Anti-cancer drug's cytotoxicity is determined by their ability to induce predetermined cell demise, commonly called apoptosis. The cancer-causing cells are able to evade cell death, which has been affiliated with both malignancy as well as resistance to cancer treatments. In order to avoid cell death, cancerous tumour cells often produce an abundance of anti-apoptotic proteins, becoming "dependent" on them. Consequently, protein inhibitors of cell death may prove to be beneficial as pharmacological targets for the future creation of cancer therapies. This article examines the molecular routes of apoptosis, its clinical manifestations, anti-cancer therapy options that target the intrinsic mechanism of apoptosis, proteins that prevent cell death, and members of the B-lymphoma-2 subset. In addition, novel approaches to cell death are highlighted, including how curcumin mitigates chemotherapy-induced apoptosis in healthy tissues and the various ways melatonin modifies apoptosis to improve cancer treatment efficacy, particularly through the TNF superfamily. Cancer treatment-induced increases in anti-apoptotic proteins lead to drug resistance; yet, ligands that trigger cell death by inhibiting these proteins are expected to improve chemotherapy's efficacy. The potential of frequency-modulated dietary phytochemicals as a cancer therapeutic pathway, including autophagy and apoptosis, is also explored. This approach may be more efficient than inhibition alone in overcoming drug resistance. Consequently, this method has the potential to allow for lower medication concentrations, reducing cytotoxicity and unwanted side effects.

Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively mediating malignant B-cell depletion. Anti-CD20 mAbs, such as rituximab and obinutuzumab, have significantly improved progression-free survival (PFS) and overall survival (OS), establishing immunochemotherapy as the standard of care for FL. However, the emergence of treatment resistance, often characterized by CD20 antigen downregulation or immune escape, has prompted the development of next-generation mAbs with enhanced effector functions. Bispecific antibodies (BsAbs), which simultaneously engage CD20-expressing tumor cells and CD3-positive cytotoxic T cells, have emerged as a novel immunotherapeutic strategy, redirecting T-cell activity to eliminate malignant B cells independently of major histocompatibility complex (MHC) antigen presentation. Additionally, antibody-drug conjugates (ADCs) offer a targeted cytotoxic approach by delivering potent chemotherapeutic payloads directly to tumor cells while limiting off-target effects. The integration of mAbs with immune checkpoint inhibitors and immunomodulatory agents is further enhancing treatment outcomes by overcoming immunosuppressive mechanisms within the tumor microenvironment. Despite these advancements, challenges remain, including optimizing the treatment sequence, mitigating immune-related toxicities-particularly cytokine release syndrome (CRS)-and identifying predictive biomarkers to guide patient selection. As the role of monoclonal antibodies continues to expand, their integration into therapeutic regimens is transforming the management of FL, paving the way for chemotherapy-free treatment approaches and long-term disease control. This review provides an updated overview of mAbs therapies for FL, emphasizing the advances brought by BsAbs and ADCs toward more tailored and effective treatments.

Diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin's lymphoma, has a high relapse/refractory rate. We previously identified sex-determining region Y (SRY)-box transcription factor (SOX9) as a transcription factor that serves as a prognostic biomarker, particularly in BCL2-overexpressing DLBCL, and plays a vital role in lymphomagenesis. However, the molecular mechanisms that modulate the aberrant expression of SOX9 in this DLBCL subset remain unknown.

Cell viability, apoptosis and cell cycle assays were performed to determine whether SOX9 contributes to DLBCL chemoresistance and rescues silencing IRF4-induced phenotypes. Protein‒protein interactions and protein ubiquitination were elucidated using immunoprecipitation, immunohistochemistry, immunofluorescence and immunoblotting. Chromatin immunoprecipitation sequencing (ChIP-seq), ChIP and dual-luciferase reporter assays were used to investigate IRF4 binding to the SOX9 promoter. The therapeutic potential of IRF4 inhibition was evaluated in vitro and in a mouse model of DLBCL xenografts.

SOX9 enhanced the resistance of the BCL2-overexpressing DLBCL subset to chemotherapy or a BCL2 inhibitor. Moreover, BCL2 inhibition downregulated SOX9 in an immunoglobulin heavy chain/BCL2-positive DLBCL subset. We further identified IRF4 as a key regulator of BCL2-induced SOX9 expression, and ChIP-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promotes IRF4 entry into the nucleus by enhancing protein stability and downregulating proteasomal ubiquitination, thereby enforcing SOX9-mediated phenotypes. Finally, in a DLBCL cell line and xenografted mouse model, in vivo inhibition of IRF4 with an hIRF4 antisense oligonucleotide repressed lymphomagenesis and DLBCL chemoresistance.

Our data support the conclusion that IRF4 plays an essential role in BCL2-induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapsed and refractory DLBCL.

BCL2 activated IRF4 by enhancing its nuclear activity to induce sex-determining region Y (SRY)-box 9 protein (SOX9) aberrant expression, which is a critical pathway for drug resistance in BCL2-overexpressing diffuse large B-cell lymphoma (DLBCL). Targeting IRF4 may be worth investigating further regarding its potential to overcome the chemoresistance of BCL2-overexpressing DLBCL to standard therapies.

Follicular lymphoma (FL) is the most common type of indolent lymphoma, and the prognosis is favorable for most patients. However, FL remains generally incurable, and relapse is common. Patients are at risk of developing treatment-resistant lymphoma, particularly when early disease progression occurs or transformation to aggressive lymphoma takes place. Furthermore, lymphoma is the leading cause of death among patients with FL, emphasizing the need for more effective treatment strategies. This review summarizes therapeutic approaches for FL, with a focus on therapies currently in development. Recent biological insights have driven the emergence of highly effective treatments, including novel immune and targeted therapies. Clinical trials are assessing the efficacy of these novel approaches, which are increasingly used in earlier line settings. In the future, FL therapy is expected to rely less on chemotherapeutic methods, extend remission, and potentially enable cures for a growing number of patients.

