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Individualized chemotherapy, which is at the forefront of acute myeloid leukemia (AML) treatment, has moderately improved outcomes over the past decade. Monitoring the peripheral blood blast burden during induction by flow cytometry has shown significant value in the evaluation of treatment responses. Our previous study reported the day 5 peripheral blast clearance rate (D5-PBCR) as an indicator of early treatment response, and D5-PBCR (+) patients showed poor outcomes. We performed the present phase 2 trial of early intervention in D5-PBCR (+) patients with homoharringtonine (HHT) introduced in the traditional induction regimen with anthracycline and cytarabine. The primary endpoint was complete remission (CR). This study enrolled 151 patients, 65 patients were D5-PBCR (+) and 55 patients completed induction with HHT addition. The overall CR rate after one course of induction was 84.4%, with 87.5% and 80.0% for the D5-PBCR (-) and D5-PBCR (+) groups, respectively. The incidence of grade 3/4 adverse events was comparable between the two groups. At the median follow-up of 53.1 months, median overall survival (OS) was not reached in the entire cohort, and median event-free survival (EFS) was 42.2 months. Neither the OS nor EFS showed significant differences between the D5-PBCR (-) and D5-PBCR (+) groups. Compared to historical data, significant improvements in both OS (p = .020) and EFS (p = .020) were observed in the D5-PBCR (+) group. In conclusion, optimization of induction chemotherapy with idarubicin and cytarabine according to D5-PBCR is feasible in patients with newly diagnosed AML. The addition of HHT demonstrated a good efficacy and safety profile.

Objectives The aim of this study is to address the difficulties encountered by public health workers in the early and middle stages of their efforts to combat COVID-19, compare the gaps among different types of institutions, and identify shortcomings in epidemic control. Methods Using multi-stage sampling, a survey of public health workers involved in the prevention and control of COVID-19 was conducted from 18 February to 1 March 2020 through a self-administered questionnaire. These public health workers were from the primary health care center (defined as “primary-urban” and “primary-rural” for those in urban and rural areas, respectively) and the center for disease control and prevention (defined as “non-primary”) in five provinces including Hubei, Guangdong, Sichuan, Jiangsu and Gansu, China. Results A total of 9,475 public health workers were surveyed, of which 40.0 %, 27.0 % and 33.0 % were from the primary-rural, primary-urban and non-primary, respectively. The resources shortage were reported by 27.9 % participants, with the primary-rural being the worst affected (OR = 1.201, 95 %CI: 1.073–1.345). The difficulties in data processing were reported by 31.5 % participants, with no significant differences among institutions. The difficulties in communication and coordination were reported by 29.8 % participants, with the non-primary being the most serious (primary-rural: OR = 0.520, 95 %CI: 0.446–0.606; primary-urban: OR = 0.533, 95 %CI: 0.454–0.625). The difficulties with target audiences were reported by 20.2 % participants, with the primary-urban being the worst (OR = 1.368, 95 %CI: 1.199–1.560). The psychological distress were reported by 48.8 % participants, with no significant differences among institutions. Conclusions Psychological distress is the most serious problem in the prevention and control of COVID-19. Resources shortage in primary-rural, difficulties in communication and coordination in non-primary, and difficulties with target audiences in the primary-urban deserve attention. This study will provide scientific evidences for improving the national public health emergency management system, especially for reducing the urban-rural differences in emergency response capacity.

Immunologic checkpoint blockade has been proven effective in a variety of malignancies. However, high rates of resistance have substantially hindered its clinical use. Understanding the underlying mechanisms may lead to new strategies for improving therapeutic efficacy. Although a number of signaling pathways have been shown to be associated with tumor cell–mediated resistance to immunotherapy, T cell–intrinsic resistant mechanisms remain elusive. Here, we demonstrated that diacylglycerol kinase alpha (Dgka) mediated T-cell dysfunction during anti–PD-1 therapy by exacerbating the exhaustion of reinvigorated tumor-specific T cells. Pharmacologic ablation of Dgka postponed T-cell exhaustion and delayed development of resistance to PD-1 blockade. Dgka inhibition also enhanced the efficacy of anti–PD-1 therapy. We further found that the expression of DGKA in cancer cells promoted tumor growth via the AKT signaling pathway, suggesting that DGKA might be a target in tumor cells as well. Together, these findings unveiled a molecular pathway mediating resistance to PD-1 blockade and provide a potential therapeutic strategy with combination immunotherapy.

