To investigate the gene mutations in tumor tissues of patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL), and analyze its relationship with clinical features and prognosis.

A total of 31 newly diagnosed PGI-DLBCL patients treated in the People's Hospital of Xinjiang Uygur Autonomous Region from March 2009 to March 2021 and 81 nodal DLBCL patients matching gender, age, and ethnic group during the same period were collected. The sequencing of patients' tumor tissues were targeted by a panel of 475 lymphoma-related genes. The differences of mutational profiles and biological signaling pathway between PGI-DLBCL and nodal DLBCL were analyzed. The relationship between mutated genes and age, lactate dehydrogenase (LDH) level, Lugano stage, IPI score, cell origin typing, overall survival (OS) and progression-free survival (PFS) of PGI-DLBCL patients were investigated.

A total of 50 high frequency mutated genes (number of gene mutations ≥3, mutation frequency ≥10%) were detected in PGI-DLBCL. The mutation rates of GNA13, EZH2, and FBXO11 genes in PGI-DLBCL patients were significantly higher than those in nodal DLBCL patients. BTG2 and CD79B mutations were closely associated with high-risk of IPI scores and the elderly. MYD88 mutations were more easily detected in the elderly patients. And mutations of the P2RY8 and KMT2D gene were related to early stage of the disease and high LDH, respectively. Only GNA13 mutations were detected in GCB subtype, while KMT2C, IRF4 and ID3 mutations were most frequent in non-GCB subtype. Further studies found that patients with CARD11, FANCA and ID3 mutations showed lower 5-year OS rate (all P < 0.05), while ID3 and NFKBIE mutations were associated with poorer PFS (both P < 0.05). The results of multivariate survival analysis suggested that ID3 mutation was an independent adverse prognostic factor for OS (HR=6.213, 95%CI : 1.215-31.770, P =0.028) and PFS (HR=0.060, 95%CI : 0.012-0.307, P =0.001) in PGI-DLBCL patients.

PGI-DLBCL has a characteristic gene mutation spectrum, which is different from the molecular mechanism of nodal DLBCL development. ID3 gene mutation is an independent prognostic factor for predicting poor prognosis of PGI-DLBCL.

To investigate whether daporinad (APO866), a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, can potently kill Philadelphia chromosome-positive (Ph⁺) acute lymphoblastic leukemia (ALL) cells via an intrinsic apoptosis-independent pathway.

Ph⁺ ALL SUP-B15 cells were treated with varying concentrations of APO866. After treatment, cell viability was measured via Deep Blue assay, while apoptosis and cell death were determined by Annexin V/7-AAD double staining. Cleavage of Caspase-3 and PARP1 was detected by Western blot, and rescue experiments with the pan-caspase inhibitor Z-VAD-FMK were performed to rule out apoptotic involvement. To determine whether APO866-induced cell killing depends on nicotinamide adenine dinucleotide (NAD⁺) depletion, the NAD⁺ precursor nicotinic acid (NA) was supplemented and NAD⁺consuming enzyme CD38 was knocked down. Furthermore, TP53 knockout and BAX/BAK double-knockout SUP-B15 cell models were used to verify that the cytotoxic effect of APO866 is independent of the intrinsic apoptotic pathway.

Both Deep Blue and Annexin V/7-AAD staining assays showed that APO866 effectively kills SUP-B15 cells. This cytotoxic effect could not be abrogated by the pan-caspase inhibitor Z-VAD-FMK, and no cleavage of Caspase-3 and PARP1 was detected during the process of cell killing. Intracellular NAD⁺ levels were markedly decreased following APO866 treatment, and supplementation with NA or knockout of CD38 partially reversed such cytotoxicity. Neither TP53 knockout nor BAX/BAK double knockout impaired the killing efficiency of APO866 against SUP-B15 cells.

APO866 could potently induce SUP-B15 cell death by depleting intracellular NAD⁺ levels, a process that lacks canonical features of the intrinsic apoptotic pathway. Moreover, its cytotoxicity persists even with deficiencies in key regulators of this pathway, indicating a mechanism of action that is independent of intrinsic apoptosis.

We reported LINGO1 as a potential marker on Ewing sarcoma cells that could enable targeted drug delivery, improving treatment effectiveness while reducing side effects.

