A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections

SARS-CoV-2 and HIV-1 are RNA viruses that have killed millions of people worldwide. Understanding the similarities and differences between these two infections is critical for understanding disease progression and for developing effective vaccines and therapies, particularly for 38 million HIV-1+ individuals who are vulnerable to SARS-CoV-2 co-infection. Here, we utilized single-cell transcriptomics to perform a systematic comparison of 94,442 PBMCs from 7 COVID-19 and 9 HIV-1+ patients in an integrated immune atlas, in which 27 different cell types were identified using an accurate consensus single-cell annotation method. While immune cells in both cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activities, and downregulated mitophagy. Our results elucidate transcriptional signatures associated with COVID-19 and HIV-1 that may reveal insights into fundamental disease biology and potential therapeutic targets to treat these viral infections.

Accentuating CircRNA-miRNA-Transcription Factors Axis: A Conundrum in Cancer Research

Circular RNAs (circRNAs) are the newly uncovered class of non-coding RNAs being cognized as profound regulators of gene expression in developmental and disease biology. These are the covalently closed RNAs synthesized when the pre-mRNA transcripts undergo a back-splicing event. In recent years, circRNAs are gaining special attention in the scientific world and are no longer considered as “splicing noise” but rather structurally stable molecules having multiple biological functions including acting as miRNA sponges, protein decoys/scaffolds, and regulators of transcription and translation. Further, emerging evidence suggests that circRNAs are also differentially expressed in multiple cancers where they play oncogenic roles. In addition, circRNAs in association with miRNAs change the expression patterns of multiple transcription factors (TFs), which play important roles in cancer. Thus, the circRNA-miRNA-TFs axis is implicated in the progression or suppression of various cancer types and plays a role in cell proliferation, invasion, and metastasis. In this review article, we provide an outline of the biogenesis, localization, and functions of circRNAs specifically in cancer. Also, we highlight the regulatory function of the circRNA-miRNA-TFs axis in the progression or suppression of cancer and the targeting of this axis as a potential therapeutic approach for cancer management. We anticipate that our review will contribute to expanding the knowledge of the research community about this recent and rapidly growing field of circRNAs for further thorough investigation which will surely help in the management of deadly disease cancer.

Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?

Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer “orphan” entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology.

Limited-stage Diffuse Large B-cell Lymphoma

DLBCL, the most common lymphoma subtype, is localized in 25-30% of patients. Prognosis in patients with limited-stage DLBCL (LS-DLBCL) is excellent with 10-year overall survival of at least 70-80%. Improved insights into the disease biology, the availability of positron-emission tomography (PET) scans and recent dedicated clinical trials within this unique population, have led to evolving treatment paradigms. However, no standard definition of LS-DLBCL exists, and while generally defined as Ann Arbor stages I-II disease with largest mass size <10cm in diameter, variations across studies cause challenges in interpretation. Similar to advanced-stage disease, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) immunochemotherapy forms the basis of treatment, with combined modality therapy including 3 cycles of systemic treatment and involved-site radiation therapy being a predominant historical standard. Yet the well-described continuous risk of relapse beyond 5 years and established late complications of radiotherapy have challenged previous strategies. More rigorous baseline staging and response assessment with PET may improve decision making. Recent clinical studies have focused on minimizing toxicities while maximizing disease outcomes using strategies such as abbreviated immunochemotherapy alone and PET-adapted radiotherapy delivery. This comprehensive review provides an update of recent literature with recommendations for integration into clinical practice for LS-DLBCL patients.

Treatment of older adult or frail patients with multiple myeloma

Older adults with multiple myeloma (MM) are a growing population, and personalizing treatment based on disease and health status is imperative. Similar to MM staging systems that provide disease-related prognostic information, myeloma-specific frailty tools can better identify subgroups at greatest risk for treatment-related toxicity and early treatment discontinuation, as well as predict overall survival. Several myeloma-specific validated tools are well studied. Although these fitness/frailty scores have shaped our understanding of the heterogeneity among older adults with myeloma, the application of such scores in treatment decision making (ie, transplant considerations, relapse) is an unmet need. Here we outline how to incorporate frailty assessments in the evaluation of older adults with MM in the clinical setting with consideration of other factors such as patient preferences, treatment risks/benefits, life expectancy, and disease biology.

