Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for ...relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.
Summary
Background
The nuclear factor‐κB (NF‐κB) pathway is a key mediator of inflammation; however, few studies have examined the direct effects of NF‐κB inhibition on the skin.
Objectives
To ...investigate NF‐κB activity in cultured human fibroblasts and to investigate the effects of 4‐hexyl‐1,3‐phenylenediol (an NF‐κB inhibitor) on elastin and collagen gene expression in vitro and on the clinical appearance of photodamaged skin.
Methods
The amount and activity of NF‐κB in human fibroblasts obtained from donors (17–78 years old) was measured after transfection with a NF‐κB reporter and a luciferase promoter system. The expression of extracellular matrix (ECM) genes was determined using quantitative polymerase chain reaction. Women with moderate skin photodamage were randomized to daily treatment with a topical lotion containing 4‐hexyl‐1,3‐phenylenediol (n = 30) or vehicle (n = 29) for 8 weeks, with clinical assessments at baseline and weeks 2, 4 and 8.
Results
Fibroblasts obtained from donors older than 50 years had higher NF‐κB activity compared with cells from younger donors; inhibition of the NF‐κB pathway with 4‐hexyl‐1,3‐phenylenediol enhanced the expression of ECM genes. In women, treatment for 8 weeks with 4‐hexyl‐1,3‐phenylenediol significantly improved crow's feet fine lines, cheek wrinkles, age spots, mottled pigmentation and radiance compared with both the vehicle and baseline. Furthermore, treatment with 4‐hexyl‐1,3‐phenylenediol resulted in a twofold greater clinical improvement in overall photodamage compared with the vehicle group.
Conclusions
Inhibition of the proinflammatory NF‐κB pathway resulted in increased expression of ECM proteins in vitro and significant clinical improvement in photodamaged skin.
What's already known about this topic?
The nuclear factor‐κB (NF‐κB) pathway is a key mediator of inflammation and may be involved in skin ageing.
What does this study add?
Cultured fibroblasts from donors ≥ 50 years old had higher levels of NF‐κB activity than fibroblasts obtained from donors < 50 years old.
In humans, treatment with an NF‐κB inhibitor significantly improved clinical parameters in photodamaged skin.
These findings support the hypothesis that NF‐κB activation may accelerate the skin ageing process.
Trisomy 18 and Smith–Lemli–Opitz syndrome are two polymalformative conditions in which a cholesterol defect has been noted. When they occur prenatally, they are associated with a decreased maternal ...unconjugated estriol (uE3) level. Cholesterol plays an essential role in the Sonic Hedgehog pathway, allowing Shh protein maturation leading to its maximal activity. Many malformations in these two syndromes occur in Shh dependent tissues. We thus sought to assess whether a cholesterol defect could affect the Shh pathway and explain some of the observed malformations.
We selected 14 cases of trisomy 18 and 3 cases of SLO in which the maternal uE3 level was decreased and reported malformations were observed after fetopathological examination. We correlated the number of malformations with maternal uE3 level. We then carried out cholesterol concentrations in separate culture media consisting of trisomy 18, SLO and control amniocytes. Finally, we analyzed the Shh pathway by testing the gene expression of several Shh components: GLI transcription factors, BMP2, BMP4, TGFβ1, COL1A1 and COL1A2.
There was an inverse correlation between phenotypic severity and maternal uE3 levels in SLO and trisomy 18. The cholesterol levels in the amniocyte culture media were correlated with maternal uE3 levels and were significantly lower in T18 and SLO amniocytes, reflecting cholesterol defects. There was an alteration in the Shh pathway since expression of several genes was decreased in T18 and SLO amniocytes. However, these cholesterol defects were not solely responsible for the altered Shh pathway and the malformations observed.
•Clinical severity inversely correlates to maternal uE3 level in T18 and SLO fetuses.•Cholesterol defect is observed in T18 and SLO amniocyte culture medium.•Shh pathway alteration in SLO and T18 amniocytes correlates to cholesterol defect.•Cholesterol defect in SLO and T18 is not responsible alone for Shh alteration.
