ABSTRACT
Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.
Subject(s)
Chromatin , Neoplasms , Animals , Humans , Mice , Chromatin/genetics , Mutation , Phosphoproteins/genetics , Phosphoproteins/metabolism , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , RNA Splicing/genetics , RNA Splicing Factors/genetics , RNA Splicing Factors/metabolismABSTRACT
The methylcytosine dioxygenase TET1 ('ten-eleven translocation 1') is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.
Subject(s)
B-Lymphocytes/physiology , Cytosine/analogs & derivatives , DNA-Binding Proteins/metabolism , Embryonic Stem Cells/physiology , Lymphoma, B-Cell/genetics , Proto-Oncogene Proteins/metabolism , Tumor Suppressor Proteins/metabolism , 5-Methylcytosine/analogs & derivatives , Animals , Cell Differentiation/genetics , Cell Lineage/genetics , Chromosomal Instability , Cytosine/metabolism , DNA Methylation , DNA Repair , DNA-Binding Proteins/genetics , Epigenesis, Genetic , Exome/genetics , Gene Expression Profiling , Humans , Mice , Mutation/genetics , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
A metronomic, low-dose schedule of decitabine and Venetoclax was safe and effective in myeloid malignancies with few dose reductions or interruptions in an older diverse population. Median OS for AML and TP53 mutated patients was 16.1 and 11.3 months respectively.
ABSTRACT
The area surrounding the tunnel exit of the 60S ribosomal subunit is a hub for proteins involved in maturation and folding of emerging nascent polypeptide chains. How different factors vie for positioning at the tunnel exit in the complex cellular environment is not well understood. We used in vivo site-specific cross-linking to approach this question, focusing on two abundant factors-the nascent chain-associated complex (NAC) and the Hsp70 chaperone system that includes the J-domain protein co-chaperone Zuotin. We found that NAC and Zuotin can cross-link to each other at the ribosome, even when translation initiation is inhibited. Positions yielding NAC-Zuotin cross-links indicate that when both are present the central globular domain of NAC is modestly shifted from the mutually exclusive position observed in cryogenic electron microscopy analysis. Cross-linking results also suggest that, even in NAC's presence, Hsp70 can situate in a manner conducive for productive nascent chain interaction-with the peptide binding site at the tunnel exit and the J-domain of Zuotin appropriately positioned to drive stabilization of nascent chain binding. Overall, our results are consistent with the idea that, in vivo, the NAC and Hsp70 systems can productively position on the ribosome simultaneously.
Subject(s)
HSP70 Heat-Shock Proteins , Ribosomes , Saccharomyces cerevisiae , Binding Sites , HSP70 Heat-Shock Proteins/genetics , Peptides/chemistry , Protein Biosynthesis , Protein Domains , Ribosomes/metabolismABSTRACT
Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening treatment is that Mycobacterium tuberculosis becomes tolerant to the administered drugs, starting early after infection and within days of infecting macrophages. Multiple lines of evidence suggest that macrophage-induced drug tolerance is mediated by mycobacterial drug efflux pumps. Here, using assays to directly measure drug efflux, we find that M. tuberculosis transports the first-line antitubercular drug rifampicin through a proton gradient-dependent mechanism. We show that verapamil, a known efflux pump inhibitor, which inhibits macrophage-induced rifampicin tolerance, also inhibits M.tuberculosis rifampicin efflux. As with macrophage-induced tolerance, the calcium channel-inhibiting property of verapamil is not required for its inhibition of rifampicin efflux. By testing verapamil analogs, we show that verapamil directly inhibits M. tuberculosis drug efflux pumps through its human P-glycoprotein (PGP)-like inhibitory activity. Screening commonly used drugs with incidental PGP inhibitory activity, we find many inhibit rifampicin efflux, including the proton pump inhibitors (PPIs) such as omeprazole. Like verapamil, the PPIs inhibit macrophage-induced rifampicin tolerance as well as intramacrophage growth, which has also been linked to mycobacterial efflux pump activity. Our assays provide a facile screening platform for M. tuberculosis efflux pump inhibitors that inhibit in vivo drug tolerance and growth.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Humans , Rifampin/pharmacology , Proton Pump Inhibitors/pharmacology , Antitubercular Agents/pharmacology , Verapamil/pharmacology , Macrophages , Tuberculosis/drug therapy , Drug Tolerance , Bacterial Proteins , Microbial Sensitivity TestsABSTRACT
How hematopoietic stem cells (HSCs) coordinate the regulation of opposing cellular mechanisms such as self-renewal and differentiation commitment remains unclear. Here we identified the transcription factor and chromatin remodeler Satb1 as a critical regulator of HSC fate. HSCs lacking Satb1 had defective self-renewal, were less quiescent and showed accelerated lineage commitment, which resulted in progressive depletion of functional HSCs. The enhanced commitment was caused by less symmetric self-renewal and more symmetric differentiation divisions of Satb1-deficient HSCs. Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc, which encode two key factors for the specification of stem-cell fate. Thus, Satb1 is a regulator that promotes HSC quiescence and represses lineage commitment.
