Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity.

cytohesin-2 is a guanine nucleotide exchange factor to activate ARF1 and ARF6, which are involved in various biological processes, including signal transduction, cell differentiation, cell structure organization, and survival. Nevertheless, there is a lack of evidence revealing the role of cytohesin-2 in osteoclast differentiation and in the development of osteoporosis. In this study, we find cytohesin-2 and ARF1 positively regulate osteoclast differentiation and function. Blocking the cytohesin-2 /ARF1 axis with SecinH3 or by genetic silencing of cytohesin-2 inhibits osteoclast formation and function in vitro. In vivo treatment with SecinH3 ameliorates ovariectomy-induced osteoporosis. Mechanistically, RNA-sequencing combined with molecular biological methodologies reveal that the regulatory function of cythohesin-2/ARF1 axis in osteoclast differentiation is mainly dependent on activating the JNK pathway. Further, in addition to the common viewpoint that JNK is activated by IRE1 via its kinase activity, we found that JNK can act upstream and regulate the endoribonuclease activity of IRE1 to promote XBP1 splicing. Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis.

Characteristics of older-patient-specif ic oncological trials: a cross-sectional analysis of ClinicalTrials.gov.

BACKGROUND: clinical trials dedicated to the older patients with cancer are essential to help to define optimal cancer therapy for this rapidly growing population. Our study aimed to analyse the characteristics and the evolution of older-patient-specific oncological trials registered in ClinicalTrials.gov. METHODS: a dataset of 61,120 oncological trials registered in ClinicalTrials.gov between 2000 and 2019 was downloaded. Characteristics of older-patient-specific trials were compared with characteristics of age-unspecified trials. Chronological shifts in older-patient-specific trials were also analysed. RESULTS: of the 49,273 interventional trials eligible for analysis, only 490 (1.0%) were older-patient-specific. More than half of the older-patient-specific trials were phase 2 and enrolled less than 100 patients. Compared with age-unspecified trials, older-patient-specific trials were less likely to be funded by industry (26.9 vs 37.1%), and more likely to be conducted in Europe (44.5 vs 28.3%). During the two time periods between 2000 and 2009, and 2010 and 2019, the proportion of supportive care-oriented trials increased from 1.9 to 13.9%. Concerningly, the use of clinically meaningful end points in older patients such as disease-specific survival, patient-reported outcomes and functional status as a primary end point was uncommon (0.4, 8.1 and 7.3%, respectively). There was no correlation between the number of trials for a given cancer type and relative incidence and mortality. 196/490 (40.0%) of the trials were conducted for patients with haematological cancer. CONCLUSION: our study helps us to better understand the current state of older-patient-specific oncological trials and provide insights for future development, resulting in the improvement of the care of older patients with cancer.

Immediate risk of non-cancer deaths after a cancer diagnosis.

BACKGROUND: Receiving a cancer diagnosis may trigger immediate fatal non-cancer health outcomes in addition to dying of cancer itself. We aim to investigate the full pattern of non-cancer deaths in patients within a year of a cancer diagnosis. METHODS: Patients diagnosed with cancer between 1990 and 2016 were identified from the SEER program. Standardized mortality ratios (SMRs) were calculated to characterize the relative risks of non-cancer deaths compared with the general population. RESULTS: Among 7,366,229 patients, 241,575 non-cancer deaths (15.9%) were recorded in the first year following a cancer diagnosis. The relative risk of non-cancer deaths was 2.34-fold (95% confidence interval (CI): 2.33-2.35) that of the general population. The majority of non-cancer deaths were caused by cardiovascular diseases (21.8%), followed by infectious diseases (7.2%). Significant elevations in mortality risks were observed for nearly all non-cancer causes, particularly in infectious diseases (SMR: 5.08; 95% CI: 5.03-5.13). Patients with liver cancer (SMR: 12.29; 95% CI: 12.06-12.53) were at the highest risk of early non-cancer deaths. The risks of non-cancer deaths were highest within the first month after diagnosis, and decreased rapidly thereafter. CONCLUSIONS: Risks of non-cancer deaths vary by the types of causes and anatomic sites of cancer. Our data underscore the importance of close observation and early multidisciplinary care for noncancer conditions in patients who have recently received a cancer diagnosis.

Spatial omics: An innovative frontier in aging research.

