A blood-brain barrier- and blood-brain tumor barrier-penetrating siRNA delivery system targeting gliomas for brain tumor immunotherapy.

Glioma is recognized as the most infiltrative and lethal form of central nervous system tumors and is known for its limited response to standard therapeutic interventions, high recurrence rate, and unfavorable prognosis. Recent progress in gene and immunotherapy presents a renewed sense of optimism in the treatment of glioblastoma. However, the barriers to overcome include the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB), as well as the suppressive immune microenvironment. Overcoming these barriers remains a significant challenge. Here, we developed a lipid nanoparticle platform incorporating a dual-functional peptide (cholesterol-DP7-ACP-T7-modified DOTAP or DAT-LNP) capable of targeting glioma across the BBB and BBTB for brain tumor immunotherapy. This system was designed to achieve two key functions. First, the system could effectively penetrate the BBB during accumulation within brain tissue following intravenous administration. Second, this system enhances the maturation of dendritic cells, the polarization of M1 macrophages, and the activation of cytotoxic CD8+ T cells. This multifaceted approach effectively mitigates the immunosuppressive tumor microenvironment of glioma and promotes robust antitumor immune responses. Overall, the intravenous administration of the delivery system designed in this study demonstrates significant therapeutic potential for glioma and holds promising applications in the field of cancer immunotherapy.

Identification of Potent siRNA Delivery Peptides Using Computer Modeling.

Peptides with suitable aggregation behavior and electrical properties are potential siRNA delivery vectors. However, identifying suitable peptides with ideal delivery and safety features is difficult owing to the variations in amino acid sequences. Here, a holistic program based on computer modeling and single-cell RNA sequencing (scRNA-seq) is used to identify ideal siRNA delivery peptides. Stage one of this program consists of a sequential screening process for candidates with ideal assembly and delivery ability; stage two is a cell subtype-level analysis program that screens for high in vivo tissue safety. The leading candidate peptide selected from a library containing 12 amino acids showed strong lung-targeted siRNA delivery capacity after hydrophobic modification. Systemic administration of these compounds caused the least damage to liver and lung tissues and has little impact on macrophage and neutrophil numbers. By loading STAT3 siRNA, strong anticancer effects are achieved in multiple models, including patient-derived xenografts (PDX). This screening procedure may facilitate the development of peptide-based RNA interference (RNAi) therapeutics.

Nomogram predicts survival and surgical benefits for patients with breast cancer with initial bone metastasis: A population-based study.

BACKGROUND: Primary stage IV breast cancer is associated with a poor prognosis. At present, the value of local surgical treatment for patients with stage IV breast cancer remains uncertain; therefore, treatment principles remain controversial. Because of the high heterogeneity of these patients, it is often difficult to evaluate their prognoses. As a result, this study aimed to establish a prognostic nomogram to evaluate the prognosis of patients with breast cancer experiencing primary bone metastasis. METHODS: The clinical characteristics and follow-up data of patients with primary breast cancer and bone metastasis from 2010 to 2018 were collected from the Surveillance, Epidemiology, and End Results database and from 2013 to 2021 at the Peking Union Medical College Hospital. Patients were divided into training and validation groups. Multivariate Cox regression analysis was used to identify the independent prognostic variables for predicting cancer-specific survival (CSS). On the basis of these independent risk factors, a nomogram was developed and used calibration curves to evaluate its accuracy. Patients were divided into three risk groups according to their scores and surgery-related survival curves plotted using the log-rank test. RESULTS: Overall, 6372 patients were included, with 6319 from the Surveillance, Epidemiology, and End Results database and 53 from the Peking Union Medical College Hospital Breast Surgery Department. Multivariate analysis showed that age, race, marital status, grade, tumor stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, and burden of other metastatic lesions were all associated with CSS. Based on these results, a nomogram that predicted the 1-, 3-, and 5-year CSS rates in patients with primary breast cancer and bone metastasis (concordance index > 0.69) was developed. After dividing patients into low-risk, high-risk, or super-high-risk groups based on nomogram scoring criteria, survival analysis revealed that patients in the low- and high-risk groups had significant survival benefits from primary focal surgery. CONCLUSION: Independent risk factors for primary breast cancer in patients with bone metastasis were analyzed and a nomogram established to predict CSS. The prognostic tool derived in this study can assist clinicians in predicting the survival and surgical benefits of these patients through scoring, thereby providing further guidance for treatment strategies.

