Anticancer Research Articles

A PHARMACOEPIDEMIOLOGICAL STUDY OF NEW DRUG APPROVAL PATTERN OF JAPAN

Objectives: The objective of the study was to study the drug development and drug approval pattern of a developed Asian country: Japan. Methods: Data available on official website of Japan government health authority was compiled for the duration of January 2017–December 2021. The new approved drugs were classified based on different parameters such as active ingredient, drug approval date, review category, new approval or partial change, Indication of drugs, and WHO anatomic thoracic classification. The descriptive analysis of data was done using LibreOffice Calc. Results: Out of 545 drugs approved, 46% were anti-neoplastic and immunomodulating agent, 10% were anti-infective and 9% were Nervous system category. Furthermore, among all approved drugs, 51.38% were new approved drugs while 48.62% of drugs were approved with partial change in dosage, route, or indications. Conclusion: This study showed new drug development and approval was done significantly for anti-cancer agents and agents for non-communicable diseases.

The Chemistry and Pharmacological Properties of the Constituents of Toussaintia Orientalis - An Endangered Treasure of Biomedical Agents.

Toussaintia orientalis Verdc. (Annonaceae) is a medicinal plant species endemic to Tanzania. It is classified under the International Union for Conservation of Nature (IUCN) as an extremely endangered species threatened with extinction. The review covers the phytochemistry of this plant species and the pharmacological properties of the compounds obtained therefrom. The chemistry of this plant species entails natural products with different structures including uncommon cinnamoyl tetraketide derivatives, aristolactam alkaloids, and flavonoids. The review identifies 27 compounds belonging to different subclasses of natural products obtained from this species for the past fourteen years (2010-2024). These compounds are discussed along with other 13 related natural products. T. orientalis derived compounds exhibit varied potential pharmacological applications as antibacterial, anticancer, anti-inflammatory, antiviral, and neuroprotective agents. Some of the reported compounds displayed pharmacological properties corroborating the use of this plant species in traditional medicine. This review provides baseline data as one comprehensive compilation that will ignite interest and guide future research and development of therapeutic agents inspired by the chemodiversity presented by this plant species while at the same time attracting the attention of plant conservationists to initiate efforts to conserve this highly endangered biomedical treasure.

Advances in the study of DNA-metal complexes in biomedical applications

DNA-metal composites are emerging as emerging materials for biomedical applications due to their unique DNA and metal nanoparticle properties. DNA is a multifunctional macromolecule that enables targeted drug delivery through aptamer selection and gene silencing through nuclease activity. These properties make it highly selective and targeted in therapy. While conventional chemotherapy faces significant drawbacks, including poor targeting and severe side effects, DNA-metal composites with their excellent targeting and therapeutic efficiencies can significantly enhance therapeutic efficacy. This paper first describes the structural properties, synthesis methods of DNA-metal composites and their therapeutic applications. The combination of DNA and metal nanoparticles provides a novel approach to improve the effectiveness of anticancer and antimicrobial therapies, addressing key limitations in current therapeutic strategies. Innovative applications of DNA-metal composites in the anticancer and antimicrobial fields are then explored, highlighting their multiple synthesis and application possibilities through interactions with metal ions or particles. DNA-metal composites address several of the limitations of conventional chemotherapeutic and antimicrobial drugs, providing better targeting and resolving the issue of drug resistance. DNA-metal composites in biomedicine show DNA-metal composites show great promise in the biomedical field, and future research will continue to promote their application and development in clinical therapy.

