Malignant Research Articles

Characterization and Experimental Use of Multiple Myeloma Bone Marrow Endothelial Cells and Progenitors

Multiple myeloma (MM) is a plasma cell malignancy that resides within the bone marrow microenvironment, relying heavily on interactions with its cellular components. Among these, endothelial cells (ECs) play a pivotal role in MM progression and the development of therapeutic resistance. In this study, we analyzed publicly available single-cell RNA sequencing data to identify unique pathway activations distinguishing ECs from MM patients and healthy donors. We developed a novel protocol to isolate and culture endothelial progenitor cells (EPCs) and ECs directly from MM patient bone marrow, demonstrating their ability to promote myeloma cell proliferation. Validation studies confirmed that these MM-derived ECs exhibit angiogenic potential as well as the expression of characteristic endothelial lineage markers. These findings underscore the critical role of bone marrow ECs in the MM tumor microenvironment and highlight potential new therapeutic targets to disrupt MM progression.

Enhancing the diagnostic capacity of [18F]PSMA-1007 PET/MRI in primary prostate cancer staging with artificial intelligence and semi-quantitative DCE: an exploratory study

BackgroundTo investigate the ability of artificial intelligence (AI)-based and semi-quantitative dynamic contrast enhanced (DCE) multiparametric MRI (mpMRI), performed within [18F]-PSMA-1007 PET/MRI, in differentiating benign from malignant prostate tissues in patients with primary prostate cancer (PC).ResultsA total of seven patients underwent whole-body [18F]-PSMA-1007 PET/MRI examinations including a pelvic mpMRI protocol with T2w, diffusion weighted imaging (DWI) and DCE image series. Conventional analysis included visual reading of PET/MRI images and Prostate Imaging Reporting & Data System (PI-RADS) scoring of the prostate. On the prostate level, we performed manual segmentations for time-intensity curve parameter formation and semi-quantitative analysis based on DCE segmentation data of PC-suspicious lesions. Moreover, we applied a recently introduced deep learning (DL) pipeline previously trained on 1010 independent MRI examinations with systematic biopsy-enhanced histopathological targeted biopsy lesion ground truth in order to perform AI-based lesion detection, prostate segmentation and derivation of a deep learning PI-RADS score. DICE coefficients between manual and automatic DL-acquired segmentations were compared. On patient-based analysis, PET/MRI revealed PC-suspicious lesions in the prostate gland in 6/7 patients (Gleason Score-GS ≥ 7b) that were histologically confirmed. Four of these patients also showed lymph node metastases, while two of them had bone metastases. One patient with GS 6 showed no PC-suspicious lesions. Based on DCE segmentations, a distinction between PC-suspicious and normal appearing tissue was feasible with the parameters fitted maximum contrast ratio (FMCR) and wash-in-slope. DICE coefficients (manual vs. deep learning) were comparable with literature values at a mean of 0.44. Further, the DL pipeline could identify the intraprostatic PC-suspicious lesions in all six patients with clinically significant PC.ConclusionFirstly, semi-quantitative DCE analysis based on manual segmentations of time-intensity curves was able to distinguish benign from malignant tissues. Moreover, DL analysis of the MRI data could detect clinically significant PC in all cases, demonstrating the feasibility of AI-supported approaches in increasing diagnostic certainty of PSMA-radioligand PET/MRI.

Integrated analysis of single-cell and bulk RNA-sequencing identifies a metastasis-related gene signature for predicting prognosis in lung adenocarcinoma.

