Dual trigger or hCG alone: A retrospective analysis on patients with diminished ovarian reserve under in vitro fertilization and embryo transfer (IVF-ET) treatment.

OBJECTIVE: With remarkable deficiency in both oocyte stock and competence, the prognosis of IVF-ET in diminished ovarian reserve (DOR) is obstinately poor, underscoring warranted optimization to current procedures. We compared the efficacy of dual-trigger (hCG plus GnRH-a) and hCG alone on the outcomes for DOR patients. STUDY DESIGN: A total of 381 couples and 857 controlled ovarian stimulation (COS) cycles, and 222 couples and 366 frozen embryo transfer (FET) ones were included. The intermediate outcomes during oocyte retrieval and in vitro culture were compared based on COS dataset, while outcomes after embryo transfer analyzed based on FET dataset. The marginal effect of all study factors and covariates were evaluated with a cluster-weighted GEE model. RESULTS AND CONCLUSION: Neither the intermediate nor implantation outcomes were improved by dual-trigger. The OR values were 1.08 (95 % CI: 0.41-2.78) for retrieval cancellation, 1.33 (95 % CI: 0.89-2.00) for oocyte harvest, 1.04(95 %CI: 0.94-1.15) for viable embryo and 1.03(95 %CI: 0.88-1.19) for top-quality embryo. Similarly, the ORs were 0.90 (95 %CI: 0.62-1.30) for implantation and 0.97 (95 %CI: 0.56-1.69) for clinical pregnancy. This equivalence remained unchanged after adjusting for the covariates such as age, BMI, controlled ovarian stimulation protocols, etc. Thus, dual-trigger cannot provide significant advantage over hCG in related to immediate or clinical outcomes of IVF-ET treatments in DOR patients.

DNA Reaction Circuits to Establish Designated Biological Functions in Multicellular Community.

In multicellular organisms, individual cells are coordinated through complex communication networks to accomplish various physiological tasks. Aiming to establish new biological functions in the multicellular community, we used DNA as the building block to develop a cascade of nongenetic reaction circuits to establish a dynamic cell-cell communication network. Utilizing membrane-anchored amphiphilic DNA tetrahedra (TDN) as the nanoscaffold, reaction circuits were incorporated into three unrelated cells in order to uniquely regulate their sense-and-response behaviors. As a proof-of-concept, this step enabled these cells to simulate significant biological events involved in T cell-mediated anticancer immunity. Such events included cancer-associated antigen recognition and the presentation of antigen-presenting cells (APCs), APC-facilitated T cell activation and dissociation, and T cell-mediated cancer targeting and killing. By combining the excellent programmability and molecular recognition ability of DNA, our cell-surface reaction circuits hold promise for mimicking and manipulating many biological processes.

Corrigendum: Therapeutic strategies targeting folate receptor α for ovarian cancer.

[This corrects the article DOI: 10.3389/fimmu.2023.1254532.].

Aptamer-Based Nongenetic Reprogramming of CARs Enables Flexible Modulation of T Cell-Mediated Tumor Immunotherapy.

Innovating the design of chimeric antigen receptors (CARs) beyond conventional structures would be necessary to address the challenges of efficacy, safety, and applicability in T cell-based cancer therapy, whereas excessive genetic modification might complicate CAR design and manufacturing, and increase gene editing risks. In this work, we used aptamers as the antigen-recognition unit to develop a nongenetic CAR engineering strategy for programming the antitumor activity and specificity of CAR T cells. Our results demonstrated that aptamer-functionalized CAR (Apt-CAR) T cells could be directly activated by recognizing target antigens on cancer cells, and then impart a cytotoxic effect for cancer elimination in vitro and in vivo. The designable antigen recognition capability of Apt-CAR T cells allows for easy modulation of their efficacy and specificity. Additionally, multiple features, e.g., tunable antigen-binding avidity and the tumor microenvironment responsiveness, could be readily integrated into Apt-CAR design without T cell re-engineering, offering a new paradigm for developing adaptable immunotherapeutics.

