Proteogenomic insights into the biology and treatment of pan-melanoma.

Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.

Potential Associations Between Vitamin Intake and Leukemia: A Cross-Sectional Study.

The present study assessed potential associations between vitamin intake and leukemia in a national sample of adults in the United States. A total of 5520 participants were included in this cross-sectional study to investigate the relationship between vitamin intake (including vitamins A, C, D, and E) and leukemia. Results revealed negative associations between vitamin C and E intake and leukemia, whereas associations between vitamin A and D and leukemia were not statistically significant. For vitamin C, compared with the first tertile, the odds ratio (OR) and corresponding 95% confidential interval (CI) was 0.90 (0.75-0.95) for the second tertile and 0.82 (0.61-0.90) for the third tertile (p < 0.01). For vitamin E, compared with the first tertile, the OR and 95% CI was 0.92 (0.80-0.96) for the second tertile and 0.86 (0.71-0.92) for the third tertile (p < 0.01). Furthermore, the inverse relationship between intake of vitamins C and E and leukemia were more evident for individuals ≥60 years of age and those with a body mass index >30 kg/m2. Results of this study provide evidence suggesting that intake of vitamin C and E intake may decrease the prevalence of leukemia; however, further large-scale prospective cohort studies are needed to verify these findings.

Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma.

Soft tissue sarcoma is a broad family of mesenchymal malignancies exhibiting remarkable histological diversity. We portray the proteomic landscape of 272 soft tissue sarcomas representing 12 major subtypes. Hierarchical classification finds the similarity of proteomic features between angiosarcoma and epithelial sarcoma, and elevated expression of SHC1 in AS and ES is correlated with poor prognosis. Moreover, proteomic clustering classifies patients of soft tissue sarcoma into 3 proteomic clusters with diverse driven pathways and clinical outcomes. In the proteomic cluster featured with the high cell proliferation rate, APEX1 and NPM1 are found to promote cell proliferation and drive the progression of cancer cells. The classification based on immune signatures defines three immune subtypes with distinctive tumor microenvironments. Further analysis illustrates the potential association between immune evasion markers (PD-L1 and CD80) and tumor metastasis in soft tissue sarcoma. Overall, this analysis uncovers sarcoma-type-specific changes in proteins, providing insights about relationships of soft tissue sarcoma.

Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing.

Skeletal stem/progenitor cell (SSPC) senescence is a major cause of decreased bone regenerative potential with aging, but the causes of SSPC senescence remain unclear. In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers SSPC senescence and impairs fracture healing. Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

Bone marrow immune cells respond to fluctuating nutritional stress to constrain weight regain.

Weight regain after weight loss is a major challenge in the treatment of obesity. Immune cells adapt to fluctuating nutritional stress, but their roles in regulating weight regain remain unclear. Here, we identify a stem cell-like CD7+ monocyte subpopulation accumulating in the bone marrow (BM) of mice and humans that experienced dieting-induced weight loss. Adoptive transfer of CD7+ monocytes suppresses weight regain, whereas inducible depletion of CD7+ monocytes accelerates it. These cells, accumulating metabolic memories via epigenetic adaptations, preferentially migrate to the subcutaneous white adipose tissue (WAT), where they secrete fibrinogen-like protein 2 (FGL2) to activate the protein kinase A (PKA) signaling pathway and facilitate beige fat thermogenesis. Nevertheless, CD7+ monocytes gradually enter a quiescent state after weight loss, accompanied by increased susceptibility to weight regain. Notably, administration of FMS-like tyrosine kinase 3 ligand (FLT3L) remarkably rejuvenates CD7+ monocytes, thus ameliorating rapid weight regain. Together, our findings identify a unique bone marrow-derived metabolic-memory immune cell population that could be targeted to combat obesity.

SARS-CoV-2 Omicron BA.5.2-infection and COVID-19 in persons with chronic myeloid leukaemia.