BOX-BEHNKEN DESIGN ASSISTED ECO-FRIENDLY RP-HPLC-PDA METHOD FOR THE QUANTIFICATION OF PACLITAXEL: APPLICATION TO EVALUATE THE SOLUBILITY OF PACLITAXEL-CYCLODEXTRIN COMPLEX

Objective: Paclitaxel (PTX) is one of the oldest chemotherapeutic agents for cancer treatment. However, PTX is a class IV drug under the Biopharmaceutical Classification System (BCS), and its oral administration is restricted due to its low bioavailability. Complexing PTX with Beta-Cyclodextrin (β-CD) is an option to overcome the low solubility and bioavailability. This study aims to optimize and develop an RP-HPLC analytical method for quantifying PTX from the fabricated β-CD complex. Methods: The HPLC settings were optimized using Design-of-Experiments (DOE) software. The independent variables for the optimization process were buffer ratio, buffer pH, flow rate, and injection volume. The responses were Retention Time (RT), peak area, Tailing Factor (TF), and number of Theoretical Plates (TP) of PTX. The validated method was then used to measure the % entrapment from the PTX-β-CD complex. Results: The developed and optimized RP-HPLC method was validated as per International Council for Harmonisation (ICH) Q2 (R1) guidelines. The developed method showed linearity R2 = 0.999 with a 0.5-20 µg/ml range. The Limit of Detection (LOD) and Limit of Quantification (LOQ) were 95 and 125 ng/ml, respectively. The accuracy and precision for the developed method came under the acceptance criteria. The developed method was used to evaluate the enhancement of solubility of the prepared PTX-β-CD complex. The method was also used in the evaluation of % drug loading, % drug release and stability of the PTX-β-CD complex. The study clearly showed that the solubility of PTX increased from 0 to 1.14±0.53 µg/ml at pH 1.2 and 0 to 3.18±0.61 µg/ml at pH 6.8, respectively. The PTX-β-CD complex showed 73±3.75% drug release in 120 min at pH 1.2 and 87±3.51% at pH 6.8. The developed RP-HPLC method was found to be eco-friendly as per the Analytical Greenness (AGREE) metric approach and software analysis. Conclusion: An eco-friendly RP-HPLC analytical method was successfully developed and optimized for the quantification of PTX from the PTX-β-CD complex.

First Vesicular Self-Assembly of an Apocarotenoid Bixin in Aqueous Liquids and Its Antibacterial Activity.

Bixin 1 is the major constituent of the reddish carotenoids present in the seed-coat of Bixa orellana. The use of the extract of the seed-coat of Bixa orellana in food, cosmetics and garments is well known. The nano-sized long 24 C chain molecule has nine conjugated double bonds having extended conjugation with the '-COOH' and '-COOMe' groups present at the two ends of the molecule. Herein, we report the first self-assembly of bixin in several aqueous liquids. The molecule undergoes spontaneous self-assembly in several liquids yielding vesicular self-assembly. Characterizations of the self-assemblies of bixin were carried out by various microscopic techniques, X-ray diffraction and FTIR studies. The critical vesicular concentrations (CVCs) of the compound carried out in DMSO-water in three different solvent ratios as 2: 1 (v/v), 1: 1 (v/v) and 1: 4 (v/v) were determined to be 100 μM, 90 μM and 60 μM respectively indicating lower CVC values at higher proportion of water. Utilization of the vesicular self-assemblies of bixin have been demonstrated in the entrapment and release of fluorophores including the anticancer drugs doxorubicin and curcumin. Self-assembled bixin and curcumin loaded self-assembled bixin showed significant antibacterial activity with both Gram positive as well as Gram negative bacteria.

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

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

Investigation of Novel Quinoline Derivatives Targeting Epidermal Growth Factor Receptors as Anticancer Agents a Computational Approach