Subject(s)
Hematopoietic Stem Cells/physiology , Matrix Attachment Region Binding Proteins/metabolism , Animals , Cell Differentiation/genetics , Cell Lineage/genetics , Cell Polarity/genetics , Cell Survival/genetics , Cells, Cultured , Chromatin Assembly and Disassembly/genetics , Gene Expression Regulation, Developmental/genetics , Matrix Attachment Region Binding Proteins/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolismABSTRACT
The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000-2021) and Montefiore Medical Center (2000-2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival.
Subject(s)
Primary Myelofibrosis , SEER Program , Humans , Primary Myelofibrosis/epidemiology , Primary Myelofibrosis/mortality , Male , Female , Aged , Middle Aged , Retrospective Studies , Survival Rate , Aged, 80 and over , Socioeconomic Factors , Adult , Databases, Factual , United States/epidemiology , IncidenceABSTRACT
Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with morphologic dysplasia and a propensity to transform into overt acute myeloid leukemia (AML). Our analysis of two cohorts of 20 MDS and 49 AML with multi-lineage dysplasia patients shows a reduction in Nucleophosmin 1 (NPM1) expression in 70% and 90% of cases, respectively. A mouse model of Npm1 conditional knockout (cKO) in hematopoietic cells reveals that Npm1 loss causes premature aging of hematopoietic stem cells (HSCs). Mitochondrial activation in Npm1-deficient HSCs leads to aberrant activation of the NLRP3 inflammasome, which correlates with a developing MDS-like phenotype. Npm1 cKO mice exhibit shortened survival times, and expansion of both the intra- and extra-medullary myeloid populations, while evoking a p53-dependent response. After transfer into a p53 mutant background, the resulting Npm1/p53 double KO mice develop fatal leukemia within 6 months. Our findings identify NPM1 as a regulator of HSC aging and inflammation and highlight the role of p53 in MDS progression to leukemia.
Subject(s)
Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Aging/genetics , Animals , Hematopoietic Stem Cells/metabolism , Humans , Inflammation/genetics , Inflammation/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Mice , Mutation , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Nucleophosmin , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
PURPOSE: To determine 6-month interim safety, effectiveness, and multimodal imageability of imageable glass microsphere yttrium-90 (90Y) radioembolization for unresectable hepatocellular carcinoma (HCC) in a first-in-human trial. MATERIALS AND METHODS: Imageable microspheres (Eye90 Microspheres; ABK Biomedical, Halifax, Nova Scotia, Canada), a U.S. Food and Drug Administration (FDA) Breakthrough-Designated Device consisting of glass radiopaque 90Y microspheres visible on computed tomography (CT) and single photon emission CT (SPECT), were used to treat 6 subjects with unresectable HCC. Patients underwent selective (≤2 segments) treatment in a prospective open-label pilot trial. Key inclusion criteria included liver-only HCC, performance status ≤1, total lesion diameter ≤9 cm, and Child-Pugh A status. Prospective partition dosimetry was utilized. Safety (measured by Common Terminology Criteria for Adverse Events [CTCAE] v5), multimodal imageability on CT and SPECT, and 3- and 6-month imaging response by modified Response Evaluation Criteria in Solid Tumors on magnetic resonance (MR) imaging were evaluated. RESULTS: Seven tumors in 6 subjects were treated and followed to 180 days. Administration success was 100%. Microsphere distribution measured by radiopacity on CT correlated with SPECT. Ninety-day target lesion complete response (CR) was observed in 3 of 6 subjects (50%) and partial response (PR) in 2 (33.3%). At 180 days, target lesion CR was maintained in 3 subjects (50%) and PR in 1 (16.7%). Two subjects could not be reassessed, having undergone intervening chemoembolization. All subjects reported adverse events (AEs), and 5 reported AEs related to treatment. There were no treatment-related Grade ≥3 AEs. CONCLUSIONS: Radioembolization using imageable microspheres was safe and effective in 6 subjects with unresectable HCC at 6-month interim analysis. Microsphere distribution by radiopacity on CT correlated with radioactivity distribution by SPECT, providing previously unavailable CT-based tumor targeting information.