Therapeutic strategies targeting folate receptor α for ovarian cancer.

Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, and presents a major clinical challenge due to limited treatment options. Folate receptor alpha (FRα), encoded by the FOLR1 gene, is an attractive therapeutically target due to its prevalent and high expression in EOC cells. Recent basic and translational studies have explored several modalities, such as antibody-drug conjugate (ADC), monoclonal antibodies, small molecules, and folate-drug conjugate, to exploit FRα for EOC treatment. In this review, we summarize the function of FRα, and clinical efficacies of various FRα-based therapeutics. We highlight mirvetuximab soravtansine (MIRV), or Elahere (ImmunoGen), the first FRα-targeting ADC approved by the FDA to treat platinum-resistant ovarian cancer. We discuss potential mechanisms and management of ocular adverse events associated with MIRV administration.

LepR+ niche cell-derived AREG compromises hematopoietic stem cell maintenance under conditions of DNA repair deficiency and aging.

The cross talk between extrinsic niche-derived and intrinsic hematopoietic stem cell (HSC) factors controlling HSC maintenance remains elusive. Here, we demonstrated that amphiregulin (AREG) from bone marrow (BM) leptin receptor (LepR+) niche cells is an important factor that mediates the cross talk between the BM niche and HSCs in stem cell maintenance. Mice deficient of the DNA repair gene Brca2, specifically in LepR+ cells (LepR-Cre;Brca2fl/fl), exhibited increased frequencies of total and myeloid-biased HSCs. Furthermore, HSCs from LepR-Cre;Brca2fl/fl mice showed compromised repopulation, increased expansion of donor-derived, myeloid-biased HSCs, and increased myeloid output. Brca2-deficient BM LepR+ cells exhibited persistent DNA damage-inducible overproduction of AREG. Ex vivo treatment of wild-type HSCs or systemic treatment of C57BL/6 mice with recombinant AREG impaired repopulation, leading to HSC exhaustion. Conversely, inhibition of AREG by an anti-AREG-neutralizing antibody or deletion of the Areg gene in LepR-Cre;Brca2fl/fl mice rescued HSC defects caused by AREG. Mechanistically, AREG activated the phosphoinositide 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, promoted HSC cycling, and compromised HSC quiescence. Finally, we demonstrated that BM LepR+ niche cells from other DNA repair-deficient and aged mice also showed persistent DNA damage-associated overexpression of AREG, which exerts similar negative effects on HSC maintenance. Therefore, we identified an important factor that regulates HSCs function under conditions of DNA repair deficiency and aging.

An Aptamer-Functionalized DNA Circuit to Establish an Artificial Interaction between T Cells and Cancer Cells.

Nongenetic strategies that enable control over the cell-cell interaction network would be highly desired, particularly in T cell-based cancer immunotherapy. In this work, we developed an aptamer-functionalized DNA circuit to modulate the interaction between T cells and cancer cells. This DNA circuit was composed of recognition-then-triggering and aggregation-then-activation modules. Upon recognizing target cancer cells, the triggering strand was released to induce aggregation of immune receptors on the T cell surface, leading to an enhancement of T cell activity for effective cancer eradication. Our results demonstrated the feasibility of this DNA circuit for promoting target cancer cell-directed stimulation of T cells, which, consequently, enhanced their killing effect on cancer cells. This DNA circuit, as a modular strategy to modulate intercellular interactions, could lead to a new paradigm for the development of nongenetic T cell-based immunotherapy.

Oral contraceptives (OCs) in combination with metformin versus OCs alone on metabolism in nonobese polycystic ovary syndrome: A meta-analysis and systematic review of randomized controlled trials.