Metastasis has been documented as an independent and significant prognostic feature of lung adenocarcinoma (LUAD) patients. However, the underlying genetic and molecular mechanisms responsible for LUAD metastasis and their prognostic significance are not exactly defined. The single-cell transcriptomic profiles of primary and metastatic LUAD samples were integrated as a whole dataset. Enrichment analysis and pseudotime trajectory analysis were performed to illustrate the cellular origins and changes during the metastatic process. The LUAD metastasis-related genes (LMRGs) molecular cluster and signature was constructed through unsupervised consensus clustering and ten machine-learning algorithms in The Cancer Genome Atlas (TCGA) LUAD cohort using ten machine-learning algorithms. Validation of the signature was conducted using four independent cohorts from the Gene Expression Omnibus (GEO) database. Kaplan-Meier, ROC, univariate and multivariate Cox-regression analyses were performed to test the stability of the signature. The gene CCT6A was subjected to knockdown, followed by validation through western blot analysis, flow cytometry, wound healing and transwell-migration assays to determine its potential significance. First, the signaling pathway networks remodeling and metabolic reprogramming were demonstrated to be involved in the metastasis of malignant LUAD cells, which facilitate their extravasation and adaptation to other organs. Furthermore, distinct subtypes of malignant LUAD cells exhibit tissue-specific patterns. Then, two distinct molecular patterns of LMRGs were established, which showed diverse prognoses. A LUAD metastasis-related gene signature (LMRGS) was constructed via a multiple machine-learning-based integrative procedure, which possesses distinctly superior accuracy than most common clinical features and 69 published prognostic signatures. The patients stratified by the signature into high-risk group had a significantly poorer prognosis compared to those in the low-risk group, and this was well validated across different clinical subgroups. In addition, the risk score calculated by LMRGS remained an independent prognostic parameter in both univariate and multivariate Cox regression. Notably, knockdown of CCT6A gene promoted cell apoptosis and decelerated the cell migration obviously. LMRGS could serve as a novel and promising tool to improve clinical outcomes for individual LUAD patients.

Cuproptosis-related lncRNA JPX regulates malignant cell behavior and epithelial-immune interaction in head and neck squamous cell carcinoma via miR-193b-3p/PLAU axis

The development, progression, and curative efficacy of head and neck squamous cell carcinoma (HNSCC) are influenced by complex interactions between epithelial and immune cells. Nevertheless, the specific changes in the nature of these interactions and their underlying molecular mechanisms in HNSCC are not yet fully understood. Cuproptosis, a form of programmed cell death that is dependent on copper, has been implicated in cancer pathogenesis. However, the understanding of cuproptosis in the context of HNSCC remains limited. In this study, we have discovered that cuproptosis-related long non-coding RNAs (CRLs) known as JPX play a role in promoting the expression of the oncogene urokinase-type plasminogen activator (PLAU) by competitively binding to miR-193b-3p in HNSCC. The increased activity of the JPX/miR-193b-3p/PLAU axis in malignant epithelial cells leads to enhanced cell proliferation, migration, and invasion in HNSCC. Moreover, the overexpression of PLAU in tumor epithelial cells facilitates its interaction with the receptor PLAUR, predominantly expressed on macrophages, thereby influencing the abnormal epithelial–immune interactome in HNSCC. Notably, the JPX inhibitor Axitinib and the PLAU inhibitor Palbociclib may not only exert their effects on the JPX/miR-193b-3p/PLAU axis that impacts the malignant tumor behaviors and the epithelial–immune cell interactions but also exhibit synergistic effects in terms of suppressing tumor cell growth and arresting cell cycle by targeting epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK4/6) for the treatment of HNSCC.

Activated Charcoal-Alginate Platform for Simultaneous Local Delivery of Bioactive Agents: At the Nexus of Antimicrobial and Cytotoxic Activity of Zn2+ Ions

Antimicrobial resistance (AMR) is a global public health threat that affects cancer patients more than the general population. In this work, a composite system based on Zn-alginate hydrogel and activated charcoal (AC) particles that, upon contact with physiological fluids, simultaneously releases bioactive agents (Zn2+ and AC particles impregnated with povidone–iodine) was designed to locally address specific problems characteristic for malignant wounds (MWs). This composite was comprehensively investigated in vitro regarding its morphology (field-emission scanning electron microscopy), Zn2+ release (flame atomic absorption spectrometry), iodine adsorption and desorption from AC particles (energy dispersive X-ray analysis and UV–visible spectroscopy) as well as its antimicrobial and antitumor activity. With respect to the ongoing AMR crises, antimicrobial activity was tested against a wide range of wild multi-drug resistant bacterial and yeast strains, all isolated from patient wounds. Since Zn2+ ions proved to be selectors of resistant strains of bacteria, the synergistic activity of AC particles and adsorbed iodine was shown to be crucial for excellent antibacterial activity. On the other hand, the synergy of AC particles and Zn2+ ions showed an equally strong antifungal effect. In addition, antimicrobial concentrations of Zn2+ ions showed cytotoxic activity against two cancer cell lines derived from cancers affecting skin either as metastatic cancer (breast cancer MDA-MB-453 cell line) or primary cancer of the skin (malignant melanoma Fem-X cell line), which enables Zn2+ ions to be further investigated as potent local agents targeting malignant cells.