Subject(s)
Carcinoma, Hepatocellular , Embolization, Therapeutic , Liver Neoplasms , Microspheres , Radiopharmaceuticals , Yttrium Radioisotopes , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/radiotherapy , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/radiotherapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Yttrium Radioisotopes/administration & dosage , Male , Prospective Studies , Middle Aged , Treatment Outcome , Female , Aged , Pilot Projects , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/adverse effects , Embolization, Therapeutic/adverse effects , Time Factors , Tomography, Emission-Computed, Single-Photon , Predictive Value of Tests , Single Photon Emission Computed Tomography Computed TomographyABSTRACT
BACKGROUND: Age-related loss of midfacial contour is frequently corrected using dermal fillers. A validated photonumeric scale is beneficial when evaluating post-treatment aesthetic improvement. OBJECTIVE: To present scale-development activities for the Merz Cheek Fullness Assessment Scale (MCFAS) and report pilot-study results of a hyaluronic-acid filler (Belotero Volume with Lidocaine; CPM-HA-V) to treat midfacial volume loss. METHODS: A 5-point photonumeric scale was developed to objectively assess midface volume loss. Rater reliability was evaluated using live assessments. The clinical relevance of a 1-point difference in severity grade was evaluated using photographic comparisons. Pilot-study participants, with moderate-to-severe volume loss on the MCFAS, were randomized 2:1 to treatment or untreated control. Effectiveness was evaluated using the MCFAS, and adverse events were recorded. RESULTS: The MCFAS demonstrated substantial intra- and interrater agreement among physicians (weighted kappa > 0.6). The mean absolute difference (95% confidence interval) in scale ratings was 1.12 (1.00, 1.24) for photographic pairs differing by one grade and was 0.55 (0.48, 0.63) for pairs of the same grade, suggesting a 1-point difference is clinically relevant. In the pilot study, significant (P < 0.0001) differences were observed in MCFAS response rates between treatment and control. No safety concerns were identified. CONCLUSION: The MCFAS is a validated, reliable, and clinically relevant photonumeric scale for rating midfacial volume loss in males and females of various ages and skin types. In a pilot study, CPM-HA-V was found to be safe and tolerable, and the MCFAS was able to detect clinically meaningful post-treatment changes. J Drugs Dermatol. 2024;23(1): doi:10.36849/JDD.7981.
Subject(s)
Excipients , Research Design , Female , Male , Humans , Pilot Projects , Reproducibility of Results , EstheticsABSTRACT
BACKGROUND: Post herpetic neuralgia (PHN) is a chronic neuropathic pain syndrome which presents after an episode of herpes zoster caused by the reactivation of varicella zoster virus. Conservative treatment starts with pharmacological measures using Anti-epileptics and Antidepressants. Some patients also respond well to epidural steroid injections too, but the effect is usually short lasting. Dorsal Root Ganglion Stimulator (DRG-S) has recently been suggested as a new treatment modality for PHN due to its selective targeting of the pathophysiologic focus. CASE SERIES: We are reporting three cases, who were suffering from neuropathic pain after an episode of herpes zoster. Pain and pain related suffering scores were high, even with multiple antiepileptics and opioid medications. They underwent DRG-S implant and appreciated more than 50% reduction of their pain score, meaningful reduction in the dose of medications along with significant improvement of their general well being measured using Generalized Anxiety Disorder Questionnaire (GAD-7), pain disability index (PDI), and 9 Question Patient Health Questionnaire (PHQ-9). To our knowledge this is the first report on DRG stimulator from the Middle East Region. CONCLUSION: DRG-S has potential to be a preferable treatment option in patients with refractory PHN and acts as a specific targeted therapy in the treatment of these patients.