BACKGROUND: To compare OCs(oral contraceptives) + metformin and OCs alone for metabolic effects in nonobese polycystic ovary syndrome (PCOS) patients. METHODS: The search was performed in PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for all published studies up to 30 April 2022 and was limited to English-language articles. All randomized controlled trials (RCTs) comparing OCs + metformin and OCs alone for reproductive-age women with PCOS were included. Data were processed using Revman 5.3 software. RESULTS: Of 396 studies identified, 14 RCTs were included for analysis comprising 707 women. OCs+metformin significantly modified fasting glucose (MD = -0.21 [95% confidence interval (CI) = -0.31, -0.12], p < .00001) and fasting insulin (MD = -2.54 [95%CI = -4.04, -1.04], p = .0009) at study completion compared with OCs alone in nonobese PCOS subjects. There was no statistic difference in the homoeostasis model assessment of insulin resistance (HOMA-IR), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol or triglycerides at study end between the two groups. CONCLUSIONS: Metformin, via its positive effects on insulin clearance, in combination with OCs, improved glucose metabolism and offered a good treatment alternative in nonobese women with PCOS.

EPSTI1 promotes monocyte adhesion to endothelial cells in vitro via upregulating VCAM-1 and ICAM-1 expression.

Atherosclerosis is a chronic inflammatory disease of arterial wall, and circulating monocyte adhesion to endothelial cells is a crucial step in the pathogenesis of atherosclerosis. Epithelial-stromal interaction 1 (EPSTI1) is a novel gene, which is dramatically induced by epithelial-stromal interaction in human breast cancer. EPSTI1 expression is not only restricted to the breast but also in other normal tissues. In this study we investigated the role of EPSTI1 in monocyte-endothelial cell adhesion and its expression pattern in atherosclerotic plaques. We showed that EPSTI1 was dramatically upregulated in human and mouse atherosclerotic plaques when compared with normal arteries. In addition, the expression of EPSTI1 in endothelial cells of human and mouse atherosclerotic plaques is significantly higher than that of the normal arteries. Furthermore, we demonstrated that EPSTI1 promoted human monocytic THP-1 cell adhesion to human umbilical vein endothelial cells (HUVECs) via upregulating VCAM-1 and ICAM-1 expression in HUVECs. Treatment with LPS (100, 500, 1000 ng/mL) induced EPSTI1 expression in HUVECs at both mRNA and protein levels in a dose- and time-dependent manner. Knockdown of EPSTI1 significantly inhibited LPS-induced monocyte-endothelial cell adhesion via downregulation of VCAM-1 and ICAM-1. Moreover, we revealed that LPS induced EPSTI1 expression through p65 nuclear translocation. Thus, we conclude that EPSTI1 promotes THP-1 cell adhesion to endothelial cells by upregulating VCAM-1 and ICAM-1 expression, implying its potential role in the development of atherosclerosis.

Aptamer-Based Cancer Cell Analysis and Treatment.

Aptamers are a class of single-stranded DNA or RNA oligonucleotides that can exclusively bind to various targets with high affinity and selectivity. Regarded as "chemical antibodies", aptamers possess several intrinsic advantages, including easy synthesis, convenient modification, high programmability, and good biocompatibility. In recent decades, many studies have demonstrated the superiority of aptamers as molecular tools for various biological applications, particularly in the area of cancer theranostics. In this review, we focus on recent progress in developing aptamer-based strategies for the precise analysis and treatment of cancer cells.

Suspicious symptom monitoring for leprosy: an optimal practice for early detection under a low endemic situation in Zhejiang Province, China.

BACKGROUND: Leprosy is a chronic infectious disease that causes disabilities and deformities. Early detection is a major strategy for leprosy control. This study reported a new practice of suspicious symptom monitoring for early detection of leprosy. METHODS: A descriptive and comparative analysis between a non-strategy group of pre-implementation of suspicious symptom monitoring in 2005-2011 and a strategy group of strategy implementation in 2012-2018 was conducted through indicators of the number of times of misdiagnoses, delayed period, proportion of early detected cases, and proportion of disabilities. RESULT: Compared with the non-strategy group in 2005-2011, the median number of times of misdiagnoses was decreased from two times to zero times (z = 4.387, P < 0.001), and the median delayed period of newly detected cases were shortened from 24 months to 13 months (z = 2.381, P < 0.001), the proportion of early detected cases was increased from 43.7% to 75.2% (χ2 = 29.464, P < 0.001), the proportion of grade 2 disabilities was decreased from 28.6% in the highest year of 2005 to 4.0% in the lowest year of 2014, and the average proportion of disabilities was decreased from 33.5% to 17.6% (χ2 = 9.421, P = 0.002) in the strategy group in 2012-2018, respectively. CONCLUSION: Suspicious symptom monitoring promoted early detection of cases by reducing the number of times misdiagnosis of leprosy patients, shortening the delayed period, increasing the proportion of early detection, and decreasing the proportion of disabilities. It is an important and recommendable public health strategy for leprosy prevention and control in a low epidemic condition.

