Updated review on analysis of long non-coding RNAs as emerging diagnostic and therapeutic targets in prostate cancers.

Despite advancements, prostate cancers (PCa) pose a significant global health challenge due to delayed diagnosis and therapeutic resistance. This review delves into the complex landscape of prostate cancer, with a focus on long-noncoding RNAs (lncRNAs). Also explores the influence of aberrant lncRNAs expression in progressive PCa stages, impacting traits like proliferation, invasion, metastasis and therapeutic resistance. The study elucidates how lncRNAs modulate crucial molecular effectors, including transcription factors and microRNAs, affecting signaling pathways such as androgen receptor signaling. Besides, this manuscript sheds light on novel concepts and mechanisms driving PCa progression through lncRNAs, providing a critical analysis of their impact on the disease's diverse characteristics. Besides, it discusses the potential of lncRNAs as diagnostics and therapeutic targets in PCa. Collectively, this work highlights state of art mechanistic comprehension and rigorous scientific approaches to advance our understanding of PCa and depict innovations in this evolving field of research.

Creating a novel multiparametric magnetic resonance imaging-based biopsy strategy for reducing unnecessary prostate biopsies: a retrospective cohort study.

Background: The overdiagnosis of prostate cancer (PCa) caused by unnecessary prostate biopsy has become a worldwide problem that urgently requires a solution. We aimed to reduce the unnecessary prostate biopsies and increase the detection rate of clinically significant PCa (csPCa) by creating a novel multiparametric magnetic resonance imaging (mpMRI)-based strategy. Methods: A total of 1,194 eligible patients who underwent transperineal prostate biopsies from January 2018 to December 2022 were included in this retrospective study. Of these patients, 1,080 who received prostate biopsies from January 2018 to July 2022 were regarded as cohort 1 for primary analysis, and 114 patients who received prostate biopsies from August 2022 to December 2022 were collected in cohort 2 for validation. All the mpMRI images were quantitatively evaluated by the Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v. 2.1). The diagnostic performances were assessed through the receiver operating characteristic (ROC) curve and area under the curve (AUC) and were compared with the DeLong test. Cancer diagnosis-free survival analysis was performed using the Kaplan-Meier method and log-rank test. The primary endpoint of this study was clinically significant PCa with an International Society of Urological Pathology (ISUP) grade ≥2. Results: In cohort 1, the results of ROC curves demonstrated that the PI-RADS score had a higher diagnostic accuracy (AUC =0.898 for any-grade PCa; AUC =0.917 for csPCa) than did the other clinical variables (P<0.001). Under the novel mpMRI-based biopsy strategy, all patients with PI-RADS 1 can safely avoid prostate biopsy. For patients with PI-RADS 2, prostate biopsy should be considered for patients with prostate-specific antigen density (PSAD) ≥0.3 ng/mL2 and prostate volume <65 mL. As for patients with PI-RADS 3, structured surveillance programs can be a viable option if PSAD <0.3 ng/mL2 and prostate volume ≥65 mL. Finally, patients with a PI-RADS score of 4 and 5 should undergo prostate biopsy due to the high probability of clinically significant PCa. In the validation analysis of cohort 2, 48 patients were placed into a biopsy-spared group with no csPCa cases, while 66 patients were placed in a biopsy-needed group, with an csPCa detection rate of 50.0%. Overall, the novel strategy demonstrated a sensitivity, specificity, positive predictive value, and negative predictive value of 98.9%, 57.5%, 50.5%, and 99.2%, respectively, for diagnosing csPCa. Conclusions: An mpMRI-based biopsy strategy can effectively avoid about 40% of prostate biopsies and maintain a high detection rate for clinically significant PCa. It can further provide valuable guidance for patients and physicians in considering the necessity of prostate biopsy.

Comparison of physics-based deformable registration methods for image-guided neurosurgery.