Subject(s)
Herpes Zoster , Neuralgia, Postherpetic , Neuralgia , Humans , Neuralgia, Postherpetic/drug therapy , Ganglia, Spinal , Neuralgia/etiology , Herpes Zoster/complications , AnticonvulsantsABSTRACT
BACKGROUND: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor ß superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).
Subject(s)
Activin Receptors, Type II/therapeutic use , Anemia, Sideroblastic/drug therapy , Erythrocyte Transfusion , Hematinics/therapeutic use , Immunoglobulin Fc Fragments/therapeutic use , Myelodysplastic Syndromes/drug therapy , Recombinant Fusion Proteins/therapeutic use , Activin Receptors, Type II/adverse effects , Adult , Aged , Aged, 80 and over , Anemia, Sideroblastic/therapy , Double-Blind Method , Female , Hematinics/adverse effects , Hemoglobins/analysis , Humans , Immunoglobulin Fc Fragments/adverse effects , Infusions, Subcutaneous , Male , Middle Aged , Myelodysplastic Syndromes/therapy , Recombinant Fusion Proteins/adverse effectsABSTRACT
J-domain proteins (JDPs) are critical components of the cellular protein quality control machinery, playing crucial roles in preventing the formation and, solubilization of cytotoxic protein aggregates. Bacteria, yeast, and plants additionally have large, multimeric heat shock protein 100 (Hsp100)-class disaggregases that resolubilize protein aggregates. JDPs interact with aggregated proteins and specify the aggregate-remodeling activities of Hsp70s and Hsp100s. However, the aggregate-remodeling properties of plant JDPs are not well understood. Here we identify eight orthologs of Sis1 (an evolutionarily conserved Class II JDP of budding yeast) in Arabidopsis thaliana with distinct aggregate-remodeling functionalities. Six of these JDPs associate with heat-induced protein aggregates in vivo and co-localize with Hsp101 at heat-induced protein aggregate centers. Consistent with a role in solubilizing cytotoxic protein aggregates, an atDjB3 mutant had defects in both solubilizing heat-induced aggregates and acquired thermotolerance as compared with wild-type seedlings. Next, we used yeast prions as protein aggregate models to show that the six JDPs have distinct aggregate-remodeling properties. Results presented in this study, as well as findings from phylogenetic analysis, demonstrate that plants harbor multiple, evolutionarily conserved JDPs with capacity to process a variety of protein aggregate conformers induced by heat and other stressors.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/genetics , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , HSP40 Heat-Shock Proteins , HSP70 Heat-Shock Proteins/metabolism , Phylogeny , Protein AggregatesABSTRACT
Over the past two decades, there have been significant advances in the treatment of multiple myeloma which has led to an improvement in overall survival (OS) (1,2). However, a notable proportion of patients continue to experience early mortality (EM), defined as two years from the time of diagnosis. This raises the possibility that improvements in myeloma survival have not extended equally to all groups. Using the latest data drawn from the Surveillance Epidemiology and End Results (SEER) database of patients in the United States spanning 2000-2019, we study impact of important sociodemographic factors on EM. Through regression modeling, we demonstrate that patients diagnosed from 2000-2005, of older age, male sex, and of certain racial minority status (non-Hispanic Black and Hispanic) have higher odds of EM. Of these factors, minority status contributed to worse 2-year overall survival as well. We evaluate whether income, as a surrogate to access to care, could potentially explain this finding, but find that race has a distinct relationship with EM that is not modified by income. This is further reinforced by subgroup analysis. After characterizing groups vulnerable to EM, we examine reasons for these disparities and potential avenues to address them.
