Indole moiety is well-known as a superlative framework in many natural products and synthetic pharmaceuticals. Herein, we report an efficient procedure to synthesize a series of functionalized 2-methyl-1H-indole-3-carboxylate derivatives from commercially available anilines properly functionalized by different electron-withdrawing and -donating groups through a palladium-catalyzed intramolecular oxidative coupling. The conversion of a variety of enamines into the relevant indole was optimized by exposing the neat mixture of reactants to microwave irradiation, obtaining the desired products in excellent yields and high regioselectivity. The synthesized compounds were confirmed by ¹H and ¹³C spectroscopic means as well as by high-resolution mass spectrometry.

Glioblastoma (GBM), a highly malignant brain tumor, arises within a complex microenvironment that plays a critical role in facilitating tumor progression, ensuring survival, and enabling immune evasion, ultimately contributing to therapeutic resistance. Cancer-associated fibrosis is increasingly recognized as a key factor in the tumor pathophysiology, particularly in extracranial cancers, and reported therapeutic strategies in several cancers consist of the current use of the standard-of-care treatment combined with anti-fibrotic drugs. However, it remains unclear how the fibrotic changes associated with the GBM microenvironment contribute to the transformation of GBM from a chemosensitive state to a chemoresistant one. Here, we developed an in vitro model that mimics a fibrosis-like mechanism using the U-87MG GBM cell line. To achieve this, we identified the optimal experimental conditions (i.e., U-87MG cultured in serum-deprivation medium in the presence of recombinant TGF-B1 at 5 ng/mL for 72 h) that effectively induced fibrosis, as suggested by the counter-regulated expression of E- and N-cadherin and sustained levels of α-SMA and collagen I. As expected, U-87MG fibrotic cells were demonstrated to be more resistant to TMZ (predicted EC₅₀ = 35 µM) as compared to the non-fibrotic counterpart (EC₅₀ not achieved here; predicted EC₅₀ = 351 µM). Accordingly, the anti-fibrotic uPAcyclin—a new derivative cyclic compound inspired as a A6 decapeptide drug—showed a significant cytotoxic effect, sensitizing resistant U-87MG fibrotic cells to TMZ. This highlights that targeting fibrosis may help to overcome TMZ resistance in GBM.

Introduction Hepatitis B reactivation is a potentially life-threatening complication of immunosuppression in patients with serological evidence of current or past exposure to Hepatitis B Virus (HBV). Rituximab is a widely used B-cell depleting medication widely used to treat haematological cancers and rheumatological disease. The British Society of Rheumatology, British Society of Haematology and the European Association of Study of the Liver guidelines all recommend patients must all be assessed for HBV before rituximab initiation. This is a single-centre five-year retrospective review of our Trusts Rituximab prescribing and HBV screening. Methods We included all adult patients receiving rituximab between 1st October 2015 and 30th September 2020 at our Trust. Patients were identified using hospital pharmacy Rituximab prescribing logs. Indications, HBV screening bloods and outcomes were collected using electronic records (Allscripts, Telepath). Patients with incomplete or missing records were excluded. Results A total of 870 patients were included in this study. Seventy percent (n = 611) were for oncohaematological indications and 30% (n =258) for rheumatological. There were 606 patients newly initiated on Rituximab during the study period (Table 1). HBV screening improved from 62% to 94% during the study period. Newly initiated patients on Rituximab (1/10/2015 to 30/09/2020) Eighteen patients were positive or equivocal for Hepatitis B core antibody and 1 for Hepatitis B Surface Antigen. Four patients were prescribed lamivudine prophylaxis, 2 Tenofovir and 1 entecavir. The other patients had no treatment or monitoring. Only 1 case was on adequate length of prophylaxis after being referred to the hepatobiliary service. There were no cases of hepatitis B reactivation in the study period. Conclusions A significant number of patients are not being screened for Hepatitis B core antibodies, despite local education programmes in 2016 and 2018. Low background rates of HBV in the local community may account for low levels of previous and current HBV infections. Education of prescribers, modifications to the initiation pharmacy checklists and simplification of computer request process should help to improve Hepatitis B screening in our patients and avoid potentially life-threatening reactivation.