Exploring the Biological Activity of a Humanized Anti-CD99 ScFv and Antibody for Targeting T Cell Malignancies

CD99, a type I transmembrane protein, emerges as a promising therapeutic target due to its heightened expression in T cell acute lymphoblastic leukemia (T-ALL). This characteristic renders it a potential marker for minimal residual disease detection and an appealing target for antibody-based treatments. Previous studies have revealed that a mouse monoclonal antibody, mAb MT99/3, selectively binds to CD99, triggering apoptosis in T-ALL/T-LBL cells while preserving the integrity of healthy cells. By targeting CD99, mAb MT99/3 suppresses antigen presentation and disrupts T cell functions, offering promise for addressing hyperresponsive T cell conditions. To facilitate clinical translation, we developed a humanized ScFv variant of mAb MT99/3, termed HuScFvMT99/3 in “ScFvkh” design. Structural analysis confirms its resemblance to the original antibody, and the immunoreactivity of HuScFvMT99/3 against CD99 is preserved. The fully humanized version of antibody HuMT99/3 was further engineered, exhibiting similar binding affinity at the 10−10 M level and specificity to the CD99 epitope without antigenic shift. HuMT99/3 demonstrates remarkable selectivity, recognizing both malignant and normal T cells but inducing apoptosis only in T-ALL/T-LBL cells, highlighting its potential for safe and targeted therapy.

Combination CXCR4 and PD1 blockade enhances intratumoral dendritic cell activation and immune responses against hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of unresectable hepatocellular carcinoma (HCC), but their impressive efficacy is seen in just a fraction of patients. One key mechanism of immunotherapy resistance is the paucity of dendritic cells (DCs) in liver malignancies. Here, we tested combination blockade of programmed death receptor 1 (PD1) and CXCR4, a receptor for CXCL12, a pleiotropic factor that mediates immunosuppression in tumors. Using orthotopic grafted and autochthonous HCC models with underlying liver damage, we evaluated treatment feasibility and efficacy. In addition, we examined the effects of treatment using immunofluorescence, flow cytometric analysis of DCs in vivo and in vitro, and RNA-sequencing. Combination anti-CXCR4 and anti-PD1therapy was safe and significantly inhibited tumor growth and prolonged survival in all murine preclinical models of HCC tested. The combination treatment successfully reprogrammed antigen-presenting cells, revealing the potential role of conventional type 1 DCs (cDC1s) in the HCC microenvironment. Moreover, DC reprogramming enhanced anticancer immunity by facilitating CD8+ T-cell accumulation and activation in the HCC tissue. The effectiveness of anti-CXCR4/PD1 therapy was compromised entirely in Batf3-KO mice deficient in cDC1s. Thus, combined CXCR4/PD1 blockade can reprogram intra-tumoral cDC1s and holds the potential to potentiate antitumor immune response against HCC.

New Horizons in Cancer Progression and Metastasis: Hippo Signaling Pathway

The Hippo pathway is highly evolved to maintain tissue homeostasis in diverse species by regulating cell proliferation, differentiation, and apoptosis. In tumor biology, the Hippo pathway is a prime example of signaling molecules involved in cancer progression and metastasis. Hippo core elements LATS1, LATS2, MST1, YAP, and TAZ have critical roles in the maintenance of traditional tissue architecture and cell homeostasis. However, in cancer development, dysregulation of Hippo signaling results in tumor progression and the formation secondary cancers. Hippo components not only transmit biochemical signals but also act as mediators of mechanotransduction pathways during malignant neoplasm development and metastatic disease. This review confers knowledge of Hippo pathway core components and their role in cancer progression and metastasis and highlights the clinical role of Hippo pathway in cancer treatment. The Hippo signaling pathway and its unresolved mechanisms hold great promise as potential therapeutic targets in the emerging field of metastatic cancer research.