The landmark discovery of the BCL-2 gene and then its function marked the identification of inhibition of apoptotic cell death as a crucial novel mechanism driving cancer development and launched the quest to discover the molecular control of apoptosis. This work culminated in the generation of specific inhibitors that are now in clinical use, saving and improving tens of thousands of lives annually. Here, some of the original players of this story, describe the sequence of critical discoveries. The t(14;18) chromosomal translocation, frequently observed in follicular lymphoma, allowed the identification and the cloning of a novel oncogene (BCL-2) juxtaposed to the immunoglobulin heavy chain gene locus (IgH). Of note, BCL-2 acted in a distinct manner as compared to then already known oncogenic proteins like ABL and c-MYC. BCL-2 did not promote cell proliferation but inhibited cell death, as originally shown in growth factor dependent haematopoietic progenitor cell lines (e.g., FDC-P1) and in Eμ-Myc/Eμ-Bcl-2 double transgenic mice. Following a rapid expansion of the BCL-2 protein family, the Abbott Laboratories solved the first structure of BCL-XL and subsequently the BCL-XL/BAK peptide complex, opening the way to understanding the structures of other BCL-2 family members and, finally, to the generation of inhibitors of the different pro-survival BCL-2 proteins, thanks to the efforts of Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude and Gilead. Although the BCL-2 inhibitor Venetoclax is in clinical use and inhibitors of BCL-XL and MCL-1 are undergoing clinical trials, several questions remain on whether therapeutic windows can be achieved and what other agents should be used in combination with BH3 mimetics to achieve optimal therapeutic impact for cancer therapy. Finally, the control of the expression of BH3-only proteins and pro-survival BCL-2 family members needs to be better understood as this may identify novel targets for cancer therapy. This story is still not concluded!

Cancer is complex because of the critical imbalance in genetic regulation as characterized by both the overexpression of oncogenes (OGs), mainly through mutations, amplifications, and translocations, and the inactivation of tumor-suppressor genes (TSGs), which entail the preservation of genomic integrity by inducing apoptosis to counter the malignant growth. Reviewing the intricate molecular interplay between OGs and TSGs draws attention to their cell cycle, apoptosis, and cancer metabolism regulation. In the present review, we discuss seminal discoveries, such as Knudson's two-hit hypothesis, which framed the field's understanding of cancer genetics, leading to the next breakthroughs with next-generation sequencing and epigenetic profiling, revealing novel insights into OG and TSG dysregulation with opportunities for targeted therapy. The key pathways, such as MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin, are presented in the context of tumor progression. Importantly, we further highlighted the advances in therapeutic strategies, including inhibitors of KRAS and MYC and restoration of TSG function, despite which mechanisms of resistance and tumor heterogeneity pose daunting challenges. A high-level understanding of interactions between OG-TSGs forms the basis for effective, personalized cancer treatment-something to strive for in better clinical outcomes. This synthesis should integrate foundational biology with translation and, in this case, contribute to the ongoing effort against cancer.

The B cell lymphoma 2 (BCL2) protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria. In this cutting-edge review, we summarize the basic biology regulating the BCL2 family including canonical and non-canonical functions, and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions. We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and tools targeting the BH4 domain of BCL2. The first BCL2-selective BH3-mimetic, venetoclax, showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies. Following its success, several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation, alone and in combination. Genetic analysis highlights the importance of BCL-XL and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins. However, the development of BH3-mimetics targeting BCL-XL or MCL1 has been more challenging, with on-target toxicities including thrombocytopenia for BCL-XL and cardiac toxicities for MCL1 inhibitors precluding clinical development. Tumor-specific BCL-XL or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy. Taken together, we envision that the targeting of BCL2 proteins, while already a success story of translational research, may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.

Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia. It typically occurs in older patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and apoptosis in clonal B-cells.

The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers.

Two clinical staging systems, Rai and Binet, provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict a shorter time to progression with most targeted therapies. The CLL international prognostic index (CLL-IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL. The CLL-IPI retains its significance in the era of targeted agents, but the overall prognosis of CLL patients with high-risk stages has improved.

Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: combinations of the BCL2 inhibitor venetoclax with obinutuzumab, or venetoclax with ibrutinib, or monotherapy with one of the inhibitors of Bruton tyrosine kinase (BTK). At relapse, the initial treatment may be repeated if the treatment-free interval exceeds 3 years. If the leukemia relapses earlier, therapy should be changed using an alternative regimen.

Combinations of targeted agents now provide efficient therapies with a fixed duration that generate deep and durable remissions. These fixed-duration therapies have gained territory in the management of CLL, as they are cost-effective, avoid the emergence of resistance, and offer treatment free time to the patient. The cure rate of these novel combination regimens is unknown. Moreover, the optimal sequencing of targeted therapies remains to be determined. A medical challenge is to treat patients who are double-refractory to both BTK and BCL2 inhibitors. These patients need to be treated within experimental protocols using novel drugs.

Backbone therapy for acute myeloid leukemia for younger adults has for 50 years been based on a combination of cytarabine and anthracycline. Over the past 10 years the addition of several targeted agents has been found to improve the outcomes of subsets of AML with particular molecular changes. In this review we will examine the data generated to date on the addition of agents targeting CD33, FLT3, IDH, and BCL2 to standard high intensity therapies. We will also review the potential for future studies evaluating the application of highly active lower intensity therapies developed in older adults to patients considered "fit for high intensity induction." Lastly, we review the data around the role of stem cell transplant in the modern targeted era.

Diabetes is a chronic metabolic disorder whose prevalence increases every year, affecting more than 530 million adults worldwide. Type 1 (T1D) and type 2 diabetes (T2D), the most common forms of diabetes, are characterized by the loss of functional pancreatic β-cells, mostly due to apoptosis. B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), two anti-apoptotic proteins belonging to the Bcl-2 family, are crucial for regulating the intrinsic pathway of apoptosis. However, over the years, they have been implicated in many other cellular processes, including intracellular Ca2+ homeostasis and the regulation of mitochondrial metabolism. Thus, understanding the biological processes in which these proteins are involved may be crucial to designing new therapeutic targets. This review summarizes the roles of Bcl-2 and Bcl-xL in apoptosis and metabolic homeostasis. It focuses on how the dysregulation of Bcl-2 and Bcl-xL affects pancreatic β-cell function and survival, and the consequences for diabetes development.