Hematopoietic stem cell regeneration through paracrine regulation of the Wnt5a/Prox1 signaling axis.

The crosstalk between the BM microenvironment (niche) and hematopoietic stem cells (HSCs) is critical for HSC regeneration. Here, we show that in mice, deletion of the Fanconi anemia (FA) genes Fanca and Fancc dampened HSC regeneration through direct effects on HSCs and indirect effects on BM niche cells. FA HSCs showed persistent upregulation of the Wnt target Prox1 in response to total body irradiation (TBI). Accordingly, lineage-specific deletion of Prox1 improved long-term repopulation of the irradiated FA HSCs. Forced expression of Prox1 in WT HSCs mimicked the defective repopulation phenotype of FA HSCs. WT mice but not FA mice showed significant induction by TBI of BM stromal Wnt5a protein. Mechanistically, FA proteins regulated stromal Wnt5a expression, possibly through modulating the Wnt5a transcription activator Pax2. Wnt5a treatment of irradiated FA mice enhanced HSC regeneration. Conversely, Wnt5a neutralization inhibited HSC regeneration after TBI. Wnt5a secreted by LepR+CXCL12+ BM stromal cells inhibited ß-catenin accumulation, thereby repressing Prox1 transcription in irradiated HSCs. The detrimental effect of deregulated Wnt5a/Prox1 signaling on HSC regeneration was also observed in patients with FA and aged mice. Irradiation induced upregulation of Prox1 in the HSCs of aged mice, and deletion of Prox1 in aged HSCs improved HSC regeneration. Treatment of aged mice with Wnt5a enhanced hematopoietic repopulation. Collectively, these findings identified the paracrine Wnt5a/Prox1 signaling axis as a regulator of HSC regeneration under conditions of injury and aging.

Persistent DNA damage and oncogenic stress-induced Trem1 promotes leukemia in mice.

The immune receptor TREM1 (Triggering receptor expressed on myeloid cells 1) is a master regulator of inflammatory response. Compelling evidence suggests important pathological roles for TREM1 in various types of solid tumors. However, the role of TREM1 in hematologic malignancies is not known. Our previous study demonstrated that TREM1 cooperates with diminished DNA damage response to induce expansion of pre-leukemic hematopoietic stem cells (HSC) in mice deficient for the Fanconi anemia gene Fanca. Here we investigated TREM1 in leukemogenesis using mouse models of the DNA repair-deficient Fanca-/- and the oncogenic MLL-AF9 or KrasG12D. We found that Trem1 was highly expressed in preleukemic HSC and leukemia stem cells (LSC). By selective deletion of the Trem1 gene in the hematopoietic compartment, we showed that ablation of Trem1 reduced leukemogenic activity of the pre-leukemic HSC and LSC in mice. Trem1 was required for the proliferation of the pre-leukemic HSC and LSC. Further analysis revealed that Trem1 expression in preleukemic HSC and LSC was associated with persistent DNA damage, prolonged oncogenic stress, and a strong inflammatory signature. Targeting several top Trem1 inflammatory signatures inhibited the proliferation of pre-leukemic HSC and LSC. Collectively, our observations uncover previously unknown expression and function of TREM1 in malignant stem cells, and identify TREM1 as a driver of leukemogenesis.

