Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms.

There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.

Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes.

The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.

Antibiotic resistance in dermatology: The scope of the problem and strategies to address it.

Antibiotic resistance is a growing health concern that has attracted increasing attention from clinicians and scientists in recent years. Although resistance is an inevitable consequence of bacterial evolution and natural selection, misuse and overuse of antibiotics play a significant role in its acceleration. Antibiotics are the mainstay of therapy for common dermatoses, including acne and rosacea, as well as for skin and soft tissue infections. Therefore, it is critical for dermatologists and physicians across all disciplines to identify, appropriately manage, and prevent cases of antibiotic resistance. This review explores dermatologic conditions in which the development of antibiotic resistance is a risk and discusses mechanisms underlying the development of resistance. We discuss disease-specific strategies for overcoming resistant strains and improving antimicrobial stewardship along with recent advances in the development of novel approaches to counter antibiotic resistance.

The ubiquitin ligase Siah1 controls ELL2 stability and formation of super elongation complexes to modulate gene transcription.

Super elongation complexes (SECs) contain two different transcription elongation factors, P-TEFb and ELL1/2, linked by the scaffolding protein AFF4 or AFF1. They stimulate the expression of both normal and disease-related genes, especially those of HIV or those involved in leukemogenesis. Among all SEC subunits, ELL2 is stoichiometrically limiting and uniquely regulated at the level of protein stability. Here we identify the RING domain protein Siah1, but not the homologous Siah2, as the E3 ubiquitin ligase for ELL2 polyubiquitination and proteasomal degradation. Siah1 cannot access and ubiquitinate ELL2 bound to AFF4, although, at high concentrations, it also degrades AFF4/1 to destroy SECs. Prostratin and HMBA, two well-studied activators of HIV transcription and latency, enhance ELL2 accumulation and SECs formation largely through decreasing Siah1 expression and ELL2 polyubiquitination. Given its importance in formation of SECs, the Siah1 ubiquitination pathway provides a fresh avenue for developing strategies to control disease-related transcription.

Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies.

Genetic ablation as well as pharmacological inhibition of sirtuin 2 (SIRT2), an NAD+-dependent protein deacylase, have therapeutic effects in various cancers and neurodegenerative diseases. Previously, we described the discovery of a dual SIRT1/SIRT2 inhibitor called cambinol (IC50 56 and 59 µM, respectively), which showed cytotoxic activity against cancer cells in vitro and a marked anti-proliferative effect in a Burkitt lymphoma mouse xenograft model. A number of recent studies have shown a protective effect of SIRT1 and SIRT3 in neurodegenerative and metabolic diseases as well as in certain cancers prompting us to initiate a medicinal chemistry effort to develop cambinol-based SIRT2-specific inhibitors devoid of SIRT1 or SIRT3 modulating activity. Here we describe potent cambinol-based SIRT2 inhibitors, several of which show potency of ~600 nM with >300 to >800-fold selectivity over SIRT1 and 3, respectively. In vitro, these inhibitors are found to be toxic to lymphoma and epithelial cancer cell lines. In particular, compounds 55 (IC50 SIRT2 0.25 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) and 56 (IC50 SIRT2 0.78 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) showed apoptotic as well as strong anti-proliferative properties against B-cell lymphoma cells.

HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription.

Recruitment of the P-TEFb kinase by HIV-1 Tat to the viral promoter triggers the phosphorylation and escape of RNA polymerase II from promoter-proximal pausing. It is unclear, however, if Tat recruits additional host factors that further stimulate HIV-1 transcription. Using a sequential affinity-purification scheme, we have identified human transcription factors/coactivators AFF4, ENL, AF9, and elongation factor ELL2 as components of the Tat-P-TEFb complex. Through the bridging functions of Tat and AFF4, P-TEFb and ELL2 combine to form a bifunctional elongation complex that greatly activates HIV-1 transcription. Without Tat, AFF4 can mediate the ELL2-P-TEFb interaction, albeit inefficiently. Tat overcomes this limitation by bringing more ELL2 to P-TEFb and stabilizing ELL2 in a process that requires active P-TEFb. The ability of Tat to enable two different classes of elongation factors to cooperate and coordinate their actions on the same polymerase enzyme explains why Tat is such a powerful activator of HIV-1 transcription.

A Test of Web and Mail Mode Effects in a Financially Sensitive Survey of Older Americans.

