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Oral complications in hematopoietic stem cell recipients: the role of inflammation.

Hematopoietic stem cell transplantation (HSCT) is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and

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… Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. Journal of the National Cancer Institute. 1974;52(2):401–404. doi: 10.1093/jnci/52.2.401. 95. Hill GR, Ferrara JLM. …

Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.

Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective aut

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… T-siHDGF chimera-capped MSN (TMSN@siHDGF-Gint4.T) enables the precise co-delivery of therapeutic agents, facilitating synergistic GBM suppression through the sequential release of siHDGF and TMZ [ 425 ]. …

Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies.

Hematologic malignancies are one of the most common cancers, and the incidence has been rising in recent decades. The clinical and molecular features of hematologic malignancies are highly heterogenous, and some hematologic malignancies are incurable, challenging the treatment, and prognosis of the patients. However, hematopoiesis and oncogenesis of hematologic malignancies are profoundly affected by epigenetic regulation. Studies have found that methylation-related mutations, abnormal methylation profiles of DNA, and abnormal histone deacetylase expression are recurrent in leukemia and lympho

Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments.

Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues f

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… CED is particularly used for the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) and works by using a pressure gradient within a catheter to deliver therapeutic agents into the interstitial spaces of the brain parenchyma ( 113 ). …

Emerging Targets in Non-Small Cell Lung Cancer.

Lung cancer is responsible for a high burden of disease globally. Over the last two decades, the discovery of targetable oncogenic genomic alterations has revolutionized the treatment landscape for early-stage and advanced non-small cell lung cancer (NSCLC). New molecular drivers continue to emerge as promising therapeutic targets, including KRAS non-G12C, RAF/MEK, HER3, Nectin-4, folate receptor alpha, ITGB6, and PRMT5. In this review, we summarize the emerging molecular targets with a potential clinical impact in advanced NSCLC, elaborating on their clinical characteristics and specific mech

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… Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules that recruit a protein of interest, such as KRAS, to the cell’s ubiquitin-proteasome system for degradation [ 40 ]. …

A review on in silico virtual screening methods in COVID-19 using anticancer drugs and other natural/chemical inhibitors.

The present coronavirus disease 2019 (COVID-19) pandemic scenario has posed a difficulty for cancer treatment. Even under ideal conditions, malignancies like small cell lung cancer (SCLC) are challenging to treat because of their fast development and early metastases. The treatment of these patients must not be jeopardized, and they must be protected as much as possible from the continuous spread of the COVID-19 infection. Initially identified in December 2019 in Wuhan, China, the contagious coronavirus illness 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (S

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… The UCSF Chimera tools to determine the crystal structure of SARS-CoV-2 Nsp16 were utilized by Jiang et al. [ 74 ]. Then they compared it to a Medications-lib of 7,173 stereoisomers representing 4,574 “licensed” medications using the MTiOpenScreen service. …

Therapeutic targeting in pediatric acute myeloid leukemia with aberrant HOX/MEIS1 expression.

Despite advances in the clinical management of childhood acute myeloid leukemia (AML) during the last decades, outcome remains fatal in approximately one third of patients. Primary chemoresistance, relapse and acute and long-term toxicities to conventional myelosuppressive therapies still constitute significant challenges and emphasize the unmet need for effective targeted therapies. Years of scientific efforts have translated into extensive insights on the heterogeneous spectrum of genetics and oncogenic signaling pathways of AML and identified a subset of patients characterized by upregulati

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… AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol. Cell. 37, 429–437. 10.1016/j.molcel.2010.01.026. …

The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia.

Disease relapse represents by far the most frequent cause of hematopoietic cell transplantation (HCT) failure. Patients with acute leukemia suffering relapse after HCT have limited conventional treatment options with little possibility of cure and represent, de facto, suitable candidates for the evaluation of novel cellular and biological-based therapies. Donor lymphocyte infusions (DLI) has been one of the first cellular therapies adopted to treat post HCT relapse of acute leukemia patients and still now, it is widely adopted in preemptive and prophylactic settings, with renewed interest for

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… Graft-versus-leukemia reactions in allogeneic chimeras. Blood. (2004) 103:767–76. doi: 10.1182/blood-2003-02-0342 29. Collins RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R, et al. …

Current and Emerging Therapies for Targeting the ERK1/2 & PI3K Pathways in Cancer.

