强生

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease characterized by progressive joint involvement. The disease is associated with reduced health-related quality of life, functional ability, work productivity, and daily activity, in addition to pain, fatigue, and inflammation-induced structural damage. RA emerges through a complex interplay of multiple factors, including the release of inflammatory cytokines. One such cytokine is tumor necrosis factor (TNF), which is inhibited by golimumab, an approved treatment for the disease. Golimumab is produced using a recombinant cell line that originated from genetically modified mice immunized with human TNF. This narrative review presents the efficacy and safety outcomes from the golimumab pivotal randomized controlled trials (RCTs) that evaluated the subcutaneous and intravenous formulations. Across the RCTs, treatment was associated with an American College of Rheumatology ≥ 20

Most novel anti-cancer therapies involve combining multiple immuno-oncology and/or targeted drugs. The historical paradigm of exploring combination regimens only after approval of the individual drugs is changing rapidly leading to clinical development of ‘novel-novel’ combination therapies consisting of at least two investigational agents. Initiating those combination efforts early in development is an important strategy to accelerate evolution of the standard of care for high unmet need cancer indications. However, there are specific challenges associated with such development programs, with additional complexity if more than one company is involved. Representing a consortium of major oncology drug developers, we critically discuss those challenges and suggest potential solutions to encourage the development of novel multi-company combination therapies for solid and hematological tumors. The areas covered include trial strategies for early and late clinical development, including dose/regimen optimization, statistical considerations, optimizing safety profiles, dose modification approaches, contribution of components, choice of standard of care backbone and comparator regimens as well as regulatory strategies.

Hexosylceramides (HexCers) and hexosylsphingosines (HexSphs) are bioactive glycosphingolipids implicated in neurodegenerative diseases such as Parkinson’s disease (PD), Gaucher disease, and Krabbe disease. Despite their biological relevance, no existing method enables the simultaneous quantification of both HexCers and HexSphs across multiple biological matrices. In this study, we report the development, validation, and application of a novel LC-MS/MS method capable of quantifying 11 lipid species, including glucosylceramides, galactosylceramides, glucosylsphingosine, galactosylsphingosine, ceramide, lactosylceramide, and sphingosine, in a single chromatographic run. The method integrates optimized liquid-liquid extraction and solid-phase extraction protocols, achieving high recovery and selectivity. Validation was performed according to internal and external (e.g., ICH and FDA guidelines) international guidelines, demonstrating excellent sensitivity, linearity (R2 > 0.99), precision (cv < 15

This paper investigates the interplay of socio-economic factors, vaccination, and the dynamics of COVID-19 across New Jersey (NJ), New York State, California, and Florida. Utilizing a diverse set of explanatory variables, including those related to food and health access, geographic factors, demographic attributes, and vaccine-related variables, we employ statistical models to discern patterns and trends. Our investigation delves into the influence of socio-economic factors on COVID-19 cases and deaths, considering variations across different periods. We employ two distinct models, Univariate modeling and linear model with backward selection, to gain comprehensive insights into the evolving dynamics of the pandemic. Our analysis of New Jersey data unveils notable trends, particularly in vaccination effectiveness. Our findings demonstrate that while vaccinations significantly lower COVID-19 mortality rates, they may not consistently reduce case numbers. Expanding our investigation to other states underscores regional disparities, underscoring the necessity for customized public health approaches. The results imply the relationship between socio-economic dynamics and vaccination campaigns, guiding targeted interventions to alleviate the pandemic’s repercussions effectively.

BACKGROUND:In CARTITUDE-4, a single infusion of ciltacabtagene autoleucel (cilta-cel) significantly prolonged progression-free survival in patients with lenalidomide-refractory multiple myeloma. We report updated overall survival and longer-term efficacy and safety outcomes. METHODS:CARTITUDE-4 is an open-label, multicentre, randomised, phase 3 trial at 81 hospital sites in the USA, Europe, Asia, and Australia. Eligible patients were adults (aged >18 years) with lenalidomide-refractory multiple myeloma, with one to three previous treatment lines, including a proteasome inhibitor and an immunomodulatory drug, and an Eastern Cooperative Oncology Group performance status of 0 or 1. After the trial started, the threshold defining measurable disease was lowered to 0·5 g/dL from 1·0 g/dL serum monoclonal paraprotein on July 2, 2021, to increase trial access. Patients were randomly assigned (1:1) via a computerised algorithm and balanced with permuted blocks, with stratification by physician's choice of pomalidomide-bortezomib-dexamethasone versus daratumumab-pomalidomide-dexamethasone, International Staging System stage, and number of previous treatment lines. Patients were assigned to cilta-cel (apheresis, bridging therapy [at least one pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone cycle], lymphodepletion, then cilta-cel infusion [0·75 × 106 CAR T cells per kg]) or standard of care (pomalidomide-bortezomib-dexamethasone [21-day cycles: 4 mg/day oral pomalidomide on days 1-14; 1·3 mg/m2 subcutaneous bortezomib twice a week for 2 weeks for eight cycles, then once a week for 2 weeks per cycle; 20 mg or, if aged >75 years, 10 mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 for eight cycles, then days 1, 2, 8, and 9 per cycle] or daratumumab-pomalidomide-dexamethasone [28-day cycles: 1800 mg subcutaneous daratumumab weekly for 2 cycles, every 2 weeks for four cycles, then every 4 weeks; 4 mg/day oral pomalidomide on days 1-21; 40 mg/week or, if aged >75 years, 20 mg/week oral or intravenous dexamethasone]). The primary endpoint was progression-free survival, previously published. In this Article, we report a prespecified second interim analysis of overall survival and an updated analysis of progression-free survival in the intention-to-treat population. This trial was registered at ClinicalTrials.gov (NCT04181827) and is ongoing. FINDINGS:Patients were randomly assigned between July 10, 2020, and Nov 17, 2021, to receive cilta-cel (n=208) or standard of care (n=211). At a median follow-up of 33·6 months (IQR 20·3-35·0), median progression-free survival was not reached (95% CI 34·5 months-not evaluable) in the cilta-cel group versus 11·8 months (9·7-14·0) in the standard-of-care group (HR 0·29 [95% CI 0·22-0·39]). Median overall survival was not reached (95% CI not evaluable) with cilta-cel versus not reached (37·7 months-not evaluable) with standard of care (HR 0·55 [95% CI 0·39-0·79]; p=0·0009). 30 (14%) of 208 patients in the cilta-cel group and 77 (37%) of 208 in the standard-of-care group had maximum grade 3 treatment-emergent adverse events, most commonly anaemia (72 [35%]) in the cilta-cel group and neutropenia (59 [28%]) in the standard-of-care group. Rates of maximum grade 4 treatment-emergent adverse events were 156 (75%) with cilta-cel and 116 (56%) with standard of care, most commonly neutropenia (152 [73%] with cilta-cel and 112 [54%] with standard of care). Serious treatment-emergent adverse events occurred in 98 (47%) patients in each group. Deaths in the safety population occurred in 50 (24%) in the cilta-cel group and 82 (39%) in the standard-of-care group, including due to treatment-related adverse events in six (3%; four due to infection) in the cilta-cel group and five (2%; all due to infection) in the standard-of-care group. INTERPRETATION:The significantly improved overall survival and patient-reported measures in CARTITUDE-4 reinforce the use of cilta-cel in treating relapsed or refractory multiple myeloma as early as after first relapse. FUNDING:Johnson & Johnson, Legend Biotech USA.