Disentangling the impact of aging on health and disease has become critical as population aging progresses rapidly. Studying aging at the molecular level is complicated by the diverse aging profiles and dynamics. However, the examination of cellular states within aging tissues in situ is hampered by the lack of high-resolution spatial data. Emerging spatial omics technologies facilitate molecular and spatial analysis of tissues, providing direct access to precise information on various functional regions and serving as a favorable tool for unraveling the heterogeneity of aging. In this review, we summarize the recent advances in spatial omics application in multi-organ aging research, which has enhanced the understanding of aging mechanisms from multiple standpoints. We also discuss the main challenges in spatial omics research to date, the opportunities for further developing the technology, and the potential applications of spatial omics in aging and aging-related diseases.

Cancer-Erythrocyte Membrane-Mimicking Fe3O4 Nanoparticles and DHJS for Ferroptosis/Immunotherapy Synergism in Tumors.

Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of Fe3O4 nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by Fe3O4 nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with Fe3O4 nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded Fe3O4 and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and Fe3O4 in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of Fe3O4 nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.

Impact of Limb Salvage on Prognosis of Patients Diagnosed With Extremity Bone and Soft Tissue Sarcomas.

Background: Although clinicians and patients with extremity bone and soft tissue (EBST) are increasingly interested in limb salvage surgery (LSS), because of the minimal damage to physical appearance and function, however, there is still a lack of large-scale population studies on whether LSS improves the prognosis of patients. Purpose: The aim of this study was to compare the survival of patients with EBST sarcomas after receiving LSS and amputation. Methods: To conduct the population-based study, we identified 6,717 patients with a histologically diagnosed bone sarcoma and 24,378 patients with a histologically diagnosed soft tissue sarcoma from the Surveillance, Epidemiology, and End Results database. We analyzed overall survival (OS), cancer-specific survival (CSS), and non-sarcoma survival (NSS) using the Kaplan-Meier method, log-rank test or Gray test, Cox regression model, propensity score-matched analysis, and landmark analysis. Results: LSS could improve the prognosis in patients with most EBST subtypes, except for Ewing sarcomas and MPNST. However, in the subgroup without distant metastases, limb salvage increased CSS only for patients with osteosarcoma, Ewing sarcoma, and leiomyosarcoma, as well as NSS for patients with chondrosarcoma and synovial sarcoma. Landmark analysis further demonstrated that sarcoma survivors surviving <10 years could benefit from LSS but not for long-term survivors ≥10 years. Moreover, for patients with distant metastases, LSS could improve survival of osteosarcoma patients but worsen CSS among patients with MPNST. Landmark analysis further demonstrated that LSS improved survival among osteosarcomas patients with distant metastases only within 1 year after surgery. Moreover, patients receiving LSS and those receiving amputation had a high risk of dying from different non-sarcoma diseases during the postoperative follow-up. Conclusions: The impact of limb salvage on the prognosis of patients depends on the pathological subtype and stage of EBST sarcomas.

Suicide and Accidental Death Among Women With Primary Ovarian Cancer: A Population-Based Study.

Background: Women with ovarian cancer had the highest suicidal rate among all patients with gynecological malignancies, but no large studies about suicide and accidental death for women with ovarian cancers in detail were conducted. We aimed to determine the relative risk of suicide and accidental death among patients with ovarian cancer to that of the general population, and to identify risk factors associated with suicide and accidental death. Methods: Data are from the SEER (surveillance, epidemiology, and end results) cancer registry of women diagnosed with ovarian cancer data from 18 registries for the years 1973-2016. The study population comprised 149,204 patients after inclusion and exclusion criteria were applied. Standardized mortality ratios (SMRs) were calculated and Fine-Gray models were fitted to identify risk factors associated with suicidal and accidental death among cancer patients, with stratifications on demographic and tumor-related characteristics. Results: Women with ovarian cancer had a higher risk of suicide and accidental death than the cancer-free group [SMR = 1.86; 95% CI (1.54-2.25) and SMR = 1.54; 95% CI (1.39-1.71)]. Subgroup analysis indicated that only patients with type II epithelial ovarian cancer [SMR = 2.31; 95% CI (1.83-2.91)] had an increased risk of suicide, and those with type I and type II epithelial ovarian cancer [SMR = 1.65; 95% CI (1.39-1.97) and SMR = 1.49; 95% CI (1.30-1.70)] were at a higher risk of accidental death. Patients with ovarian cancer who were younger, white, diagnosed with high-grade, non-metastatic cancer and pelvic exenteration were at a higher risk of suicide. The advanced age, earlier year of diagnosis, and non-metastatic cancer were associated with a higher risk of accidental death. Additionally, pelvic exenteration increased the risk of suicide but not the risk of accidental death among women with primary ovarian cancer. Conclusions: Women with ovarian cancer had a higher risk of suicide and accidental death compared with the general population. The findings suggested that clinicians should identify high-risk subgroups of ovarian cancer patients for suicide and accidental death as early as possible, with appropriate prevention strategies.