Background: Newer chemical entities are created and synthesis has been made feasible by a variety of computer-aided drug design (CAAD) techniques. In addition to facilitating the visualisation of the ligand-target binding process, the application of in silico methodologies and structure-based drug design (SBDD) allows for the prediction of receptor affinities and significant binding pocket locations. Objective: The goal of the current study was to identify new quinoline derivatives by computational methods specially designed to bind the EGFR receptor in the treatment of breast cancer. Materials and Methods: ChemAxon Marvin Sketch 5.11.5 was used to create derivatives of quinolines. The admetSAR online web tools and SwissADME were utilised to forecast the toxicity and pharmacokinetic characteristics of several substances. A multitude of software programmes, such as Autodock 1.1.2, MGL Tools 1.5.6, Procheck, Protparam ExPasy tool, PyMOL, and Biovia Discovery Studio Visualizer v20.1.0.19295 were also employed to ascertain the ligand-receptor interactions between quinoline derivatives and the target receptor (PDB -5GNK). Result: Almost all components were shown to be less hazardous, orally consumable and to have the appropriate pharmacokinetic characteristics based on in silico study. All newly generated derivative compounds have higher docking scores when compared to the widely used medication sorafenib. Conclusion: Interactions with quinoline analogues boost binding energy and the number of Hbonds produced, making them a suitable place to start when creating compounds for further exploration. The quinoline moiety increases its potential as a novel therapy alternative for breast cancer and could facilitate more comprehensive in vivo, in vitro, chemical-based, and pharma studies by medicinal chemists.

Optical and structural characterization of Au@ZnO core–shell nanoparticles prepared by pulsed laser ablation as anticancer agents for skin cancer

Optical and structural characterization of Au@ZnO core–shell nanoparticles prepared by pulsed laser ablation as anticancer agents for skin cancer

Oocyte death is triggered by the stabilization of TAp63α dimers in response to cisplatin

The TAp63α protein is highly expressed in primordial follicle oocytes, where it typically exists in an inactive dimeric form. Upon DNA damage, TAp63α undergoes hyperphosphorylation, transitioning from a dimeric to a tetrameric structure, which initiates oocyte apoptosis by upregulating pro-apoptotic gene. Our results demonstrate that cisplatin, an alkylating anti-cancer agent, predominantly produced the TAp63α dimer rather than the tetramer. We further observed that TAp63α protein accumulation occurred in primordial follicle oocytes following cisplatin treatment, and this accumulation was significantly reduced by cycloheximide, a protein synthesis inhibitor. These findings suggest that TAp63α accumulation is driven primarily by de novo protein synthesis in response to DNA damage. Notably, cycloheximide protected oocytes from cisplatin-induced apoptosis, as evidenced by reduced levels of both PUMA, a known pro-apoptotic target gene of TAp63α, and TAp63α itself. Additionally, TAp63α turnover appears to be regulated by ubiquitination and proteasome degradation, as evidenced by TAp63α accumulation without oocyte death when treated with PYR-41, a pharmacological inhibitor. However, when TAp63α was stabilized by PYR-41 and subsequently activated by cisplatin, oocyte death occurred, marked by increased γH2AX and Cleaved PARP. Moreover, the Casein kinase 1 inhibitor PF-670462 effectively blocked cisplatin-induced oocyte death, indicating that CK1-mediated phosphorylation is essential for TAp63α activation, even in the absence of tetramer formation. The ATR inhibitor BEZ235 prevented cisplatin-induced TAp63α accumulation, suggesting that TAp63α accumulation precedes its phosphorylation-driven activation. Collectively, our study reveals a novel mechanism of cisplatin-induced apoptosis in primordial follicle oocyte through TAp63α stabilization and accumulation, independent of tetramerization.

The Risk Genes SIRP5, CMC1, and ASAH1 as Potential Targets for the Diagnosis, Immunotherapy, and Treatment of Colon Adenocarcinoma by Single-Cell and Bulk RNA Sequencing Analysis.