Identify a DNA Damage Repair Gene Signature for Predicting Prognosis and Immunotherapy Response in Cervical Squamous Cell Carcinoma.

The DNA damage repair (DDR) genes are increasingly gaining attention as potential therapeutic targets in cancers. In this study, we identified the DDR genes associated with the tumor mutation burden (TMB) and prognosis of cervical squamous cell carcinoma (CESC) based on The Cancer Genome Atlas (TCGA) database. Through LASSO Cox regression, the prognostic signature involving five DDR genes (ACTR2, TEX12, UBE2V1, HSF1, and FBXO6) was established, and the risk score was identified as an independent risk factor for CESC. The nomogram consisting of the five genes accurately predicted the overall survival (OS) and the immunotherapeutic response of CESC patients. Finally, the loss of the copies of the transcription factor (TF) SP140 in CESC patients may decrease the expression of FBXO6, improve DNA repair function, and reduce the diversity of neoantigens, thereby lowering the response to immunotherapies. Therefore, the DDR gene signature is a novel prognostic model and a biomarker for immunotherapies in CESC patients.

Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia.

Chemoresistance posts a major hurdle for treatment of acute leukemia. There is increasing evidence that prolonged and intensive chemotherapy often fails to eradicate leukemic stem cells, which are protected by the bone marrow niche and can induce relapse. Thus, new therapeutic approaches to overcome chemoresistance are urgently needed. By conducting an ex vivo small molecule screen, here we have identified Quinacrine (QC) as a sensitizer for Cytarabine (AraC) in treating acute lymphoblastic leukemia (ALL). We show that QC enhances AraC-mediated killing of ALL cells, and subsequently abrogates AraC resistance both in vitro and in an ALL-xenograft model. However, while combo AraC+QC treatment prolongs the survival of primary transplanted recipients, the combination exhibits limited efficacy in secondary transplanted recipients, consistent with the survival of niche-protected leukemia stem cells. Introduction of Cdc42 Activity Specific Inhibitor, CASIN, enhances the eradication of ALL leukemia stem cells by AraC+QC and prolongs the survival of both primary and secondary transplanted recipients without affecting normal long-term human hematopoiesis. Together, our findings identify a small-molecule regimen that sensitizes AraC-mediated leukemia eradication and provide a potential therapeutic approach for better ALL treatment.

Iron overload in endometriosis peritoneal fluid induces early embryo ferroptosis mediated by HMOX1.

Endometriosis is one of the most common disorders that causes infertility in women. Iron is overloaded in endometriosis peritoneal fluid (PF), with harmful effects on early embryo development. However, the mechanism by which endometriosis peritoneal fluid affects embryonic development remains unclear. Hence, this study investigated the effect of iron overload on mouse embryos and elucidated the molecular mechanism. Iron overload in endometriosis PF disrupted blastocyst formation, decreased GPX4 expression and induced lipid peroxidation, suggesting that iron overload causes embryotoxicity and induces ferroptosis. Moreover, mitochondrial damage occurs in iron overload-treated embryos, presenting as decreased ATP levels, increased ROS levels and MMP hyperpolarization. The cytotoxicity of iron overload is attenuated by the ferroptosis inhibitor Fer-1. Furthermore, Smart-seq analysis revealed that HMOX1 is upregulated in embryo ferroptosis and that HMOX1 suppresses ferroptosis by maintaining mitochondrial function. This study provides new insight into the mechanism of endometriosis infertility and a potential target for future endometriosis infertility treatment efforts.

The patterns of distant metastasis and prognostic factors in patients with primary metastatic Ewing sarcoma of the bone.