Genital epithelial barrier function is conserved by intravaginal rings releasing etonogestrel and ethinyl estradiol.

The injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing® is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing®re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract.

TEAD4: A key regulator of tumor metastasis and chemoresistance - Mechanisms and therapeutic implications.

Cancer metastasis is a complex process influenced by various factors, including epithelial-mesenchymal transition (EMT), tumor cell proliferation, tumor microenvironment, and cellular metabolic status, which remains a significant challenge in clinical oncology, accounting for a majority of cancer-related deaths. TEAD4, a key mediator of the Hippo signaling pathway, has been implicated in regulating these factors that are all critical in the metastatic cascade. TEAD4 drives tumor metastasis and chemoresistance, and its upregulation is associated with poor prognosis in many types of cancers, making it an attractive target for therapeutic intervention. TEAD4 promotes EMT by interacting with coactivators and activating the transcription of genes involved in mesenchymal cell characteristics and extracellular matrix remodeling. Additionally, TEAD4 enhances the stemness of cancer stem cells (CSCs) by regulating the expression of genes associated with CSC maintenance. TEAD4 contributes to metastasis by modulating the secretion of paracrine factors and promoting heterotypic cellular communication. In this paper, we highlight the central role of TEAD4 in cancer metastasis and chemoresistance and its impact on various aspects of tumor biology. Understanding the mechanistic basis of TEAD4-mediated processes can facilitate the development of targeted therapies and combination approaches to combat cancer metastasis and improve treatment outcomes.

Oncolytic adenoviruses expressing checkpoint inhibitors for cancer therapy.

Despite the remarkable success of immune checkpoint inhibitors (ICIs), primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment (TME). Oncolytic viruses (OVs) can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts. Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy. According to the diverse immune cell landscapes among different types of tumors, we rationally and precisely generated three recombinant oncolytic adenoviruses (OAds): OAd-SIRPα-Fc, OAd-Siglec10-Fc and OAd-TIGIT-Fc. These viruses were designed to locally deliver SIRPα-Fc, Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47, CD24 or CD155, respectively, in the TME to achieve enhanced antitumor effects. Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors, while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+ T-cell-dominated tumors. Importantly, the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory. In addition, the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME. In summary, rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.

Considerable Long-Term Aesthetic Outcomes and Oncologic Safety of Breast-Conserving Surgery Via a Periareolar Incision: A Retrospective Study.

BACKGROUND: To investigate the application effect of periareolar incision breast-conserving surgery in patients with early breast cancer. METHODS: From January 2017 to November 2021, a clinician in our research center performed a total of 533 breast-conserving surgery. After screening, we collected the information of 209 patients through telephone, online questionnaires, and outpatient follow-up. One hundred seventeen patients with early breast cancer underwent breast-conserving surgery under the periareolar incision, while 92 patients underwent surgery through the tumor surface incision. We compared the differences between the 2 groups in the length of stay, postoperative complications, adjuvant therapy, and other clinical indicators, as well as the subjective and objective evaluation of the long-term postoperative breast aesthetic outcome, local recurrence, distant metastasis, and survival. RESULTS: With a mean follow-up of 3.9 years, patients in the periareolar incision group (PAIG) and tumor surface incision group (TSIG) had no significant differences in clinical indicators, local recurrence, distant metastasis, and survival. However, PAIG patients had better subjective satisfaction with postoperative breast appearance. In the evaluation of objective aesthetic outcomes, PAIG was significantly better than TSIG in texture and elasticity, symmetry, sunken degree of the operative side, skin color, surgical scar, and breast compliance difference. CONCLUSION: By observing and comparing the clinical indicators, postoperative recurrence, and metastasis of the enrolled patients, this study found that periareolar incision surgery could achieve radical therapeutic effects similar to those achieved through tumor surface incision, and had advantages in improving postoperative aesthetic outcomes, which could provide certain references for clinical practice.