This paper compares three finite element-based methods used in a physics-based non-rigid registration approach and reports on the progress made over the last 15 years. Large brain shifts caused by brain tumor removal affect registration accuracy by creating point and element outliers. A combination of approximation- and geometry-based point and element outlier rejection improves the rigid registration error by 2.5 mm and meets the real-time constraints (4 min). In addition, the paper raises several questions and presents two open problems for the robust estimation and improvement of registration error in the presence of outliers due to sparse, noisy, and incomplete data. It concludes with preliminary results on leveraging Quantum Computing, a promising new technology for computationally intensive problems like Feature Detection and Block Matching in addition to finite element solver; all three account for 75% of computing time in deformable registration.

Real-Time Dynamic Data Driven Deformable Registration for Image-Guided Neurosurgery: Computational Aspects.

Current neurosurgical procedures utilize medical images of various modalities to enable the precise location of tumors and critical brain structures to plan accurate brain tumor resection. The difficulty of using preoperative images during the surgery is caused by the intra-operative deformation of the brain tissue (brain shift), which introduces discrepancies concerning the preoperative configuration. Intra-operative imaging allows tracking such deformations but cannot fully substitute for the quality of the pre-operative data. Dynamic Data Driven Deformable Non-Rigid Registration (D4NRR) is a complex and time-consuming image processing operation that allows the dynamic adjustment of the pre-operative image data to account for intra-operative brain shift during the surgery. This paper summarizes the computational aspects of a specific adaptive numerical approximation method and its variations for registering brain MRIs. It outlines its evolution over the last 15 years and identifies new directions for the computational aspects of the technique.

Development and validation of a prognostic model incorporating tumor thrombus grading for nonmetastatic clear cell renal cell carcinoma with tumor thrombus: A multicohort study.

There is significant variability with respect to the prognosis of nonmetastatic clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT). By applying multiregion whole-exome sequencing on normal-tumor-thrombus-metastasis quadruples from 33 ccRCC patients, we showed that metastases were mainly seeded by VTT (81.8%) rather than primary tumors (PTs). A total of 706 nonmetastatic ccRCC patients with VTT from three independent cohorts were included in this study. C-index analysis revealed that pathological grading of VTT outperformed other indicators in risk assessment (OS: 0.663 versus 0.501-0.610, 0.667 versus 0.544-0.651, and 0.719 versus 0.511-0.700 for Training, China-Validation, and Poland-Validation cohorts, respectively). We constructed a risk predicting model, TT-GPS score, based on four independent variables: VTT height, VTT grading, perinephric fat invasion, and sarcomatoid differentiation in PT. The TT-GPS score displayed better discriminatory ability (OS, c-index: 0.706-0.840, AUC: 0.788-0.874; DFS, c-index: 0.691-0.717, AUC: 0.771-0.789) than previously reported models in risk assessment. In conclusion, we identified for the first-time pathological grading of VTT as an unheeded prognostic factor. By incorporating VTT grading, the TT-GPS score is a promising prognostic tool in predicting the survival of nonmetastatic ccRCC patients with VTT.

Association of BMI with erectile dysfunction: A cross-sectional study of men from an andrology clinic.

Abnormal body mass index (BMI) is associated with an increased risk of erectile dysfunction (ED). However, the relationship between different BMI categories and the levels of ED severity remains unclear. In the current study, 878 men from the andrology clinic in Central China were recruited. Erectile function was assessed by the International Index of Erectile Function (IIEF) scores. Questionnaires included questions about demographic characteristics (age, height, weight, educational status), lifestyle habits (drinking, smoking, sleep time), and medical history. Logistic regression was used to examine the association between ED risk and BMI. The incidence of ED was 53.1%. BMI was significantly higher in men from the ED group than in those from the non-ED group (P = 0.01). Compared with the normal weight group, obese men had a higher risk of ED (OR = 1.97, 95% CI = 1.25-3.14, P = 0.004), even after adjustment for potential confounders (OR = 1.78, 95% CI = 1.10-2.90, P = 0.02). Moreover, the positive correlation between obesity and moderate/severe ED severity was confirmed by logistic regression analysis (moderate/severe ED, OR = 2.71, 95% CI = 1.44-5.04, P = 0.002), even after adjusting for potential confounders (OR = 2.51 95% CI = 1.24-5.09, P = 0.01). Collectively, our findings indicate a positive correlation between obesity and the risk of moderate/severe ED. Clinicians could pay more attention to moderate/severe ED patients to maintain a healthy body weight to improve erectile function.