The ubiquitin-proteasome pathway (UPP) regulates protein stability and normal cellular functions with the help of autocatalytic proteasome complex. Studies have linked aberrant proteasome activity to malignant cells and found that proteasome inhibitors play a significant role as therapeutic drugs for various types of cancer, specifically multiple myeloma and mantle cell lymphoma. Bortezomib, the first FDA-approved proteasome inhibitor for treating different stages of multiple myeloma, acts on cancer cells by inhibiting the 26S proteasome, modulating NF-κB, phosphorylating Bcl-2, upregulating of NOXA, blocking p53 degradation, activating caspase, generating reactive oxygen species (ROS), and inhibiting angiogenesis. However, its efficacy is limited due to side effects such as peripheral neuropathy (PN), thrombotic microangiopathy (TMA), and acute interstitial nephritis (AIN). Therefore, a better understanding of its precise mechanism of action may help mitigate these side effects. In this review, we have discussed the proposed mechanisms of action and off target effects of Bortezomib, along with the prospects of next generation potential proteasome inhibitor drugs in the treatment of cancer.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with poor response to conventional therapy, derived from hematopoietic progenitors committed to T-cell lineage. Relapsed/Refractory patients account for nearly 20% of childhood and 45% of adult cases. Aberrant Notch signaling plays a critical role in T-ALL pathogenesis and therapy resistance. Notch inhibition is a promising therapeutic target for personalized medicine, and a variety of strategies to prevent Notch activation, including γ-secretase (GS) inhibitors (GSIs) and antibodies neutralizing Notch receptors or ligands, have been developed. Disruption of apoptosis is pivotal in cancer development and progression. Different reports evidenced the interplay between Notch and the anti-apoptotic Bcl-2 family proteins in T-ALL. Although based on early research data, this review discusses recent advances in directly targeting Notch receptors and the use of validated BH3 mimetics for the treatment of T-ALL and their combined action in light of current evidence of their use.

Chimeric antigen receptor (CAR)-T-cell therapy has transformed cancer treatment, leading to remarkable clinical outcomes. However, resistance continues to be a major obstacle, significantly limiting its efficacy in numerous patients.

This review critically examines the challenges associated with CAR-T-cell therapy, with a particular focus on the role of apoptotic pathways in overcoming resistance.

We explore various strategies to sensitize tumor cells to CAR-T-cell-mediated apoptosis, including the use of combination therapies with BH3 mimetics, Mcl-1 inhibitors, IAP inhibitors, and HDAC inhibitors. These agents inhibit anti-apoptotic proteins and activate intrinsic mitochondrial pathways, enhancing the susceptibility of tumor cells to apoptosis. Moreover, targeting the extrinsic pathway can increase the expression of death receptors on tumor cells, further promoting their apoptosis. The review also discusses the development of novel CAR constructs that enhance anti-apoptotic protein expression, such as Bcl-2, which may counteract CAR-T cell exhaustion and improve antitumor efficacy. We assess the impact of the tumor microenvironment (TME) on CAR-T cell function and propose dual-targeting CAR-T cells to simultaneously address both myeloid-derived suppressor cells (MDSCs) and tumor cells. Furthermore, we explore the potential of combining agents like PPAR inhibitors to activate the cGAS-STING pathway, thereby improving CAR-T cell infiltration into the tumor.

This review highlights that enhancing tumor cell sensitivity to apoptosis and increasing CAR-T cell cytotoxicity through apoptotic pathways could significantly improve therapeutic outcomes. Targeting apoptotic proteins, particularly those involved in the intrinsic mitochondrial pathway, constitutes a novel approach to overcoming resistance. The insights presented herein lay a robust foundation for future research and clinical applications aimed at optimizing CAR-T cell therapies.

Permeabilization of the outer mitochondrial membrane is а physiological process that can allow certain molecules to pass through it, such as low molecular weight solutes required for cellular respiration. This process is also important for the development of various modes of cell death. Depending on the severity of this process, cells can die by autophagy, apoptosis, or necrosis/necroptosis. Distinct types of pores can be opened at the outer mitochondrial membrane depending on physiological or pathological stimuli, and different mechanisms can be activated in order to open these pores. In this comprehensive review, all these types of permeabilization, the mechanisms of their activation, and their role in various diseases are discussed.

Resistance to cancer drugs is a complex phenomenon that poses a significant challenge in the treatment of various malignancies. This review comprehensively explores cancer resistance mechanisms and discusses emerging strategies and modalities to overcome this obstacle. Many factors contribute to cancer resistance, including genetic mutations, activation of alternative signaling pathways, and alterations in the tumor microenvironment. Innovative approaches, such as targeted protein degradation, immunotherapy combinations, precision medicine, and novel drug delivery systems, hold promise for improving treatment outcomes. Understanding the intricacies of cancer resistance and leveraging innovative modalities are essential for advancing cancer therapy.

The accumulation of senescent cells is an important factor in the complex progression of aging, with significant implications for the development of numerous diseases. Thus, understanding the fundamental mechanisms of senescence is paramount for advancing preventive and therapeutic approaches to age-related conditions. Important to this pursuit is the precise identification and examination of senescent cells, contingent upon the recognition of specific biomarkers. Historically, detection methods relied on assessing molecular protein and mRNA levels and various staining techniques. While these conventional approaches have contributed substantially to the field, they possess limitations in capturing the dynamic evolution of cellular aging in real time. The emergence of novel technologies has led to a paradigm shift in senescence research. Gene-edited mouse models and the application of advanced probes have revolutionized our ability to detect senescent cells. These cutting-edge methodologies provide a more detailed and accurate means of dynamically monitoring, characterizing and potentially eliminating senescent cells, thus enhancing our understanding of the complex mechanisms of aging. This review comprehensively explores both traditional and innovative senescent cell detection methods, elucidating their advantages, limitations and implications for future investigations and could serve as a comprehensive guide and catalyst for further advancements in the understanding of aging and associated pathologies.

Animal-derived venom, like snake venom, has been proven to be valuable natural resources for the drug development. Previously, snake venom was mainly investigated in its pharmacological activities in regulating coagulation, vasodilation, and cardiovascular function, and several marketed cardiovascular drugs were successfully developed from snake venom. In recent years, snake venom fractions have been demonstrated with anticancer properties of inducing apoptotic and autophagic cell death, restraining proliferation, suppressing angiogenesis, inhibiting cell adhesion and migration, improving immunity, and so on. A number of active anticancer enzymes and peptides have been identified from snake venom toxins, such as L-amino acid oxidases (LAAOs), phospholipase A2 (PLA2), metalloproteinases (MPs), three-finger toxins (3FTxs), serine proteinases (SPs), disintegrins, C-type lectin-like proteins (CTLPs), cell-penetrating peptides, cysteine-rich secretory proteins (CRISPs). In this review, we focus on summarizing these snake venom-derived anticancer components on their anticancer activities and underlying mechanisms. We will also discuss their potential to be developed as anticancer drugs in the future.