In Situ Cocktail Nanovaccine for Cancer Immunotherapy.

In situ vaccination is a desirable strategy for cancer immunotherapy due to its convenience and capacity to target tumor antigens. Here, an in situ nanovaccine based on a cationic peptide with cholesterol-modified, DP7-C, for cancer immunotherapy is rationally designed, and developed a cancer nanovaccine that is easy to preparate. The nanovaccine includes cocktail small interfering RNAs (siRNAs) and immunologic adjuvant CpG ODNs, has synergistic effect in the cancer treatment. This nanovaccine can induce tumor cell death, promote antigen presentation and relieve immune suppression in the tumor microenvironment (TME). Moreover, this nanovaccine is administered to CT26 (hot) and B16F10 (cold) tumor model mice, in which it targeted the primary tumors and induced systemic antitumor immunity to inhibit metastasis. It is validated that the nanovaccine can convert cold tumors into hot tumors. Furthermore, the nanovaccine increased the immune response to anti-PD-1 therapy by modulating the TME in both CT26- and B16F10-tumor-bearing mice. The siRNA cocktail/CpG ODN/self-assembling peptide nanovaccine is a simple and universal tool that can effectively generate specific tumor cell antigens and can be combined with immuno-oncology agents to enhance antitumor immune activity. The versatile methodology provides an alternative approach for developing cancer nanovaccines.

Fine-Tuning through Generations: Advances in Structure and Production of CAR-T Therapy.

Chimeric antigen receptor (CAR)-T cell therapy is a promising form of immunotherapy that has seen significant advancements in the past few decades. It involves genetically modifying T cells to target cancer cells expressing specific antigens, providing a novel approach to treating various types of cancer. However, the initial success of first-generation CAR-T cells was limited due to inadequate proliferation and undesirable outcomes. Nonetheless, significant progress has been made in CAR-T cell engineering, leading to the development of the latest fifth-generation CAR-T cells that can target multiple antigens and overcome individual limitations. Despite these advancements, some shortcomings prevent the widespread use of CAR-T therapy, including life-threatening toxicities, T-cell exhaustion, and inadequate infiltration for solid tumors. Researchers have made considerable efforts to address these issues by developing new strategies for improving CAR-T cell function and reducing toxicities. This review provides an overview of the path of CAR-T cell development and highlights some of the prominent advances in its structure and manufacturing process, which include the strategies to improve antigen recognition, enhance T-cell activation and persistence, and overcome immune escape. Finally, the review briefly covers other immune cells for cancer therapy and ends with the discussion on the broad prospects of CAR-T in the treatment of various diseases, not just hematological tumors, and the challenges that need to be addressed for the widespread clinical application of CAR-T cell therapies.

COVID-19 vaccination status, side effects, and perceptions among breast cancer survivors: a cross-sectional study in China.

Introduction: Breast cancer is the most prevalent malignancy in patients with coronavirus disease 2019 (COVID-19). However, vaccination data of this population are limited. Methods: A cross-sectional study of COVID-19 vaccination was conducted in China. Multivariate logistic regression models were used to assess factors associated with COVID-19 vaccination status. Results: Of 2,904 participants, 50.2% were vaccinated with acceptable side effects. Most of the participants received inactivated virus vaccines. The most common reason for vaccination was "fear of infection" (56.2%) and "workplace/government requirement" (33.1%). While the most common reason for nonvaccination was "worry that vaccines cause breast cancer progression or interfere with treatment" (72.9%) and "have concerns about side effects or safety" (39.6%). Patients who were employed (odds ratio, OR = 1.783, p = 0.015), had stage I disease at diagnosis (OR = 2.008, p = 0.019), thought vaccines could provide protection (OR = 1.774, p = 0.007), thought COVID-19 vaccines were safe, very safe, not safe, and very unsafe (OR = 2.074, p < 0.001; OR = 4.251, p < 0.001; OR = 2.075, p = 0.011; OR = 5.609, p = 0.003, respectively) were more likely to receive vaccination. Patients who were 1-3 years, 3-5 years, and more than 5 years after surgery (OR = 0.277, p < 0.001; OR = 0.277, p < 0.001, OR = 0.282, p < 0.001, respectively), had a history of food or drug allergies (OR = 0.579, p = 0.001), had recently undergone endocrine therapy (OR = 0.531, p < 0.001) were less likely to receive vaccination. Conclusion: COVID-19 vaccination gap exists in breast cancer survivors, which could be filled by raising awareness and increasing confidence in vaccine safety during cancer treatment, particularly for the unemployed individuals.