Globally, one of the main causes of cancer-related mortality is Colon Adenocarcinoma (COAD). In this study, a new special Immune Cell Functions (ICF) risk model was constructed using single-cell and bulk RNA sequencing data to develop a new understanding and clinical applications for COAD. The immune function gene sets were downloaded from a literature reference, and the COAD single-cell dataset GSE146771 was downloaded from the Tumour Immune Single Cell Hub database. Using Lasso analysis, a multiple gene signature was made from the enrichment scores of immune function gene sets that were enriched in different ways. Robust validation of the signature was then performed in multiple independent cohorts. After that, we built the model using a 10-fold cross-test and evaluated its independence for clinical usage using a nomogram. We also investigated the connection between signature and immune function, genetic variation, immunotherapy, and the cancer immunological microenvironment. Lastly, we used qPCR and immunohistochemistry to examine the expression of the unreported model genes. To find the regulatory functions of unreported model genes, an EdU assay was employed. First, 20 differentially enriched immune function gene sets were identified. Ten genes can be used as a risk profile to assess the prognosis of colon cancer, according to Lasso regression analysis. Signature performance was stable in both the training cohort and two independent GEO external cohorts, and risk scores were confirmed as independent prognostic factors. At the same time, our risk model continued to be highly predictive across various clinical clusters and clinical characteristics, such as immune checkpoints, tumour genome mutations, and chemotherapeutic drug resistance. Patients in the low-risk group have exhibited a higher chance of benefiting from immunotherapy, according to immunotherapy response research. qPCR and immunohistochemistry analysis have revealed SIRP5 expression as high in COAD tissues, while CMC1 and ASAH1 expression has been found to be low. According to the findings of the functional experiment, SIRP5, CMC1, and ASAH1 may control the ability of CRC cells to proliferate. In this study, using scRNA-seq and bulk RNA-seq data, we created a risk model to predict the prognosis and effectiveness of immunotherapy in patients with COAD. In addition, we have discovered three model genes (SIRP5, CMC1, and ASAH1) that have not been reported before. These genes have the potential to be novel therapeutic targets in Colorectal Cancer (CRC). These findings suggest that this model could be used to evaluate the prognostic risk and identify potential targets for COAD patient treatment.

Enhanced Payload Localization in Antibody-Drug Conjugates Using a Middle-Down Mass Spectrometry Approach with Proton Transfer Charge Reduction.

Antibody-drug conjugates (ADCs) represent a novel class of immunoconjugates with growing therapeutic relevance, since they combine the efficacy of cytotoxic drugs with the specificity of antibodies. However, by design, ADCs introduce structural features into the monoclonal antibody scaffold that complicate their analysis. Payload attachment to cysteine or lysine residues can often result in product heterogeneity, regarding both the number of attached drug molecules and their conjugation site, necessitating the use of state-of-the-art MS instrumentation to elucidate their complexity. In middle-down mass spectrometry (MD MS), the gas-phase sequencing of ∼25 kDa ADC subunits with different ion activation techniques generally produces rich fragmentation mass spectra; however, spectral congestion can cause some fragment ions to go undetected, including those that can pinpoint the exact location of payload conjugation sites. Proton transfer charge reduction (PTCR) can substantially simplify fragment ion spectra, thereby unveiling the presence of product ions whose signals were previously suppressed. Herein, we present an MD MS strategy relying on the use of PTCR to investigate a cysteine-based ADC mimic with a variable drug-to-antibody ratio, targeting the unambiguous localization of payload conjugation sites. Unlike traditional tandem MS experiments (MS2), which could not provide a complete map of conjugation sites, a single PTCR-based experiment (MS3) proved to be sufficient to achieve this goal across all variably modified ADC subunits, including isomeric ones. Combining the results obtained from orthogonal ion activation techniques followed by PTCR further strengthened the confidence in the assignments.

Early Endocrine and Metabolic Complications in Childhood Cancer Survivors—Experience from a Tertiary Care Pediatric Oncology Center in South India