The ERK1/2 and PI3K signaling pathways play important roles in cellular proliferation, survival, differentiation, and metabolism. In cancer, these pathways are frequently dysregulated and overactivated, resulting in poor patient prognosis and resistance to treatment. These pathways are activated by receptor tyrosine kinases and send downstream signals to effectors such as RAS, RAF, MEK, AKT, and mTOR. In this review, we highlight the key components of the ERK1/2 and PI3K pathways, the roles they play in tumor progression, and the development of inhibitors and combination therapies designed to

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… To counteract drug resistance, FGFR degraders like Proteolysis Targeting Chimeras (PROTAC) are employed, inducing selective intracellular proteolysis to inhibit FGFR signaling pathways effectively [ 41 ]. …

Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma.

Therapy for multiple myeloma (MM), a hematologic neoplasm of plasma cells, has undergone remarkable changes over the past 25 years. Small molecules (molecular weight of less than one kDa), together with newer immunotherapies that include monoclonal antibodies, antibody-drug conjugates, and most recently, chimeric antigen receptor (CAR) T-cells, have combined to double the disease's five-year survival rate to over 50% during the past few decades. Despite these advances, the disease is still considered incurable, and its treatment continues to pose substantial challenges, since therapeutic refra

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… A related strategy known as proteolysis-targeting chimera (PROTAC), which generally employs a small molecule linker that bridges an E3 ubiquitin ligase and a protein targeted for degradation, represents an extension of this approach also with potential application to cancer treatment [ 22 ]. …

T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential therapeutic modality for patients with hematological malignancies and other blood disorders. Unfortunately, acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following allo-HCT, which limits its use in a broader spectrum of patients. Chronic graft-versus-host disease (cGVHD) also remains the most common long-term complication of allo-HCT, occurring in reportedly 30-70% of patients surviving more than 100 days. Chronic GVHD is also the leading cause of non-relapse mortality (NRM) occ

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… Graft-Versus-Leukemia and Graft-Versus-Host Reactions After Donor Lymphocyte Infusion Are Initiated by Host-Type Antigen-Presenting Cells and Regulated by Regulatory T Cells in Early and Long-Term Chimeras. Biol Blood Marrow Transplant (2006) 12(4):397–407. doi: 10.1016/j.bbmt.2005.11.519 10. …

Circular RNAs in cancer.

Circular RNA (circRNA), a subtype of noncoding RNA, has emerged as a significant focus in RNA research due to its distinctive covalently closed loop structure. CircRNAs play pivotal roles in diverse physiological and pathological processes, functioning through mechanisms such as miRNAs or proteins sponging, regulation of splicing and gene expression, and serving as translation templates, particularly in the context of various cancers. The hallmarks of cancer comprise functional capabilities acquired during carcinogenesis and tumor progression, providing a conceptual framework that elucidates t

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… F‐circRNAs originate from fusion genes formed by chromosomal translocations in cancer cells. 65 , 66 , 67 Rt‐circRNAs result from read‐through transcription, producing hybrid transcripts that include coding exons from two adjacent and similarly oriented genes. 64 , 68 While f‐circRNAs are interchromosomal chimeras … between distant genes, rt‐circRNAs are intrachromosomal chimeras involving adjacent genes on the same strand. 63 Biogenesis of circRNAs Maintaining cellular physiological balance involves the regulated generation of circRNAs through multiple cis‐acting elements and trans‐acting factors, mirroring …

Deciphering and targeting oncogenic pathways through integrated approaches and amino acid metabolism in hematologic malignancies.

Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, represent a diverse group of blood cancers driven by complex oncogenic pathways and genetic aberrations. Despite advances in treatment, resistance and relapse remain significant clinical challenges. This review presents an integrative approach to blood cancer therapy, highlighting the convergence of precision medicine, CRISPR-based gene editing, immunotherapy (including CAR-T cells and immune checkpoint inhibitors), and targeted modulation of amino acid metabolism. We investigate the molecular pathways driving tumour

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… Lastly, ongoing research into MEK and ERK allosteric inhibitors, PROTACs (Proteolysis-targeting chimeras), and RAS-specific drugs promises to enable even more sophisticated and potent interventions in the future. …

Epi-Immunotherapy in Cancer Treatment: Mechanisms, Clinical Progress, and Future Directions.

Cancer immunotherapy is a groundbreaking therapeutic strategy, yet it continues to face significant challenges, including limited overall response rates and treatment resistance. Emerging research has demonstrated the pivotal role of epigenetic modifications in tumor immune evasion, providing a strong rationale for developing "epi-immunotherapy"-an innovative approach that combines epigenetic therapy with immunotherapy. This comprehensive review systematically examines how epigenetic regulation mediates tumor immune escape and the mechanisms involved, including suppression of tumor antigen exp

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… New approaches using nanotechnology and biotechnology, including the development of proteolysis targeting chimeras and molecular glues, show potential for improving drug targeting and efficacy while maintaining safety. …

Unraveling the mechanisms of bone diseases: targeting dendritic cells in osteoimmunology for internal homeostasis balance.