5-aminolevulinic acid photodynamic therapy combined with wart curettage treatment for intractable urethral condylomata acuminata. A case report.

Condylomata acuminata (CA) is caused by human papillomavirus (HPV). It is one of the most common sexually transmitted diseases (STD). The lesions mainly occur in the external genitalia and perianal areas, rarely involves in urethral and usually localized at the distal 3 cm of the urethral orifice. Because of the special anatomical site, treating urethral CA is challenging and it has high recurrence rate after treatment. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) can successfully treat urethral CA, however, the experience of using ALA-PDT combined with wart curettage to treat intractable urethral CA is still very limited. In here, we reported an intractable urethral CA case with effective remission after receiving combination therapy. Wart curettage combine with ALA-PDT is an expeditious, economical, and well-tolerated treatment method.

Extracellular HSPs: The Potential Target for Human Disease Therapy.

Heat shock proteins (HSPs) are highly conserved stress proteins known as molecular chaperones, which are considered to be cytoplasmic proteins with functions restricted to the intracellular compartment, such as the cytoplasm or cellular organelles. However, an increasing number of observations have shown that HSPs can also be released into the extracellular matrix and can play important roles in the modulation of inflammation and immune responses. Recent studies have demonstrated that extracellular HSPs (eHSPs) were involved in many human diseases, such as cancers, neurodegenerative diseases, and kidney diseases, which are all diseases that are closely linked to inflammation and immunity. In this review, we describe the types of eHSPs, discuss the mechanisms of eHSPs secretion, and then highlight their functions in the modulation of inflammation and immune responses. Finally, we take cancer as an example and discuss the possibility of targeting eHSPs for human disease therapy. A broader understanding of the function of eHSPs in development and progression of human disease is essential for developing new strategies to treat many human diseases that are critically related to inflammation and immunity.

Automatic Brain Midline Surface Delineation on 3D CT Images With Intracranial Hemorrhage.

Brain midline delineation plays an important role in guiding intracranial hemorrhage surgery, which still remains a challenging task since hemorrhage shifts the normal brain configuration. Most previous studies detected brain midline on 2D plane and did not handle hemorrhage cases well. We propose a novel and efficient hemisphere-segmentation framework (HSF) for 3D brain midline surface delineation. Specifically, we formulate the brain midline delineation as a 3D hemisphere segmentation task, and employ an edge detector and a smooth regularization loss to generate the midline surface. We also introduce a distance-weighted map to keep the attention on the midline. Furthermore, we adopt rectification learning to handle various head poses. Finally, considering the complex situation of ventricle break-in for hemorrhages in bilateral intraventricular (B-IVH) cases, we identify those cases via a classification model and design a midline correction strategy to locally adjust the midline. To our best knowledge, it is the first study focusing on delineating the brain midline surface on 3D CT images of hemorrhage patients and handling the situation of ventricle break-in. Extensive validation on our large in-house datasets (519 patients) and the public CQ500 dataset (491 patients), demonstrates that our method outperforms state-of-the-art methods on brain midline delineation.

[Correlation of the platelet count in the peripheral blood with the prostate volume].

OBJECTIVE: To investigate the relationship of the prostate volume with the count of inflammatory cells in the peripheral blood and clarify the pathogenesis of BPH. METHODS: From 2015 to 2019, we enrolled 104 men pathologically diagnosed with BPH. Using univariate and multivariate linear regression analysis models, we analyzed the correlation of the prostate volume with the neutrophil count, platelet count, neutrophil-lymphocyte ratio (NLR), platelet-WBC ratio (PWR), and lymphocyte-monocyte ratio (LMR) in the peripheral blood of the patients. RESULTS: Both the platelet count (r = 0.401, P < 0.001) and PWR (r = 0.343, P < 0.001) in the peripheral blood were positively correlated with the prostate volume and serum PSA level, but not with IPSS. No evident relationship was found between the prostate volume and the systemic inflammatory markers NLR and LMR. CONCLUSIONS: The platelet count in the peripheral blood is an important predictor of BPH and may play an important role in the development and progression of BPH.