Rare and Complex Epilepsies from Childhood to Adulthood: Requirements for Separate Management or Scope for a Lifespan Holistic Approach?

Purpose In this descriptive review, we describe current models of transition in rare and complex epilepsy syndromes and propose alternative approaches for more holistic management based on disease biology. Recent Findings Previously published guidance and recommendations on transition strategies in individuals with epilepsy have not been systematically and uniformly applied. There is significant heterogeneity in models of transition/transfer of care across countries and even within the same country. Summary We provide examples of the most severe epilepsy and related syndromes and emphasise the limited data on their outcome in adulthood. Rare and complex epilepsy syndromes have unique presentations and require high levels of expertise and multidisciplinary approach. Lifespan clinics, with no transition, but instead continuity of care from childhood to adulthood with highly specialised input from healthcare providers, may represent an alternative effective approach. Effectiveness should be measured by evaluation of quality of life for both patients and their families/caregivers.

Minority Health Disparities in Acute Myeloid Leukemia: A Metropolitan, Single-Center Retrospective Analysis

Background: Acute myeloid leukemia (AML) is an aggressive bone marrow cancer affecting 20,000 adults in the United States yearly. Five-year relative survival remains poor at 29.5%, though this has been steadily increasing. There are no known differences in diagnostic rates between racial and ethnic groups. Previous work has shown being African American is an independent predictor of poorer survival - particularly in impoverished areas and those with Medicaid. We aimed to identify potential racial disparities amongst our AML population - with special attention to insurance coverage, access to care, disease biology, regimen selection, toxicities, referral for allogeneic hematopoietic stem cell transplant (alloHSCT), and overall survival with non-Hispanic Whites as a control. Methods: This study is a retrospective analysis of patients diagnosed with AML and treated at Virginia Commonwealth University/Massey Cancer Center identified by our data analytics core from June 2018 to December 2020. Data were extracted and manually verified from the electronic medical record into an AML database instrument created in RedCap. Race was determined by self-report. Statistical analysis was performed using GraphPad Prism. Descriptive and inferential statistics were performed with comparisons between groups using an unpaired t-test with Welch's correction or with Fischer's exact test. Overall survival rates were evaluated using Kaplan-Meier analyses and compared using log-rank test. The event date was death and patients were otherwise censored at the date of last contact. Results: Our cohort consisted of 160 patients: 26.3% African Americans, 68.8% Whites, 1.9% Hispanic/Latinos, 1.9% other or declined to state, and 1.3% were unknown. To analyze the impact of minority populations, Hispanic/Latino and "other" categories were combined with African American into a "Non-White" cohort (N = 48) and compared to the "White" cohort (N = 110). There was no baseline difference in age (p= 0.212), Charleson Comorbidity Index (CCI) at presentation (p = 0.692), or ECOG status (p = 0.920) at presentation (Table 1). Assessment of disease biology, including European Leukemia Network risk stratification (p = 0.507), presence of complex karyotype (p = 0.366) and presence of TP53 mutations (p = 0.776) did not detect a statistically significant difference between the two groups (Table 1). Choice of intensive (vs non-intensive) induction based on physician's discretion was also similar (62.5% in non-White, 68.2% in Caucasians, p = 0.583). Toxicity analysis such as ICU during induction (p = 0.519) and death within 60 days of induction (p = 0.8) showed no difference between groups. In parameters assessing access to care, non-Whites were more likely than Whites to have either Medicaid or no insurance coverage, opposed to private insurance or Medicare (p = 0.0166). Despite this, there was no difference in overall survival assessed by log-rank test (p = 0.068) across all cytogenetic cohorts or with respect to the adverse risk cohort (p = 0.143), though the non-White cohort had a mOS of 286 days (9.4 months) compared to 764 days (25.1 months) in the White cohort. Rates of being lost to follow up were not different between the two groups (p = 0.34). However, rates of alloHSCT were approaching significance with p = 0.0528 favoring Caucasians. Discussion: Our data suggest similar disease biology at presentation amongst racial and ethnic groups, as well as similar comorbidities, performance status at diagnosis, and choice of induction regimen. As previous research has shown, our minority cohort was more likely to have no insurance or Medicaid than the Caucasian population. However, this did not lead to a statistically significant overall survival difference. Rates of alloHSCT were approaching statistical significance between the groups. This suggests that improving access to transplant might be one of the more effective tools for improving outcomes in this group. Additionally, demographics in the Richmond metro area demonstrate a population of 47% African American and 48% Whites, whereas our data showed 26% African Americans and 69% Whites, with no known strong racial predilection of AML based on SEER data (46% vs 54%, respectively). Thus, concern remains that there may be a significant number of patients with AML who either do not seek care, or present in a condition where treatment is no longer possible. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Hispanic or Latin American Ancestry Is Associated with a Similar Genomic Profile and a Trend Toward Inferior Outcomes in Newly Diagnosed Multiple Myeloma As Compared to Non-Hispanic White Patients in the Multiple Myeloma Research Foundation (MMRF) CoMMpassstudy