B-cell lymphoma/leukemia-2 (BCL2), an anti-apoptotic factor in the mitochondrial regulatory pathway of apoptosis, is critically important in immune defenses. In this study, a novel BCL2 gene was characterized from Pteria penguin (P. penguin). The PpBCL2 was 1482 bp long, containing an open reading frame (ORF) of 588 bp encoding 195 amino acids. Four highly conserved BCL-2 homology (BH) domains were found in PpBCL2. Amino acid alignment and phylogenetic tree showed that PpBCL2 had the highest similarity with BCL2 of Crassostrea gigas at 65.24 %. Tissue expression analysis showed that PpBCL2 had high constitutive expression in gill, digestive diverticulum and mantle, and was significantly increased 72 h of Vibrio parahaemolyticus (V. parahaemolyticus) challenge in these immune tissues. Furthermore, PpBCL2 silencing significantly inhibited antimicrobial activity of hemolymph supernatant by 1.4-fold, and significantly reduced the survival rate by 51.7 % at 72 h post infection in P. penguin. These data indicated that PpBCL2 played an important role in immune response of P. penguin against V. parahaemolyticus infection.

Regulated cell death (RCD) is a form of cell death that can be regulated by numerous biomacromolecules. Accumulating evidence suggests that dysregulated expression and altered localization of related proteins in RCD promote the development of cancer. Targeting subroutines of RCD with pharmacological small-molecule compounds is becoming a promising therapeutic avenue for anti-tumor treatment, especially in hematological malignancies. Herein, we summarize the aberrant mechanisms of apoptosis, necroptosis, pyroptosis, PANoptosis, and ferroptosis in hematological malignancies. In particular, we focus on the relationship between cell death and tumorigenesis, anti-tumor immunotherapy, and drug resistance in hematological malignancies. Furthermore, we discuss the emerging therapeutic strategies targeting different RCD subroutines. This review aims to summarize the significance and potential mechanisms of RCD in hematological malignancies, along with the development and utilization of pertinent therapeutic strategies.

For over two decades, the development of B-cell lymphoma-2 (Bcl-2) family therapeutics has primarily focused on anti-apoptotic proteins, resulting in the first-in-class drugs called BH3 mimetics, especially for Bcl-2 inhibitor Venetoclax. The pro-apoptotic protein Bcl-2-associated X protein (BAX) plays a crucial role as the executioner protein of the mitochondrial regulated cell death, contributing to organismal development, tissue homeostasis, and immunity. The dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death, such as cancer, neurodegeneration, and heart failure. In addition to conducting thorough investigations into the physiological modulation of BAX, research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX, as well as diverse all-molecule BAX modulators. This review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on BAX. Furthermore, it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX, offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.

Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

The BCL2 family of proteins controls cell death by modulating the permeabilization of the mitochondrial outer membrane through a fine-tuned equilibrium of interactions among anti- and pro-apoptotic members. The upregulation of anti-apoptotic BCL2 proteins represents an unfavorable prognostic factor in many tumor types due to their ability to shift the equilibrium toward cancer cell survival. Furthermore, cancer-associated somatic mutations in BCL2 genes interfere with the protein interaction network, thereby promoting cell survival. A range of studies have documented how these mutations affect the interactions between the cytosolic domains of BCL2 and evaluate the impact on cell death; however, as the BCL2 transmembrane interaction network remains poorly understood, somatic mutations affecting transmembrane regions have been classified as pathogenic-based solely on prediction algorithms. We comprehensively investigated cancer-associated somatic mutations affecting the transmembrane domain of BCL2 proteins and elucidated their effect on membrane insertion, hetero-interactions with the pro-apoptotic protein BAX, and modulation of cell death in cancer cells. Our findings reveal how specific mutations disrupt switchable interactions, alter the modulation of apoptosis, and contribute to cancer cell survival. These results provide experimental evidence to distinguish BCL2 transmembrane driver mutations from passenger mutations and provide new insight regarding selecting precision anti-tumor treatments.

Leber congenital amaurosis (LCA) is the most common genetic cause of congenital visual impairment in infants and children. Patients with LCA who harbor RPE65 mutations exhibit a deficiency in photoreceptor rhodopsin, leading to severe night blindness and visual impairment following birth. Since either gene replacement therapy or anti-apoptosis therapy alone cannot maintain both functional and morphological normality for a long time in the animal model, we propose a robust treatment strategy, that is, gene replacement therapy combined with anti-apoptotic therapy to protect photoreceptors from further degeneration while compensating for lost RPE65 function. Here, rd12 mice were injected subretinally at postnatal day 14 with four vector administrations, respectively. At 6 months after treatment, it was discovered that injection of three vectors, AAV8 (Y733F)-CBA-hRPE65, AAV8(Y733F)-CBA-hRPE65-BCL-2-L10 and mixture of half-dose AAV8(Y733F)-CBA-hRPE65 and half-dose AAV8 (Y733F)-CBA-BCL-2-L10, could partially restore the visual function of rd12 mice. Meanwhile, these treated eyes also exhibited a thicker outer nuclear layer (ONL) structure. However, despite the fact that the eyes of rd12 mice injected with the AAV8 (Y733F)-CBA-BCL-2-L10 vector displayed a slightly thicker ONL structure compared to untreated eyes, the visual function of the treated eyes did not recover. Continuing the observation period to 12 months after treatment, we found that compared to rd12 mice at 6-month post-treatment, rd12 mice injected with AAV8 (Y733F)-CBA-hRPE65 or mixture of half-dose AAV8(Y733F)-CBA-hRPE65 and half-dose AAV8 (Y733F)-CBA-BCL-2-L10 exhibited varying degrees of decline in both visual function and ONL thickness. However, in the case of rd12 mice injected with the AAV8(Y733F)-CBA-hRPE65-BCL-2-L10 vector, the ONL thickness remains consistent at both 6 and 12 months after treatment. These mice continued to maintain a relatively strong visual function and showed restoration in the levels of RPE65 and Rhodopsin protein expression. Our findings illustrate that early postnatal treatment with AAV vectors containing both the hRPE65 gene and the Bcl-2L10 anti-apoptotic gene provide enhanced and sustained retinal protection.

Chronic lymphocytic leukaemia (CLL) is the most common lymphoproliferative disease in adults and currently remains incurable. As the progression-free period shortens after each successive treatment, strategies such as maintenance therapy are needed to improve the degree and duration of response to previous therapies. Monoclonal antibodies, immunomodulatory agents, and targeted therapies are among the available options for maintenance therapy. People with CLL who achieve remission after previous therapy may choose to undergo medical observation or maintenance therapy to deepen the response. Even though there is widespread use of therapeutic maintenance agents, the benefits and harms of these treatments are still uncertain.

To assess the effects and safety of maintenance therapy, including anti-CD20 monoclonal antibody, immunomodulatory drug therapy, anti-CD52 monoclonal antibody, Bruton tyrosine kinase inhibitor, and B-cell lymphoma-2 tyrosine kinase inhibitor, for individuals with CLL.