Background Public health workers at the Chinese Centre for Disease Control and Prevention (China CDC) and primary health care institutes (PHIs) were among the main workers who implemented prevention, control, and containment measures. However, their efforts and health status have not been well documented. We aimed to investigate the working conditions and health status of front line public health workers in China during the COVID-19 epidemic. Methods Between 18 February and 1 March 2020, we conducted an online cross-sectional survey of 2,313 CDC workers and 4,004 PHI workers in five provinces across China experiencing different scales of COVID-19 epidemic. We surveyed all participants about their work conditions, roles, burdens, perceptions, mental health, and self-rated health using a self-constructed questionnaire and standardised measurements (i.e., Patient Health Questionnaire and General Anxiety Disorder scale). To examine the independent associations between working conditions and health outcomes, we used multivariate regression models controlling for potential confounders. Results The prevalence of depression, anxiety, and poor self-rated health was 21.3, 19.0, and 9.8%, respectively, among public health workers (27.1, 20.6, and 15.0% among CDC workers and 17.5, 17.9, and 6.8% among PHI workers). The majority (71.6%) made immense efforts in both field and non-field work. Nearly 20.0% have worked all night for more than 3 days, and 45.3% had worked throughout the Chinese New Year holiday. Three risk factors and two protective factors were found to be independently associated with all three health outcomes in our final multivariate models: working all night for >3 days (multivariate odds ratio [ORm]=1.67~1.75, pppp=0.002~0.008), and ability to persist for > 1 month at the current work intensity (ORm=0.44~0.55, p Conclusions Chinese public health workers made immense efforts and personal sacrifices to control the COVID-19 epidemic and faced the risk of mental health problems. Efforts are needed to improve the working conditions and health status of public health workers and thus maintain their morale and effectiveness during the fight against COVID-19.

Quarantine plays a key role in controlling the pandemic of 2019 coronavirus disease (COVID-19). This study investigated (a) the associations between mandatory quarantine status and negative cognitions (perceived discrimination because of COVID-19 and perceived risk of COVID-19 infection)/mental health status (emotional distress because of COVID-19, probable depression, and self-harm/suicidal ideation), (b) the associations between the negative cognitions and mental health status, and (c) potential mediations between quarantined status and probable depression and self-harm/suicidal ideation via COVID-19-related negative cognitions/emotional distress. An online cross-sectional survey was conducted among 24,378 students of 26 universities in 16 Chinese cities (February 1-10, 2020). Correlation coefficients, odds ratios (OR), structural equation modeling, and other statistics were used for data analysis. Mandatory quarantined status was significantly and positively associated with perceived discrimination (Cohen's d = 0.62), perceived high/very high risk of infection (OR = 1.61), emotional distress (Cohen's d = 0.46), probable depression (OR = 2.54), and self-harm/suicidal ideation (OR = 4.98). Perceived discrimination was moderately and positively associated with emotional distress (Spearman correlation = 0.44). Associations between perceived risk of infection and mental health variables were significant but relatively weak. Cross-sectional mediation models showed good model fit, but the overall indirect paths via COVID-19-related negative cognitions/emotional distress only accounted for 12-15% of the total effects between quarantined status and probable depression and self-harm/suicidal ideation. In conclusion, quarantined participants were more likely than others to perceive discrimination and exhibit mental distress. It is important to integrate mental health care into the planning and implementation of quarantine measures. Future longitudinal studies to explore mechanisms underlying the mental health impact of quarantines are warranted. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Primary central nervous system lymphoma (PCNSL), a rare variant of non-Hodgkin's lymphoma, is characterized by distinct biological characteristics and clinical behaviors, and patient prognosis is not satisfactory. The advent of high-dose (HD) methotrexate (HD-MTX) therapy has significantly improved PCNSL prognosis. Currently, HD-MTX-based chemotherapy regimens are recognized as first-line treatment. PCNSL is sensitive to radiotherapy, and whole-brain radiotherapy (WBRT) can consolidate response to chemotherapy; however, WBRT-associated delayed neurotoxicity leads to neurocognitive impairment, especially in elderly patients. Other effective approaches include rituximab, temozolomide, and autologous stem-cell transplantation (ASCT). In addition, new drugs against PCNSL such as those targeting the B-cell receptor signaling pathway, are undergoing clinical trials. However, optimal therapeutic approaches in PCNSL remain undefined. This review provides an overview of advances in surgical approaches, induction chemotherapy, radiotherapy, ASCT, salvage treatments, and novel therapeutic approaches in immunocompetent patients with PCNSL in the past 5 years. Additionally, therapeutic progress in elderly patients and in those with relapsed/refractory PCNSL is also summarized based on the outcomes of recent clinical studies.

In obesity, macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR). The ribosome biosynthesis protein NOC4 (NOC4) mediates 40 S ribosomal subunits synthesis in yeast. Hereby, we reported an unexpected location and function of NOC4L, which was preferentially expressed in human and mouse macrophages. NOC4L was decreased in both obese human and mice. The macrophage-specific deletion of Noc4l in mice displayed IR and LSI. Conversely, Noc4l overexpression by lentivirus treatment and transgenic mouse model improved glucose metabolism in mice. Importantly, we found that Noc4l can interact with TLR4 to inhibit its endocytosis and block the TRIF pathway, thereafter ameliorated LSI and IR in mice., Macrophage inflammation promotes insulin resistance during diet-induced obesity. Here the authors show that macrophage NOC4L is decreased in humans and mice with obesity, that macrophage NOC4L deficiency aggravated high-fat diet induced inflammation and insulin resistance, and that NOC4L interacts with toll-like receptor 4, to inhibit endocytosis, and thus blocks TLF4/TRIF inflammatory signaling.