This study leverages a randomized experimental design of a mixed-mode mail- and web-based survey to examine mode effects separately from sample selectivity issues. Using data from the Cognitive Economics Study, which contains some sensitive financial questions, we analyze two sets of questions: fixed-choice questions posed nearly identically across mode, and dollar-value questions that exploit features available only on web mode. Focusing on differences in item nonresponse and response distributions, our results indicate that, in contrast to mail mode, web mode surveys display lower item nonresponse for all questions. While respondents appear to prefer providing financial information in ranges, use of reminder screens on the web version yields greater use of exact values without large sacrifices in item response. Still, response distributions for all questions are similar across mode, suggesting that data on sensitive financial questions collected from the two modes can be pooled.

SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cells.

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase, Mg2+/Mn2+ dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacologic target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress in PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells.

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

Clonal evolution of hematopoietic stem cells after cancer chemotherapy.

Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies 1 . The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such as TET2 and PPM1D . Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such as TP53 and PPM1D . Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy.

Chromosome-specific DNA repeats: rapid identification in silico and validation using fluorescence in situ hybridization.

Chromosome enumeration in interphase and metaphase cells using fluorescence in situ hybridization (FISH) is an established procedure for the rapid and accurate cytogenetic analysis of cell nuclei and polar bodies, the unambiguous gender determination, as well as the definition of tumor-specific signatures. Present bottlenecks in the procedure are a limited number of commercial, non-isotopically labeled probes that can be combined in multiplex FISH assays and the relatively high price and effort to develop additional probes. We describe a streamlined approach for rapid probe definition, synthesis and validation, which is based on the analysis of publicly available DNA sequence information, also known as "database mining". Examples of probe preparation for the human gonosomes and chromosome 16 as a selected autosome outline the probe selection strategy, define a timeline for expedited probe production and compare this novel selection strategy to more conventional probe cloning protocols.

Chronic Urticaria.

• A thorough history and physical examination are vital for accurate diagnosis of chronic urticaria.• Extended laboratory tests rarely yield clinically significant or actionable findings, and hence are not recommended.• Most patients experience symptomatic relief following treatment with H1 antihistamines, omalizumab, or cyclosporine, with eventual spontaneous remission.

Chronic Urticaria.

• A thorough history and physical examination are vital for accurate diagnosis of chronic urticaria.• Extended laboratory tests rarely yield clinically significant or actionable findings, and hence are not recommended.• Most patients experience symptomatic relief following treatment with H1 antihistamines, omalizumab, or cyclosporine, with eventual spontaneous remission.

PPM1D in Solid and Hematologic Malignancies: Friend and Foe?

In the face of constant genomic insults, the DNA damage response (DDR) is initiated to preserve genome integrity; its disruption is a classic hallmark of cancer. Protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D) is a central negative regulator of the DDR that is mutated or amplified in many solid cancers. PPM1D overexpression is associated with increased proliferative and metastatic behavior in multiple solid tumor types and patients with PPM1D-mutated malignancies have poorer prognoses. Recent findings have sparked an interest in the role of PPM1D in hematologic malignancies. Acquired somatic mutations may provide hematopoietic stem cells with a competitive advantage, leading to a substantial proportion of mutant progeny in the peripheral blood, an age-associated phenomenon termed "clonal hematopoiesis" (CH). Recent large-scale genomic studies have identified PPM1D to be among the most frequently mutated genes found in individuals with CH. While PPM1D mutations are particularly enriched in patients with therapy-related myeloid neoplasms, their role in driving leukemic transformation remains uncertain. Here, we examine the mechanisms through which PPM1D overexpression or mutation may drive malignancy by suppression of DNA repair, cell-cycle arrest, and apoptosis. We also discuss the divergent roles of PPM1D in the oncogenesis of solid versus hematologic cancers with a view to clinical implications and new therapeutic avenues.

Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 (HDAC3) Stabilization and Chromatin Condensation.

Proteasome inhibitors have become the standard of care for multiple myeloma (MM). Blocking protein degradation particularly perturbs the homeostasis of short-lived polypeptides such as transcription factors and epigenetic regulators. To determine how proteasome inhibitors directly impact gene regulation, we performed an integrative genomics study in MM cells. We discovered that proteasome inhibitors reduce the turnover of DNA-associated proteins and repress genes necessary for proliferation through epigenetic silencing. Specifically, proteasome inhibition results in the localized accumulation of histone deacetylase 3 (HDAC3) at defined genomic sites, which reduces H3K27 acetylation and increases chromatin condensation. The loss of active chromatin at super-enhancers critical for MM, including the super-enhancer controlling the proto-oncogene c-MYC, reduces metabolic activity and cancer cell growth. Epigenetic silencing is attenuated by HDAC3 depletion, suggesting a tumor-suppressive element of this deacetylase in the context of proteasome inhibition. In the absence of treatment, HDAC3 is continuously removed from DNA by the ubiquitin ligase SIAH2. Overexpression of SIAH2 increases H3K27 acetylation at c-MYC-controlled genes, increases metabolic output, and accelerates cancer cell proliferation. Our studies indicate a novel therapeutic function of proteasome inhibitors in MM by reshaping the epigenetic landscape in an HDAC3-dependent manner. As a result, blocking the proteasome effectively antagonizes c-MYC and the genes controlled by this proto-oncogene.