Background Endocrine abnormalities and metabolic complications remain one of the common late effects after cancer therapy in children. Data on the incidence and pattern of complications would help to guide appropriate monitoring and treatment of childhood cancer survivors. Methods, Aims, and Objectives Purpose of study is to determine endocrine and metabolic effects in childhood cancer survivors including both hematological malignancies and solid tumors due to cancer per se and treatment-related, including different chemotherapeutic agents and radiotherapy. Results Among 97 participants, 84 children (84.5%) had at least one endocrine or metabolic complication; 41 children (42.3%) had more than two endocrine/metabolic complications. Common endocrine complications included precocious puberty (6.2%), short stature (6.2%), and hypothyroidism (5.1%). Among metabolic complications, dyslipidemia was the highest with an incidence of 68%, followed by fasting hyperinsulinism (32%), diastolic hypertension (18.6%), systolic hypertension (11.3%), obesity (8.8%), and metabolic syndrome (8.2%) and impaired fasting glucose (4.1%).Among endocrine complications, there was a significant increase in incidence of hypothyroidism among children receiving radiotherapy (odds ratio [OR]: 7.13, 95% confidence interval [CI]: 1.1–46.2), and among metabolic complications, a significant increase in incidence of metabolic syndrome in children treated with L-asparaginase compared with those not treated with L-asparaginase was observed (OR: 5.61, 95% CI: 1.07–29.5). There was no significant difference between incidence of observed endocrine and metabolic complications based on type of tumor, gender, and puberty status of study participants. Conclusion This study suggests that there is significant incidence of endocrine and metabolic complications in childhood cancer survivors, hence timely and appropriate recognition of these complications by appropriate screening recommendations and pursuing further endocrine evaluation rationally is needed.

DNA damage-induced EMT controlled by the PARP-dependent chromatin remodeler ALC1 promotes DNA repair efficiency through RAD51 in tumor cells.

Epithelial-to-mesenchymal transition (EMT) allows cancer cells to metastasize while acquiring resistance to apoptosis and chemotherapeutic agents with significant implications for patients' prognosis and survival. Despite its clinical relevance, the mechanisms initiating EMT during cancer progression remain poorly understood. We demonstrate that DNA damage triggers EMT and that activation of poly (ADP-ribose) polymerase (PARP) and the PARP-dependent chromatin remodeler ALC1 (CHD1L) was required for this response. Our results suggest that this activation directly facilitates access to the chromatin of EMT transcriptional factors (TFs) which then initiate cell reprogramming. We also show that EMT-TFs bind to the RAD51 promoter to stimulate its expression and to promote DNA repair by homologous recombination. Importantly, a clinically relevant PARP inhibitor reversed or prevented EMT in response to DNA damage while resensitizing tumor cells to other genotoxic agents. Overall, our observations shed light on the intricate relationship between EMT, DNA damage response, and PARP inhibitors, providing potential insights for in cancer therapeutics.

A case of methotrexate toxicity in induced abortion

Background: Methotrexate is an anticancer drug from the antimetabolite class which is being used in cases of unruptured ectopic pregnancy and as an abortifacient as well. Giving correct dosage according to the body weight and body surface area is of utmost importance to avoid the complications.Case: A 29-year-old, G4P3L3 at 8+3 weeks of gestation with previous three cesarean sections, presented to our hospital with complaints of fever, abdominal pain, multiple episodes of diarrhea and vomiting and oral ulcers for two days. On enquiring, it was found that she received two doses of injection methotrexate (75 and 50 mg) as an abortifacient for an unwanted intrauterine pregnancy from a local doctor nearby. On presentation, her general condition was poor, she was dehydrated, temperature was 101.3°F, pulse rate was 130 beats/minute, blood pressure was 102/64mmHg, respiratory rate was 25/minute and SPO2 was 99% on room air. Her body weight was 55 kgs. Skin pigmentation and multiple oral ulcers were present. Per speculum and per vaginal examination was suggestive of minimal spotting and bulky uterus. Initial blood investigations revealed a hemoglobin level of 8.8 gm/dl, TLC of 1000/mm3, platelet count of 1.45L, INR of 1.37, and normal liver and renal function tests. A provisional diagnosis of methotrexate toxicity was made. Management of the patient was started in consultation with medical oncologist along with supportive treatment. She received IV fluids, antibiotics, and blood products (2-unit PCV and 12-RDP). She received oral leucoverin 15 mg QID and two doses of 300 mg granulocyte stimulating factor each. Gradually, her condition improved and thereafter tablet misoprostol was given for abortion. She was discharged after 13 days of hospital stay with contraceptive advice.Conclusion: The successful management of this case who presented with a constellation of symptoms and deteriorating hematological parameters exhibits the significance of a multidisciplinary approach and vigilant monitoring. Strategies to reduce the side effects and their early recognition include a safety checking procedure like SMART (safety of methotrexate therapy by assessing risks and toxicity) and determining plasma methotrexate concentrations.

