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Nature Jul 2023Human genomics is witnessing an ongoing paradigm shift from a single reference sequence to a pangenome form, but populations of Asian ancestry are underrepresented. Here...
Human genomics is witnessing an ongoing paradigm shift from a single reference sequence to a pangenome form, but populations of Asian ancestry are underrepresented. Here we present data from the first phase of the Chinese Pangenome Consortium, including a collection of 116 high-quality and haplotype-phased de novo assemblies based on 58 core samples representing 36 minority Chinese ethnic groups. With an average 30.65× high-fidelity long-read sequence coverage, an average contiguity N50 of more than 35.63 megabases and an average total size of 3.01 gigabases, the CPC core assemblies add 189 million base pairs of euchromatic polymorphic sequences and 1,367 protein-coding gene duplications to GRCh38. We identified 15.9 million small variants and 78,072 structural variants, of which 5.9 million small variants and 34,223 structural variants were not reported in a recently released pangenome reference. The Chinese Pangenome Consortium data demonstrate a remarkable increase in the discovery of novel and missing sequences when individuals are included from underrepresented minority ethnic groups. The missing reference sequences were enriched with archaic-derived alleles and genes that confer essential functions related to keratinization, response to ultraviolet radiation, DNA repair, immunological responses and lifespan, implying great potential for shedding new light on human evolution and recovering missing heritability in complex disease mapping.
Topics: Humans; East Asian People; Ethnicity; Genome, Human; Sequence Analysis, DNA; Ultraviolet Rays; Human Genetics; Minority Groups; Ethnic and Racial Minorities; Reference Standards; Haplotypes; Euchromatin; Genetic Variation; Alleles; DNA Repair; Keratins; Longevity; Immunity
PubMed: 37316654
DOI: 10.1038/s41586-023-06173-7 -
Frontiers in Immunology 2023Immunotherapy has transformed treatment for various types of malignancy. However, the benefit of immunotherapy is limited to a minority of patients with... (Review)
Review
Immunotherapy has transformed treatment for various types of malignancy. However, the benefit of immunotherapy is limited to a minority of patients with mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) (dMMR-MSI-H) colorectal cancer (CRC). Understanding the complexity and heterogeneity of the tumor immune microenvironment (TIME) and identifying immune-related CRC subtypes will improve antitumor immunotherapy. Here, we review the current status of immunotherapy and typing schemes for CRC. Immune subtypes have been identified based on TIME and prognostic gene signatures that can both partially explain clinical responses to immune checkpoint inhibitors and the prognosis of patients with CRC. Identifying immune subtypes will improve understanding of complex CRC tumor heterogeneity and refine current immunotherapeutic strategies.
Topics: Humans; Immunotherapy; Prognosis; Colorectal Neoplasms; Microsatellite Instability; Tumor Microenvironment
PubMed: 37876934
DOI: 10.3389/fimmu.2023.1259461 -
Cell Oct 2023The mpox outbreak of 2022-2023 involved rapid global spread in men who have sex with men. We infected 18 rhesus macaques with mpox by the intravenous, intradermal, and...
The mpox outbreak of 2022-2023 involved rapid global spread in men who have sex with men. We infected 18 rhesus macaques with mpox by the intravenous, intradermal, and intrarectal routes and observed robust antibody and T cell responses following all three routes of infection. Numerous skin lesions and high plasma viral loads were observed following intravenous and intradermal infection. Skin lesions peaked on day 10 and resolved by day 28 following infection. On day 28, we re-challenged all convalescent and 3 naive animals with mpox. All convalescent animals were protected against re-challenge. Transcriptomic studies showed upregulation of innate and inflammatory responses and downregulation of collagen formation and extracellular matrix organization following challenge, as well as rapid activation of T cell and plasma cell responses following re-challenge. These data suggest key mechanistic insights into mpox pathogenesis and immunity. This macaque model should prove useful for evaluating mpox vaccines and therapeutics.