Hypoxic niches help maintain mesenchymal stromal cell properties, and their amplification under hypoxia sustains their immature state. However, how MSCs maintain their genomic integrity in this ...context remains elusive, since hypoxia may prevent proper DNA repair by downregulating expression of BRCA1 and RAD51. Here, we find that the ING1b tumor suppressor accumulates in adipose-derived stromal cells (ADSCs) upon genotoxic stress, owing to SUMOylation on K193 that is mediated by the E3 small ubiquitin-like modifier (SUMO) ligase protein inhibitor of activated STAT protein γ (PIAS4). We demonstrate that ING1b finely regulates the hypoxic response by triggering HIF1α proteasomal degradation. On the contrary, when mutated on its SUMOylation site, ING1b failed to efficiently decrease HIF1α levels. Consistently, we observed that the adipocyte differentiation, generally described to be downregulated by hypoxia, was highly dependent on ING1b expression, during the early days of this process. Accordingly, contrary to what was observed with HIF1α, the absence of ING1b impeded the adipogenic induction under hypoxic conditions. These data indicate that ING1b contributes to adipogenic induction in adipose-derived stromal cells, and thus hinders the phenotype maintenance of ADSCs.
ING3 (Inhibitor of Growth 3) is a candidate tumor suppressor gene whose expression is lost in tumors. Aims: We want to identify and characterize new tumor suppresor functions for ING3. Methods: We ...conduct experiments in yeast and human cells depleted or not for ING3 and exposed to genotoxic agents. Results: - ING3-depleted human cells and yeast cells deleted for its ortholog YNG2 are sensitive to DNA damage suggesting a conserved role in response to such stress. - In human cells, ING3 is recruited to DNA double strand breaks and is required for ATM activation. - In response to doxorubicin, ATM activation is dependent on ING3 but not on TIP60, whose recruitment to DNA breaks also depends on ING3. - These events lead to ATM-mediated phosphorylation of NBS1 and of major mediators of the DNA damage response. - Upon genotoxic stress, DNA repair by Non Homologous End Joining (NHEJ) or Homologous Recombination (HR) were impaired in absence of ING3. - Immunoglobulin Class Switch Recombination (CSR), a physiological mechanism requiring NHEJ repair, was impaired in the absence of ING3. Conclusions: Since deregulation of DNA double strand break repair is associated with genomic instability, we propose a novel function of ING3 as a caretaker tumor suppressor involved in the DNA damage signaling and repair. Funding: A.M. was a recipient of a doctoral fellowship from La Ligue Contre le Cancer and Region Bretagne. R.P. & M.G. were recipients of from Ulysses “The France – Ireland Exchange Scheme”. N. Bigot was a recipient of ANR program (SAFE 2012) (ANR-11-RPIB-0012). C. References: Cell Death Differ. 2019 Feb 25. doi: 10.1038/s41418-019-0305-x. Epub ahead of print
Inhibitor of Growth 3 (ING3) is a candidate tumor suppressor gene whose expression is lost in tumors such as hepatocellular carcinoma, head and neck squamous cell carcinoma and melanoma. In the ...present study, we show that ING3-depleted human cells and yeast cells deleted for its ortholog YNG2 are sensitive to DNA damage suggesting a conserved role in response to such stress. In human cells, ING3 is recruited to DNA double strand breaks and is required for ATM activation. Remarkably, in response to doxorubicin, ATM activation is dependent on ING3 but not on TIP60, whose recruitment to DNA breaks also depends on ING3. These events lead to ATM-mediated phosphorylation of NBS1 and the subsequent recruitment of RNF8, RNF168, 53BP1, and BRCA1, which are major mediators of the DNA damage response. Accordingly, upon genotoxic stress, DNA repair by non-homologous end joining (NHEJ) or homologous recombination (HR) were impaired in absence of ING3. Finally, immunoglobulin class switch recombination (CSR), a physiological mechanism requiring NHEJ repair, was impaired in the absence of ING3. Since deregulation of DNA double strand break repair is associated with genomic instability, we propose a novel function of ING3 as a caretaker tumor suppressor involved in the DNA damage signaling and repair.
Abstract
Background
Crohn’s disease (CD) progression can lead to bowel damage (BD) and disability. However, the longitudinal characterization of BD and disability in early CD patients remains ...limited.
Methods
The Crohn´s Disease Cohort (CROCO) is a multicentre, European cohort study of newly diagnosed CD patients (<12 months following diagnosis) intended to prospectively characterize BD progression and disability. At one year following inclusion (Y1), BD progression was evaluated using the Lémann Index (LI). Magnetic resonance enterography was completed by all patients, with additional endoscopy and/or pelvic MRI based on disease location. Absence of BD was defined as a LI=0, and any presence of bowel damage was indicated by LI>0. Disability was assessed using the validated IBD-disability index (IBD-DI) encompassing various domains. We report the LI at Y1 and its association with significant disease features and with the IBD-DI.