Financial Presentation of Alzheimer Disease and Related Dementias.

Importance: Alzheimer disease and related dementias (ADRD), currently incurable neurodegenerative diseases, can threaten patients' financial status owing to memory deficits and changes in risk perception. Deteriorating financial capabilities are among the earliest signs of cognitive decline, but the frequency and extent of adverse financial events before and after diagnosis have not been characterized. Objectives: To describe the financial presentation of ADRD using administrative credit data. Design, Setting, and Participants: This retrospective secondary data analysis of consumer credit report outcomes from 1999 to 2018 linked to Medicare claims data included 81 364 Medicare beneficiaries living in single-person households. Exposures: Occurrence of adverse financial events in those with vs without ADRD diagnosis and time of adverse financial event from ADRD diagnosis. Main Outcomes and Measures: Missed payments on credit accounts (30 or more days late) and subprime credit scores. Results: Overall, 54 062 (17 890 [33.1%] men; mean [SD] age, 74 [7.3] years) were never diagnosed with ADRD during the sample period and 27 302 had ADRD for at least 1 quarter of observation (8573 [31.4%] men; mean [SD] age, 79.4 [7.5] years). Single Medicare beneficiaries diagnosed with ADRD were more likely to miss payments on credit accounts as early as 6 years prior to diagnosis compared with demographically similar beneficiaries without ADRD (7.7% vs 7.3%; absolute difference, 0.4 percentage points [pp]; 95% CI, 0.07-0.70:) and to develop subprime credit scores 2.5 years prior to diagnosis (8.5% vs 8.1%; absolute difference, 0.38 pp; 95% CI, 0.04-0.72). By the quarter after diagnosis, patients with ADRD remained more likely to miss payments than similar beneficiaries who did not develop ADRD (7.9% vs 6.9%; absolute difference, 1.0 pp; 95% CI, 0.67-1.40) and more likely to have subprime credit scores than those without ADRD (8.2% vs 7.5%; absolute difference, 0.70 pp; 95% CI, 0.34-1.1). Adverse financial events were more common among patients with ADRD in lower-education census tracts. The patterns of adverse events associated with ADRD were unique compared with other medical conditions (eg, glaucoma, hip fracture). Conclusions and Relevance: Alzheimer disease and related dementias were associated with adverse financial events years prior to clinical diagnosis that become more prevalent after diagnosis and were most common in lower-education census tracts.

Identifying Cohabiting Couples in Administrative Data: Evidence from Medicare Address Data.

Marital status is recognized as an important social determinant of health, income, and social support, but is rarely available in administrative data. We assessed the feasibility of using exact address data and zip code history to identify cohabiting couples using the 2018 Medicare Vital Status file and ZIP codes in the 2011-2014 Master Beneficiary Summary Files. Medicare beneficiaries meeting our algorithm displayed characteristics consistent with assortative mating and resembled known married couples in the Health and Retirement Study linked to Medicare claims. Address information represents a promising strategy for identifying cohabiting couples in administrative data including healthcare claims and other data types.

Ocular complications of atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that can present with ocular comorbidities. Ocular complications are more prevalent in individuals with AD compared to the general population and can cause notable morbidity. This article reviews the clinical presentation, pathophysiology, and management of common ocular complications associated with AD, including blepharitis, keratoconjunctivitis, keratoconus, glaucoma, cataracts, retinal detachment, ophthalmic herpes simplex virus infections, and dupilumab-associated ocular complications. It is important for dermatologists to be aware of the signs and symptoms of these ocular complications, as timely diagnosis and treatment can prevent irreversible vision loss.

PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.

Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. VIDEO ABSTRACT.

Heaping at Round Numbers on Financial Questions: The Role of Satisficing.

Survey responses to quantitative financial questions frequently display strong patterns of heaping at round numbers. This paper uses two studies to examine variation in rounding across questions and by individual characteristics. Rounding was more common for respondents low in ability, for respondents low in motivation, and for more difficult questions, all consistent with theories of satisficing. Questions that require more difficult information retrieval and integration of information exhibit more heaping. The use of records, which lowers task difficulty, reduces rounding as well. Higher episodic memory is associated with less rounding, and standard measures of motivation are negatively associated with rounding. These relationships, along with the fact that longer response latencies are associated with less rounding, all support the idea that rounding is a manifestation of satisficing on open-ended financial questions. Rounding patterns also appear remarkably similar across the two studies, despite being fielded in different modes and employing different question order and wording.