ABSTRACT
INTRODUCTION: Myeloid malignancies are a heterogeneous group of clonal bone marrow disorders that are complex to manage in the community and therefore often referred to subspecialists at tertiary oncology referral centers. Many patients do not live in close proximity to tertiary referral centers and are unable to commute long distances due to age, comorbidities, and frailty. Interventions that minimize the travel time burden without compromising quality of care are an area of unmet need. We describe a cancer care delivery model for patients with myeloid malignancies that is built around telehealth and enables this vulnerable population access to care at an NCI-designated cancer center while receiving majority of their care close to home. METHODS AND MATERIALS: We report on a cohort of patients with myeloid malignancies who were co-managed by a general community oncologist and an academic leukemia subspecialist at Montefiore Einstein Cancer Center in New York. Patients were initially referred to our institute for a second opinion by community practices that are in partnership with Montefiore Health System, and initial visits were in-person or via telehealth. Treatment plans were made after discussion with patient's local community oncologist. Patients then continued to receive majority of their treatment and supportive care including transfusion support with their local oncologist, and follow-up visits were mainly via telehealth with the academic leukemia subspecialist. RESULTS: Our cohort of 12 patients had a median age of 81 years (range, 59-88 years). Patients remained on active treatment for a median time of 357 days (range, 154-557 days). Most of our patients had a performance status of ECOG 2 or higher. Three patients had myelodysplastic syndromes, 7 patients had acute myeloid leukemia, and 2 patients had myelofibrosis. The median number of hospitalizations over the total treatment time period was one. CONCLUSION: We demonstrate a shared academic and community care co-management model for the treatment of myeloid malignancies in elderly, frail patients using telehealth as a backbone with a very low hospitalization rate.
Subject(s)
COVID-19 , Delivery of Health Care , Disease Management , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Primary Myelofibrosis , Aged , Aged, 80 and over , Humans , Middle Aged , COVID-19/epidemiology , COVID-19/therapy , Delivery of Health Care/methods , Frail Elderly , Health Services Accessibility , Hospitalization/statistics & numerical data , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/epidemiology , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/therapy , Pandemics , Primary Myelofibrosis/epidemiology , Primary Myelofibrosis/therapy , Telemedicine , New York City/epidemiology , Academic Medical Centers , Community Health Services , ComorbidityABSTRACT
Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.
Subject(s)
Drug Resistance, Neoplasm/genetics , E2F1 Transcription Factor/genetics , Histones/genetics , Melanoma/genetics , Protein Serine-Threonine Kinases/genetics , Base Sequence , Cell Line, Tumor , Cell Proliferation/genetics , E2F1 Transcription Factor/metabolism , HeLa Cells , Histones/biosynthesis , Humans , Melanocytes/cytology , Melanoma/pathology , Protein Serine-Threonine Kinases/metabolism , RNA Interference , RNA, Small Interfering , S Phase Cell Cycle Checkpoints/genetics , Sequence Analysis, RNA , Transcription Factors , Transcriptional ActivationABSTRACT
BACKGROUND: The infraorbital hollow is characterized by a sunken hollowing appearance of the junction between the lower eyelid and the cheek. Dermal fillers provide a suitable option to reduce the appearance of infraorbital hollowing. To objectively evaluate treatmentrelated improvements in clinical practice and research, a validated photonumeric scale is needed. OBJECTIVE: To present the scale development methods for the Merz Infraorbital Hollow Assessment Scale and establish its reliability and clinical relevance. METHODS: A 5-point photonumeric scale was developed to objectively assess the infraorbital hollowing among subjects of varying sex, age, and skin type. Intra- and inter-rater reliability was evaluated using live assessments conducted 2 weeks apart. The clinical relevance of a 1-point difference in scale-severity grade was evaluated through side by-side comparisons of photographs with either same grade or a one-grade difference. RESULTS: The scale demonstrated excellent reliability when used by trained physicians and other healthcare practitioners. Intra-rater agreement between the 2 live-subject rating sessions was nearly perfect. Substantial inter-rater agreement between the raters from both live sessions was also demonstrated. The mean absolute difference (95% confidence interval) in scale ratings was 1.08 (1.02, 1.14) for "clinically different" pairs and was 0.34 (0.27, 0.41) for "clinically same" pairs, suggesting a 1-point difference is clinically relevant. CONCLUSION: The Merz Infraorbital Hollow Assessment Scale is a validated, reliable, and clinically relevant photonumeric scale for rating infraorbital hollowing. The scale maintains its validity and reliability with reproducible results across a diverse group of males and females of various ages and Fitzpatrick Skin Types. J Drugs Dermatol. 2023;22(1):74-81.doi:10.36849/JDD.7191.