Amide Functionalized Novel Pyrrolo-pyrimidine Derivative as Anticancer Agents: Synthesis, Characterization and Molecular Docking Studies.

The development of new therapies targeting crucial kinases involved in cancer progression is a promising area of research. Pyrazolo pyrimidine derivatives have emerged as potential candidates for this purpose. This study aims to synthesize pyrazolo pyrimidine derivatives (5a-5r), evaluate their molecular docking against key kinases, and assess their anticancer activity. The synthesis involved a multi-step procedure starting with the cyclization of 6-amino-2- methylpyrimidin-4(3H)-one (1) to form 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-ol (2). This was followed by chlorination to yield 4-chloro-2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine (3) and nucleophilic substitution to produce 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-amine (4). The final derivatives (5a-5r) were synthesized through amide bond formation with various carboxylic acids using DCC and DMAP. Structural elucidation was confirmed via NMR, mass spectrometry, and HRMS. Molecular docking studies were conducted against Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), and cyclin-dependent kinase 4 (CDK4). Anticancer activity was evaluated against MCF-7, SET-2, and HCT-116 cell lines. Structural elucidation confirmed the successful synthesis of the derivatives. Molecular docking studies revealed promising binding affinities for selected derivatives, particularly those with heterocyclic substitutions. Anticancer activity evaluation showed diverse potency profiles, with several derivatives demonstrating IC50 values comparable to the reference drug, doxorubicin. Derivatives featuring nitro and heterocyclic moieties exhibited significant anticancer activity. The synthesized pyrazolo pyrimidine derivatives showed potential as lead compounds for further development due to their promising binding affinities and significant anticancer activity, particularly those with nitro and heterocyclic moieties.

Spatio-temporal localization of P21-activated kinase in endometrial cancer.

Endometrial cancer is the sixth most common gynecologic cancer, and has been reported as a malignancy arising due to the idiopathic effects of certain anticancer agents. Tamoxifen is the drug of choice in ER-positive breast cancer, and several studies have shown better disease-free survival in these patients. However, the long-term usage of tamoxifen has been associated with resistance and risk for endometrial malignancy. A direct mechanistic basis for tamoxifen-induced endometrial tumorigenesis is still unclear. Hyperactivation of PAK1 in endometrial cancer correlates with poor overall survival. The present study demonstrates that tamoxifen treatment induces nuclear localization of PAK1 in endometrial carcinoma cells. This nuclear transit is mediated through JAK2 phosphorylation of PAK1 and binding of β-PIX. In addition, a computational approach involving molecular modeling and simulation of phosphorylated and unphosphorylated forms of PAK1 was used to elucidate the dynamics of nuclear localization. Thus, PAK1 phosphorylation by JAK2 is a prerequisite for its nuclear localization and its tumorigenic effects on endometrial cancer cells.

Case report: High grade serous fallopian tube carcinoma with rare NRG1 gene fusion presenting as widespread peritoneal carcinomatosis

The discovery of gene fusions involving Neuregulin-1 (NRG1) within solid tumors has important therapeutic implications, as they are being actively explored as targets for emerging ERBB/ERBB2/ERBB3-directed anti-cancer agents. NRG1 fusions are very uncommon across all tumor types and are infrequently documented in the medical literature. We report a female patient presenting with widespread peritoneal carcinomatosis diagnosed as high grade serous fallopian tube carcinoma, which harbored a previously undescribed MYH10::NRG1 fusion. Moreover, we queried the whole transcriptome sequencing results of neoplasms analyzed by a commercial laboratory (Caris Life Sciences) to determine the overall incidence of NRG1 fusions in carcinomas of the ovary, fallopian tube, and peritoneum (0.18%). Twenty-five additional tumors were found to demonstrate NRG1 fusions, including 20 new genes partners that had not been previously identified in gynecologic carcinomas. Overall, NRG1 fusion events are rare in ovarian, fallopian tube, and primary peritoneal carcinomas, but they may carry diagnostic significance in the context of borderline/low grade serous tumors, which demonstrated exclusively CLU::NRG1 fusions, and could have important predictive implications for response to ERBB/ERBB2/ERBB3-directed therapies.

