Re-expression of epigenetically silenced PTPRR by histone acetylation sensitizes RAS-mutant lung adenocarcinoma to SHP2 inhibition.

Silenced protein tyrosine phosphatase receptor type R (PTPRR) participates in mitogen-activated protein kinase (MAPK) signaling cascades during the genesis and development of tumors. Rat sarcoma virus (Ras) genes are frequently mutated in lung adenocarcinoma, thereby resulting in hyperactivation of downstream MAPK signaling. However, the molecular mechanism manipulating the regulation and function of PTPRR in RAS-mutant lung adenocarcinoma is not known. Patient records collected from the Cancer Genome Atlas and Gene Expression Omnibus showed that silenced PTPRR was positively correlated with the prognosis. Exogenous expression of PTPRR suppressed the proliferation and migration of lung cancer cells. PTPRR expression and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibition acted synergistically to control ERK1/2 phosphorylation in RAS-driven lung cancer cells. Chromatin immunoprecipitation assay revealed that HDAC inhibition induced enriched histone acetylation in the promoter region of PTPRR and recovered PTPRR transcription. The combination of the HDAC inhibitor SAHA and SHP2 inhibitor SHP099 suppressed the progression of lung cancer markedly in vitro and in vivo. Therefore, we revealed the epigenetic silencing mechanism of PTPRR and demonstrated that combination therapy targeting HDAC and SHP2 might represent a novel strategy to treat RAS-mutant lung cancer.

The effect of extracellular polymeric substances on MICP solidifying rare earth slags and stabilizing Th and U.

Microbially induced carbonate precipitation (MICP) has been used to cure rare earth slags (RES) containing radionuclides (e.g. Th and U) and heavy metals with favorable results. However, the role of microbial extracellular polymeric substances (EPS) in MICP curing RES remains unclear. In this study, the EPS of Lysinibacillus sphaericus K-1 was extracted for the experiments of adsorption, inducing calcium carbonate (CaCO3) precipitation and curing of RES. The role of EPS in in MICP curing RES and stabilizing radionuclides and heavy metals was analyzed by evaluating the concentration and morphological distribution of radionuclides and heavy metals, and the compressive strength of the cured body. The results indicate that the adsorption efficiencies of EPS for Th (IV), U (VI), Cu2+, Pb2+, Zn2+, and Cd2+ were 44.83%, 45.83%, 53.7%, 61.3%, 42.1%, and 77.85%, respectively. The addition of EPS solution resulted in the formation of nanoscale spherical particles on the microorganism surface, which could act as an accumulating skeleton to facilitate the formation of CaCO3. After adding 20 mL of EPS solution during the curing process (Treat group), the maximum unconfined compressive strength (UCS) of the cured body reached 1.922 MPa, which was 12.13% higher than the CK group. The contents of exchangeable Th (IV) and U (VI) in the cured bodies of the Treat group decreased by 3.35% and 4.93%, respectively, compared with the CK group. Therefore, EPS enhances the effect of MICP curing RES and reduces the potential environmental problems that may be caused by radionuclides and heavy metals during the long-term sequestration of RES.

Systematical identification of cell-specificity of CTCF-gene binding based on epigenetic modifications.

The CCCTC-binding factor (CTCF) mediates transcriptional regulation and implicates epigenetic modifications in cancers. However, the systematically unveiling inverse regulatory relationship between CTCF and epigenetic modifications still remains unclear, especially the mechanism by which histone modification mediates CTCF binding. Here, we developed a systematic approach to investigate how epigenetic changes affect CTCF binding. Through integration analysis of CTCF binding in 30 cell lines, we concluded that CTCF generally binds with higher intensity in normal cell lines than that in cancers, and higher intensity in genome regions closed to transcription start sites. To facilitate the better understanding of their associations, we constructed linear mixed-effect models to analyze the effects of the epigenetic modifications on CTCF binding in four cancer cell lines and six normal cell lines, and identified seven epigenetic modifications as potential epigenetic patterns that influence CTCF binding intensity in promoter regions and six epigenetic modifications in enhancer regions. Further analysis of the effects in different locations revealed that the epigenetic regulation of CTCF binding was location-specific and cancer cell line-specific. Moreover, H3K4me2 and H3K9ac showed the potential association with immune regulation of disease. Taken together, our method can contribute to improve the understanding of the epigenetic regulation of CTCF binding and provide potential therapeutic targets for treating tumors associated with CTCF.