Supramolecular Co (II) Complex Fabricated From Adenine Derivative: Synthesis, Crystal Structure, Hirshfeld Surface, DFT Optimization, Anticancer, and Molecular Docking Studies

ABSTRACTThis article presents the synthesis of a novel mononuclear Co (II) complex [Co(9‐BuA)2Cl2] (1), its characterization, supramolecular packing pattern, theoretical calculations, anticancer properties, and molecular docking studies. Complex 1 was generated from 9‐butyl adenine (9‐BuA) building block and characterized by spectroscopic methods (FT‐IR, mass, elemental analysis) and single crystal X‐ray diffraction analysis. The cobalt (II) ion in complex 1 is distorted in its tetrahedral environment. The Co+2 is coordinated to the two rare N1 binding sites of the pyrimidinate moiety of two 9‐BuA ligands and two chlorine atoms occupying the axial positions. Both intramolecular and intermolecular hydrogen bonds support the formation of supramolecular assembly and stabilize the crystal structure. The nature of the intermolecular interactions in the supramolecular network was also decoded by Hirshfeld surface analysis and molecular surface contours (dnorm). The percentage contributions are represented by 2D fingerprint plots. The average energy between dimers was determined by the energy framework analysis, and the crystal packing's three‐dimensional topology was also investigated. Density functional theory (DFT) has been used to ascertain the geometry and interactions in the complex. The cytotoxic effects of Co (II) complex 1 and corresponding 9‐BuA ligand were investigated in Dalton's lymphoma (DL) malignant cancer cells and on normal peripheral blood mononuclear cells (PBMCs) to evaluate their anticancer activity. Finally, molecular docking analyses have been carried out to analyze the nature of molecular interactions between Co (II) complex 1 and the receptor.

Perspectives on Ergodic Cancer Therapy Derived from Cloning Genome Chaos via In Vivo Rhabdomyosarcoma RA-2 Models: a Narrative Review.

This review explores articles concerning the experimental research cycle on genome instability in cell populations of highly malignant recurrent organotropic rhabdomyosarcoma RA- 2 in rats. Clonal analysis and cloning were pivotal components of this research, which relies on the frequency of cells with micronuclei and internuclear bridges to gauge the intensity of chromothripsis and break-fusion-bridge cycles. The efficacy of cloning, determined by these indicators, stemmed from the deliberate isolation of tumor stem cells, yielding clones in which chromothripsis activity and breakage-fusion-bridge cycles were sustained. Notably, it is plausible that the stem cells themselves, progenitors of these clones, harbor dicentric chromosomes and chromosomal fragments, contributing to the formation of "fatal micronuclei" in their karyotype. Cloning based on bridges and micronuclei has proven effective up to a certain threshold (15%-18%), reaffirming the predicted reproductive extinction of malignant cell populations under mutational pressure and genome chaos, as posited by the genetic theory of cell populations. Furthermore, this review highlights the potential of ergodic cancer therapy as a novel therapeutic strategy. Ergodic therapy offers promising prospects for late-stage and terminal malignant tumors, where conventional treatments may fall short due to advanced progression. Furthermore, by "enhancing chromothripsis" through the induction of additional micronuclei and bridges, ergodic cancer therapy seeks to increase genome chaos to a critical threshold, potentially halting malignant progression. This innovative approach presents opportunities to explore new drugs and targets for chromothripsis-based oncotherapy, addressing the pressing need for effective treatments in advanced stages of malignancy.

Overexpression of Pin1 regulated by TOP2A, which subsequently stabilizes Pyk2 to promote bortezomib resistance in multiple myeloma.

Multiple myeloma (MM), a hematological malignancy of plasma cells, has remained largely incurable owing to drug resistance and disease relapse, which requires novel therapeutic targets and treatment approaches. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) acts as an oncoprotein linked to the development of various tumors. However, the functional consequence of Pin1 overexpression in modulating MM biology has not been established. In the present study, we show that Pin1 expression is highly variable in myeloma cell lines and primary MMs and that high Pin1 expression is associated with poor survival of MM patients. Next, TOP2A is identified to be a Pin1 promoter-binding protein and CK2 activates TOP2A to promote the expression level of Pin1. Additionally, we demonstrate that Pin1 positively modulates the stability and function of Pyk2 to enhance bortezomib resistance in MM. Pin1 recognizes three phosphorylated Ser/Thr-Pro motifs in Pyk2 via its WW domain and increases the cellular levels of Pyk2 in an isomerase activity-dependent manner by inhibiting the ubiquitination and proteasomal degradation of Pyk2. Moreover, Pin1 inhibition combined with Pyk2 inhibition decreases myeloma burden both in vitro and in vivo. Altogether, our findings reveal the tumor-promoting role of Pin1 in MM and provide evidence that targeting Pin1 could be a therapeutic strategy for MM.