Inhibition of IRE1 suppresses the catabolic effect of IL-1ß on nucleus pulposus cell and prevents intervertebral disc degeneration in vivo.

Neck pain and low back pain are two of the major diseases, which causes patients a low quantify of life and a heavy economic burden, intervertebral disc degeneration (IDD) contributes to them, and the mechanism is not totally clear. The increased inflammatory cytokines including interleukin (IL)-1ß and tumor necrosis factor (TNF)α and downstream signaling pathways are involved. Inositol requiring enzyme 1 (IRE1) is a crucial enzyme that regulates endoplasmic reticulum (ER) stress. It is reported that IRE1 plays an important role in the activation of NF-κB, PI3K/Akt and MAPK signaling pathways. Considering this, we performed a series of experiments in vitro and in vivo to evaluate the role of IRE1 in the progress of IDD. We demonstrated that IRE1 pathway was induced by IL-1ß, inhibition of IRE1 suppressed the matrix degeneration of NP cells and ameliorated IDD grade in the punctured rat model. Further results indicated that inhibition of IRE1 suppressed H2O2 induced cell senescence, IL-1ß-induced cellular reactive oxygen species (ROS) level and the activation of NF-κB, PI3K/Akt and MAPK signaling pathways. It also played a crucial role in the apoptosis of NP cells and the progress of macrophage polarization. Our findings demonstrated that inhibition of IRE1 could suppress the degeneration of NP cells and prevent IDD in vivo. IRE1 may be a potential target for IDD treatment.

Maternal deaths among patients with cancer in the United States.

ABSTRACT: Our objective was to characterize the risks of maternal deaths in cancer patients compared to the general population using a large population-based cohort.Female patients with a cancer first diagnosed at ages 15 to 39 years between 2000 and 2016 (N = 240,561) from the surveillance, epidemiology, and end results database were extracted, among which 165 maternal deaths were observed.We found Hispanic ethnic groups, advanced cancer stage, receiving chemotherapy were associated with a higher risk of maternal deaths compared to the general the United States population. Patients with cancers of the respiratory system were at the highest risk of maternal deaths, followed by cancers of the digestive system, and hematological malignancies.

Characteristics, incidence, and risk factors for death from fatal pneumonia among patients with primary malignant bone tumors: a SEER-based observational study.

BACKGROUND: (I) To determine whether patients with malignant bone tumors had a higher risk of dying from pneumonia compared with the general US population; (II) to identify the independent risk factor associated with fatal pneumonia among these patients. METHODS: We identified 18,583 patients diagnosed with primary malignant bone tumors between 1973 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Standardized mortality ratios (SMRs) were calculated based on the mortality data of the general population gathered by the National Center for Health Statistics, which provided the risk of death from pneumonia among cancer patients relative to that of the general population. Given that other causes of death were considered as competing events, we also designed the Fine-Gray model to identify demographic and tumor-related characteristics associated with a higher risk of dying from pneumonia among these patients. RESULTS: Patients with primary malignant bone tumors had a higher risk of dying from pneumonia than the general population after adjusting the distribution difference of age, sex, and race among them (SMR =2.79; 95% CI: 2.17-3.59). The older age, Black and earlier period of diagnosis were found to be the independent prognostic factor for a higher risk of death from pneumonia for these patients. Additionally, amputation due to malignant bone tumors significantly increased the risk of death from pneumonia compared with non-surgery. The highest mortality rate of pneumonia was observed among patients with chordoma. Interaction tests demonstrated that amputation only increased the relative risk of fatal pneumonia among patients with osteosarcoma. Throughout the follow-up period, the mortality rate of fatal pneumonia was the highest within the first year after diagnosis, and the highest relative suicide risks persisted over time in patients with osteosarcoma. CONCLUSIONS: To mitigate the risk of fatal pneumonia among patients with bone tumors, we call for long-term clinical monitoring of the lung condition among these patients, especially for those after amputation for bone tumors.

Suicide and accidental deaths among patients with primary malignant bone tumors.