Topics: Animals; Humans; Male; Homosexuality, Male; Macaca mulatta; Mpox (monkeypox); Sexual and Gender Minorities; Monkeypox virus
PubMed: 37734373
DOI: 10.1016/j.cell.2023.08.023 -
Current Opinion in Psychology Feb 2024Bereavement is a common and often challenging experience in late life. Evidence shows that while many older adults manage to adjust well and demonstrate resilience in... (Review)
Review
Bereavement is a common and often challenging experience in late life. Evidence shows that while many older adults manage to adjust well and demonstrate resilience in response to the death of a close person, bereavement puts a substantial minority at risk of adverse mental and physical health impacts including mortality. Current research further indicates that 1) this is the case across different countries and cultures across the globe; 2) that the COVID-19 pandemic posed unprecedented challenges for coping with late-life bereavement; 3) that loneliness and social isolation among bereaved older adults tend to be prevalent and harmful, particularly under pandemic but also in nonpandemic circumstances; and, recently, 4) that bereavement may be a risk factor for cognitive decline in this population.
Topics: Female; Humans; Aged; Pandemics; Widowhood; Bereavement; Grief; Loneliness
PubMed: 38071788
DOI: 10.1016/j.copsyc.2023.101748 -
Frontiers in Plant Science 2023Leaf phenology (evergreen vs. deciduous) and morphology (simple vs. compound) are known to be related to water use strategies in tree species and critical adaptation to...
Leaf phenology (evergreen vs. deciduous) and morphology (simple vs. compound) are known to be related to water use strategies in tree species and critical adaptation to certain climatic conditions. However, the effect of these two traits and their interactions on the coordination between minor vein density (MVD) and stomatal density (SD) remains unclear. In this study, we examined the leaves of 108 tree species from plots in a primary subtropical forest in southern China, including tree species with different leaf morphologies and phenologies. We assessed nine leaf water-related functional traits for all species, including MVD, SD, leaf area (LA), minor vein thickness (MVT), and stomatal length (SL). The results showed no significant differences in mean LA and SD between either functional group (simple vs. compound and evergreen vs. deciduous). However, deciduous trees displayed a significantly higher mean MVD compared to evergreen trees. Similarly, compound-leaved trees have a higher (marginally significant) MVD than simple-leaved trees. Furthermore, we found that leaf morphology and phenology have significantly interactive effects on SL, and the compound-leafed deciduous trees exhibited the largest average SL among the four groups. There were significant correlations between the MVD and SD in all different tree groups; however, the slopes and interceptions differed within both morphology and phenology. Our results indicate that MVD, rather than SD, may be the more flexible structure for supporting the coordination between leaf water supply and demand in different leaf morphologies and phenologies. The results of the present study provide mechanistic understandings of the functional advantages of different leaf types, which may involve species fitness in community assembly and divergent responses to climate changes.
PubMed: 37564389
DOI: 10.3389/fpls.2023.1051692 -
JAMA Network Open Dec 2023Prosocial interventions encourage voluntary actions that benefit others. Community solidarity in response to the COVID-19 pandemic, expanding mutual aid programs, and... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Prosocial interventions encourage voluntary actions that benefit others. Community solidarity in response to the COVID-19 pandemic, expanding mutual aid programs, and health workforce issues have accelerated prosocial health interventions.
OBJECTIVE
To investigate the association of prosocial interventions with health outcomes in clinical trials and observational studies.
DATA SOURCES
In this systematic review and meta-analysis informed by the Cochrane Handbook for Systematic Reviews of Interventions, 5 databases (MEDLINE [via PubMed], Embase, CINAHL, PsycInfo, and Scopus) were searched from database inception through February 23, 2023. The search included terms for altruism and prosocial behaviors, health outcomes, and study type.
STUDY SELECTION
Included studies, determined by multiple reviewers, compared health outcomes in a prosocial intervention group with a nonintervention group.
DATA EXTRACTION AND SYNTHESIS
Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, data extraction and synthesis captured quantitative and qualitative data. To pool data from quantitative studies, random-effects meta-analyses were used to estimate the impact of prosocial interventions. To combine data from quantitative and qualitive studies, data were transformed into qualitative narratives using meta-aggregation.