Prognostic value of the nutritional risk index in patients with newly diagnosed multiple myeloma.

The nutritional risk index (NRI), which is based on weight and albumin levels, is closely associated with the prognosis of many cancers. However, its prognostic value has not been investigated in patients with newly diagnosed multiple myeloma (NDMM). We aimed to assess the association between the NRI and survival outcomes in patients with NDMM. We retrospectively collected and analyzed clinical and laboratory data from patients with NDMM between 2005 and 2019 at our center. Patients were stratified into the high NRI (> 89) and low NRI (≤ 89) groups for prognostic analysis. The NRI and other variables were also explored to evaluate their prognostic value for overall survival (OS). A total of 638 patients diagnosed with NDMM were retrospectively included. Patients in the high NRI group had a significantly better median OS than those in the low NRI group (64 months vs 43 months, p < 0.001). In the multivariate analysis, a high NRI was shown to be an independent prognostic factor for OS (hazard ratio, 0.758; 95% confidence interval, 0.587-0.977; p = 0.033). Age, performance status, transplant status, and lactate dehydrogenase level were also independent prognostic factors for OS. In conclusion, our study demonstrates that the NRI is a simple and useful predictor of survival outcomes in patients with NDMM.

SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling.

The metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tumor proliferation and development. However, the precise role and function of SHMT2 in gastric cancer (GC) remain poorly understood. In this study, we presented evidence that SHMT2 was necessary for hypoxia-inducible factor-1α (HIF1α) stability and contributed to GC cells' hypoxic adaptation. The analysis of datasets retrieved from The Cancer Genome Atlas and the experimentation with human cell lines revealed a marked increase in SHMT2 expression in GC. The SHMT2 knockdown in MGC803, SGC7901, and HGC27 cell lines inhibited cell proliferation, colony formation, invasion, and migration. Notably, SHMT2 depletion disrupted redox homeostasis and caused glycolytic function loss in GC cells under hypoxic circumstances. Mechanistically, we discovered SHMT2 modulated HIF1α stability, which acted as a master regulator of hypoxia-inducible genes under hypoxic conditions. This, in turn, regulated the downstream VEGF and STAT3 pathways. The in vivo xenograft experiments showed that SHMT2 knockdown markedly reduced GC growth. Our results elucidate the novel function of SHMT2 in stabilizing HIF1α under hypoxic conditions, thus providing a potential therapeutic strategy for GC treatment.

Extraction of extracellular polymeric substances (EPS) from indigenous bacteria of rare earth tailings and application to removal of thorium ions (Th4+).

Thorium, as an important radioactive element, is widely present in nature, and its accompanying environmental pollution is also serious. Extracellular polymeric substances (EPS) are commonly found on the surface of microbial bodies and have strong adsorption capacity for metal ions. In this study, four methods were used to extract EPS from indigenous bacteria of rare earth tailings and to determine the best extraction method. The extracted EPS was applied to treat Th4+, and the changes in functional groups and composition of EPS were investigated. The results showed that the ultrasonic method was more efficient than other methods. The best removal efficiency was observed at pH 3.5, Th4+ concentration of 20 mg/L, and EPS dosage of 30 mL at 25 °C. After 9 h, the adsorption process reached equilibrium with a maximum removal efficiency of 75.93% and a maximum theoretical adsorption capacity of 25.96 mg/g. The Th4+ removal process was consistent with the Langmuir and Freundlich adsorption isotherms and the kinetic data were consistent with the pseudo-second-order kinetic model, which is mainly based on chemisorption. Amide I and amide II of proteins, C-H from aliphatic, as well as O-H and C = O from carboxylic acid play important roles in the adsorption process.

Malignant clonal evolution drives multiple myeloma cellular ecological diversity and microenvironment reprogramming.