OBJECTIVE: A SARS-CoV-2 Omicron (BA.5.2) epidemic began in China in December, 2022 following stopping the zero COVID policy. METHODS: We studied features of the epidemic in 1,121 persons with chronic myeloid leukaemia (CML). RESULTS: 1103 (98%) were in chronic, 10 in accelerated and 8 in acute phases. 834 (74%) became infected almost all of whom met criteria for COVID-19. The most common symptoms were fever (91%), cough (90%) and fatigue (82%). 42 infected persons were asymptomatic. Most people quarantined at home and self-medicated. 22 were hospitalized for COVID-19. At admission 5 had mild, 14, moderate and 3, severe/critical disease according to World Health Organization (WHO) criteria. 5 received respiratory assistance, 3 were admitted to the intensive care unit (ICU) and 1 in accelerated phase died from COVID-19. Co-variates associated with a risk of COVID-19 in SARS-CoV-2-infected subjects include age ≥ 65 years, higher education level and imatinib therapy. CONCLUSION: In conclusion, most SARS-CoV-2 Omicron BA.5.2 infections in persons with CML resulted in COVID-19 most of which cases are mild with only 1 death.

Splicing factor YBX1 regulates bone marrow stromal cell fate during aging.

Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms.

Diffuse gliomas are devastating brain tumors. Here, we perform a proteogenomic profiling of 213 retrospectively collected glioma tumors. Proteogenomic analysis reveals the downstream biological events leading by EGFR-, IDH1-, TP53-mutations. The comparative analysis illustrates the distinctive features of GBMs and LGGs, indicating CDK2 inhibitor might serve as a promising drug target for GBMs. Further proteogenomic integrative analysis combined with functional experiments highlight the cis-effect of EGFR alterations might lead to glioma tumor cell proliferation through ERK5 medicates nucleotide synthesis process. Proteome-based stratification of gliomas defines 3 proteomic subgroups (S-Ne, S-Pf, S-Im), which could serve as a complement to WHO subtypes, and would provide the essential framework for the utilization of specific targeted therapies for particular glioma subtypes. Immune clustering identifies three immune subtypes with distinctive immune cell types. Further analysis reveals higher EGFR alteration frequencies accounts for elevation of immune check point protein: PD-L1 and CD70 in T-cell infiltrated tumors.

Mutated lncRNA increase the risk of type 2 diabetes by promoting ß cell dysfunction and insulin resistance.

Islet ß cell dysfunction and insulin resistance are the main pathogenesis of type 2 diabetes (T2D), but the mechanism remains unclear. Here we identify a rs3819316 C > T mutation in lncRNA Reg1cp mainly expressed in islets associated with an increased risk of T2D. Analyses in 16,113 Chinese adults reveal that Mut-Reg1cp individuals had higher incidence of T2D and presented impaired insulin secretion as well as increased insulin resistance. Mice with islet ß cell specific Mut-Reg1cp knock-in have more severe ß cell dysfunction and insulin resistance. Mass spectrometry assay of proteins after RNA pulldown demonstrate that Mut-Reg1cp directly binds to polypyrimidine tract binding protein 1 (PTBP1), further immunofluorescence staining, western blot analysis, qPCR analysis and glucose stimulated insulin secretion test reveal that Mut-Reg1cp disrupts the stabilization of insulin mRNA by inhibiting the phosphorylation of PTBP1 in ß cells. Furthermore, islet derived exosomes transfer Mut-Reg1cp into peripheral tissue, which then promote insulin resistance by inhibiting AdipoR1 translation and adiponectin signaling. Our findings identify a novel mutation in lncRNA involved in the pathogenesis of T2D, and reveal a new mechanism for the development of T2D.

A mechanosensitive lipolytic factor in the bone marrow promotes osteogenesis and lymphopoiesis.