Protein neddylation is an evolutionarily conserved posttranslational modification that conjugates NEDD8 to its substrate, catalyzed by an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase. Neddylation is essential for cellular homeostasis, and its dysregulation has been implicated in diverse human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, making the process a promising therapeutic target. In this Review, we systematically summarize the biochemical activity and biological functions of neddylation; its alterations in human diseases, particularly in cancers; and its validation as an attractive target for cancer therapy. We provide an overview on the discovery of neddylation inhibitors and the progress of MLN4924 (pevonedistat) and TAS4464 clinical trials and critically evaluate the core challenges and emerging opportunities for therapeutic strategies targeting neddylation.

Fibroblast growth factor receptor 3 (FGFR3) is one of the most frequently altered genes in bladder cancer, primarily through activating mutations that drive oncogenesis and are enriched in luminal tumors. However, the underlying gene regulatory network (GRN) remains poorly characterized. Here, we constructed an FGFR3-mutated GRN using a bottom-up bioinformatics approach, integrating transcriptomic data from bladder cancer cell lines, FGFR3-mutated tumors, and FGFR3 perturbation experiments in human and mouse models. Using publicly available CRISPR/Cas9 screening data, we identified transcription factors from this GRN that regulate the viability of FGFR3-mutated cells, with a focus on p63 (TP63). We showed that FGFR3 activation upregulates p63 in patient-derived xenografts and cell lines, while single-cell RNA sequencing revealed heterogeneous p63 activation associated with basal differentiation. Functional studies, including TP63 knockdown in FGFR3-dependent in vitro and in vivo models and RNA-seq along with p63 ChIP-seq, demonstrated that p63 directly promotes cell proliferation and migration and uncovered a positive feedback loop between FGFR3 and p63. Together, these findings support p63 as a protumorigenic regulator in FGFR3-mutated tumors despite their luminal differentiation and provide a detailed FGFR3-driven GRN, offering insights into FGFR3-induced oncogenic dependency and potential strategies to circumvent resistance to FGFR inhibitors.

BRAF inhibitors have advanced treatment for patients with BRAF-altered high and low-grade glioma (HGG and LGG, respectively). Clinically-available therapies are effective but require selection by mutation type and careful, proactive toxicity management to maximize patient quality of life and treatment duration. While pediatric LGG patients often experience durable responses, adults with LGG and patients with HGG frequently develop treatment resistance and disease progression while on treatment. Strategies to prevent or overcome resistant disease are under active preclinical and clinical investigation. This review serves as a primer to BRAF-altered therapy in glioma, outlines best practices for using available BRAF inhibitors, and highlights emerging therapeutic approaches aimed at improving outcomes in resistant disease. It serves as a forward-looking, practical guide for clinicians treating patients with BRAF-altered glioma.Article highlightsBRAF inhibitors are effective in both pediatric and adult low- and high-grade gliomas (LGG and HGG), but treatment should be tailored to the specific BRAF alteration (Table 1).Dabrafenib combined with trametinib is FDA-approved for BRAF V600E-mutant gliomas, while tovorafenib is approved for pediatric LGGs harboring BRAF V600 mutations or BRAF fusions.Proactive management, including anticipatory guidance and dose reduction for some patients, is essential to mitigate toxicity and avoid treatment interruptions.Tumor progression can occur during treatment interruptions or drug cessation; however, some patients may respond to BRAF inhibitor rechallenge.Emerging strategies focus on combination with other therapies including radiation, autophagy inhibitors, additional targeted agents, and others to overcome acquired resistance.Next-generation BRAF inhibitors-including paradox breakers, dimer disruptors, and protein degraders-are under clinical investigation (Table 2).

Denosumab, a monoclonal antibody (mAb) targeting receptor activator of nuclear factor-κB ligand (RANKL), is commonly used in managing metabolic bone diseases and giant cell tumors (GCTs) of bone. Growing evidence suggests that RANKL inhibition may influence cardiovascular health by impacting endothelial function, inflammatory pathways, vascular smooth muscle cell behavior, and systemic calcium regulation. We report a case of a 48-year-old Caribbean-South Asian man with recurrent GCTs who received three subcutaneous doses of denosumab and soon thereafter developed an anterior ST-elevation acute coronary syndrome (STE-ACS). The patient had no traditional cardiometabolic risk factors. Coronary angiography revealed thrombotic occlusion of the proximal left anterior descending artery (LAD), which was successfully treated with primary percutaneous coronary intervention (PPCI) and guideline-directed medical therapy (GDMT). Given the lack of modifiable risk factors, a significant family history, and biologically plausible mechanisms linking RANKL inhibition to atherothrombotic events, a denosumab-associated myocardial infarction was considered the most probable cause.