5-aminolevulinic acid photodynamic therapy and holmium laser treatment for intraurethral condylomata acuminata in a renal transplant patient.

Condylomata acuminata (CA) caused by human papillomavirus, often involves the external genitalia, perianal skin, and other moist mucous membranes. Urethral involvement is uncommon and little recognized, and usually limited to the distal 3 cm of the meatus. It is difficult to treat CA involving the urethra because of the anatomical location, risk of complications and recurrence. One effective method for the treatment of CA located at the urinary meatus is 5-aminolevulinic acid photodynamic therapy (ALA-PDT). However, experience of using this method for the treatment of whole urethral CA is still very limited. Herein, we treated a whole urethral CA successfully with photodynamic and holmium laser therapies. The case of a 25-year-old patient who underwent kidney transplant effected by intraurethral CA is presented and discussed. Catheter implantation and (or) immunosuppression treatment increases the risk of urethral condyloma acuminatum. The ALA-PDT is a safe, straightforward, effective, and well-tolerated treatment procedure for intraurethral CA. ALA-PDT combined with holmium laser treatment can successfully treat kidney transplant patients with intraurethral CA.

Conditional deletion of Wntless in granulosa cells causes impaired corpora lutea formation and subfertility.

WNT proteins are widely expressed in the murine ovaries. WNTLESS is a regulator essential for all WNTs secretion. However, the complexity and overlapping expression of WNT signaling cascades have prevented researchers from elucidating their function in the ovary. Therefore, to determine the overall effect of WNT on ovarian development, we depleted the Wntless gene in oocytes and granulosa cells. Our results indicated no apparent defect in fertility in oocyte-specific Wntless knockout mice. However, granulosa cell (GC) specific Wntless deletion mice were subfertile and recurred miscarriages. Further analysis found that GC-specific Wntless knockout mice had noticeably smaller corpus luteum (CL) in the ovaries than control mice, which is consistent with a significant reduction in luteal cell marker gene expression and a noticeable increase in apoptotic gene expression. Also, the deletion of Wntless in GCs led to a significant decrease in ovarian HCGR and ß-Catenin protein levels. In conclusion, Wntless deficient oocytes had no discernible impact on mouse fertility. In contrast, the loss of Wntless in GCs caused subfertility and impaired CL formation due to reduced LHCGR and ß-Catenin protein levels, triggering GC apoptosis.

Human Umbilical Cord Mesenchymal Stem Cells for Adjuvant Treatment of a Critically Ill COVID-19 Patient: A Case Report.

BACKGROUND: COVID-19 (coronavirus disease 2019) has become a global public health emergency since patients were first detected in Wuhan, China, in December 2019. Currently, there are no satisfying antiviral medications and vaccines available. CASE PRESENTATION: We reported the treatment process and clinical outcome of a 48-year-old man critically ill COVID-19 patient who received transfusion of allogenic human umbilical cord mesenchymal stem cells (UC-MSCs). CONCLUSIONS: We proposed that UC-MSC transfusion might be a new option for critically ill COVID-19. Although only one case we were shown, more similar clinical cases are inquired for further evidence providing the potential effectiveness of UC-MSC treatment.

CD83, a Novel MAPK Signaling Pathway Interactor, Determines Ovarian Cancer Cell Fate.

Ovarian cancer is a leading cause of death from gynecologic malignancies worldwide. Although CD83 is widely described as a solid marker for mature dendritic cells, emerging pieces of evidence indicate the expression of membrane protein CD83 by various tumor cells, including ovarian cancer cells. However, the potential role of CD83 in ovarian cancer cell properties and development remains absolutely unknown. By using human CD83 stable overexpression and knockdown sublines of several ovarian cancer cells, we observed that CD83 advanced the growth proliferation, colony formation ability, spheroid formation, and in vivo tumorigenicity of ovarian cancer cells; surprisingly, CD83 limited their migration and invasion potentials. Positive regulation of proliferation/stemness factors (e.g., cyclin-CDKs and KIT/CD44) but negative regulation of matrix metallopeptidases (e.g., MMP1 and 7) by CD83 were revealed by the integrated analysis of transcriptome and proteome. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) first identified the association of CD83 with MAP3K7 (also known as TAK1) and MAP3K7-binding protein TAB1 on the cell membrane. Moreover, CD83 functions through the activation of MAP3K7-MEK1/2-ERK1/2 cascades to further regulate downstream FOXO1/p21/CDK2/CCNB1 and STAT3/DKK1 signaling pathways, thus activating proliferation and spheroid formation of ovarian cancer cells, respectively. Collectively, our findings define a CD83-MAPK pathway in the regulation of proliferation and stemness in ovarian cancer cells, with potential therapeutic applications in blocking their progression.