Introduction Large clinical data sets suggest that the natural history and prognosis of newly diagnosed multiple myeloma (NDMM) differs between patients of European and African ancestry, with the latter group exhibiting an earlier age at onset and poorer overall prognosis in some studies. The use of next generation sequencing (NGS) to characterize the genomic landscape of multiple myeloma (MM) suggests that the observed phenotypic differences between these groups of patients may reflect distinct underlying genomic profiles and mutational processes. Thus far, characterizations of this type have focused principally on patients of African ancestry (AA). Here, we characterize the genomic features and outcomes of a large series of patients of Hispanic or Latin American ancestry (HL) as compared to their Non-Hispanic white (NHW) counterparts. Methods Subjects were selected from the MMRF CoMMpass SM trial, a study that includes 1,154 patients with updated outcome data as of March, 2020. Within this data set, 760 patients had information on race and ethnicity. Among these, 55 HL patients and 478 NHW patients possessed complete clinical and genomic information. We analyzed baseline whole exome sequencing (WES) and long insert whole genome sequencing (WGS) as previously described (Walker, et al. Blood 2019). Our analysis focused on 63 known driver mutations in multiple myeloma and 39 sites of common copy number variation across the study population. Complex structural variants and tumor telomere length were called using previously described bioinformatic tools (Boyle et al. Leukemia 2021). Survival analysis was undertaken using the Kaplan-Meier method with hazard ratios determined by the Cox proportional hazards model. Results In a comparison of clinical features between the Hispanic and NHW population, we did not identify any differences in age of onset, gender, presenting cytogenetics, International Staging System Score (ISS), and IMWG Risk Category. The proportion of patients undergoing autologous stem cell transplantation was similar between groups. We identified no statistically significant differences in the presence of characteristic translocations involving IgH locus or in hyperdiploidy status. No statistically significant differences in tumor mutational burden or loss-of-heterozygosity percentage emerged between HL and NHW patients. We examined non-synonymous variations (NSV) and copy number variations at the loci of known MM driver genes and encountered no statistically significant differences in NSV, copy number, or biallelic status. We further categorized genes into pathways relevant to the pathogenesis of MM and discovered no difference in the proportions of patients harboring mutations in genes related to the MEK/ERK and NF-κB pathways, cell cycle regulation, and epigenetic modification. We were unable to the distinguish either population based on the presence of chromothripsis or in the overall preponderance of an APOBEC mutational signature. Tumor telomere length was not significantly different between the populations. An analysis of overall and progression free survival (PFS) with a median duration of follow up of 44 months revealed a trend toward poorer outcomes among the HL population that did not reach statistical significance. Median PFS was 24 months in HL patients and 35 months in the NHW population (p = 0.19). Median OS was not reached in either ethnic subgroup. In terms of overall survival, age, ISS score, overall number of driver mutations, and the presence of chromothripsis emerged with a negative impact on outcome (Figures 1a, 1b). These variables with the exception of chromothripsis retained their significant impact on progression free survival (Figure 2a, 2b). Conclusion The correlation between Hispanic or Latin American ancestry and underlying disease biology in MM has yet to be fully elucidated. In our analysis, which was based on self-declared ancestry as opposed to admixture, no obvious differences in significant measures of genomic variation known to impact prognosis in MM emerged between HL and NHW patients. These results may help to inform the future large-scale studies to ascertain the impact of genomics, disease biology and socioeconomic factors on outcomes in this heterogeneous patient population. Figure 1 Figure 1. Disclosures Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.