EGFR inhibitor erlotinib plus monoclonal antibody versus erlotinib alone for first-line treatment of advanced non-small cell lung carcinoma: A systematic review and meta-analysis.

PURPOSE: Immuno-combination therapy is emerging as an effective treatment for advanced non-small cell lung carcinoma (NSCLC). However, compared to monotherapy, such as monoclonal antibodies or kinase inhibitors, whether combination therapy can enhance antitumor efficacy or alleviate side effects remains unclear. METHODS: A systematic literature search was undertaken using the PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials databases to identify eligible studies concentrating on treatment with erlotinib or erlotinib plus monoclonal antibodies in NSCLC patients published between January 2017 and June 2022. The primary outcomes included progression-free survival (PFS), overall survival (OS), response rate (RR) and treatment-related adverse events (AEs). RESULTS: Seven independent randomized, controlled clinical trials including 1513 patients were obtained for the final analysis. Erlotinib plus monoclonal antibodies was significantly associated with the improvement of PFS (hazards ratio [HR], 0.60; 95% CI 0.53-0.69; z = 7.59, P < 0.01) and with moderate performance regarding OS (HR, 0.81; 95% CI 0.58-1.13; z = 1.23, P = 0.22) and RR (odds ratio [OR], 1.25; 95% CI 0.98-1.59; z = 1.80, P = 0.07), irrespective of EGFR mutation status. In the safety evaluation, erlotinib plus monoclonal antibodies had a markedly higher occurrence of adverse events (AEs) of Clavien grade 3 or higher (OR, 3.32; 95% CI 2.66-4.15; z = 10.64, P < 0.01). CONCLUSION: Compared with erlotinib alone, combination therapy (erlotinib plus monoclonal antibodies) was associated with significantly improved PFS in NSCLC therapy, accompanied by increased treatment-related AEs. REGISTRATION: Our systematic review protocol was registered in the PROSPERO international register of systematic reviews (CRD42022347667).

Population-based genetic analysis in infertile men reveals novel mutations of ADAD family members in patients with impaired spermatogenesis.

The testis-specific adenosine deaminase domain-containing (ADAD) protein family, including ADAD1 and ADAD2, has been confirmed to be essential in mouse male fertility. However, the roles of ADAD1 and ADAD2 in human reproductive biology are unclear. Herein, whole-exome sequencing was conducted for 337 infertile patients to detect pathogenic variants in ADAD1 and ADAD2. Importantly, a novel deleterious biallelic variant of NM_001159285.2:c.1408G > T (p.V470F) and NM_001159285.2:c.1418A > G (p.E473G) in ADAD1 and a pathogenic homozygous missense variant of NM_001145400.2:c.1381C > T (p.R461W) in ADAD2 were identified in this infertile cohort with frequencies of 0.29 (1/337) and 0.59% (2/337), respectively. Electron microscopy revealed an abnormal morphology and severely disorganized ultrastructure of sperm from the patients. Immunofluorescence and western blotting showed a sharp decrease in ADAD1 and ADAD2 expression in sperm from the patients. Mechanistically, bioinformatics analysis suggested that ADAD2 interacts with DNAH17. Furthermore, we demonstrated that the expression of DNAH17 was markedly downregulated in the sperm of patients harboring ADAD2 variants. In addition, the expression of several autophagy regulators was significantly disrupted in the sperm of patients harboring ADAD2 variants. In conclusion, we identified novel ADAD1 and ADAD2 variants in three infertile patients from a large infertile cohort, first providing evidence that ADAD1 and ADAD2 variants might be a candidate genetic cause of human male infertility. Moreover, an important new dimension to our understanding of the genotype-phenotype correlations between the ADAD gene family and male infertility in humans has been uncovered, providing valuable information for the genetic diagnosis of male infertility.

