF REVIEW: In this article, we present recent research in tumor immunotherapy, provide an overview of how nanomedicine-induced PCD is involved in tumor therapy, and review how nanomedicine-induced PCD can improve the limitations of immunotherapy to enhance tumor immunotherapy. The future development of nanomedicine-mediated PCD tumor therapy and tumor immunotherapy is also proposed Key scientific concepts of overview Nanomedicine-induced PCD is a prospective method of tumor immunotherapy. Nanomedicines increase tumor site penetration and targeting ability, and nanomedicine-mediated PCD activation can stimulate powerful anti-tumor immune effects, which has a good contribution to immunotherapy of tumors.

Effect of Chinese patent medicine Kunling Pill on endometrial receptivity: A clinical trial, network pharmacology, and animal-based study.

Although pregnancy success rates are raised with assisted reproductive technology, it still cannot meet clinical demands. Kunling Pill (KLP), a traditional Chinese medicine, is widely used in various gynecological disorders, particularly in improving fertility and pregnancy rates. However, the underlying mechanism of how KLP affects pregnancy outcomes remains unclear. This study aimed to explore the effects and mechanisms of KLP on endometrial receptivity. Firstly, a retrospective trial was conducted to validate the efficacy of KLP on repeated implantation failure (RIF) patients. The result indicated a significant increase in the proportion of live birth in KLP group (30.56%) compared to the control group (16.89%). Secondly, network pharmacology methods predicted the active components and network targets of KLP. Endometrial receptivity is closely associated with the activation of inflammatory factors, predicting the function of KLP on the immune system. The estrogen and apoptotic signaling pathways were also highlighted in the gene ontology enrichment analysis. Thirdly, a decreased endometrial receptivity model was established by controlled ovarian hyperstimulation (COH) in female C57BL/6 mice, divided into the COH and KLP groups. Normal female mice are as control group. In vivo, KLP administration could increase endometrial thickness and the number of endometrial glands and pinopodes. In the endometrium, KLP supplementation upregulated the expressions of estrogen receptor α, progesterone receptor, endothelial nitric oxide synthase, and integrin αVß3 in the murine uterus and reduced serum levels of estrogen and progesterone. KLP regulated the uterine immune cells and inhibited cell apoptosis in the ovary via Bcl-2/Bax/caspase-3 pathway. In conclusion, KLP administration raised the live birth rate in RIF patients to optimize medication regimens, mainly because KLP ameliorated impaired endometrial receptivity.

Apolipoprotein E deficiency attenuated osteogenesis via down-regulating osterix.

Apolipoprotein E (ApoE), a ligand for low-density lipoprotein receptors, is strongly induced during osteogenesis and has a physiologic role in regulating osteoblast function, but the mechanisms of its action are still unclear. The study aims to elucidate the influence and molecular mechanisms of ApoE on bone formation. An ovariectomy-induced osteoporotic model were conducted in ApoE knockout (ApoE-/-) mice to study the effect of ApoE on the bone system. Bone quality were assessed through bone mineral density and histomorphometric analysis. To investigate the underlying role and mechanisms of ApoE during osteogenesis, primary osteoblasts from the calvariums of newborn ApoE-/- or wild-type (WT) mice were cultured in the osteoblastic differentiation medium in vitro for further research. Our animal experiment data showed that ApoE-/- mice exhibited bone loss, exacerbated by estrogen deprivation after ovariectomy. ApoE deficiency attenuated osteoblast activity and inhibited osteoblast osteogenesis, accompanied by decreased osterix expression. ApoE deficiency did not affect primary osteoblast viability and collagen-1 expression. Moreover, osteoprotegerin expression in ApoE-/- osteoblasts was reduced compared to WT controls. Our study demonstrated that ApoE gene deficiency contributed to bone loss and attenuated osteogenesis by down-regulating osterix expression.

Single­cell multi­omics advances in lymphoma research (Review).

The evolution of lymphoma is a multifactorial process that leads to unavoidable lymphoma heterogeneity in the form of genetic mutations, chromosomal translocations and other variations. Multi­omics analyses based on single­cell assays can reveal and characterize tumor components, enabling us to determine the timing of mutations and to profile disease progression. Increasing numbers of studies are using single­cell transcriptomics to unravel the mechanisms of lymphoma evolution, drug resistance and therapeutic approaches. Various single­cell multi­omics measurements involving genomics, transcriptomics and epigenomics have improved knowledge of the complex lymphatic system and made it possible to obtain individualized and precise tumor biological characteristics, which cannot be accessed from bulk cell analysis, and this can facilitate individualized treatment. In the present review, the advances in multi­omics analysis based on single­cell assays of lymphoma specimens were systematically discussed, including the sequencing of the single­cell from genomic and transcriptomic perspectives, the landscape of the lymphoma microenvironment, the development of single­cell histology biomarkers, the identification of lymphoma origin and evolution, as well as the current challenges and future prospects of single­cell multi­omics. The authors' insights may contribute to the exploration of novel lymphoma biomarkers and the discovery of efficient treatment combinations that target immunological checkpoints and underlying molecular mechanisms.

Pretreatment high cholesterol and low neutrophils predict complete pathological response after neoadjuvant short­course radiotherapy followed by chemotherapy and immunotherapy in locally advanced rectal cancer.

The present study was aimed at looking for hematological indicators that could predict pathological complete response (pCR) in patients with locally advanced rectal cancer (LARC) treated with short-course radiotherapy (SCRT) followed by chemotherapy and immunotherapy. A total of 171 patients were enrolled in this observational retrospective study. Pretreatment values of albumin, total cholesterol, lactate dehydrogenase, neutrophil, platelet and lymphocytes were available. Univariate and multivariate logistics analyses were used to determine the prognostic factor for pCR. SCRT followed by chemotherapy and immunotherapy was demonstrated to double the pCR rate (50.5%) compared with long-course chemoradiotherapy. For the former group, baseline high platelet to lymphocyte ratio (P=0.047), high cholesterol (P=0.026) and low neutrophils (P=0.012) level were associated with high pCR rate and baseline high cholesterol (P=0.016) and low neutrophils (P=0.020) level were the independent prognostic factors for pCR. In conclusion, pretreatment high cholesterol and low neutrophils were the independent prognostic predictors of pCR in patients with LARC treated with SCRT followed by chemotherapy and immunotherapy. Clinical trial no. NCT04928807, June 16, 2021.