We conducted a comprehensive literature search for randomised controlled trials (RCTs) with no language or publication status restrictions. We searched CENTRAL, MEDLINE, Embase, and three trials registers in January 2022 together with reference checking, citation searching, and contact with study authors to identify additional studies.

We included RCTs with prospective identification of participants. We excluded cluster-randomised trials, cross-over trial designs, and non-randomised studies. We included studies comparing maintenance therapies with placebo/observation or head-to-head comparisons.

We used standard Cochrane methodological procedures. We assessed risk of bias in the included studies using Cochrane's RoB 1 tool for RCTs. We rated the certainty of evidence for the following outcomes using the GRADE approach: overall survival (OS), health-related quality of life (HRQoL), grade 3 and 4 adverse events (AEs), progression-free survival (PFS), treatment-related mortality (TRM), treatment discontinuation (TD), and all adverse events (AEs).

We identified 11 RCTs (2393 participants) that met the inclusion criteria, including seven trials comparing anti-CD20 monoclonal antibodies (mAbs) (rituximab or ofatumumab) with observation in 1679 participants; three trials comparing immunomodulatory drug (lenalidomide) with placebo/observation in 693 participants; and one trial comparing anti-CD 52 mAbs (alemtuzumab) with observation in 21 participants. No comparisons of novel small molecular inhibitors were found. The median age of participants was 54.1 to 71.7 years; 59.5% were males. The type of previous induction treatment, severity of disease, and baseline stage varied among the studies. Five trials included early-stage symptomatic patients, and three trials included advanced-stage patients (Rai stage III/IV or Binet stage B/C). Six trials reported a frequent occurrence of cytogenic aberrations at baseline (69.7% to 80.1%). The median follow-up duration was 12.4 to 73 months. The risk of selection bias in the included studies was unclear. We assessed overall risk of performance bias and detection bias as low risk for objective outcomes and high risk for subjective outcomes. Overall risk of attrition bias, reporting bias, and other bias was low. Anti-CD20 monoclonal antibodies (mAbs): rituximab or ofatumumab maintenance versus observation Anti-CD20 mAbs maintenance likely results in little to no difference in OS (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.73 to 1.20; 1152 participants; 3 studies; moderate-certainty evidence) and likely increases PFS significantly (HR 0.61, 95% CI 0.50 to 0.73; 1255 participants; 5 studies; moderate-certainty evidence) compared to observation alone. Anti-CD20 mAbs may result in: an increase in grade 3/4 AEs (rate ratio 1.34, 95% CI 1.06 to 1.71; 1284 participants; 5 studies; low-certainty evidence); little to no difference in TRM (risk ratio 0.82, 95% CI 0.39 to 1.71; 1189 participants; 4 studies; low-certainty evidence); a slight reduction to no difference in TD (risk ratio 0.93, 95% CI 0.72 to 1.20; 1321 participants; 6 studies; low-certainty evidence); and an increase in all AEs (rate ratio 1.23, 95% CI 1.03 to 1.47; 1321 participants; 6 studies; low-certainty evidence) compared to the observation group. One RCT reported that there may be no difference in HRQoL between the anti-CD20 mAbs (ofatumumab) maintenance and the observation group (mean difference -1.70, 95% CI -8.59 to 5.19; 480 participants; 1 study; low-certainty evidence). Immunomodulatory drug (IMiD): lenalidomide maintenance versus placebo/observation IMiD maintenance therapy likely results in little to no difference in OS (HR 0.91, 95% CI 0.61 to 1.35; 461 participants; 3 studies; moderate-certainty evidence) and likely results in a large increase in PFS (HR 0.37, 95% CI 0.19 to 0.73; 461 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. Regarding harms, IMiD maintenance therapy may result in an increase in grade 3/4 AEs (rate ratio 1.82, 95% CI 1.38 to 2.38; 400 participants; 2 studies; low-certainty evidence) and may result in a slight increase in TRM (risk ratio 1.22, 95% CI 0.35 to 4.29; 458 participants; 3 studies; low-certainty evidence) compared to placebo/observation. The evidence for the effect on TD compared to placebo is very uncertain (risk ratio 0.71, 95% CI 0.47 to 1.05; 400 participants; 2 studies; very low-certainty evidence). IMiD maintenance therapy probably increases all AEs slightly (rate ratio 1.41, 95% CI 1.28 to 1.54; 458 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. No studies assessed HRQoL. Anti-CD52 monoclonal antibodies (mAbs): alemtuzumab maintenance versus observation Maintenance with alemtuzumab may have little to no effect on PFS, but the evidence is very uncertain (HR 0.55, 95% CI 0.32 to 0.95; 21 participants; 1 study; very low-certainty evidence). We did not identify any study reporting the outcomes OS, HRQoL, grade 3/4 AEs, TRM, TD, or all AEs.

There is currently moderate- to very low-certainty evidence available regarding the benefits and harms of maintenance therapy in people with CLL. Anti-CD20 mAbs maintenance improved PFS, but also increased grade 3/4 AEs and all AEs. IMiD maintenance had a large effect on PFS, but also increased grade 3/4 AEs. However, none of the above-mentioned maintenance interventions show differences in OS between the maintenance and control groups. The effects of alemtuzumab maintenance are uncertain, coupled with a warning for drug-related infectious toxicity. We found no studies evaluating other novel maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.

This review examines and compares the diagnostic and prognostic capabilities of miRNAs and lncRNAs derived from pseudogenes in cancer patients. Additionally, it delves into their roles in cancer pathogenesis. Both miRNAs and pseudogene-derived lncRNAs have undergone thorough investigation as remarkably sensitive and specific cancer biomarkers, offering significant potential for cancer detection and monitoring. . Extensive research is essential to gain a complete understanding of the precise roles these non-coding RNAs play in cancer, allowing the development of novel targeted therapies and biomarkers for improved cancer detection and treatment approaches.

The BCL-2 family is crucial for cell death regulation and is involved in development, tissue homeostasis, and immunity. This study aimed to investigate the association between genetic variants in BCL-2 family genes and non-syndromic cleft lip with or without cleft palate (NSCL/P) risk.

A two-stage case-control study was conducted in this association study. Gene-based analysis using Multi-marker Analysis of GenoMic Annotation was performed in the first stage cohort, which included 565 cases and 1269 controls. A logistic regression model was employed to assess the effect of single nucleotide polymorphisms (SNPs) on susceptibility to NSCL/P. Candidate SNPs were replicated by extra dbGaP case-parent trios. Haploreg, RegulomeDB, and UCSC Genome Browser were used to identify enhancer effects of promising SNPs. Bulk RNA sequencing data obtained from the Gene Expression Omnibus was used to identify co-expressed genes. Single-cell RNA sequencing dataset was used to infer the cell population of the candidate gene. The "Monocle" package was used to analyze the pseudotime cell trajectories.