Deficiency of cancer/testis antigen gene CT55 causes male infertility in humans and mice.

The Cancer/Testis Antigen (CTA) genes comprise a group of genes whose expression under physiological conditions is restricted to the testis but is activated in many human cancers. Depending on the particular expression pattern, the CTA genes are speculated to play a role in spermatogenesis, but evidence is limited thus far. Here, we reported patients with a hemizygous nonsense mutation in cancer-testis antigen 55 (CT55) suffering from male infertility with extreme disruption in sperm production, morphology, and locomotion. Specifically, the insufficiency of sperm individualization, excessive residue of unnecessary cytoplasm, and defects in acrosome development were evident in the spermatozoa of the patients. Furthermore, mouse models with depletion of Ct55 showed accelerated infertility with age, mimicking the defects in sperm individualization, unnecessary cytoplasm removal, and meanwhile exhibiting the disrupted cumulus-oocyte complex penetration. Mechanistically, our functional experiments uncovered CT55 as a new autophagic manipulator to regulate spermatogenesis via selectively interacting with LAMP2 and GABARAP (which are key regulators in the autophagy process) and further fine-tuning their expression. Therefore, our findings revealed CT55 as a novel CTA gene involved in spermatogenesis due to its unprecedented autophagy activity.

Comparison of ultrasound and mammography for early diagnosis of breast cancer among Chinese women with suspected breast lesions: A prospective trial.

BACKGROUND: Ultrasound is more widely used than mammography for early diagnosis of breast cancer in China as most Chinese women have small and dense mammary glands. This study compared the diagnostic performance of ultrasound and mammography for breast cancer among Chinese women with suspected breast lesions. METHODS: From November 2019 to November 2021, we compared the results of ultrasound and mammography for breast lesion diagnosis in 2737 consecutive participants with suspected breast lesions; all patients underwent biopsies. We measured the sensitivity, specificity, and diagnostic accuracy separately. RESULTS: Among the 2737 participants, 2844 breast lesions were detected, including 1935 (68.0%) breast cancers and 909 (32.0%) benign lesions. Of the breast cancers, ultrasound detected 1851 (95.7%), whereas mammography detected 1527 (78.9%). The sensitivity of ultrasound for breast cancer diagnosis was significantly higher than that of mammography (95.7% vs. 78.9%, p < 0.001), whereas the specificity was significantly lower than that of mammography (42.9% vs. 62.3%, p < 0.001). The receiver operating characteristic curves revealed that ultrasound was more accurate in detecting breast cancer than mammography (76.8% vs. 71.3%, p < 0.001). Age, body mass index, and breast density did not influence ultrasound sensitivity and accuracy. CONCLUSIONS: Ultrasound is more sensitive and accurate than mammography and detects more breast cancers with a lower specificity.

PRSS55 is a novel potential causative gene for human male infertility.

RESEARCH QUESTION: Testis-specific PRSS55 is a chymotrypsin-like serine protease that is highly conserved among mammalian species. The essential role of Prss55 in mouse male fertility has been established. What is the role of PRSS55 in human reproduction? DESIGN: Whole exome sequencing was used to identify the genetic cause in an infertile male with teratozoospermia. Papanicolaou staining, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to explore morphological defects in the patient's spermatozoa. Immunofluorescence staining and western blot analysis were conducted to assess the pathogenicity of the identified variant. Intracytoplasmic sperm injection (ICSI) was used to assist the patient with fertilization. RESULTS: Sanger sequencing of the pedigree demonstrated that the infertile man carried a novel homozygous mutation in PRSS55 (c.575C>T [p.A192V]). Morphological defects in the sperm head, neck, midpiece and tail were demonstrated by Papanicolaou staining, SEM and TEM. Immunofluorescence staining and western blotting of the patient's spermatozoa showed that the point mutation changed the conformation of PRSS55 and caused a sharp decrease in the PRSS55 protein concentration. The expression and subcellular localization of PRSS55 in the testis and spermatozoa of mice and humans showed that PRSS55 was expressed in the head and flagella of spermatids and epididymal spermatozoa. Moreover, ICSI treatment for this kind of infertile patient was shown to be effective. CONCLUSIONS: These findings revealed a novel mutation in PRSS55 in an infertile patient, suggesting for the first time the crucial role of PRSS55 in human fertility. This study provides new insight into genetic counselling diagnoses and subsequent treatment for male infertility.