CLINICOPATHOLOGICAL CORRELATION OF P53 EXPRESSION IN BENIGN PROSTATIC HYPERPLASIA AND PROSTATE ADENOCARCINOMA

Objective: To assess clinicopathological parameters in patients with benign prostatic hyperplasia and prostate adenocarcinoma, and evaluate their correlation with p53 overexpression in these prostatic conditions. Methods: The present ambispective study was conducted in the Department of Pathology in a tertiary care hospital of Northern India from 2022 to 2024. This study included prostatic trucut biopsies, transurethral prostatic resection (TURP) chips, and radical prostatectomy specimens from patients with benign prostatic hyperplasia (BPH) or prostatic adenocarcinoma. Tissue samples were processed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H&E) for histopathological evaluation. Immunohistochemical (IHC) analysis was performed to assess p53 expression using the GenomeMe antibody. Data on age, histological type and histological grade were collected. Statistical analysis included Chi-square test was conducted to evaluate associations between p53 overexpression and clinicopathological parameters. Results: The study analyzed 50 cases, revealing significantly higher p53 expression in prostatic adenocarcinoma compared to BPH. The majority of participants were aged between 61-70 years (46%). There were 50% patients with adenocarcinoma, 26% with BPH, 20% with BPH and chronic prostatitis, and 4% with BPH with prostatic intraepithelial neoplasia. There were strong associations between p53 overexpression and specific diagnoses, histological type and histological grade (Gleason scores) in prostate cancer. Conclusion: The study findings suggest that p53 overexpression is closely linked to malignant prostate conditions and could potentially serve as a valuable biomarker for distinguishing between benign and malignant prostatic diseases, as well as predicting tumor aggressiveness.

The Prognostic Value and Immunotherapeutic Characteristics of GFPT2 in Pan-cancer.

The purpose of this study is to investigate the underlying relationship of diagnosis and therapy between glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and various cancers. The Cancer Genome Atlas (TCGA) database was utilized to get gene expression RNAseq and clinical data for 33 tumors. The immunotherapeutic cohorts, including GSE35640, GSE78220, GSE67501, GSE181815, and IMvigor210, were derived from the Gene Expression Omnibus database (GEO) and a previously released article. Differential expression analysis of GFPT2 was performed using several clinical factors, and prognostic analysis was performed using Cox proportional hazard regression. In addition, the Cell type Identification By Estimating Relative Subsets Of RNA transcripts (CIBERSORT) and the Estimation of STromal and Immune cells in MAlignant Tumor tissues utilizing Expression data (ESTIMATE) algorithms were used to investigate the connection between GFPT2 and the tumor microenvironment. This approach additionally incorporated dynamic immunological indicators, such as tumor mutational burden (TMB) and microsatellite instability (MSI). In addition, a correlation between GFPT2 expression and the effectiveness of anticancer drugs was plotted for discussion. GFPT2 expression significantly differed in 11 out of 33 cancers. Although the distinct correlation between GFPT2 expression and clinical parameters had no wide distribution in pan-cancer, it demonstrated the potential prognostic validity of gene expression. GFPT2 demonstrated a strong correlation with immune infiltration, immune modulators, and immunerelated biomarkers. Furthermore, a variance analysis demonstrated a significant relationship between GFPT2 and the efficacy of immunotherapy. In addition, GFPT2 was associated with increased sensitivity of drugs such as Olaparib and Lenvatinib and decreased sensitivity of drugs such as Nilotinib. Collectively, GFPT2 is potentially useful as a biomarker for prognostic prediction and immune infiltration in a variety of malignancies ,and could lead to exciting new approaches to personalized oncotherapy.

Differences in immune-related toxicity between PD-1 and PD-L1 inhibitors: a retrospective cohort study in patients with advanced cancer