Subject(s)
Photography , Male , Female , Humans , Reproducibility of Results , Observer Variation , Severity of Illness Index , CheekABSTRACT
BACKGROUND: The shape, proportion, and fullness of one's lips are associated with overall facial beauty and attractiveness. Lip augmentation, due to personal preference or to reverse natural aging, has become a standard clinical procedure to improve lip volume or proportion. Several options are available to redefine the lips. To objectively evaluate treatment-related improvements in clinical practice and research, a validated photonumeric scale is needed. OBJECTIVE: To present scale-development methods for the Merz Lip Fullness Assessment Scale (MLFAS) and establish its reliability. METHODS: A 5-point photonumeric scale was developed to objectively assess loss of lip volume using male and female subjects of various ages and skin types. To establish intra- and interrater reliability, 8 board-certified dermatologists and plastic surgeons evaluated 64 subjects live in 2 sessions, 2 weeks apart. RESULTS: The weighted kappa for intra- and interrater agreement were ≥ 0.6 in all cases. Intrarater agreement between the 2 rating sessions was nearly perfect (median weighted kappa = 0.911 and 0.930 for the upper lip and lower lip, respectively). Substantial interrater agreement between each rater pair was also demonstrated for both rating sessions, and ratings of upper and lower lip fullness showed comparable reliability. CONCLUSION: The MLFAS is a validated and reliable photonumeric scale for rating loss in lip volume. The scale maintains its reliability with reproducible results across a diverse group of males and females of various ages and Fitzpatrick skin types. J Drugs Dermatol. 2023;22(3): doi:10.36849/JDD.7309.
Subject(s)
Lip , Female , Humans , Male , Lip/anatomy & histology , Reproducibility of ResultsABSTRACT
BACKGROUND: A naturally aged face is often characterized by a noticeable lack of jawline contour and decreased volume in the lower region. Several options are available to redefine the jawline. To objectively evaluate treatment-related improvements in clinical practice and research, a validated photonumeric scale is needed. OBJECTIVE: To present scale-development methods for the Merz Jawline Assessment Scale and establish its reliability. METHODS: A 5-point photonumeric scale was developed to objectively assess jawline volume loss and contour disruption using male and female subjects of various ages and skin types. Seven board-certified dermatologists and plastic surgeons evaluated 90 subjects live in 2 sessions, 3 weeks apart to establish intra- and interrater reliability. RESULTS: The weighted kappa for intra- and interrater agreement were ≥ 0.7 in all cases. Intrarater agreement between the 2 rating sessions was nearly perfect (median weighted kappa = 0.908). Substantial interrater agreement between each rater pair was also demonstrated for both rating sessions. CONCLUSION: The Merz Jawline Assessment Scale is a validated and reliable photonumeric scale for rating loss of jawline volume and contour. The scale maintains its validity and reliability with reproducible results across a diverse group of males and females of various ages and Fitzpatrick skin types. J Drugs Dermatol. 2023;22(2):203-209. doi:10.36849/JDD.7193.
Subject(s)
Photography , Surgeons , Humans , Male , Female , Aged , Reproducibility of Results , Observer Variation , Severity of Illness IndexABSTRACT
Major efforts are underway to identify agents that can potentiate effects of immune checkpoint inhibition. Here, we show that ascorbic acid (AA) treatment caused genomewide demethylation and enhanced expression of endogenous retroviral elements in lymphoma cells. AA also increased 5-hydroxymethylcytosine (5hmC) levels of CD8+ T cells and enhanced their cytotoxic activity in a lymphoma coculture system. High-dose AA treatment synergized with anti-PD1 therapy in a syngeneic lymphoma mouse model, resulting in marked inhibition of tumor growth compared with either agent alone. Analysis of the intratumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intratumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intratumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and natural killer cells), and interleukin 12 production by antigen-presenting cells compared with single-agent anti-PD1. These data indicate that AA potentiates anti-PD1 checkpoint inhibition through synergistic mechanisms. The study provides compelling rationale for testing combinations of high-dose AA and anti-PD1 agents in patients with aggressive B cell lymphoma as well as in preclinical models of other malignancies.