Adaptive Physics-Based Non-Rigid Registration for Immersive Image-Guided Neuronavigation Systems.

Objective: In image-guided neurosurgery, co-registered preoperative anatomical, functional, and diffusion tensor imaging can be used to facilitate a safe resection of brain tumors in eloquent areas of the brain. However, the brain deforms during surgery, particularly in the presence of tumor resection. Non-Rigid Registration (NRR) of the preoperative image data can be used to create a registered image that captures the deformation in the intraoperative image while maintaining the quality of the preoperative image. Using clinical data, this paper reports the results of a comparison of the accuracy and performance among several non-rigid registration methods for handling brain deformation. A new adaptive method that automatically removes mesh elements in the area of the resected tumor, thereby handling deformation in the presence of resection is presented. To improve the user experience, we also present a new way of using mixed reality with ultrasound, MRI, and CT. Materials and methods: This study focuses on 30 glioma surgeries performed at two different hospitals, many of which involved the resection of significant tumor volumes. An Adaptive Physics-Based Non-Rigid Registration method (A-PBNRR) registers preoperative and intraoperative MRI for each patient. The results are compared with three other readily available registration methods: a rigid registration implemented in 3D Slicer v4.4.0; a B-Spline non-rigid registration implemented in 3D Slicer v4.4.0; and PBNRR implemented in ITKv4.7.0, upon which A-PBNRR was based. Three measures were employed to facilitate a comprehensive evaluation of the registration accuracy: (i) visual assessment, (ii) a Hausdorff Distance-based metric, and (iii) a landmark-based approach using anatomical points identified by a neurosurgeon. Results: The A-PBNRR using multi-tissue mesh adaptation improved the accuracy of deformable registration by more than five times compared to rigid and traditional physics based non-rigid registration, and four times compared to B-Spline interpolation methods which are part of ITK and 3D Slicer. Performance analysis showed that A-PBNRR could be applied, on average, in <2 min, achieving desirable speed for use in a clinical setting. Conclusions: The A-PBNRR method performed significantly better than other readily available registration methods at modeling deformation in the presence of resection. Both the registration accuracy and performance proved sufficient to be of clinical value in the operating room. A-PBNRR, coupled with the mixed reality system, presents a powerful and affordable solution compared to current neuronavigation systems.

Melatonin Reduces Androgen Production and Upregulates Heme Oxygenase-1 Expression in Granulosa Cells from PCOS Patients with Hypoestrogenia and Hyperandrogenia.

BACKGROUND/AIMS: Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by abnormal hormone levels in peripheral blood and poor-quality oocytes. PCOS is a pathophysiological syndrome caused by chronic inflammation and oxidative stress. The aim of this study was to investigate the mechanism of melatonin regulation on androgen production and antioxidative damage in granulosa cells from PCOS patients with hypoestrogenia and hyperandrogenia. METHODS: Cumulus-oocyte complexes were collected from PCOS patients who had low levels of estrogen in follicular fluids. RESULTS: Melatonin triggered upregulation of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) expression via the extracellular signal-regulated kinase pathway in luteinized granulosa cells. As a result, conversion of androgen to 17ß-estradiol was accelerated. We also found that melatonin significantly reduced the levels of inducible nitric oxide (NO) synthetase and NO in luteinized granulosa cells. Levels of transcripts encoding NF-E2-related factor-2 and its downstream target heme oxygenase-1 were also increased, leading to anti-inflammatory and antioxidant effects. We also found that melatonin could improve oocyte development potential. CONCLUSION: Our preliminary results showed that melatonin had a positive impact on oocyte quality in PCOS patients with hypoestrogenia and hyperandrogenia.