Immunotherapy with PD-1 or PD-L1 inhibitors has become an essential treatment strategy for a growing number of malignancies. These treatments have a risk for immune-related adverse events (IRAEs). Pooled analyses based on clinical trials show a favorable toxicity profile for treatment with PD-L1 compared to PD-1 inhibitors. This study aimed to investigate differences in IRAEs between patients with advanced solid malignances treated with PD-L1 and PD-1 inhibitors in a real-world setting. We conducted a retrospective cohort study at four Swedish Regions. Patients (n = 605) treated for advanced cancer with a PD-L1 or PD-1 inhibitor in monotherapy between June 2016 and August 2022 were included. Non-small cell lung cancer (NSCLC) was the most common malignant disease (n = 251; 41.5%), followed by malignant melanoma (n = 173; 28.6%), renal cell carcinoma (n = 71; 11.7%) and urothelial carcinoma (n = 35; 5.8%). Among patients receiving PD-L1 inhibitors, NSCLC (94.4%) was the predominant malignancy, whereas for those treated with PD-1 inhibitor, malignant melanoma constituted the most prevalent malignancy (34.5%). Discontinuation of treatment due to IRAEs overall and IRAEs grade ≥ 2 were significantly less common in patients treated with PD-L1 compared to PD-1 inhibitors [Odds Ratio (OR): 0.38 (95% Confidence Interval (CI) 0.16–0.88) and OR: 0.63 (95% CI 0.35–0.98) respectively]. Any grade IRAE, IRAE grade ≥ 3 and multiple IRAEs were numerically more frequent in patients treated with PD-1 inhibitors.In conclusion, our study of patients with advanced solid malignancies in a real-world setting supports the results from clinical trials demonstrating a favorable toxicity profile for PD-L1 inhibitors versus PD-1 inhibitors.

Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant haematological disorders. Peripheral blood stem cells represent the main stem cell source in malignant diseases due to faster engraftment and practicability issues compared with bone marrow stem cells. Since the early 2000s, there have been many developments in the clinical field. Allo-HSCT using haploidentical family donors (haplo-HSCT) has emerged as an alternative for people who do not have human leukocyte antigen (HLA)-matched siblings or unrelated donors. In addition, the introduction of new methods and strategies in allo-HSCT, such as the use of post-transplant cyclophosphamide (PT-Cy), better donor selection, the more frequent administration of anti-thymocyte globulins (ATGs), but also improved management of side effects such as graft-versus-host disease (GvHD) and infection, have impacted outcomes after allo-HSCT. In addition, as transplant indications and strategies continue to adapt in line with novel research findings, the effect of the stem cell source on post-transplant outcomes is unclear. For our analysis, we considered peripheral blood stem cells as the standard graft source for adults with haematological malignancies. This is an update of a review first published in 2014. To assess the effect of bone marrow transplantation versus peripheral blood stem cell transplantation in adults with haematological malignancies with regard to overall survival, disease-free survival, incidence of non-relapse or transplant-related mortality, incidence of extensive chronic graft-versus-host disease (GvHD), incidence of acute GvHD grades III to IV, incidence of overall chronic GvHD, and quality of life. For this update we searched CENTRAL, MEDLINE, Embase, and two trials registries on 2 November 2022 with no language restrictions. We included randomised controlled trials (RCTs) comparing bone marrow transplantation (BMT) with peripheral blood stem cell transplantation (PBSCT) in adults (aged ≥ 18 years) with haematological malignancies. Two review authors independently selected studies and extracted data. We evaluated risk of bias using the original Cochrane risk of bias tool (RoB 1), and we evaluated the certainty of the evidence using the GRADE approach. The updated search identified no new studies for inclusion. We found two additional reports relating to a previously included study; they provided new data on quality of life and infection rates after transplantation. As these are clinically relevant outcomes, quality of life was added to the summary of findings table (replacing acute GvHD II to IV), and rate of infection was added to our list of secondary outcomes. We included nine RCTs with a total of 1521 participants. Overall, the risk of bias in the included studies was low. Median participant age across studies ranged from 21 to 45 years, and studies took place in Canada, the USA, New Zealand, Brazil, Australia, Egypt, and across Europe. Bone marrow transplantation (BMT) compared with peripheral blood stem cell transplantation (PBSCT) likely results in little to no difference in overall survival (hazard ratio (HR) for all-cause death 1.07, 95% CI 0.91 to 1.25; 6 studies, 1330 participants; moderate-certainty evidence). There may be little to no difference between BMT and PBSCT in terms of disease-free survival (HR for disease recurrence or all-cause death 1.04, 95% CI 0.89 to 1.21; 6 studies, 1225 participants; low-certainty evidence) and non-relapse or transplant-related mortality (HR 0.98, 95% CI 0.76 to 1.28; 3 studies, 758 participants; low-certainty evidence). BMT compared with PBSCT likely results in lower rates of extensive chronic GvHD (HR 0.69, 95% CI 0.54 to 0.90; 4 studies, 765 participants; moderate-certainty evidence) and overall chronic GvHD (HR 0.72, 95% CI 0.61 to 0.85; 4 studies, 1121 participants; moderate-certainty evidence). BMT compared with PBSCT may reduce the incidence of acute GvHD grades III to IV, although the 95% CI of the HR is also compatible with no effect (HR 0.75, 95% CI 0.55 to 1.02; 3 studies, 925 participants; moderate-certainty evidence). Evidence from two trials that used different quality of life assessment instruments suggests that BMT compared with PBSCT may be associated with higher quality of life five years after transplantation. Moderate-certainty evidence suggests little to no difference in overall survival following allo-HSCT using bone marrow versus peripheral blood stem cells (the current clinical standard stem cell source). Low-certainty evidence suggests little to no difference between the stem cell sources in terms of disease-free survival and non-relapse or transplant-related survival. BMT likely reduces the risk of extensive chronic GvHD and overall chronic GvHD compared with PBSCT. Evidence from two RCTs suggests that BMT compared with PBSCT may result in higher long-term quality of life, possibly due to the lower chronic GvHD incidence. With this update, we aimed to supply the most recent data on the choice of stem cell source for allo-HSCT in adults by including new evidence published up to November 2022. We identified no new ongoing studies and no new RCTs with published results. Further research in this field is warranted.

