IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptional networks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities, integrating functional genomics screening, spatial proteomics, and global chromatin mapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is required for IRF4 expression and functionally associates with IRF4 protein on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitors remain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinations of SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providing a promising strategy for relapsed/refractory disease.

Old and newly synthesized histones are asymmetrically distributed in Drosophila intestinal stem cell divisions.

We report that preexisting (old) and newly synthesized (new) histones H3 and H4 are asymmetrically partitioned during the division of Drosophila intestinal stem cells (ISCs). Furthermore, the inheritance patterns of old and new H3 and H4 in postmitotic cell pairs correlate with distinct expression patterns of Delta, an important cell fate gene. To understand the biological significance of this phenomenon, we expressed a mutant H3T3A to compromise asymmetric histone inheritance. Under this condition, we observe an increase in Delta-symmetric cell pairs and overpopulated ISC-like, Delta-positive cells. Single-cell RNA-seq assays further indicate that H3T3A expression compromises ISC differentiation. Together, our results indicate that asymmetric histone inheritance potentially contributes to establishing distinct cell identities in a somatic stem cell lineage, consistent with previous findings in Drosophila male germline stem cells.

Bronchoalveolar Lavage in a Pediatric Population.

OBJECTIVES: The cytomorphologic findings of bronchoalveolar lavage (BAL) in pediatrics were correlated with clinical symptoms. METHODS: Patient demographics, clinical symptoms/history, cytomorphologic findings, and oil red O (ORO) staining of 100 pediatric patients who underwent BAL between 2014 and 2016 were reviewed at a large academic institution. RESULTS: Of the 100 patients (males/females, 62:38), the most common conditions for BAL included cough (46/100), reflux (39/100), pneumonia (30/100), dysphagia (22/100), asthma (19/100), and cystic fibrosis (15/100). Sixteen of 100 patients were admitted with pulmonary symptoms from the emergency department. Cytomorphologic findings showed acute inflammation in 37 BALs and chronic inflammation in 9. Abundant thick mucin was present in 3 cytology cases from patients with cystic fibrosis. Fungal elements were detected in 3 cases (Candida, Aspergillus, and Pneumocystis jirovecii) and viral effects (rhinovirus) in one. Thirty-seven of 100 had rare ORO-positive lipid-laden macrophages (LLMs), 7 of 100 had moderate LLMs, 11 of 100 had numerous LLMs, 18 of 100 had positive staining without the degree of staining, 25 of 100 had negative ORO staining, and 2 of 100 had noncontributory ORO staining. An iron stain was done on 15 BALs (2 positive, 9 negative, and 4 noncontributory). CONCLUSIONS: BAL cytology is a useful tool in pediatrics to discriminate underlying causes of aerodigestive system conditions, while ORO staining may occasionally help.

The ABCs of Kidney Disease: Knowledge Retention and Healthcare Involvement.

Low health literacy in the chronic kidney disease population results in lower rates of pre-dialysis preparation and understanding of management to slow progression. The ABCs of Kidney Disease education class provided education in a more consistent manner outside of routine office visits. We aimed to study whether a structured education program would increase kidney disease-specific knowledge and healthcare involvement. Knowledge retention at least 6 months after the class assessed by the Kidney Disease Knowledge Surveys (KiKS) and healthcare involvement based on surveys sent to referring providers were found to have increased. Incorporation of a structured education program would be important for providers to improve long-term knowledge and lead to greater healthcare involvement. Providing an education class outside of the routine office visits will provide a greater impact on health literacy.