BACKGROUND: It has been recognized that cancer is associated with a higher risk of suicide or accidental death. Earlier studies have evidenced that patients with malignant bone tumors usually experience psychological dysfunction and physical disability following surgery, which are shared risk factors between suicidal and accidental deaths. To our knowledge, there is no large population-based study on the risk of suicide or accidental death among patients with malignant bone tumors. QUESTIONS/PURPOSES: This study aimed to determine whether patients with primary malignant bone tumors are at a higher risk of suicide and accidental death than the general population and to identify the demographic and tumour-related characteristics and type of surgery associated with a higher risk of suicide and accidental death among these patients. METHODS: Overall, 50,817 patients diagnosed with primary malignant bone tumors between 1973 and 1975 were identified from the Surveillance, Epidemiology, and End Results database. The standardised mortality ratio (SMR) was calculated based on the general population's mortality data, gathered by the National Center for Health Statistics. The Cox regression model was developed to determine risk factors associated with a higher risk of suicide and accidental death. RESULTS: Patients with primary malignant bone tumors had a higher risk of suicide and accidental death than the general population in the United States (US) (SMR = 2.17; 95% confidence interval (CI) [1.80-2.62] and SMR = 1.73; 95% CI [1.54-1.95]). Compared with limb salvage, amputation significantly increased the risk of suicide (SMR = 3.99; 95% CI [2.52-6.34], hazard ratio (HR) = 2.32; 95% CI [1.31-4.09]; P < 0.01) but did not increase the risk of accidental death (SMR = 1.61; 95% CI [1.07-2.42], HR = 1.11; 95% CI [0.71-1.74]; P = 0.65). Higher suicide risk was observed among older patients whose age at diagnosis was more than 60 years (HR = 4.04; 95% CI [1.98-8.26]; P < 0.001), males (HR = 3.48; 95% CI [2.16-5.62]; P < 0.001), and whites (HR = 3.71; 95% CI [1.17-11.73]; P < 0.001). The risk of suicide and accidental death was highest in the first year after diagnosis (SMR = 2.95; 95% CI [1.86-4.69] and SMR = 2.02; 95% CI [1.48-2.74]). CONCLUSION: We first reported that patients with primary malignant bone tumors had a higher risk of suicide and accidental death than the general US population. Therefore, clinicians should pay more attention to the psychological status, physical function, and cognitive level of these survivors.

Fatal Infections Among Cancer Patients: A Population-Based Study in the United States.

INTRODUCTION: Cancer patients are prone to infections, but the mortality of fatal infections remains unclear. Understanding the patterns of fatal infections in patients with cancer is imperative. In this study, we report the characteristics, incidence, and predictive risk factors of fatal infections among a population-based cancer cohort. METHODS: A total of 8,471,051 patients diagnosed with cancer between 1975 and 2016 were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) program. The primary outcome was dying from fatal infections. Mortality rates and standardized mortality ratios (SMRs) adjusted for age, sex, race, and calendar year were calculated to characterize the relative risks of dying from fatal infections and to compare with the general population. Furthermore, cumulative mortality rates and the Cox regression models were applied to identify predictive risk factors of fatal infections. RESULTS: In cancer patients, the mortality rate of fatal infections was 260.1/100,000 person-years, nearly three times that of the general population [SMR, 2.92; 95% (confidence interval) CI 2.91-2.94]. Notably, a decreasing trend in mortality rate of fatal infections was observed in recent decades. SMRs of fatal infections were highest in Kaposi sarcoma (SMR, 162.2; 95% CI 159.4-165.1), liver cancer (SMR, 30.9; 95% CI 30.0-31.8), acute lymphocytic leukemia (SMR, 19.1; 95% CI 17.0-21.4), and acute myeloid leukemia (SMR, 13.3; 95% CI 12.4-14.3). Patients aged between 20 and 39 years old exhibited a higher cumulative mortality rate in the first few years after cancer diagnosis, whereas the cumulative mortality rate of those > 80 years old was rapidly increasing and became the highest approximately 3 years post-cancer diagnosis. Predictive risk factors of dying from fatal infections in cancer patients were the age of 20-39 or > 80 years, male sex, black race, diagnosed with cancer before 2000, unmarried status, advanced cancer stage, and not receiving surgery and radiotherapy, but receiving chemotherapy. CONCLUSION: Cancer patients were at high risks of dying from infectious diseases. Certain groups of cancer patients, including those aged between 20 and 39 or > 80 years, as well as those receiving chemotherapy, should be sensitized to the risk of fatal infections.

Deaths from COPD in patients with cancer: a population-based study.