Rs3943258 located in the enhancer region was associated with the risk of NSCL/P (Pmeta  = 5.66 × 10-04 ) and exhibited an eQTL effect for BCL2 (P = 3.96 × 10-02 ). Co-expression and pathway enrichment analysis revealed that genes related to Bcl2 were significantly enriched in the PI3K-Akt signaling pathway, MAPK signaling pathway, and Wnt signaling pathway. Five cell clusters were identified in single-cell RNA sequencing, and Bcl2 was mainly located in the mesenchyme.

The rs3943258 located within BCL2 was probably related to NSCL/P susceptibility.

t(14;18)(q32;q21) translocation is an important genetic feature of follicular lymphoma resulting in antiapoptotic B-cell lymphoma 2 (BCL2) protein overexpression. On chromosome 18 breakpoint-site variation is high but does not affect BCL2. Breakpoint most commonly occurs at major breakpoint region (MBR) but may happen at minor cluster region (mcr) and between MBR and mcr at 3'MBR and 5'mcr. The aim of this study was to analyze the correlation of t(14;18)(q32;q21) breakpoint site with clinical characteristics in follicular lymphoma.

We included patients diagnosed with follicular lymphoma who received at least 1 cycle of systemic treatment and had the t(14;18)(q32;q21) translocation detected by polymerase chain reaction (PCR) at MBR, mcr or 3'MBR prior to first treatment. Among patients with different breakpoints, sex, age, disease grade, stage, B-symptoms, follicular lymphoma international prognostic index (FLIPI), presence of bulky disease, progression free survival and overall survival were compared.

Of 84 patients, 63 had breakpoint at MBR, 17 at mcr and 4 at 3'MBR. At diagnosis, the MBR group had a significantly lower disease stage than the mcr group. Although not significant, in the MBR group we found a higher progression-free survival (PFS) and overall survival (OS), lower grade, age, FLIPI, and less B-symptoms.

Compared to patients with mcr breakpoint, those with MBR breakpoint seem to be characterised by more favourable clinical characteristics. However, a larger study would be required to support our observation.

Decitabine, a member of the 5-azanucleosides, has a dose-dependent mechanism of action in vitro: termination of DNA replication at high doses, and inhibition of DNA methyltransferase at low doses. The alteration of DNA methylation patterns by low-dose decitabine is hypothesized to upregulate genes, which promote myeloblast differentiation. In a phase III clinical trial, low-dose decitabine achieved a superior overall response rate (ORR) when compared with 'treatment choice' [consisting of low-dose cytarabine (80%) and supportive care (20%)] as a frontline treatment for elderly patients with acute myeloid leukemia (AML). Despite an improved ORR, the median overall survival (OS) for elderly patients with AML was poor, <1 year. In turn, venetoclax was added to low-dose decitabine, the combination of which significantly improved the ORR and median OS in elderly patients with AML. Currently, hypomethylating agents are being combined with other novel therapies as investigational strategies for elderly and unfit patients with AML. They are also being evaluated as components of maintenance therapy in patients achieving remission. An oral formulation of decitabine has been developed which relies on the concomitant use of oral cedazuridine to protect against first pass metabolism. This oral formulation, which has been approved in myelodysplastic syndrome, is intended to increase convenience of use and therefore compliance in patients. This review characterizes the evolution of decitabine, its oral formulation, and its future in the treatment of AML.

Targeting the B-cell lymphoma 2 (Bcl-2) family proteins has been the backbone for hematological malignancies with overall survival improvements. The Bcl-2 family is a major player in apoptosis regulation and, has captured the researcher's interest in the treatment of solid tumors. Sarcomas are a heterogeneous group of diseases, comprising several entities, with high morbidity and mortality and with few specific therapies available. The treatment for sarcomas is based on platinum regimens, with variable results and poor outcomes, especially in advanced lesions. The high number of different sarcoma entities makes treatment standardization as well as the performance of clinical trials difficult. The use of Bcl-2 family members modifiers has revealed promising results in in vitro and in vivo models and may be a valid option, especially when used in combination with chemotherapy. In this article, a revision of these results and possibilities for the use of Bcl-2 family members inhibitors in sarcomas was performed.

In the era of personalized medicine greatly improved by molecular diagnosis and tailor-made therapies, the survival rate of acute myeloid leukemia (AML) at 5 years remains unfortunately low. Indeed, the high heterogeneity of AML clones with distinct metabolic and molecular profiles allows them to survive the chemotherapy-induced changes, thus leading to resistance, clonal evolution, and relapse. Moreover, leukemic stem cells (LSCs), the quiescent reservoir of residual disease, can persist for a long time and activate the recurrence of disease, supported by significant metabolic differences compared to AML blasts. All these points highlight the relevance to develop combination therapies, including metabolism inhibitors to improve treatment efficacy. In this review, we summarized the metabolic differences in AML blasts and LSCs, the molecular pathways related to mitochondria and metabolism are druggable and targeted in leukemia therapies, with a distinct interest for Venetoclax, which has revolutionized the therapeutic paradigms of several leukemia subtype, unfit for intensive treatment regimens.

Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic nature of these mutations, they often result in profound alterations of cellular behavior. The identification of oncofusions has revolutionized cancer research, with advancements in sequencing technologies facilitating the discovery of novel fusion events at an accelerated pace. Oncofusions exert their effects through the manipulation of critical cellular signaling pathways that regulate processes such as proliferation, differentiation, and survival. Extensive investigations have been conducted to understand the roles of oncofusions in solid tumors, leukemias, and lymphomas. Large-scale initiatives, including the Cancer Genome Atlas, have played a pivotal role in unraveling the landscape of oncofusions by characterizing a vast number of cancer samples across different tumor types. While validating the functional relevance of oncofusions remains a challenge, even non-driver mutations can hold significance in cancer treatment. Oncofusions have demonstrated potential value in the context of immunotherapy through the production of neoantigens. Their clinical importance has been observed in both treatment and diagnostic settings, with specific fusion events serving as therapeutic targets or diagnostic markers. However, despite the progress made, there is still considerable untapped potential within the field of oncofusions. Further research and validation efforts are necessary to understand their effects on a functional basis and to exploit the new targeted treatment avenues offered by oncofusions. Through further functional and clinical studies, oncofusions will enable the advancement of precision medicine and the drive towards more effective and specific treatments for cancer patients.