Exercise can prevent osteoporosis and improve immune function, but the mechanism remains unclear. Here, we show that exercise promotes reticulocalbin-2 secretion from the bone marrow macrophages to initiate bone marrow fat lipolysis. Given the crucial role of lipolysis in exercise-stimulated osteogenesis and lymphopoiesis, these findings suggest that reticulocalbin-2 is a pivotal regulator of a local adipose-osteogenic/immune axis. Mechanistically, reticulocalbin-2 binds to a functional receptor complex, which is composed of neuronilin-2 and integrin beta-1, to activate a cAMP-PKA signaling pathway that mobilizes bone marrow fat via lipolysis to fuel the differentiation and function of mesenchymal and hematopoietic stem cells. Notably, the administration of recombinant reticulocalbin-2 in tail-suspended and old mice remarkably decreases bone marrow fat accumulation and promotes osteogenesis and lymphopoiesis. These findings identify reticulocalbin-2 as a novel mechanosensitive lipolytic factor in maintaining energy homeostasis in bone resident cells, and it provides a promising target for skeletal and immune health.

A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population.

Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1-3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline.

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome.

Senescent immune cells release grancalcin to promote skeletal aging.

Skeletal aging is characterized by low bone turnover and marrow fat accumulation. However, the underlying mechanism for this imbalance is unclear. Here, we show that during aging in rats and mice proinflammatory and senescent subtypes of immune cells, including macrophages and neutrophils, accumulate in the bone marrow and secrete abundant grancalcin. The injection of recombinant grancalcin into young mice was sufficient to induce premature skeletal aging. In contrast, genetic deletion of Gca in neutrophils and macrophages delayed skeletal aging. Mechanistically, we found that grancalcin binds to the plexin-b2 receptor and partially inactivates its downstream signaling pathways, thus repressing osteogenesis and promoting adipogenesis of bone marrow mesenchymal stromal cells. Heterozygous genetic deletion of Plexnb2 in skeletal stem cells abrogated the improved bone phenotype of Gca-knockout mice. Finally, we developed a grancalcin-neutralizing antibody and showed that its treatment of older mice improved bone health. Together, our data suggest that grancalcin could be a potential target for the treatment of age-related osteoporosis.

Systemic risk factors correlated with hyperhomocysteinemia for specific MTHFR C677T genotypes and sex in the Chinese population.

BACKGROUND: Methyltetrahydrofolate reductase (MTHFR) is a main regulatory enzyme in homocysteine (Hcy) metabolism. A common C677T mutation in the MTHFR gene results in decreased enzyme activity, which contributes to hyperhomocysteinemia (HHcy). Previous studies have shown that HHcy was correlated with various systemic diseases, such as cardiovascular disease, stroke, cancer, renal failure and so on. However, we hypothesized that HHcy in different genotype and sex groups may have different risk factors, which would lead to various pathologic states. Therefore, the aim of this study was to explore systemic information that are correlated with HHcy for specific MTHFR C677T genotypes and sex, which might be useful for predicting and preventing systemic diseases. METHODS: This cross-sectional study was performed through November 2017 to July 2019. A total of 4,534 adults aged 20-75 y were selected for this study. All the participants underwent a physical examination, blood tests and MTHFRC677T genotyping. Multivariable linear regression was performed to explore the risk factors for HHcy for each sex and genotype. RESULTS: The average of Hcy level is higher in the TT genotype than CC and CT genotypes (P=0.000). Multiple linear regression analysis identified the common protective factors (folate and Vit B12) and risk factor (Cr) for HHcy. Besides that, each group has its specific risk factors-female-CT (age, SBP, and Hb), female-TT (SBP and AST); male-CC (age, AST and Hb), male-CT (age and AST) and male-TT (SBP, AST, and Hb). CONCLUSIONS: HHcy was associated with different risk factors for each specific sex and genotype. These risk factors might be useful for predicting and preventing systemic diseases.

Ophiopogonin D promotes bone regeneration by stimulating CD31hi EMCNhi vessel formation.