BACKGROUND: Multiple myeloma (MM) is a heterogeneous disease with different patterns of clonal evolution and a complex tumor microenvironment, representing a challenge for clinicians and pathologists to understand and dissect the contribution and impact of polyclonality on tumor progression. METHODS: In this study, we established a global cell ecological landscape of the bone marrow (BM) from MM patients, combining single-cell RNA sequencing and single-molecule long-read genome sequencing data. RESULTS: The malignant mutation event was localized to the tumor cell clusters with shared mutation of ANK1 and IFITM2 in all malignant subpopulations of all MM patients. Therefore, these two variants occur in the early stage of malignant clonal origin to mediate the malignant transformation of proplasmacytes or plasmacytes to MM cells. Tumor cell stemness index score and pseudo-sequential clonal evolution analysis can be used to divide the evolution model of MM into two clonal origins: types I and IX. Notably, clonal evolution and the tumor microenvironment showed an interactive relationship, in which the evolution process is not only selected by but also reacts to the microenvironment; thus, vesicle secretion enriches immune cells with malignant-labeled mRNA for depletion. Interestingly, microenvironmental modification exhibited significant heterogeneity among patients. CONCLUSIONS: This characterization of the malignant clonal evolution pattern of MM at the single-cell level provides a theoretical basis and scientific evidence for a personalized precision therapy strategy and further development of a potential new adjuvant strategy combining epigenetic agent and immune checkpoint blockade.

Fear of cancer recurrence in patients with multiple myeloma: Prevalence and predictors based on a family model analysis.

OBJECTIVE: Fear of cancer recurrence (FCR) is a common psychosocial sequela among cancer survivors, but data on patients with multiple myeloma are scarce. This study calculated the prevalence of FCR and identified family and social factors that predict FCR in the study population. METHODS: We recruited 127 myeloma patients and their partners to participate in a cross-sectional survey from a regional tertiary cancer centre in China. The questionnaires included items on demographic characteristics and from the fear of disease progression simplified scale, family hardiness index and Social Support Scale. Univariate and multivariate regression was used to identify predictors of FCR. RESULTS: Of the participants, 56.4% patients reported high-level FCR, which was similar to the partner-reported proportion. The partners' FCR was positively associated with the patients' FCR, while family hardiness and social support were statistically significant, negative predictors. CONCLUSIONS: Interventions to mitigate partners' FCR and improve family hardiness and social support may help with the psychological adjustment and well-being of myeloma patients.

Serum interleukin-6 is an indicator for severity in 901 patients with SARS-CoV-2 infection: a cohort study.

BACKGROUND: Interleukin-6 (IL-6) was proposed to be associated with the severity of coronavirus disease 2019 (COVID-19). The present study aimed to explore the kinetics of IL-6 levels, validate this association in COVID-19 patients, and report preliminary data on the efficacy of IL-6 receptor blockade. METHODS: We conducted a retrospective single-institutional study of 901 consecutive confirmed cases. Serum IL-6 concentrations were tested on admission and/or during hospital stay. Tocilizumab was given to 16 patients with elevated IL-6 concentration. RESULTS: 366 patients were defined as common cases, 411 patients as severe, and 124 patients as critical according to the Chinese guideline on diagnosis and treatment of COVID-19. The median concentration of IL-6 was < 1.5 pg/ml (IQR < 1.50-2.15), 1.85 pg/ml (IQR < 1.50-5.21), and 21.55 pg/ml (IQR 6.47-94.66) for the common, severe, and critical groups respectively (P < 0.001). The follow-up kinetics revealed serum IL-6 remained high in critical patients even when cured. An IL-6 concentration higher than 37.65 pg/ml was predictive of in-hospital death (AUC 0.97 [95% CI 0.95-0.99], P < 0.001) with a sensitivity of 91.7% and a specificity of 95.7%. In the 16 patients who received tocilizumab, IL-6 concentrations were significantly increased after administration, and survival outcome was not significantly different from that of propensity-score matched counterparts (n = 53, P = 0.12). CONCLUSION: Serum IL-6 should be included in diagnostic work-up to stratify disease severity, but the benefit of tocilizumab needs further confirmation. Trial registration retrospectively registered.