Results
Among the 261 included patients, 135 have completed the Y1 visit, with 100 having their LI calculated 57% male, median age at diagnosis of 36 years old (IQR 26-48). Most patients (90%) had ileal or ileocolonic involvement, 68% had inflammatory phenotype, and 11% had perianal disease. At inclusion, 7% of patients had undergone surgery (5 intestinal and 2 perianal), and 53% had initiated biological therapy within the first year of disease, primarily anti-TNF in mono or combination therapy. Of those with stricturing (B2) or penetrating (B3) behaviour, 77% and 79%, respectively, were on anti-TNF therapy. Overall, 61% of the patients exhibited some degree of BD (LI>0), yet the median LI at Y1 was low 0.6 (IQR 0-2). Univariate analysis revealed an association between the presence of any bowel damage at Y1 and disease behaviour at inclusion (B2 OR 3.33, 95%CI 0.84-13.18 and B3 OR 8.5, 95%CI 1.82, 39.66; p<0.01). Additionally, there was a significant association with anti-TNF therapy (OR 2.88, 95%CI 1.24-6.66, p=0.012). In a multivariate logistic model, only older age at diagnosis appeared protective against any BD (Table 1). Among those evaluated for the LI, 84 completed the IBD-DI at Y1. The median IBD-DI was 17.3 (IQR 10.7-32.6) and 30% experienced moderate-to-severe disability (IBD-DI>35). No association was observed between LI and IBD-DI at Y1 (OR 1.09, 95%CI 0.39-3.04, p=0.86) and there were no differences in the median LI across disability categories (p=0.67) (Figure 1).
Conclusion
In a cohort of newly diagnosed CD patients, one-third exhibited no bowel damage as per the LI evaluation. For those presenting any degree of damage, the global LI remained low. No association was found with disability assessed by the IBD-DI. These data add to the growing concept that early disease represents a window of opportunity.
Abstract
Background
Crohn’s disease (CD) can lead to progressive bowel damage and disability. Disability has been proposed by the SPIRIT-IOIBD consensus as an endpoint in disease-modification trials. ...Despite this, there is scarce data on disability at CD diagnosis.
Methods
The Crohn´s Disease Cohort (CROCO) is an ongoing prospective cohort study with newly diagnosed CD patients (within 12 months of diagnosis) aiming to assess the evolution of bowel damage and disability over time. Disability evaluation was conducted via the validated IBD-Disability Index (IBD-DI), which encompasses 14 questions ranging from 0-100 intended to measure overall health, sleep and energy, affect, body image, pain, defecation, interpersonal activities, and work and education.1 This study explored disability scores (DS) and their association with disease features and activity at diagnosis in patients with newly diagnosed CD. The IBD-DI was categorized as previously reported in no disability (scores 0-20), mild disability (scores 21-35), and moderate-severe disability (scores 36-100).2
Results
From a cohort of 261 patients 58% male, median age at diagnosis of 35yo (IQR 25-49), 224 completed the IBD-DI at inclusion. Median time from inclusion to baseline visit was 4 months (IQR 1.7-7.8). Most patients presented with ileal or ileocolonic disease location (87%) and an inflammatory phenotype (69%); 16% had perianal disease and 27% had extraintestinal manifestations. At inclusion, 21% had been hospitalised, and 10% had a CD-related surgery. Treatments included steroids (56%), immunosuppressants (34%), and anti-TNF therapy (40%). The median DS at inclusion was 22.2 (IQR 10.4-37.9), with 48% exhibiting no disability and 30% displaying moderate-severe disability (Figure 1). Moderate-severe disability at baseline visit was associated with female gender (OR 3.65, 95%CI 2.01-6.62, p<0.001), stricturing behaviour (OR 2.34, 95%CI 1.1-4.98), Harvey-Bradshaw Index (OR 1.36, 95%CI 1.23-1.5, p<0.001), extraintestinal manifestations (OR 2.61, 95%CI 1.41-4.84, p<0.002), and steroid use (OR 1.89, 95%CI 1.04-3.45, p=0.034). No significant associations were found with age, smoking, or biomarkers (Table 1).
Conclusion
One-third of newly diagnosed CD patients have moderate-severe disability. Disability was associated with female gender, disease phenotype, clinical severity, extraintestinal manifestations, and steroid usage. Disability is an important feature of newly diagnosed CD and may characterize a unique group of patients at diagnosis.
References
1 - PMID: 26646934
2 - PMID: 27516406
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