B-cell lymphoma-2 (Bcl-2) is the first identified member of the Bcl-2 family that performs an anti-apoptotic function in mammals. However, its role in teleosts is not fully understood. In this study, Bcl-2 of Trachinotus ovatus (TroBcl2) was cloned, and its role in apoptosis was investigated.

In this study, Bcl-2 of Trachinotus ovatus (TroBcl2) was cloned by PCR. Quantitative real-time PCR (qRT-PCR) was used to detect its mRNA expression level in healthy condition and after LPS stimulation. Subcellular localization was performed by transfecting the pTroBcl2-N3 plasmid into golden pompano snout (GPS) cells and observed under an inverted fluorescence microscope DMi8 and further verified by immunoblotting. In vivo overexpression and RNAi knockdown method were performed to evaluate the role of TroBcl2 in apoptosis. The anti-apoptotic activity of TroBcl2 was detected by flow cytometry. The effect of TroBcl2 on the mitochondrial membrane potential (MMP) was measured by an enhanced mitochondrial membrane potential assay kit with JC-1. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method was performed to evaluate the role of TroBcl2 in the DNA fragmentation. Immunoblotting was used to verify whether TroBcl2 inhibits the release of cytochrome c from mitochondria into the cytoplasm. The Caspase 3 and Caspase 9 Activity Assay Kits were used to investigate the effect of TroBcl2 on caspase 3 and caspase 9 activities. The effects of TroBcl2 on the expression of apoptosis-related and nuclear factor- κB (NF-κB) signaling pathway-related genes in vitro were evaluated by qRT-PCR and Enzyme linked immunosorbent assay (ELISA). Luciferase reporter assay was used to evaluate the activity in NF-κB signaling pathway.

The full-length coding sequence of TroBcl2 contains 687 bp and encodes a protein containing 228 amino acids. Four conserved Bcl-2 homology (BH) domains and one invariant "NWGR" motif located in BH1 were identified in TroBcl2. In healthy T. ovatus, TroBcl2 was widely distributed in the eleven tested tissues, and higher expression levels were found in immune-related tissues, such as spleen and head kidney tissues. After stimulation with lipopolysaccharide (LPS), the expression of TroBcl2 in the head kidney, spleen, and liver was significantly upregulated. In addition, subcellular localization analysis revealed that TroBcl2 was localized in both the cytoplasm and nucleus. Functional experiments showed that TroBcl2 inhibited apoptosis, possibly by reducing mitochondrial membrane potential loss, decreasing DNA fragmentation, preventing cytochrome c release into cytoplasm, and reducing the caspase 3 and caspase 9 activations. Moreover, upon LPS stimulation, overexpression of TroBcl2 suppressed the activation of several apoptosis-related genes, such as BOK, caspase-9, caspase-7, caspase-3, cytochrome c, and p53. Furthermore, knockdown of TroBcl2 significantly increased the expression of those apoptosis-related genes. In addition, TroBcl2 overexpression or knockdown induced or inhibited, respectively, the transcription of NF-κB and regulated the expression of genes (such as NF-κB1 and c-Rel) in the NF-κB signaling pathway as well as the expression of the downstream inflammatory cytokine IL-1β. Overall, our study suggested that TroBcl2 performs its conserved anti-apoptotic function via the mitochondrial pathway and may serve as an anti-apoptotic regulator in T. ovatus.

Follicular lymphoma (FL) is a mature B-cell neoplasm with a mostly indolent course. Genetic hallmark characteristics are Bcl-2 overexpression based on a t(14;18) translocation and additional secondary genetic and epigenetic aberrations. Standard treatment for early-stage patients has curative intent and usually consists of radiotherapy with or without rituximab. In the advanced stage, the main therapeutic focus is on prolonged remissions. Therefore, treatment in asymptomatic patients is usually deferred. Symptomatic patients are subject to immunochemotherapy induction followed by antibody maintenance. Importantly, about one in five patients subsequently experiences a more rapid clinical course, achieving only short remissions with multiple relapses (POD24). In those patients, there is still an urgent need for improved therapeutic options. Accordingly, a plethora of targeted and immunotherapeutic options, including immunomodulatory drugs, small molecule inhibitors, monoclonal antibodies as well as bispecific T-cell engager antibodies and CAR-T cell products have been recently evaluated in such relapsed high-risk patients.

Velvet antler is a traditional Chinese medicine with various pharmacological values, which is an important raw material for traditional Chinese medicinal wine. Nevertheless, the chemical compositions and bioactivities of velvet antler residue used for making medicinal wine are rarely reported, leading to a waste of resources. In this study, a velvet antler protein (VA-pro) was extracted from velvet antler residue by simulating the gastrointestinal digestion, and its composition, structural characteristics and in vivo anti-tumor activities were determined and investigated. VA-pro possessed high purity with a relatively low molecular weight as 22.589 kDa under HPLC, one- and two-dimensional electrophoresis, and it contained high contents of Pro, Gly, Glu and Ala. Besides, the secondary structure of VA-pro was dominated by β-turn and β-sheet, and VA-pro possessed similar protein sequence, isoelectric point and amino acid compositions to hypothetical protein G4228_020061. The in vivo results substantiated that VA-pro could improve the body weights and immune organ indices, increase the expressions of sera cytokines and regulate the distributions of T and B lymphocytes subsets in peripheral blood of S180 tumor-bearing mice. Furthermore, VA-pro could effectively inhibit solid S180 tumors growth by inducing S phase cell cycle arrest mediated through mitochondria. To summarize, our study provided theoretical support that VA-pro had the potential to be used as an immunopotentiator in immunocompromised or cancer-bearing hosts.

Meningiomas are the most common primary central nervous system (CNS) tumors in adults, representing approximately one-third of all primary adult CNS tumors. Although several recent publications have proposed alternative grading systems of meningiomas that incorporate genomic and/or epigenomic data to better predict meningioma recurrence and progression-free survival, our understanding of driving forces of meningioma development is still limited.

To define gene expression signatures of the most common subtypes of meningiomas to better understand cellular processes and signaling pathways specific for each tumor genotype.

We used RNA sequencing (RNA-seq) to determine whole transcriptome profiles of twenty meningiomas with genomic alterations including NF2 inactivation, loss of chr1p, and missense mutations in TRAF7, AKT1 and KLF4.