Population Pharmacokinetics of Elagolix in Combination with Low-Dose Estradiol/Norethindrone Acetate in Women with Uterine Fibroids.

BACKGROUND AND OBJECTIVES: Elagolix is an orally active, gonadotropin-releasing hormone receptor antagonist approved for the management of endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. Elagolix population pharmacokinetics and factors affecting elagolix exposure in healthy women and women with endometriosis have been reported previously. The purpose of this study was to extend the population pharmacokinetics model with additional modifications to incorporate data from phase III studies of elagolix with hormonal add-back therapy in women with uterine fibroids. METHODS: Data from 13 clinical studies (a total of 2168 women) consisting of six phase I studies in healthy premenopausal women, four phase III studies in premenopausal women with endometriosis, and three phase III studies in premenopausal women with uterine fibroids were analyzed using a non-linear mixed-effects modeling approach. RESULTS: Elagolix population pharmacokinetics was best described by a two-compartment model with first-order absorption, lag time in absorption, and first-order elimination. Out of the covariates tested on elagolix apparent clearance, apparent volume of distribution, and/or relative bioavailability, only organic anion transporting polypeptide 1B1 genotype status and body weight had a statistically significant but no clinically meaningful effect on elagolix relative bioavailability and apparent volume of distribution, respectively. There were no clinically meaningful differences in elagolix population pharmacokinetics in healthy women or women with endometriosis or uterine fibroids. CONCLUSIONS: Elagolix population pharmacokinetics modeling did not reveal any patient-related factors or clinical parameters that would require dose adjustments for the approved dosage of 300 mg twice daily with estradiol 1 mg /norethindrone acetate 0.5 mg daily, in women with heavy menstrual bleeding associated with uterine fibroids. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01620528 (EM-1), NCT01760954 (EM-1-Extend), NCT01931670 (EM-2), NCT02143713 (EM-2-Extend), NCT02654054 (UF-1), NCT02691494 (UF-2), NCT0295494 (UF-Extend).

Novel immune-related prognostic model and nomogram for breast cancer based on ssGSEA.

This study aimed to construct an immune-related prognostic model and a nomogram to predict the 1-, 3-, and 5-year overall survival (OS) of breast cancer patients. We applied single-sample gene set enrichment analysis to classify 1,053 breast cancer samples from The Cancer Genome Atlas (TCGA) database into high and low immune cell infiltration clusters. In cluster construction and validation, the R packages "GSVA," "hclust," "ESTIMATE," and "CIBERSORT" and GSEA software were utilized. ImmPort, univariate Cox regression analysis, and Venn analysis were then used to identify 42 prognostic immune-related genes. Eventually, the genes TAPBPL, RAC2, IL27RA, ULBP2, PSMB8, SOCS3, NFKBIE, IGLV6-57, CXCL1, IGHD, AIMP1, and CXCL13 were chosen for model construction utilizing least absolute shrinkage and selection operator regression analysis. The Kaplan-Meier curves of both the training and validation sets indicated that the overall survival of patients in the low-risk group was superior to that of patients in the high-risk group (p < .05). The areas under curves (AUCs) of the model at 1, 3, and 5 years were, respectively, .697, .710, and .675 for the training set and .930, .688, and .712 for the validation set. Regarding clinicopathologic characteristics, breast cancer-related genes, and tumor mutational burden, effective differentiation was achieved between high-risk and low-risk groups. A nomogram integrating the risk model and clinicopathologic factors was constructed using the "rms" R software package. The nomogram's 1-, 3-, and 5-year AUCs were .828, .783, and .751, respectively. Overall, our study developed an immune-related model and a nomogram that could reliably predict OS for breast cancer patients, and offered insights into tumor immune and pathological mechanisms.

In Vivo Insulin Peptide Autoantigen Delivery by Mannosylated Sodium Alginate Nanoparticles Delayed but Could Not Prevent the Onset of Type 1 Diabetes in Nonobese Diabetic Mice.