OBJECTIVES: CD31hi EMCNhi vessels (CD31, also known as PECAM1 [platelet and endothelial cell adhesion molecule 1]; EMCN, endomucin), which are strongly positive for CD31 and endomucin, couple angiogenesis and osteogenesis. However, the role of CD31hi EMCNhi vessels in bone regeneration remains unknown. In the present study, we investigated the role of CD31hi EMCNhi vessels in the process of bone regeneration. MATERIALS AND METHODS: We used endothelial-specific Krüppel like factor 3 (Klf3) knockout mice and ophiopogonin D treatment to interfere with CD31hi EMCNhi vessel formation. We constructed a bone regeneration model by surgical ablation of the trabecular bone. Immunofluorescence and micro-computed tomography (CT) were used to detect CD31hi EMCNhi vessels and bone formation. RESULTS: CD31hi EMCNhi vessels participate in the process of bone regeneration, such that endothelial-specific Klf3 knockout mice showed increased CD31hi EMCNhi vessels and osteoprogenitors in the bone regeneration area, and further accelerated bone formation. We also demonstrated that the natural compound, ophiopogonin D, acts as a KLF3 inhibitor to promote vessels formation both in vitro and in vivo. Administration of ophiopogonin D increased the abundance of CD31hi Emcnhi vessels and accelerated bone healing. CONCLUSIONS: Our findings confirmed the important role of CD31hi Emcnhi vessels in bone regeneration and provided a new target to treat bone fracture or promote bone regeneration.

Reducing Hypothalamic Stem Cell Senescence Protects against Aging-Associated Physiological Decline.

Age-dependent loss of hypothalamic neural stem cells (htNSCs) is important for the pathological consequences of aging; however, it is unclear what drives the senescence of htNSCs. Here, we report that a long non-coding RNA, Hnscr, is abundantly expressed in the htNSCs of young mice but decreases markedly in middle-aged mice. We show that depletion of Hnscr is sufficient to drive the senescence of htNSCs and aging-like phenotypes in mice. Mechanistically, Hnscr binds to Y-box protein 1 (YB-1) to prevent its degradation and thus the attenuation of transcription of the senescence marker gene p16INK4A. Through molecular docking, we discovered that a naturally occurring small compound, theaflavin 3-gallate, can mimic the activity of Hnscr. Treatment of middle-aged mice with theaflavin 3-gallate reduced the senescence of htNSCs while improving aging-associated pathology. These results point to a mediator of the aging process and one that can be pharmacologically targeted to improve aging-related outcomes.

Copper-Indium Binary Catalyst on a Gas Diffusion Electrode for High-Performance CO2 Electrochemical Reduction with Record CO Production Efficiency.

Cu-In metallic hybrid is a promising non-noble catalyst for selective electrochemical CO2 reduction (eCO2R) to CO, but the lack of direct assembly with a gas diffusion electrode (GDE) limits the further development of eCO2R to CO with both high Faradaic efficiency (FE) and high current density. In this study, an in situ electrochemical spontaneous precipitation (ESP) method was applied for the first time to prepare GDE-combined Cu-In electrocatalysts. The optimum Cu-In catalyst consists of a nanoscale "core-shell" structure of polycrystalline CuxO covered by the amorphous In(OH)3 interface. Higher than 90% FE of CO production has been achieved. With the synergy of a GDE flow cell and 1 M KOH catholyte, a current density of ∼200 mA cm-2 was reached at -1.17 V (reversible hydrogen electrode), which enabled a CO yield efficiency record of 3.05 mg min-1(CO2/15 mL min-1 with a 2 cm2 electrode). The ratios between CO and H2 produced can be effectively modulated via fine-tuning ESP conditions demonstrating possibility of generating CO or syngas with tuneable ratios. The present study provides a simple approach for constructing novel catalytic interfaces with dual active centers for eCO2R and other emerging electrochemical catalysis research.

Krüppel-like factor 3 inhibition by mutated lncRNA Reg1cp results in human high bone mass syndrome.

High bone mass (HBM) is usually caused by gene mutations, and its mechanism remains unclear. In the present study, we identified a novel mutation in the long noncoding RNA Reg1cp that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous Reg1cp individuals had higher bone density compared with subjects with WT Reg1cp Mutant Reg1cp increased the formation of the CD31hiEmcnhi endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant Reg1cp directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of Klf3 in endothelial cells showed a high abundance of CD31hiEmcnhi vessels and increased bone mass. Notably, we identified a natural compound, Ophiopogonin D, which functions as a KLF3 inhibitor. Administration of Ophiopogonin D increased the abundance of CD31hiEmcnhi vessels and bone formation. Our findings revealed a specific mutation in lncRNA Reg1cp that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis.