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Background: Biologics are essential in treating psoriasis. In recent years, the pathogenesis exploration and development of new target drugs have provided a more complete evidence-based foundation for the biological treatment of psoriasis. This study aims to use bibliometrics to analyze the research status and development trends of biologics in psoriasis. Methods: The bibliometric analysis of publications related to biologics in psoriasis from 2004 to 2023 was conducted using the Web of Science Core Collection (WoSCC) database as the search data source. To perform the bibliometric analysis and create visual knowledge graphs, CiteSpace, the Bibliometrix R package, and VOSviewers were utilized. Results: The study included a total of 3800 articles. The United States had the highest number of publications. The leading authors and institutions were Steven R. Feldman and the University of Manchester, respectively, in the global partnership. The cluster plot divided all keywords into 11 categories. Currently, Secukinumab and Guselkumab are representative biological agents being studied due to their considerable efficacy and long-term safety. Conclusions: Targeted therapy has emerged as a significant trend in the current treatment of psoriasis. Early and active use of biologics can effectively control disease progression, prevent or delay the occurrence of comorbidities, and may even alter the natural course of psoriasis. However, further investigation is required to fully understand the specific mechanisms of psoriasis and the use of biological agents. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores Warburg's paradox, whereby cancer cells use both glucose and oxygen to survive, even though glucose is converted to lactate instead of being oxidized. By systematically investigating cellular metabolism during each phase of cell division and comparing the metabolic profiles of lymphoma cells and non-malignant lymphocytes, we discovered that pyruvate, the end-product of glucose metabolism, is converted into alanine. This conversion directs glutamine carbon, rather than glucose, into the TCA cycle. Furthermore, using fludarabine to selectively inhibit lymphoma cell proliferation, we showed that blocking the conversion of pyruvate to alanine disrupts the TCA cycle and interferes with the supply of nucleotides and the energy necessary for cancer cell growth. Our findings suggest that with the suppression of glucose oxidation, the conversion of pyruvate to alanine is the crucial metabolic link that connects glucose and oxygen metabolism and serves as a key component of Warburg's paradox. Background/Objectives: Warburg's metabolic paradox illustrates that malignant cells require both glucose and oxygen to survive, even after converting glucose into lactate. It remains unclear whether sparing glucose from oxidation intersects with TCA cycle continuity and if this confers any metabolic advantage in proliferating cancers. This study seeks to understand the mechanistic basis of Warburg's paradox and its overall implications for lymphomagenesis. Methods: Using metabolomics, we first examined the metabolomic profiles, glucose, and glutamine carbon labeling patterns in the metabolism during the cell cycle. We then investigated proliferation-specific metabolic features of malignant and nonmalignant cells. Finally, through bioinformatics and the identification of appropriate pharmacological targets, we established malignant-specific proliferative implications for the Warburg paradox associated with metabolic features in this study. Results: Our results indicate that pyruvate, lactate, and alanine levels surge during the S phase and are correlated with nucleotide synthesis. By using 13C1,2-Glucose and 13C6, 15N2-Glutamine isotope tracers, we observed that the transamination of pyruvate to alanine is elevated in lymphoma and coincides with the entry of glutamine carbon into the TCA cycle. Finally, by using fludarabine as a strong inhibitor of lymphoma, we demonstrate that disrupting the transamination of pyruvate to alanine correlates with the simultaneous suppression of glucose-derived nucleotide biosynthesis and glutamine carbon entry into the TCA cycle. Conclusions: We conclude that the transamination of pyruvate to alanine intersects with reduced glucose oxidation and maintains the TCA cycle as a critical metabolic feature of Warburg's paradox and lymphomagenesis. [ABSTRACT FROM AUTHOR]

Purpose of Review: Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a rare, aggressive malignancy that can arise from any organ and frequently presents with distant metastases. Advanced disease has a poor prognosis with median overall survival (OS) rarely exceeding 1 year even with systemic therapy. The management paradigm of advanced/metastatic EP-NEC has been extrapolated from small cell lung cancer (SCLC) and commonly consists of 1st line therapy with etoposide and platinum (cisplatin or carboplatin), followed by alternative cytotoxic regimens at the time of progression. Only a minority of patients are able to receive 2nd line therapy, and cytotoxics derived from the SCLC paradigm such as topotecan or lurbinectedin have very limited activity. We aimed to evaluate emerging therapeutic options in the 2nd and later lines and survey potential future developments in this space. Recent Findings: After a long period of stagnation in treatment options and outcomes, more promising regimens are gradually being utilized in the 2nd line setting including systemic therapy combinations such as FOLFIRI, FOLFOX, modified FOLFIRINOX, CAPTEM, and, more recently, novel checkpoint inhibitors such as nivolumab and ipilimumab. Simultaneously, advances in the understanding of disease biology are helping to refine patient selection and identify commonalities between NEC and their sites of origin which may eventually lead to additional targeted therapy options. Summary: While many questions remain, contemporary developments give grounds for optimism that improved outcomes for EP-NEC will soon be within reach. [ABSTRACT FROM AUTHOR]

Simple Summary: For the last 35 years, various systemic therapies for recurrent or refractory meningiomas have been investigated. The present review aggregated the currently available evidence in the literature regarding the safety and efficacy of these treatments and assessed the ongoing trials of medical therapy for meningiomas. The findings of the present study would assist future research in seeing what therapeutic regimens have been investigated, which targets are promising candidates for interventions, and how the ongoing clinical trials are currently designed. The safety and efficacy of various pharmacotherapeutic regimens on refractory meningiomas have been the focus of investigations. We present a comprehensive review of the previous efforts and the current state of ongoing clinical trials. A PRISMA-compliant review of the MEDLINE and ClinicalTrial.gov databases of the National Library of Medicine were performed. The primary outcomes of interest for included articles were radiographic response, overall survival, progression-free survival, six-month progression-free survival, and adverse events. Overall, 34 completed trials and 27 ongoing clinical trials were eligible. Six-month progression-free survival was reported in 6–100% of patients in the completed studies. Hematological disorders were the most common adverse events. Of the ongoing clinical trials identified, nine studies are phase I clinical trials, eleven are phase II trials, two are phase I and II trials, one is phase II and III, and two trials do not have a designated phase. Currently, there is no effective chemotherapy for refractory or recurrent meningiomas. Several promising targeted agents have been developed and are currently being investigated in the hope of identifying novel therapeutic strategies for the treatment of this pathology. [ABSTRACT FROM AUTHOR]

Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10-20% of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.

Despite improved outcomes achieved in the last decades for children with newly diagnosed leukaemia and lymphoma, treatment of patients with refractory/relapsed disease remains a challenge. The cure rate is still unsatisfactory and often achieved at the cost of significant morbidity. Exploring treatment with novel agents should offer less toxic therapeutic options, without compromising efficacy. Bispecific and antibody–drug conjugates targeting CD19 and CD22 (blinatumomab and inotuzumab ozogamicin) play an important role in the treatment of relapsed and refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL); antibodies targeting CD123 and CD38 are also under investigation for acute myeloid leukaemia (AML) and T-ALL, respectively. Targeted therapy with small molecules is of primary importance for specific genetic subtypes, such as BCR-ABL-positive ALL, FLT3- ITD AML and anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. KMT2A -directed targeted therapy with menin inhibitors holds promise to be of relevance in KMT2A -rearranged leukaemias, known to have dismal prognosis. Target inhibition in cellular pathways such as BCL-2 , RAS , MEK , Bruton's tyrosine kinase , JAK-STAT or CDK4/CDK6 inhibition may be suitable for different diseases with common mutated pathways. Nevertheless, development and approval of new agents for paediatric cancers lags behind adult therapeutic options. New regulations were implemented to accelerate drug development for children. Considering the number of oncology medicinal products available for adults and the rarity of paediatric cancers, prioritisation based on scientific evidence and medical need, as well as international collaboration, is critical. Herein, we review the current status of drug development for children with leukaemia and lymphoma, excluding cellular therapy despite its well-known significance. • Development and approval of new agents for paediatric cancers lags behind adult options. • We provide an overview of available novel agents for paediatric leukaemia and lymphoma. • Recent and upcoming early phase trials in this field are presented. • Challenges and foreseen changes in the landscape are discussed. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common form of arthritis and the fastest growing cause of chronic disability in the world. Formation of the ternary IL-1β /IL-1R1/IL-1RAcP protein complex and its downstream signaling has been implicated in osteoarthritis pathology. Current OA therapeutic approaches target either the cytokine IL-1β or the primary receptor IL-1RI but do not exploit the potential of the secondary receptor IL-1RAcP. Our previous work implicated the Arg286 residue of IL-1RAcP as a key mediator of complex formation. Molecular modeling confirmed Arg286 as a high-energy mediator of the ternary IL-1β complex architecture and interaction network. Anti-IL-1RAcP monoclonal antibodies (mAb) targeting the Arg286 residue were created and were shown to effectively reduce the influx of inflammatory cells to damaged joints in a mouse model of osteoarthritis. Inhibitory peptides based on the native sequence of IL-1RAcP were prepared and examined for efficacy at disrupting the complex formation. The most potent peptide inhibitor had an IC50 value of 304 pM in a pull-down model of complex formation, and reduced IL-1β signaling in a cell model by 90% at 2 μM. Overall, therapies that target the Arg286 region surface of IL-1RAcP, and disrupt subsequent interactions with subunits, have the potential to serve as next generation treatments for osteoarthritis.

Introduction: Meningiomas represent the most common primary intracranial tumors. Today, surgical resection, followed by radiotherapy when indicated, is still the treatment of choice. In recent years, distinct oncogenic pathways have been identified, laying the foundations of new personalized targeted therapies.Areas covered: The aim of this study was to highlight the effects, complications, possible associations with other therapeutic approaches and multi-parametric outcome evaluation of Bevacizumab for the treatment of meningiomas. A literature review according to PRISMA criteria regarding the role of Bevacizumab for the treatment of various WHO grades of meningiomas was performed. 15 relevant papers, including 6 retrospective clinical trial series, 3 prospective trials, and 6 single patient case reports for a total of 134 patients and 211 meningiomas were include.Expert opinion: Because of the lack of strong clinical evidence about improved survival and related toxicity, the use of Bevacizumab for the treatment of meningiomas should be carefully evaluated. Further exploration, ideally with randomized controlled trials, is needed to better define the role of this drug in the treatment of meningiomas. [ABSTRACT FROM AUTHOR]

Aldehyde dehydrogenases (ALDHs) are highly expressed in the chemotherapy- and radiotherapy-resistant cell subpopulations of many different cancer types. Accordingly, the development of ALDH inhibitors may be the most direct approach to target these cell populations. However, inhibiting multiple ALDH family members can be toxic and isoform-specific inhibition is often ineffective. This review discusses the role of ALDH in cancer and therapy resistance, and then overviews the various available ALDH inhibitors with a focus on the clinical potential and limitations of these agents as cancer therapeutics. Finally, challenges and future research directions to effectively target ALDH in the management of cancer therapy resistance are discussed. Aldehyde dehydrogenase (ALDH) overexpression is associated with cancer progression and therapy resistance. ALDH activity in cells is generally a combination of the activities of multiple ALDH isoforms. Targeting ALDHs is likely the most direct approach to inhibiting therapy-resistant ALDH-overexpressing cells, but inhibiting multiple ALDH family members can be toxic, and isoform-specific inhibition is often ineffective, which has limited the use of these agents. Despite the recent development of numerous ALDH inhibitors as anticancer agents, research focused on developing efficacious, non-toxic ALDH inhibitors is still needed. [ABSTRACT FROM AUTHOR]

Ovarian cancer patients in the advanced stages of the disease show clinical ascites, which is associated with a poor prognosis. There is limited understanding of the effect of ascitic fluid on ovarian cancer cells and their response to anticancer drugs. We investigated the antitumour effects of EGFR/Her-2 (canertinib) and c-Met (PHA665752) inhibitors in a 3D cell model of three ovarian cancer lines. Single and combined inhibitor treatments affected cell growth of OVCAR-5 and SKOV-3 cell lines but not OV-90 cell line. Growth reduction was correlated with the down expression of PCNA, EGFR, HER-2, c-MET, ERK and AKT and their phosphorylation status in cells in growth factor supplemented media. However, these effects were not re-producible in OVCAR-5 and SKOV-3 cell lines when they were exposed to ascitic fluid obtained from three ovarian cancer patients. Serum albumin and protein components in the ascitic fluids may reduce the cellular uptake of the inhibitors. [ABSTRACT FROM AUTHOR]

The enthusiasm about successful novel therapeutic strategies in cancer is often quickly dampened by the development of drug resistance. This is true for targeted therapies using tyrosine kinase inhibitors for EGFR or BRAF mutant cancers, but is also an increasingly recognized problem for immunotherapies. One of the major obstacles of successful cancer therapy is tumor heterogeneity of genotypic and phenotypic features. Historically, drivers for drug resistance have been suspected and found on the genetic level, with mutations either being pre-existing in a subset of cancer cells or emerging de novo to mediate drug resistance. In contrast to that, our group and others identified a non-mutational adaptive response, resulting in a reversible, drug tolerant, slow cycling phenotype that precedes the emergence of permanent drug resistance and is triggered by prolonged drug exposure. More recently, studies described the importance of initially reversible transcriptional reprogramming for the development of acquired drug resistance, identified factors important for the survival of the slow cycling phenotype and investigated the relationship of mutational and non-mutational resistance mechanisms. However, the connection and relative importance of mutational and adaptive drug resistance in relation to the in vitro models at hand and the clinically observed response patterns remains poorly defined. In this review we focus on adaptive intrinsic phenotypic plasticity in cancer cells that leads to the drug tolerant slow cycling state, which eventually transitions to permanent resistance, and propose a general model based on current literature, to describe the development of acquired drug resistance. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma is a devastating form of skin cancer and its incidence is increasing faster than any other preventable cancer in the United States. The mutant NRAS subset of melanoma is more aggressive and associated with poorer outcomes compared to non-NRAS mutant melanoma. The aggressive nature and complex molecular signaling conferred by this transformation has evaded clinically effective treatment options. This review examines the major downstream effectors of NRAS relevant in melanoma and the associated advances made in targeted therapies that focus on these effector pathways. We outline the history of MEK inhibition in mutant NRAS melanoma and recent advances with newer MEK inhibitors. Since MEK inhibitors will likely be optimized when combined with other targeted therapies, we focus on recently identified targets that can be used in combination with MEK inhibitors. [ABSTRACT FROM AUTHOR]

Nowadays, neoadjuvant endocrine therapy is a clinically acceptable (and sometimes preferred) strategy in patients with operable estrogen receptor-positive (ER+) breast cancer. Despite the overall effectiveness of endocrine therapy in breast cancer in all settings, de novo (primary) and acquired (secondary) endocrine therapy resistance remains a major clinical problem. Neoadjuvant endocrine therapy trials for breast cancer are not only a great opportunity to determine which ER+ breast cancers can be treated without chemotherapy, but also a great strategy to develop insights into the biologic basis for the efficacy of estrogen-receptor-targeting agents, alone or in combination, in an effort to counteract resistance to endocrine therapy and discover actionable molecular targets that can be the focus of future drug discovery efforts and/or translational/clinical investigation in ER+ breast cancers. [ABSTRACT FROM AUTHOR]

Enhancer of Zeste Homolog 2 (EZH2) is highly expressed in kinds of malignant tumors and related to tumor occurrence, development, and prognosis. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which promotes cell proliferation, migration, and invasion by epigenetic regulation of anti-tumor gene. It can activate numerous tumor-associated signaling pathways and interfere with DNA damage repair. In recent years, large amounts of studies have shown that EZH2 is closely related to gynecologic-related malignancies and can be used as a potential target gene for the treatment of gynecological-related malignancies. This review summarizes the oncogenic function of EZH2 and introduces the recent advances in the development of EZH2 inhibitors. On this basis, future research prospect of EZH2 is proposed. [ABSTRACT FROM AUTHOR]

Surgery is curative for most meningiomas, but a minority of these tumors recur and progress after resection. Initial trials of medical therapies for meningioma utilized nonspecific cytotoxic chemotherapies. The presence of hormone receptors on meningioma ushered in trials of hormone-mimicking agents. While these trials expanded clinical understanding of meningioma, they ultimately had limited efficacy in managing aggressive lesions. Subsequent detection of misregulated proteins and genomic aberrancies motivated the study of therapies targeting specific biological disturbances observed in meningioma. These advances led to trials of targeted kinase inhibitors and immunotherapies, as well as combinations of these agents together with chemotherapies. Prospective trials currently recruiting participants are testing a diverse range of medical therapies for meningioma, and some studies now require the presence of a specific protein alteration or genetic mutation as an inclusion criterion. Increasing understanding of the unique and heterogeneous nature of meningiomas will continue to spur the development of novel medical therapies for the arsenal against aggressive tumors.

Background Gastrointestinal stromal tumors (GISTs) arising from the interstitial cells of Cajal along the gastrointestinal tract rarely metastasize to the central nervous system (CNS) but require aggressive multimodal therapies when they do. We present a case of recurrent GIST metastasis to the skull and review the literature on management, including the role of molecular profiling in determining adjuvant treatment. Case A 64-year-old woman presented with an enlarging palpable mass over her right eye. Magnetic resonance imaging revealed an enhancing T1-hypointense, T2-hyperintense right frontal calvarial lesion with lytic features on computed tomography. Pathology confirmed metastatic GIST to the skull with dural involvement. Molecular profiling revealed a mutation in exon 11 of KIT in her primary tumor, while the skull metastasis harbored an additional mutation in exon 17 associated with acquired drug resistance. Conclusion We review the epidemiology of GIST metastases and discuss potential reasons for its rare presentation to the CNS. Additionally, we highlight the diagnostic and prognostic value of molecular profiling for metastatic GIST, as well as its influence in arbitrating targeted molecular inhibitor therapy. Evolving molecular signatures, associated with treatment resistance, may play a pivotal role in future integration with multimodality treatment strategies for CNS GIST. [ABSTRACT FROM AUTHOR]

Cancer often arises when normal cellular growth goes awry due to defects in critical signal transduction pathways. A growing number of inhibitors that target specific components of these pathways are in clinical use, but the success of these agents has been limited by the resistance to inhibitor therapy that ultimately develops. Studies have now shown that cancer cells respond to chronic drug treatment by adapting their signaling circuitry, taking advantage of pathway redundancy and routes of feedback and cross-talk to maintain their function. This review focuses on the compensatory signaling mechanisms highlighted by the use of targeted inhibitors in cancer therapy. [ABSTRACT FROM AUTHOR]