Type 1 diabetes (T1D) is an autoimmune subtype of diabetes, mainly caused by the immune attack of self-insulin-producing cells. Immune modulation that delays the onset of T1D is able to reduce diabetic complications and mortality. We have previously reported that mannosylated sodium alginate nanoparticles (MAN-ALG) exhibited excellent dendritic cell targeting and in vivo antigen delivery efficacy. To investigate the role of MAN-ALG in an autoimmune context, we loaded the MAN-ALG with Ins29-23, a T1D autoantigen [MAN-ALG(PEP)], for T1D immune tolerance induction in nonobese diabetic (NOD) mice. We observed the delayed onset of T1D occurrence and some degree of blood glucose reduction accompanied by a larger islet area, attributable to augmented T-regulatory cell proportion in mice treated with MAN-ALG(PEP). However, MAN-ALG was also found to elicit lysosomal escape and cross-presentation of Ins29-23 in bone marrow-derived dendritic cells, leading to the immune activation of Ins29-23-recognizing T cells and destruction of Ins29-23-expressing islet cells. This dual impact resulted in delayed but a nonpreventive effect of MAN-ALG(PEP) on the T1D onset in NOD mice. Considering the potent immune stimulatory property of MAN-ALG, cautions should be implemented when using alginate-based biomaterials in an autoimmune context. Moreover, it is also noted that regarding the in vivo outcome of immune therapies, biomaterial-based delivery systems and their detailed role on immune regulation need to be examined.

Epigenetic modification-dependent androgen receptor occupancy facilitates the ectopic TSPY1 expression in prostate cancer cells.

Testis-specific protein Y-encoded 1 (TSPY1), a Y chromosome-linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples. The acetyl-histone H4 and trimethylated histone H3-lysine 4, two post-translational modifications of histones occupying the TSPY1 promoter, facilitated the TSPY1 expression in PCa cells. In addition, we found that androgen accelerated the TSPY1 transcription on the condition of hypomethylated of TSPY1-CGI and promoted PCa cell proliferation. Moreover, the binding of androgen receptor (AR) to the TSPY1 promoter, enhancing TSPY1 transcription, was detected in PCa cells. Taken together, our findings identified the regulation of DNA methylation, acting as a primary mechanism, on TSPY1 expression in PCa, and revealed that TSPY1 is an androgen-AR axis-regulated oncogene, suggesting a novel and potential target for PCa therapy.

Development and Validation of a Nomogram to Predict Lymph Node Metastasis in Patients With T1 High-Grade Urothelial Carcinoma of the Bladder.

PURPOSE: This study aims to develop and validate a nomogram to predict lymph node (LN) metastasis preoperatively in patients with T1 high-grade urothelial carcinoma. METHODS: We retrospectively evaluated the data of 2,689 patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC) and bilateral lymphadenectomy in two medical centers. Eventually, 412 patients with T1 high-grade urothelial carcinoma were enrolled in the primary cohort to develop a prognostic nomogram designed to predict LN status. An independent validation cohort (containing 783 consecutive patients during the same period) was subjected to validate the predicting model. Binary regression analysis was used to develop the predicting nomogram. We assessed the performance of the nomogram concerning its clinical usefulness, calibration, and discrimination. RESULTS: Overall, 69 (16.75%), and 135 (17.24%) patients had LN metastasis in the primary cohort and external validation cohort, respectively. The final nomogram included information on tumor number, tumor size, lymphovascular invasion (LVI), fibrinogen, and monocyte-to-lymphocyte ratio (MLR). The nomogram showed good predictive accuracy and calibration with a concordance index in the primary cohort of 0.853. The application of the nomogram in the external validation cohort still gave good discrimination (C-index, 0.845) and good calibration. The analysis of the decision curve shows that the nomogram has clinical application value. CONCLUSION: The nomogram that incorporated the tumor number, tumor size, LVI, fibrinogen, and MLR showed favorable predictive accuracy for LN metastasis. It may be conveniently used to predict LN metastasis in patients with T1 high-grade urothelial carcinoma and be helpful in guiding treatment decisions.