The analysis revealed that meningiomas with NF2 gene inactivation expressed higher levels of BCL2 and GLI1 compared with tumors harboring TRAF7 missense mutations. Moreover, NF2 meningiomas were subdivided into two distinct groups based on additional loss of chr1p. NF2 tumors with intact chr1p were characterized by the high expression of tumor suppressor PTCH2 compared to NF2 tumors with chr1p loss. Taken together with the high expression of BCL2 and GLI1, these results suggest that activation of Sonic Hedgehog pathway may contribute to NF2 meningioma development. In contrast, NF2 tumors with chr1p loss expressed high levels of transcription factor FOXD3 and its antisense RNA FOXD3-AS1. Examination of TRAF7 tumors demonstrated that TRAF7 regulates a number of biomechanically responsive genes (KRT6a, KRT16, IL1RL1, and AQP3 among others). Interestingly, AKT1 and KLF4 meningiomas expressed genes specific for PI3K/AKT signaling pathway, suggesting overlapping gene signatures between the two subtypes. In addition, KLF4 meningiomas had high expression of carcinoembryonic antigen family members CEACAM6 and CEACAM5.

Each group of meningiomas displayed a unique gene expression signature suggesting signaling pathways potentially implicated in tumorigenesis. These findings will improve our understanding of meningioma tumorigenesis and prognosis.

The human APOBEC family of eleven cytosine deaminases use RNA and single-stranded DNA (ssDNA) as substrates to deaminate cytosine to uracil. This deamination event has roles in lipid metabolism by altering mRNA coding, adaptive immunity by causing evolution of antibody genes, and innate immunity through inactivation of viral genomes. These benefits come at a cost where some family members, primarily from the APOBEC3 subfamily (APOBEC3A-H, excluding E), can cause off-target deaminations of cytosine to form uracil on transiently single-stranded genomic DNA, which induces mutations that are associated with cancer evolution. Since uracil is only promutagenic, the mutations observed in cancer genomes originate only when uracil is not removed by uracil DNA glycosylase (UNG) or when the UNG-induced abasic site is erroneously repaired. However, when ssDNA is present, replication protein A (RPA) binds and protects the DNA from nucleases or recruits DNA repair proteins, such as UNG. Thus, APOBEC enzymes must compete with RPA to access their substrate. Certain APOBEC enzymes can displace RPA, bind and scan ssDNA efficiently to search for cytosines, and can become highly overexpressed in tumor cells. Depending on the DNA replication conditions and DNA structure, RPA can either be in excess or deficient. Here we discuss the interplay between these factors and how despite RPA, multiple cancer genomes have a mutation bias at cytosines indicative of APOBEC activity.

Inhibition of antiapoptotic B-cell lymphoma 2 (BCL2) proteins by small molecule Bcl-2 homology 3 (BH3) mimetics causes rapid induction of apoptosis of human hematological cancers in vitro and in vivo.

Assess in vitro sensitivity of non-neoplastic lymphocytes and primary hematological cancer cells from dogs to venetoclax (VEN) or the dual BCL2/ B-cell lymphoma-extra-large (BCLxL) inhibitor, navitoclax (NAV), and evaluate the association between BCL2 protein expression and VEN sensitivity.

Nine client-owned dogs without cancer and 18 client-owned dogs with hematological cancer.

Prospective, nonrandomized noncontrolled study. Lymphocytes isolated from peripheral blood, lymph node, or bone marrow from dogs were incubated with BH3 mimetics for 24 hours. Viable cells were counted using flow cytometry and half maximal effective concentration (EC₅₀ ) was calculated. BCL2 protein from whole cell lysates was assessed via immunoblots.

Nodal B and T lymphocytes were more sensitive to VEN than circulating lymphocytes (P = .02). Neoplastic T lymphocytes were sensitive to VEN (mean EC₅₀  ± SD = 0.023 ± 0.018 μM), whereas most non-indolent B cell cancers were resistant to killing by VEN (mean EC₅₀  ± SD = 288 ± 700 μM). Unclassified leukemias showed variable sensitivity to VEN (mean EC₅₀  ± SD = 0.49 ± 0.66 μM). Detection of BCL2 protein was not associated with VEN sensitivity.

Neoplastic canine T lymphocytes are sensitive to VEN in vitro. Quantification of BCL2 protein alone is insufficient to predict sensitivity to VEN.

Members of the Bcl-2-protein family are key controllers of apoptotic cell death. The family is divided into antiapoptotic (including Bcl-2 itself, Bcl-xL, Mcl-1, etc.) and proapoptotic members (Bax, Bak, Bim, Bim, Puma, Noxa, Bad, etc.). These proteins are well known for their canonical role in the mitochondria, where they control mitochondrial outer membrane permeabilization and subsequent apoptosis. However, several proteins are recognized as modulators of intracellular Ca²⁺ signals that originate from the endoplasmic reticulum (ER), the major intracellular Ca²⁺-storage organelle. More than 25 years ago, Bcl-2, the founding member of the family, was reported to control apoptosis through Ca²⁺ signaling. Further work elucidated that Bcl-2 directly targets and inhibits inositol 1,4,5-trisphosphate receptors (IP₃Rs), thereby suppressing proapoptotic Ca²⁺ signaling. In addition to Bcl-2, Bcl-xL was also shown to impact cell survival by sensitizing IP₃R function, thereby promoting prosurvival oscillatory Ca²⁺ release. However, new work challenges this model and demonstrates that Bcl-2 and Bcl-xL can both function as inhibitors of IP₃Rs. This suggests that, depending on the cell context, Bcl-xL could support very distinct Ca²⁺ patterns. This not only raises several questions but also opens new possibilities for the treatment of Bcl-xL-dependent cancers. In this review, we will discuss the similarities and divergences between Bcl-2 and Bcl-xL regarding Ca²⁺ homeostasis and IP₃R modulation from both a molecular and a functional point of view, with particular emphasis on cancer cell death resistance mechanisms.

Flavonoid aglycones possess biological activities, such as antioxidant and antidiabetic activities compared to glycosides. Taxifolin, a flavonoid aglycones, is detected only in trace amounts in nature and is not easily observed. Therefore, in this study, to investigate the hair tonic and hair loss inhibitors effect of taxifolin, high content of taxifolin aglycone extract was prepared by enzymatic hydrolysis. Taxifolin effectively regulates the apoptosis of dermal papilla cells, which is associated with hair loss, based on its strong antioxidant activities. However, inhibition of dihydrotestosterone (DHT), which is a major cause of male pattern hair loss, was significantly reduced with taxifolin treatment compared with minoxidil, as a positive control. It was also confirmed that a representative factor for promoting hair growth, IGF-1, was significantly increased, and that TGF-β1, a representative biomarker for hair loss, was significantly reduced with taxifolin treatment. These results suggest that taxifolin from enzymatic hydrolysis of RM is a potential treatment for hair loss and a hair growth enhancer.