Impact of KRAS G12C mutation on the efficacy of chemoradiotherapy in patients with unresectable stage II or III non-small cell lung cancer

BackgroundApproximately 35% of patients with non-small cell lung cancer (NSCLC) have locally advanced disease. Despite treatment with chemoradiotherapy (CRT) and consolidation immunotherapy, overall survival remains below 50% at 5 years. Kirsten rat sarcoma (KRAS) mutations (KRASms) are the most common lung cancer mutations, affecting 25% of NSCLC cases. KRASm can cause radioresistance, and several targeted KRASm therapies have been developed, mainly targeting the KRAS G12C mutation (KRASm G12C), but the impact of KRASm G12C on the efficacy of CRT for locally advanced NSCLC remains unclear.MethodsWe conducted a multicenter retrospective study of unresectable stage II or III NSCLC treated with CRT in four French hospitals between January 2014 and December 2022. The primary endpoint was the objective response rate (ORR) for KRASm G12C compared to KRAS wild-type (KRASwt). The main secondary objectives were to assess the difference in ORR between KRASm and KRASwt, and the difference in disease control rate (DCR), overall survival (OS), progression-free survival (PFS), time to local relapse (TTLR), and time to distant relapse (TTDR) according to KRASm status.ResultsOur study included 267 patients, and 73 patients had KRASm (27.3%). The most common KRASm was KRASm G12C (n = 42). Tumors were lung adenocarcinoma in 91% (n = 244) of patients. Two hundred (75%) patients were treated with concomitant CRT. There was no difference between KRASm G12C and KRASwt patients in terms of ORR (48% vs. 49%; p = 0.961) and DCR (86% vs. 84%; p = 0.903), nor when comparing KRASm to KRASwt in terms of OS (p = 0.64), PFS (p = 0.28), TTLR (p = 0.26), and TTDR (p = 0.3), with no impact after adjustment for durvalumab.ConclusionKRAS G12C mutation compared to KRAS wild-type did not affect response to chemoradiotherapy, and KRAS mutations compared to KRAS wild-type were not associated with worse survival in unresectable stage II or III NSCLC treated with chemoradiotherapy

SIRNA-Directed In Vivo Silencing of Androgen Receptor Inhibits the Growth of Castration-Resistant Prostate Carcinomas

BACKGROUND: Prostate carcinomas are initially dependent on androgens, and castration or androgen antagonists inhibit their growth. After some time though, tumors become resistant and recur with a poor prognosis. The majority of resistant tumors still expresses a functional androgen receptor (AR), frequently amplified or mutated. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that AR is not only expressed, but is still a key therapeutic target in advanced carcinomas, we injected siRNA targeting AR into mice bearing exponentially growing castration-resistant tumors. Quantification of siRNA into tumors and mouse tissues demonstrated their efficient uptake. This uptake silenced AR in the prostate, testes and tumors. AR silencing in tumors strongly inhibited their growth, and importantly, also markedly repressed the VEGF production and angiogenesis. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that carcinomas resistant to hormonal manipulations still depend on the expression of the androgen receptor for their development in vivo. The siRNA-directed silencing of AR, which allows targeting overexpressed as well as mutated isoforms, triggers a strong antitumoral and antiangiogenic effect. siRNA-directed silencing of this key gene in advanced and resistant prostate tumors opens promising new therapeutic perspectives and tools

Evaluation of the Effect of a Single Intra-articular Injection of Allogeneic Neonatal Mesenchymal Stromal Cells Compared to Oral Non-Steroidal Anti-inflammatory Treatment on the Postoperative Musculoskeletal Status and Gait of Dogs over a 6-Month Period after Tibial Plateau Leveling Osteotomy: A Pilot Study

ObjectiveCompare the clinical and pressure walkway gait evolution of dogs after a tibial plateau leveling osteotomy (TPLO) for a cranial cruciate ligament rupture (CrCLR) and treatment with either a 1-month course of non-steroidal anti-inflammatory drugs (NSAIDs) or a single postoperative intra-articular (IA) injection of allogeneic neonatal mesenchymal stromal cells (MSCs).Study designProspective, double-blinded, randomized, controlled, monocentric clinical study.AnimalsSixteen client-owned dogs.Materials and methodsDogs with unilateral CrCLR confirmed by arthroscopy were included. Allogeneic neonatal canine MSCs were obtained from fetal adnexa retrieved after C-section performed on healthy pregnant bitches. The dogs were randomly allocated to either the “MSCs group,” receiving an IA injection of MSCs after TPLO, followed by placebo for 1 month, or the “NSAIDs group,” receiving IA equivalent volume of MSCs vehicle after TPLO, followed by oral NSAID for 1 month. One of the three blinded evaluators assessed the dogs in each group before and after surgery (1, 3, and 6 months). Clinical score and gait and bone healing process were assessed. The data were statistically compared between the two groups for pre- and postoperative evaluations.ResultsFourteen dogs (nine in the MSCs group, five in the NSAIDs group) completed the present study. No significant difference was observed between the groups preoperatively. No local or systemic adverse effect was observed after MSCs injection at any time point considered. At 1 month after surgery, bone healing scores were significantly higher in the MSCs group. At 1, 3, and 6 months after surgery, no significant difference was observed between the two groups for clinical scores and gait evaluation.ConclusionA single IA injection of allogeneic neonatal MSCs could be a safe and valuable postoperative alternative to NSAIDs for dogs requiring TPLO surgery, particularly for dogs intolerant to this class of drugs

Genetics of emotional reactivity in bipolar disorders

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Supplementary Figure 5 from Thrombospondin-1 Triggers Cell Migration and Development of Advanced Prostate Tumors

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