Complement C1S is a potential prognostic biomarker and associated with M2 macrophage infiltration in gliomas: From bioinformatics to comprehensive experimental validation

Glioma is the most common malignant tumor of the central nervous system, and the ability of traditional clinical treatment to prolong the survival of glioma patients is limited. A substantial body of evidence underscores the pivotal role of the immune system in eradicating malignant cells and impeding tumor metastasis. Consequently, tumor immunotherapy has become a promising avenue to address the clinical conundrum faced by glioma patients. The complement system is a natural immune system that is an important line of defense in the immune response. C1S plays a key role in activating the classical complement system. Nevertheless, few studies have focused on the role of C1S in glioma tumorigenesis and progression. In this study, we demonstrated that C1S was upregulated in GBM (Grade IV) and low-grade gliomas (LGG, Grade II-III) by combining glioma cohorts from multiple public databases with our internal independent cohorts and that increased C1S expression levels predict a poor prognosis for gliomas. Cox regression analysis identified C1S as an important prognostic indicator for glioma patients. In addition, gene functional enrichment analysis demonstrated that C1S was involved in cellular immunity, T-cell activation, macrophage differentiation, and cell proliferation. Further experiments demonstrated that C1S facilitates tumor cell proliferation, cell migration and intracranial tumor growth in nude mice. More importantly, we evaluated the role of C1S in immune infiltration. These results suggested that C1S was closely related to a variety of immune cell types in glioma, especially M2 macrophages. Our findings were further validated via glioma tissue microarray immunohistochemical analysis and an M2 macrophage infiltration assay. Together, these findings revealed the underlying critical role of C1S in glioma tumorigenesis, progression, and the tumor immune microenvironment, contributing to further understanding of glioma pathogenesis and guiding immunotherapy.

Apoptosis: A Comprehensive Overview of Signaling Pathways, Morphological Changes, and Physiological Significance and Therapeutic Implications

Cell survival and death are intricately governed by apoptosis, a meticulously controlled programmed cell death. Apoptosis is vital in facilitating embryonic development and maintaining tissue homeostasis and immunological functioning. It is a complex interplay of intrinsic and extrinsic signaling pathways that ultimately converges on executing the apoptotic program. The extrinsic pathway is initiated by the binding of death ligands such as TNF-α and Fas to their respective receptors on the cell surface. In contrast, the intrinsic pathway leads to increased permeability of the outer mitochondrial membrane and the release of apoptogenic factors like cytochrome c, which is regulated by the Bcl-2 family of proteins. Once activated, these pathways lead to a cascade of biochemical events, including caspase activation, DNA fragmentation, and the dismantling of cellular components. Dysregulation of apoptosis is implicated in various disorders, such as cancer, autoimmune diseases, neurodegenerative disorders, and cardiovascular diseases. This article focuses on elucidating the molecular mechanisms underlying apoptosis regulation, to develop targeted therapeutic strategies. Modulating apoptotic pathways holds immense potential in cancer treatment, where promoting apoptosis in malignant cells could lead to tumor regression. This article demonstrates the therapeutic potential of targeting apoptosis, providing options for treating cancer and neurological illnesses. The safety and effectiveness of apoptosis-targeting drugs are being assessed in ongoing preclinical and clinical trials (phase I–III), opening the door for more effective therapeutic approaches and better patient outcomes.