Osteoid osteoma (OO) is one of the most common benign bone tumors and can occur in various skeletal structures. It often presents with symptoms, such as nocturnal pain, which may mimic constitutional conditions, and it is characterized by a distinct radiological appearance that allows for easy differentiation from other lesions. Over the past decade, numerous studies have evaluated the efficacy of both surgical and radiological interventions for treating OO. While several treatment methods are available, each carries distinct advantages and disadvantages. This study aims to report the outcomes of surgical resection for ocular (OO) lesions.

A total of 29 patients were enrolled in this study. Of these, 14 patients chose surgical resection as their primary treatment, while 15 patients opted for radiofrequency (RF) ablation. Three patients who exhibited a lack of response to RF ablation subsequently underwent surgical resection, bringing the total number of patients in the surgery group to 17. This study specifically focused on lesions located in the peritrochanteric region. For lesions that recurred at the same site, whether due to recurrence or lack of response to initial treatment, the same treatment modality used in the first instance was applied.

Among the 17 individuals who initially underwent surgical resection, 11 had extracapsular lesions, and 6 had intracapsular lesions. All patients who underwent surgical resection became symptom-free, and no complications were observed during the procedure. Furthermore, all cases that received surgical resection were confirmed through pathological assessment. Additionally, three patients with extracapsular lesions had previously been treated with RF thermoablation but had not fully recovered from their symptoms, necessitating surgical resection.

Based on the results, although RF is the first choice of treatment for OO, surgical resection could be a vital and safe option for peritrochanteric OO.

FTA is a new FT derivative developed by our team by modifying FT with aspirin, and it has been shown to boost anti-breast cancer activity.

To significantly enhance the anti-breast cancer efficacy and biosafety of FTA, this study employed Poloxamer F127 and Poloxamer F68 to construct a composite carrier system, successfully prepared FTA-loaded liposomes (FTA-LN) and their thermosensitive gel formulation (FTA-LN-TSG), with systematic in vitro and in vivo assessments performed.

Simultaneously, FTA-LN exhibited an average particle size of 131.03 ± 4.35 nm, polydispersity index (PDI) of 0.265 ± 0.003, zeta potential of -21.46 ± 2.49 mV, and encapsulation efficiency of 94.55 ± 1.10%. FTA-LN followed first-order kinetics, with a cumulative release rate of 68.48% within 4 hours. Conversely, FTA-LN-TSG displayed sustained release characteristics consistent with Higuchi kinetics, reaching a cumulative release of 52.56% at 8 hour. In vitro efficacy evaluation revealed that FTA-LN-TSG exhibited significantly superior inhibitory effects against breast cancer cells compared to FTA (24 h and 48 h inhibition rates: 2.72- and 5.02-fold of FTA; cell migration rate: 37% of FTA). Furthermore, FTA-LN-TSG demonstrated significant differences in inducing apoptosis and cell cycle arrest (Total apoptosis rate of FTA: 25.74, total apoptosis rate of FTA-LN-TSG: 48.84%). Pharmacokinetic results indicated that FTA-LN-TSG exhibited a 3.5-fold prolongation in half-life (t_1/2), and a 6-fold extension in time to peak concentration (T_max) compared with FTA group. In tumor model mice, The FTA-LN-TSG injected beside the tumor was achieved a tumor inhibition rate of 64.42 ± 5.60% (1.82-fold of the FTA group, 1.45-fold of the S-1 group) with favorable biosafety.

In summary, as a novel drug delivery system, FTA-LN-TSG may represent a promising option for breast cancer therapy.

Granular Cell Tumour (GCT) is a rare and painless benign soft tissue neoplasm of Schwann cell derivative. It is a slow-growing, firm, and solitary nodule usually smaller than 3 cm in diameter that frequently occurs in females between 4^th-6^th decade of life. We aim to describe the clinical presentation of the granular cell tumour (GCT) and the histopathological tools used to achieve its definitive diagnosis. We present a case of GCT of the tongue in a 46-year old female who presented with a year-old painless swelling on the tongue in our dental clinic. There was associated tenderness but disturbed deglutition. Clinical examination revealed a firm swelling in the right anterior two-thirds. Differential diagnoses made were chondroma, fibroma, and rhabdomyoma. Excisional biopsy for histopathological and immunohistochemical evaluation was diagnostic of GCT. GCT may be confused with other oral lesions clinically, but the use of histopathological and immunohistochemical tools confirmed its diagnosis.