Restore natural fertility of Kitw/Kitwv mouse with nonobstructive azoospermia through gene editing on SSCs mediated by CRISPR-Cas9.

BACKGROUND: Male infertility is a serious social problem in modern society. Nonobstructive azoospermia (NOA) caused by germ cell gene defects is an important reason for male infertility, but effective clinical treatment for this disease has not been established. METHODS: We choose Kitw/Kitwv mouse as a research model and try to develop a new treatment strategy and "cure" its infertility. Mutant spermatogonial stem cells (SSCs) were isolated from one single unilateral testis of a 14-day-old Kitw/Kitwv mouse and propagated in vitro. The C to T point mutation on Kitwv site of these SSCs was corrected through CRISPR-Cas9-mediated homology-directed repair (HDR) in vitro. Then, the repaired SSCs were screened out, proliferated, and transplanted into the remaining testis, and complete spermatogenesis was established in the recipient testis. RESULTS: Healthy offsprings with wild type Kit gene or Kitw mutation were obtained through natural mating 4 months after SSC transplantation. CONCLUSION: In this study, we established an effective new treatment strategy for NOA caused by germ cell gene defects through a combination of SSC isolation, CRISPR-Cas9-mediated gene editing, and SSC transplantation, which brought hope for these NOA patients to restore their natural fertility.

Recent advances in the regulation of testicular germ cell tumors by microRNAs.

Testicular germ cell tumors (TGCTs) are generally rare but represent the most common solid tumors in young men. They are classified broadly into seminoma, which resemble primordial germ cells (PGCs), and non-seminoma, which are either undifferentiated (embryonic carcinoma) or differentiated (teratoma, yolk sac tumor, choriocarcinomas) patterning. A widespread role for microRNAs (miRNAs), in diverse molecular processes driving initiation and progression of various types of TGCTs has been recently studied. We discuss the involvement of different miRNAs in the development and progression of different types of TGCTs. Moreover, we highlight the aberrant expression of miRNAs in TGCTs and several targets, which may define miRNAs as oncomiRs or tumor suppressors. A better understanding of miRNA biology may ultimately yield further insight into the molecular mechanisms of tumorigenesis and new therapeutic strategies against TGCTs.

Role of EZH2 in cell lineage determination and relative signaling pathways.

Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2 (PRC2), epigenetically regulates chromatin structure and gene expression through trimethylation at histone H3K27 and recruitment of DNA methyltransferases for gene silencing. Despite extensive studies of the role of EZH2 in cancer progression and malignancy, increasing evidences suggest that EZH2 plays a critical role in stem cells renewal, maintenance, and differentiation into specific cell lineages. Here, we reviewed the update information regarding how EZH2 contributes to stem cell maintenance and cell lineage determination (including gonadogenesis, neurogenesis, myogenesis, osteogenesis, hematopoiesis, lymphopoiesis, adipogenesis, epidermal differentiation and hepatogenesis), and the regulation of EZH2 by phosphorylation and different signaling pathways.

Regulation of follicular development and differentiation by intra-ovarian factors and endocrine hormones.

Primordial germ cell migration and homing within the gonadal ridge during early embryo development requires oocyte-secreted polypeptide, growth factors, growth and differentiation factors (GDFs), bone morphogenetic proteins, stem cell factor (SCF), and basic fibroblast growth factor (bFGF). During embryogenesis, the germ cells migrate into developing gonads and undergo intra-ovarian development which involves the contact of primordial germ cells with other cells. Further follicular development and differentiation is tightly regulated by hormones and by intraovarian regulators. Maturation of cumulus-oocyte complexes and ovulation are directly controlled by FSH and LH and requires activation of mitogen-activated protein kinase in granulosa cells. The selection of dominant follicles is driven by a series of proliferation and apoptotic events. Together, the available data suggests that follicular development is regulated both by systemic and local factors.