Feasibility, efficacy, and safety of core needle biopsy as a first-line method for cervical lymphadenopathy.

This study aimed to determine the feasibility, diagnostic efficacy, and safety of ultrasound-guided core needle biopsy (CNB) as a first-line biopsy method for cervical lymphadenopathy of non-thyroid origin. This retrospective cohort study included consecutive patients with cervical lymphadenopathy in whom US-guided CNB was used as the first-line biopsy method for cervical lymph nodes (LNs) of presumed non-thyroid origin. The coaxial CNB technique was routinely used, while the tilting and hydrodissection CNB techniques were selectively employed for small high-risk LNs. The primary endpoint of this study was the diagnostic efficacy of CNB, evaluated by the rate of inconclusive results (nondiagnostic and indeterminate) and diagnostic accuracy (criterion 1: malignant results; criterion 2: malignant or indeterminate result). The secondary outcomes included the feasibility and safety of CNB, assessed based on the technical success rate and complication rate, respectively. The rates of nondiagnostic, indeterminate, and inconclusive results were 0.7%, 3.4%, and 4.1%, respectively. The sensitivity, specificity, and accuracy of CNB for malignant LNs were 96.2%, 100%, and 97.8%, respectively, with criterion 1, and these values were all 99.8% with criterion 2. The technical success rate of CNB was 99.3%. There were no major complications and 7 cases (0.6%) of minor complications (asymptomatic hematomas). CNB was technically feasible, effective, and safe as a first-line biopsy method for cervical lymphadenopathy of non-thyroid origin with high diagnostic accuracy for malignant nodal disease. Question The role of US-guided CNB as a first-line biopsy method for cervical LNs has not yet been verified and established. Findings US-guided CNB, as a first-line method, demonstrated a high technical success rate and diagnostic accuracy for malignant nodes, with few minor complications. Clinical relevance US-guided CNB can be used as an effective first-line biopsy method for cervical lymphadenopathy and will enable accurate diagnosis of malignant LNs.

Advances in sarcopenia and urologic disorders

Sarcopenia is a loss of muscle strength, muscle mass, and function that can increase a patient’s risk of injury, illness, and can even severely impair quality of life and increase a patient’s risk of death. A growing body of research suggests that sarcopenia and urinary tract disorders are closely related. In this review, we aimed to emphasize the definition of skeletal sarcopenia, summarize the methods used to diagnose skeletal sarcopenia, discuss the advances in the study of sarcopenia in benign diseases of the urinary system, discuss the advances in the study of sarcopenia in malignant diseases of the urinary system. Sarcopenia and urologic diseases interact with each other; urologic diseases cause sarcopenia, and sarcopenia aggravates the condition of the original disease, thus falling into a vicious circle. This review provides a comprehensive understanding of sarcopenia in urologic diseases, which is very important for the management and prognosis of urologic diseases.

Effect of NK cell receptor genetic variation on allogeneic stem cell transplantation outcome and in vitro NK cell cytotoxicity

Natural killer (NK) cells recognize and may kill malignant cells via their cell surface receptors. Killer cell immunoglobulin-like receptor (KIR) genotypes of donors have been reported to adjust the risk of relapse after allogeneic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia. To test whether non-KIR NK cell receptors have a similar effect, we screened 1,638 genetic polymorphisms in 21 non-KIR NK cell receptor genes for their associations with relapse and graft-versus-host disease (GVHD) after HSCT in 1,491 HSCT donors (from Finland, the UK, Spain, and Poland), divided into a discovery and replication cohort. Eleven polymorphisms regulating or located in CD226, CD244, FCGR3A, KLRD1, NCR3, and PVRIG were associated with the risks for relapse and GVHD. These associations could not be confirmed in the replication cohort. Blood donor NK cells carrying alleles showing genetic protection for relapse had a higher in vitro NK cell killing activity than non-carriers whereas those with alleles genetically protective for GVHD had lower cytotoxicity, potentially indicating functional effects. Taken together, these results show no robust effects of genetic variation in the tested non-KIR NK cell receptors on the outcome of HSCT.