Biological Significance and Prognostic Value of Cytogenetics in 160 Patients with Multiple Myeloma: Predictivity of 13 and/or 14 Monosomies

Until recently, MM was defined using strict clinical pathological criteria that required evidence of specific end-organ damage (CRAB) attributable to the underlying clonal plasma cell disorder. In the case of absence of end-organ damage, patients with clonal plasma cell proliferation were diagnosed either with monoclonal gammopathy of undetermined significance (MGUS) or with smoldering multiple myeloma (SMM). Further, on one hand there have been on-going revisions of the diagnostic criteria for MM and SMM, on the other there have also been revisions of the molecular classification of these disorders; namely, staging and risk. These revisions regarding both the diagnostic criteria and the molecular classification of these disorders are very important because recent advances in understanding these disorders have led to significant progress in the treatment of MM and SMM, in our understanding of disease biology, and in prognostic evaluation for cancer patients. The Revised International Staging System (RISS) combines elements of tumor burden (ISS) and disease biology (presence of high-risk cytogenetic abnormalities or elevated lactate dehydrogenase level) to create a unified prognostic index that helps in clinical care, comparing clinical trial data. The RISS will be of importance in the clinic in terms of counseling patients regarding prognosis, as well as in clinical trials to compare outcomes across clinical trials. The initial cytogenetic classification of SMM also has implications for prognosis as patients with t(4;14) translocation, 17p deletion, and 1q amplification have a higher risk of progression from SMM to MM. Although patients with trisomies are considered to have a better prognosis when diagnosed with MM, they have a higher risk of progression from SMM to MM compared to patients with t(11;14). It is possible that trisomic MM manifests earlier with more obvious bone disease, producing in essence a lead-time bias. Thus, the time from SMM to MM is shortened while the time from MM to death appears longer. There are several molecular subtypes of MM, associated with several unique differences in disease presentation and prognosis. For example, trisomic MM appears to respond particularly well to lenalidomide-based therapy, while t(4;14) MM requires bortezomib-based induction and maintenance for good outcome. In terms of clinical presentation, t(4;14) MM appears to have a lower propensity for bone disease at diagnosis, while t(14;16) MM is often associated with high levels of serum free light chains (FLC) and a higher risk of acute renal failure at diagnosis. Disease biology in MM is best reflected based on the molecular subtype of the disease and the presence or absence of specific cytogenetic abnormalities. The abnormalities such as t(4;14), t(14;16), t(14;20), gain(1q), del(1p), and del(17p) influence disease course, response to therapy, and prognosis in MM. In our center we evaluated the cytogenetics data at the onset of the disease, after 1st line therapy, after transplantation and during maintenance therapy to analyze any changes in the cytogenetic panel and additional anomalies and if all this is correlated with the characteristics of the disease, patient, and risk predictor. In particular, we evaluated 160 patients and analyzed the clinical evolution in patients in which monosomies 13 and/or 14 were present, currently not classifiable in prognostic terms. The significance of these monosomies was evaluated based on the various stages of the disease and the type of therapy administered. Disclosures No relevant conflicts of interest to declare.