Features of the deaths caused by COPD (chronic obstructive pulmonary disease) in cancer patients remained a controversial issue. This study aimed to characterize the demographic characteristics and mortality rates of the deaths from COPD in patients with cancer. In total, 7,846,370 cancer patients aged 40 years or older in the United States were identified from the Surveillance, Epidemiology, and End Results database (1975-2016). Mortality rates and SMRs (standardized mortality ratios) adjusted by age, race, sex, and calendar year were calculated to investigate the risk of COPD deaths in cancer survivors and to compare it with the general population. A total of 119,228 COPD deaths in patients with cancer were recorded, with a mortality rate of 261.5/100,000 person-years, nearly two-fold that of the general population (SMR, 2.17; 95% CI [confidence interval], 2.16-2.18). The proportion of cancer survivors dying from COPD increased from 0.9% in 1975 to 3.4% in 2016. Patients with lung cancer had a higher overall risk (SMR, 9.23; 95% CI, 9.12-9.35) than those with extrapulmonary malignancies. Among all extrapulmonary sites, laryngeal (SMR, 5.54; 95% CI, 5.34-5.75) and esophageal cancers (SMR, 4.33; 95% CI, 4.04-4.63) had the highest SMR. The risk of death from COPD increased with follow-up time.

Fatal renal diseases among patients with hematological malignancies: A population-based study.

Patients with hematological malignancies might be at high risk for renal diseases as evidenced by earlier studies. We aim to investigate the mortality and risk factors of deaths due to renal diseases in this population. A total of 831 535 patients diagnosed with hematological malignancies in the Surveillance, Epidemiology, and End Results (SEER) database in the United States from 1975 to 2016 were identified. Standardized mortality ratio (SMR) was evaluated based on the general population's mortality data gathered by the National Center for Health Statistics. The mortality rate associated with renal diseases was 94.22/100 000 person-years among patients with hematological malignancies (SMR = 3.59; 95% CI, 3.48-3.70]). The highest mortality rate of dying from renal diseases was observed among multiple myeloma (MM) patients (307.99/100 000 person-years; SMR = 7.98; 95% CI, 7.49-8.50), followed by those with chronic myeloid leukemia (142.57/100 000 person-years; SMR = 6.54; 95% CI, 5.63-7.60) and chronic lymphocytic leukemia (103.66/100 000 person-years; SMR = 2.51; 95% CI, 2.27-2.77). The SMRs increased with time and were found to be the highest 10 years after cancer diagnosis. Independent predictors associated with death from renal diseases were found to be older age, male gender, blacks, unmarried, and MM, using the Cox proportional hazards model. We call for enhanced coordinated multidisciplinary care between hematologists and nephrologists to reduce the mortality rate of renal diseases among patients with hematological malignancies.

Incidence of Death From Unintentional Injury Among Patients With Cancer in the United States.

Importance: Previous studies have suggested that patients with cancer may be at an increased risk of death from unintentional injury, but to our knowledge, no large studies have examined the rates of death from unintentional injury among patients with cancer. Objective: To characterize the incidence of death from unintentional injury among patients with cancer in the United States. Design, Setting, and Participants: This retrospective cohort study included patients diagnosed with a first primary cancer between January 1, 1973, and December 31, 2015, identified from the Surveillance, Epidemiology, and End Results (SEER) program data. Comparisons with the general US population were based on mortality data collected by the National Center for Health Statistics. Analyses were performed from February 1, 2019, to August 15, 2019. Main Outcomes and Measures: Rates and standardized mortality ratios (SMRs) of death from unintentional injury among patients with cancer. Results: A total of 8 271 020 patients with cancer were included in this study (50.2% female; mean [SD] age, 63.0 [15.7] years). Among them, 40 599 deaths from unintentional injury were identified. The rates of death from unintentional injury were 81.90 per 100 000 person-years among patients with cancer and 51.21 per 100 000 person-years in the corresponding US general population. The SMR of death from unintentional injury was 1.60 (95% CI, 1.58-1.61). Higher rates of death from unintentional injury were associated with increasing age at diagnosis (≥80 years; rate ratio [RR], 2.91; 95% CI, 2.84-2.98; P < .001), male sex (RR, 1.69; 95% CI, 1.66-1.73; P < .001), American Indian or Alaskan Native population (RR, 1.48; 95% CI, 1.30-1.68; P < .001), and being unmarried (RR, 1.23; 95% CI, 1.18-1.28; P < .001). Rates of death from unintentional injury were the highest in patients with cancers of the liver (200.37 per 100 000 person-years), brain (175.04 per 100 000 person-years), larynx (148.78 per 100 000 person-years), and esophagus (144.98 per 100 000 person-years). The SMRs were the highest in the first month after cancer diagnosis. Conclusions and Relevance: This study found that the incidence of death from unintentional injury among patients with cancer was significantly higher than that in the general population in the United States. The rates of death from unintentional injury varied by age, sex, race/ethnicity, marital status, cancer site, disease stage, and time since diagnosis. The findings suggest that death from unintentional injury among patients with cancer requires further attention and that initiatives to identify patients at risk and to develop targeted prevention strategies should be prioritized.