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The shoulder and pelvic girdles represent the proximal bones of the appendicular skeleton that connect the anterior and posterior limbs to the body trunk. Although the limb is a well-known model in developmental biology, the genetic mechanisms controlling the development of the more proximal elements of the appendicular skeleton are still unknown. The knock-out of Pax1 has shown that this gene is involved in patterning the acromion, while the expression pattern candidates Hoxc6 as a gene involved in scapula development. Surprisingly, we have found that scapula and ilium do not develop in Emx2 knock-out mice. In the homozygous mutants, developmental abnormalities of the brain cortex, the most anterior structure of the primary axis of the body, are associated with important defects of the girdles, the more proximal elements of the secondary axis. These abnormalities suggest that the molecular mechanisms patterning the more proximal elements of the limb axis are different from those patterning the rest of appendicular skeleton. While Hox genes specify the different segments of the more distal part of the appendicular skeleton forming the limb, Emx2 is concerned with the more proximal elements constituting the girdles. [C] 2001 Academic Press Key Words: Emx2; knock-out; scapula; ilium; shoulder girdle; pelvic girdle; appendicular skeleton; limb development.

We found that inflammatory stimuli induce p38 mitogen-activated protein kinase?dependent phosphorylation and phosphoacetylation of histone H3; this selectively occurred on the promoters of a subset of stimulus-induced cytokine and chemokine genes. p38 activity was required to enhance the accessibility of the cryptic NF-κB binding sites contained in H3 phosphorylated promoters, which indicated that p38-dependent H3 phosphorylation may mark promoters for increased NF-κB recruitment. These results show that p38 plays an additional role in the induction of the inflammatory and immune response: the regulation of NF-κB recruitment to selected chromatin targets. [ABSTRACT FROM AUTHOR]

CD19-targeting treatments have shown promise in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]) is a CD19-targeting antibody-drug conjugate indicated for R/R DLBCL after at least two systemic treatments. CD19 expression was evaluated in patients receiving Lonca in the LOTIS-2 clinical trial with available tissue samples obtained after last systemic therapy/before Lonca treatment. Lonca cytotoxicity was evaluated in a panel of six lymphoma cell lines with various CD19 expression levels. Quantitative systems pharmacology (QSP) modelling was used to predict Lonca responses. Lonca responses were seen in patients across all CD19 expression levels, including patients with low/no detectable CD19 expression and H-scores at baseline. Similarly, Lonca induced cytotoxicity in cell lines with different levels of CD19 expression, including one with very low expression. QSP modelling predicted that CD19 expression by immunohistochemistry alone does not predict Lonca response, whereas inclusion of CD19 surface density improved response prediction. Virtual patients responded to Lonca with estimated CD19 as low as 1000 molecules/cell of CD19, normally below the immunohistochemistry detection level. We found Lonca is an effective treatment for R/R DLBCL regardless of CD19 expression by immunohistochemistry. These results provide the basis for future studies addressing CD19-targeted agent sequencing., Competing Interests: PFC was on the advisory board for ADC Therapeutics SA, Amgen, BeiGene, Bristol Myers Squibb (BMS), Genentech, Kite, MEI Pharmaceuticals and Novartis and received research funding from AbbVie, ADC Therapeutics SA, and Genentech. MH has been a consultant with AbbVie, ADC Therapeutics SA, BMS, Caribou, CRISPR, Gamida Cell, Genmab, Incyte Corporation, Kadmon, Kite, Legend Biotech, MorphoSys, Novartis, Omeros and Seagen; received research funding from ADC Therapeutics SA and Spectrum Pharmaceuticals; has speakers bureau memberships for ADC Therapeutics SA, AstraZeneca, BeiGene, Kite, and Sanofi Genzyme and participated on data monitoring committees for Genentech and Myeloid Therapeutics. CC‐S has been a consultant with Sanofi; has been on the board of directors, speakers bureau or advisory committee for ADC Therapeutics SA, BMS, Celgene, Karyopharm, Roche and Sanofi; has received research funding from ADC Therapeutics SA, Roche and Sanofi and has received honoraria from ADC Therapeutics SA, AstraZeneca, BMS, Incyte, Janssen Oncology, and Takeda. MN is currently employed at Boehringer Ingelheim Pharmaceuticals, Inc. EJ was an employee of Metrum Research Group at the time of the study. KU and TK are currently employed at Metrum Research Group. FZ and YW were employees of ADC Therapeutics SA, a publicaly traded company, at the time of the study and may hold stock. DC, SP and JB are currently employed and current stockholders at ADC Therapeutics SA, a publicly traded company. KH is currently employed and a current stockholder at ADC Therapeutics (UK) Ltd, a publicly traded company. ETHICS STATEMENTThe authors have confirmed an ethical approval statement is not needed for this submission., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Earlier and more reliable detection of drug-induced kidney injury would improve clinical care and help to streamline drug-development. As the current standards to monitor renal function, such as blood urea nitrogen (BUN) or serum creatinine (SCr), are late indicators of kidney injury, we conducted ten nonclinical studies to rigorously assess the potential of four previously described nephrotoxicity markers to detect drug-induced kidney and liver injury. Whereas urinary clusterin outperformed BUN and SCr for detecting proximal tubular injury, urinary total protein, cystatin C and beta2-microglobulin showed a better diagnostic performance than BUN and SCr for detecting glomerular injury. Gene and protein expression analysis, in-situ hybridization and immunohistochemistry provide mechanistic evidence to support the use of these four markers for detecting kidney injury to guide regulatory decision making in drug development. The recognition of the qualification of these biomarkers by the EMEA and FDA will significantly enhance renal safety monitoring.

Transcription factors within a family usually share the ability to recognize similar or identical consensus sites. For example, the five mammalian NF-kappaB/Rel proteins generate more than 12 dimers recognizing 9-11 nucleotide kappaB sites. Each dimer selectively regulates a few target promoters; however, several genes are redundantly induced by more than one dimer. Whether this property simply generates redundancy in target gene activation or underlies more complex regulatory mechanisms is an open issue. We show here that during dendritic cell maturation, rapidly activated dimers (e.g., p50/RelA) bound to a subset of target promoters are gradually replaced by slowly activated dimers (e.g., p52/RelB). Since the dimers have different transcriptional activity at each promoter, the dimer exchange allows fine tuning of the response over time. Further, due to the insensitivity of p52/RelB to the NF-kappaB inhibitors, the IkappaBs, dimer exchange contributes to sustained activation of selected NF-kappaB targets in spite of the resynthesis of IkappaBalpha.