Bone repair and regeneration is a complex spatiotemporal process recruiting a variety of cell types, which need to precisely mediated for effective healing post-damage. The concept of osteoimmunology emphasizes the extensive and intricate crosstalk between the bone and the immune system. Despite the significant advancements in understanding osteoimmunology, the precise role of dendritic cells (DCs) in this field remains under investigation. As key antigen-presenting cells, DCs are critical in orchestrating adaptive immune responses and maintaining tissue homeostasis. Recent researches have fur

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… critical role of BMDCs in HSPCs trafficking, thereby contributing to the regulation of hematopoiesis and establishment of the stem cell niche. 13 Specific ablation of cDCs after DT treatment in Zbtb46 dtr induced HSPCs mobilization, in a manner significantly more efficient than Cd169dtr bone marrow chimeras …

Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier.

Glioblastoma (GBM) is the most malignant form of all primary brain tumors, and it is responsible for around 200,000 deaths each year worldwide. The standard therapy for GBM treatment includes surgical resection followed by temozolomide-based chemotherapy and/or radiotherapy. With this treatment, the median survival rate of GBM patients is only 15 months after its initial diagnosis. Therefore, novel and better treatment modalities for GBM treatment are urgently needed. Mounting evidence indicates that non-coding RNAs (ncRNAs) have critical roles as regulators of gene expression. Long non-coding

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… When detoxified DT chimeras were used as protein-delivery vectors, high translocating efficiencies of cargo proteins of variable sizes (>100 kDa), structural motifs, and diverse stabilities were obtained ( 125 ). …

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost.

Gene therapy is now surpassing 30 years of clinical experience and in that time a variety of approaches has been applied for the treatment of a wide range of pathologies. While the promise of gene therapy was over-stated in the 1990's, the following decades were met with polar extremes between demonstrable success and devastating setbacks. Currently, the field of gene therapy is enjoying the rewards of overcoming the hurdles that come with turning new ideas into safe and reliable treatments, including for cancer. Among these modalities, the modification of T cells with chimeric antigen recepto

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… T cells expressing PD1:CD28 chimera showed increased effector function, with enhanced production of interferon (IFN)-γ and increased proliferation, suggesting that this approach can effectively convert an inhibitory signal to a positive one. …

The role of mesenchymal stem cells in attenuating inflammatory bowel disease through ubiquitination.

Inflammatory bowel disease (IBD), a condition of the digestive tract and one of the autoimmune diseases, is becoming a disease of significant global public health concern and substantial clinical burden. Various signaling pathways have been documented to modulate IBD, but the exact activation and regulatory mechanisms have not been fully clarified; thus, a need for constant exploration of the molecules and pathways that play key roles in the development of IBD. In recent years, several protein post-translational modification pathways, such as ubiquitination, phosphorylation, methylation, acety

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… Proteolytic targeting chimeras (PROTACs) can recruit the E3 ligase RNF43 to the lysosomes that induce PD-L1, promoting its ubiquitination and subsequent degradation ( 185 ). …

Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition.

Antimitotic agents are one of the more successful types of anticancer drugs, but they suffer from toxicity and resistance. The application of approved drugs to new indications (i.e., drug repurposing) is a promising strategy for the development of new drugs. It relies on finding pattern similarities: drug effects to other drugs or conditions, similar toxicities, or structural similarity. Here, we recursively searched a database of approved drugs for structural similarity to several antimitotic agents binding to a specific site of tubulin, with the expectation of finding structures that could f

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… Docked poses were analyzed with Chimera [ 46 ], Marvin [ 47 ], OpenEye [ 48 ], and JADOPPT [ 49 ]. 4.3.4. Molecular Dynamics Simulations and MMGBSA Re-Scoring We re-scored the consensus docking poses using the AMBER scoring functionality included in DOCK 6.11 [ 66 ]. …

Developing Actively Targeted Nanoparticles to Fight Cancer: Focus on Italian Research.

Active targeting is a valuable and promising approach with which to enhance the therapeutic efficacy of nanodelivery systems, and the development of tumor-targeted nanoparticles has therefore attracted much research attention. In this field, the research carried out in Italian Pharmaceutical Technology academic groups has been focused on the development of actively targeted nanosystems using a multidisciplinary approach. To highlight these efforts, this review reports a thorough description of the last 10 years of Italian research results on the development of actively targeted nanoparticles t

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… selected MTX as a cytotoxic drug against rat F98 glioma cells and prepared the lipophilic derivative di-dodecyl-MTX (ddMTX) to be loaded into SLNs [ 150 ]. ddMTX-loaded behenic acid-SLNs were prepared using the coacervation method, and active targeting was obtained using apolipoprotein E (ApoE), a chimera …