MAIN OUTCOMES AND MEASURES
The main outcome was whether prosocial interventions were associated with improved health outcomes. Barriers to and facilitators of implementation of these interventions were assessed.
RESULTS
The search identified 5229 citations; 30 studies were included in the synthesis. Studies indicated that prosocial interventions were associated with positive health outcomes for givers (17 studies [56.7]) and recipients (8 [26.7%]). Prosocial interventions included acts of kindness (12 studies [40.0%]), cash gifts (7 [23.3%]), pay-it-forward approaches (6 [20.0%]), and expressions of kindness (5 [16.7%]). Improvements were reported in depression, testing for sexually transmitted diseases, vaccine uptake, physical activity, and individual biomarkers. Data from 6 studies (20.0%) demonstrated that pay-it-forward approaches were associated with increased uptake of diagnostic tests or vaccines among vulnerable groups (moderate certainty of evidence). Data from 14 studies (46.7%) suggested that community connectedness facilitated prosocial interventions. Shared vulnerabilities among groups (eg, sexual minority individuals, older adults) may provide a context for collective mobilization to improve health in local communities.
CONCLUSIONS AND RELEVANCE
This systematic review and meta-analysis found that prosocial interventions were associated with improved health outcomes among vulnerable groups and have been useful for addressing health disparities. Further research is needed to develop and evaluate prosocial interventions.
Topics: Humans; Aged; Pandemics; COVID-19
PubMed: 38064214
DOI: 10.1001/jamanetworkopen.2023.46789 -
Cancers Sep 2023Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment...
Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment of relapsed and refractory neuroblastoma. Chemoimmunotherapy, using a humanized anti-GD2 mAb, demonstrated a signal of activity in a phase 2 study for the treatment of patients with newly diagnosed high-risk neuroblastoma (HRNBL). In this single-institution retrospective study, patients with HRNBL received an Induction chemotherapy regimen plus DIN in all Induction cycles. Toxicity and response data were abstracted from the electronic medical record. Toxicities were graded by CTCAE v.5.0. The end of Induction (EOI) objective response rate was determined using the Revised International Neuroblastoma Response Criteria. Twenty-seven patients with HRNBL (23 newly diagnosed, 16 females, median age 3.9 years) started Induction chemoimmunotherapy from 27 January 2017 to 28 December 2022. All patients received DIN with all cycles of Induction therapy, and all but one patient completed Induction therapy. The most common non-hematologic grade ≥ 3 toxicities included fever (44%), hypoxemia (20%), and hypoalbuminemia (11%). End of Induction responses included eighteen with a complete response (CR), seven with a partial response (PR), one with progressive disease (PD), and zero with a minor response or stable disease. Twenty-six of twenty-seven patients (96%) completed all Induction cycles and were evaluable for a response. The EOI response of PR or better in the evaluable cohort was 96%. Dinutuximab was well tolerated with all Induction cycles, demonstrated an encouraging EOI response rate, and should be evaluated in a randomized study.
PubMed: 37760578
DOI: 10.3390/cancers15184609 -
Cell Reports. Medicine Aug 2023Immune checkpoint immunotherapy (ICI) can re-activate immune reactions against neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a...
Immune checkpoint immunotherapy (ICI) can re-activate immune reactions against neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness are needed to improve the success of cancer treatments. While the tumor mutational burden (TMB) correlates positively with responsiveness and survival of patients undergoing ICI, the influence of the subcellular localizations of the neoantigens remains unclear. Here, we demonstrate in both a mouse melanoma model and human clinical datasets of 1,722 ICI-treated patients that a high proportion of membrane-localized neoantigens, particularly at the plasma membrane, correlate with responsiveness to ICI therapy and improved overall survival across multiple cancer types. We further show that combining membrane localization and TMB analyses can enhance the predictability of cancer patient response to ICI. Our results may have important implications for establishing future clinical guidelines to direct the choice of treatment toward ICI.
Topics: Animals; Humans; Mice; Biomarkers, Tumor; Immunotherapy; Melanoma
PubMed: 37552990
DOI: 10.1016/j.xcrm.2023.101145