BACKGROUND: Ewing sarcoma (ES) of bone is accounting for the second most common type of primary bone cancer in children and adolescents. However, the patterns of distant metastasis (DM) and the effect of the sites of DM on survival outcomes were not investigated. AIMS: This study aimed to investigate the patterns of DM and the prognostic factors related to outcomes in primary metastatic ES of the bone. METHODS: Patients who were diagnosed with primary metastatic ES between 2010 and 2018 were identified from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier analysis, log-rank tests, and Cox proportional-hazards regression models were used for statistical analyses. RESULTS: We identified 277 patients in this study and 95.3% of them (n = 264) receiving chemotherapy. A total of 371 sites of DM were observed. Lung was the most common distant metastatic site (n = 182, 49.1%), followed by bone (n = 139, 37.5%), distant lymph node (n = 26, 7.0%), liver (n = 14, 3.8%), and brain (n = 10, 2.7%). Three-year cause-specific survival (CSS) was 56.1% in the entire cohort. Older age (hazard ratio [HR] 2.210, P < 0.001) and bone metastasis (HR 1.903, P = 0.002) were the independent prognostic factors associated with inferior CSS. Similar results were found in those with bone-only metastasis (n = 80) or lung-only metastasis (n = 117), which showed that patients with bone-only metastasis had an inferior CSS compared to those with metastases only to the lung (HR 1.926, P = 0.005). CONCLUSIONS: Lung and bone are the most frequently distant metastatic sites in patients with primary metastatic ES of bone. Bone metastasis is an independent risk factor for inferior survival.

Laser-assisted hatching in lower grade cleavage stage embryos improves blastocyst formation: results from a retrospective study.

BACKGROUND: Laser-assisted hatching (LAH) has been widely applied to facilitate blastocyst hatching in IVF-ET treatment, however, the effect of LAH on subsequent development and clinical outcomes of the lower grade cleavage stage embryos (LGCE) remains unknown. Our study aimed at evaluating the effect of LAH on blastocyst formation and the clinical pregnancy outcomes of LGCE embryos after transfer. METHODS: A total of 608 cycles of IVF/ICSI treatment from November 2017 to September 2019 were included in our study as follows: 296 in the LAH group and 312 in the N-LAH group. The total blastocyst rate, usable blastocyst rate, good-grade blastocyst rate and clinical pregnancy rate were statistically compared between the two groups. RESULTS: The total blastocyst rate (50.7% vs 40.2%, P < 0.001), usable blastocyst rate (31.0% vs 18.6%, P < 0.001) were significantly higher in the LAH group than those in the N-LAH group. After analysis of generalized estimating equations, LAH was positively correlated with the blastocyst rate (B = 0.201, OR 95% CI = 1.074-1.393, P = 0.002), usable blastocyst rate (B = 0.478, OR 95% CI = 1.331-1.955, P < 0.001). However, the clinical pregnancy rate after blastocyst transfer did not differ between LAH group and N-LAH group (49.4% vs 40.0%, P > 0.05, respectively). CONCLUSIONS: A higher proportion of total blastocysts and usable blastocysts can be obtained by LAH in LGCE, which may be beneficial to the outcome of the IVF/ICSI-ET cycle.

Irreversible electroporation ablation against subcutaneously implanted VX2 tumors in rabbits: findings of shearwave ultrasound elastography.

PURPOSE: This study aimed to evaluate stiffness changes of rabbit subcutaneous VX2 tumors before and after irreversible electroporation (IRE) ablationby shearwave ultrasound elastography (SWE). METHODS: IRE was performed on 20 subcutaneously implanted VX2 tumors in rabbits (R-SIVX2). Tumor stiffness was measured by SWE at different time points (before IRE,120minutes after IRE,7 days after IRE and 14 days after IRE). RESULTS: Before IRE, the mean stiffness (Emean) of tumors was (10.45 ± 1.07) KPa. 120 minutes after I RE, the Emean of tumors obviously rose to (70.53 ± 9.87) KPa. 7 days after IRE, the Emean of tumors decreased to (40.22 ± 9.01) KPa. 14 days after IRE, the Emean of tumors was (15.17 ± 1.00) KPa. A clear boundary was observed between the ablation area and the normal tissues in the pathological results. CONCLUSIONS: The stiffness of the VX2 tumors experienced a first rise process and tend to be normal in the procedure of IRE. SWE could provide tissue stiffness information of different IRE ablation period as a non-invasive method.