Development of Small Molecular Hyper-activators of Human Caseinolytic Peptidase P (hClpP) with a [1,8]-Naphthyridinone Scaffold as Novel Anti-cancer Agents.

Based on a clinical staged small molecular hClpP activator ONC201, a class of novel hClpP agonists with a [1,8]naphthyridinone scaffold were designed, synthesized and evaluated in a series of biochemical and biological assays. Mechanism studies for the representative compound F20 indicated that it can potently bind to and activate hClpP, efficiently promote the degradation of hClpP substrates, robustly induce ATF4/CHOP regulated integrated stress responses, strongly inhibit cell growth and effectively induce apoptosis in a subset of cancer cell lines. F20 showed good PK profiles when dosed by intravenous injection and exhibited moderate oral bioavailability in mice.

Construction and validation of a prognostic signature based on microvascular invasion and immune-related genes in hepatocellular carcinoma

Background: Microvascular invasion (MVI) is an independent risk factor of poor prognosis in hepatocellular carcinoma (HCC) and can be used to guide the diagnosis and treatment of HCC. The immune system serves as an integral role in the incidence and progression of HCC. However, the molecular biology correlation between MVI and tumor immunity and the value of combining the two parameters to predict patient prognosis and HCC response to treatment remain to be evaluated. Results: In this study, we used univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox analysis to establish the MVI and immune-related gene index (MIRGPI) including eight genes. We demonstrated that the MIRGPI was an independent risk factor in predicting the prognosis of HCC. Subsequently, our research established a nomogram model combining pathologic characteristics and verified its good clinical application value. In addition, our study found that the TP53 gene had a higher mutation frequency and a lower degree of immune infiltration in the high-risk group. The low-risk group had higher sensitivity to immunotherapy, sorafenib, and TACE treatment, and the high-risk group had higher sensitivity to common chemotherapeutic agents. Finally, SEMA3C was found to facilitate the proliferation, migration and invasive ability of HCC by in vitro and in vivo experiments, and its mechanism may be associated with the activation of the NF-Κb/EMT signaling pathway. Conclusions: In summary, the MIRGPI signature we developed is a reliable marker for the prediction of prognosis and treatment response, and is important for the prognostic assessment and individualized treatment of HCC.

Novel Schiff bases of quinolin-4(1h)-one: Synthesis, antiproliferative evaluation, apoptosis, cell cycle, autophagy and molecular docking studies in human colon cancer cells

A green and efficient ultrasound-mediated protocol was developed for the synthesis of a series of novel Schiff bases derived from quinoline-4-one. The synthetic strategy involved the condensation of 4-oxo-1,4-dihydro-quinoline-3-carboxaldehyde with diverse anilines and heteroaryl amines. The synthesized compounds were characterized using spectroscopic techniques. A comprehensive in vitro cytotoxicity evaluation against HCT116 and HT-29 human colon cancer cell lines revealed that several compounds exhibited potent anticancer activity. Notably, compounds 3c and 3e demonstrated superior cytotoxicity compared to the clinical standard doxorubicin. Mechanistic studies indicated that these lead compounds induced apoptosis, necrosis, and cell cycle arrest at G1 and G2 phases. Furthermore, autophagy induction was observed. In silico ADMET predictions support the potential of compounds 3c and 3e as promising anticancer drug candidates. The molecular docking studies revealed that the Schiff bases 3c and 3e displayed good interaction with VEGFR-2 receptor. These findings underscore the quinoline-4-one scaffold as a valuable template for the development of novel antitumor agents.