Background The outbreak of COVID-19 in China occurred around the Chinese New Year (January 25, 2020), and infections decreased continuously afterward. General adoption of preventive measures during the Chinese New Year period was crucial in driving the decline. It is imperative to investigate preventive behaviors among Chinese university students, who could have spread COVID-19 when travelling home during the Chinese New Year break. Objective In this study, we investigated levels of COVID-19–related personal measures undertaken during the 7-day Chinese New Year holidays by university students in China, and associated COVID-19–related cognitive factors. Methods A cross-sectional anonymous web-based survey was conducted during the period from February 1 to 10, 2020. Data from 23,863 students (from 26 universities, 16 cities, 13 provincial-level regions) about personal measures (frequent face-mask wearing, frequent handwashing, frequent home staying, and an indicator that combined the 3 behaviors) were analyzed (overall response rate 70%). Multilevel multiple logistic regression analysis was performed. Results Only 28.0% of respondents (6684/23,863) had left home for >4 hours, and 49.3% (11,757/23,863) had never left home during the 7-day Chinese New Year period; 79.7% (19,026/23,863) always used face-masks in public areas. The frequency of handwashing with soap was relatively low (6424/23,863, 26.9% for >5 times/day); 72.4% (17,282/23,863) had frequently undertaken ≥2 of these 3 measures. COVID-19–related cognitive factors (perceptions on modes of transmission, permanent bodily damage, efficacy of personal or governmental preventive measures, nonavailability of vaccines and treatments) were significantly associated with preventive measures. Associations with frequent face-mask wearing were stronger than those with frequent home staying. Conclusions University students had strong behavioral responses during the very early phase of the COVID-19 outbreak. Levels of personal prevention, especially frequent home staying and face-mask wearing, were high. Health promotion may modify cognitive factors. Some structural factors (eg, social distancing policy) might explain why the frequency of home staying was higher than that of handwashing. Other populations might have behaved similarly; however, such data were not available to us.

ObjectiveTo investigate the determinants of willingness and practice of physicians’ online medical services (OMS) uptake based on social ecosystem theory, so as to formulate OMS development strategies.DesignCross-sectional survey.SettingResearch was conducted in two comprehensive hospitals and two community hospitals in Jiangsu, China, and the data were gathered from 1 June to 31 June 2020.ParticipantsWith multistage sampling, 707 physicians were enrolled in this study.Outcome measureDescriptive statistics were reported for the basic characteristics. χ2 test, Mann-Whitney U test and Spearman’s correlation analysis were used to perform univariate analysis. Linear regression and logistic regression were employed to examine the determinants of physicians’ OMS uptake willingness and actual uptake, respectively.ResultsThe mean score of the physicians’ OMS uptake willingness was 17.33 (range 5–25), with an SD of 4.39, and 53.3% of them reported having conducted OMS. In the micro system, factors positively associated with willingness included holding administrative positions (b=1.03, pConclusionMultiple determinants influence physicians’ OMS application. Comprehensive OMS promotion strategies should be put forward from multidimensional perspectives including the micro, meso and macro levels.

Glioma represents a fast proliferating and highly invasive brain tumor which is resistant to current therapies and invariably recurs. Despite some advancements in anti-glioma therapies, patients’ prognosis remains poor. Toll-like receptors (TLRs) act as the first line of defense in the immune system being the detectors of those associated with bacteria, viruses, and danger signals. In the glioma microenvironment, TLRs are expressed on both immune and tumor cells, playing dual roles eliciting antitumoral (innate and adaptive immunity) and protumoral (cell proliferation, migration, invasion, and glioma stem cell maintenance) responses. Up to date, several TLR-targeting therapies have been developed aiming at glioma bulk and stem cells, infiltrating immune cells, the immune checkpoint axis, among others. While some TLR agonists exhibited survival benefit in clinical trials, it attracts more attention when they are involved in combinatorial treatment with radiation, chemotherapy, immune vaccination, and immune checkpoint inhibition in glioma treatment. TLR agonists can be used as immune modulators to enhance the efficacy of other treatment, to avoid dose accumulation, and what brings more interests is that they can potentiate immune checkpoint delayed resistance to PD-1/PD-L1 blockade by upregulating PD-1/PD-L1 overexpression, thus unleash powerful antitumor responses when combined with immune checkpoint inhibitors. Herein, we focus on recent developments and clinical trials exploring TLR-based treatment to provide a picture of the relationship between TLR and glioma and their implications for immunotherapy.

BackgroundPrimary central nervous system lymphoma (PCNSL) is a highly aggressive and rare extranodal non-Hodgkin lymphoma (NHL). The MSKCC and the IELSG scores represent the most widely used prognostic models, but many changes have occurred in therapeutic protocols since their development. Moreover, many PCNSL patients cannot be classified using the IELSG score. We thus aimed to create a novel, effective and feasible prognostic model for PCNSL.MethodsWe included 248 PCNSL patients diagnosed with PCNSL. Our primary endpoint was the overall survival (OS) and we used the receiver operating characteristic (ROC) analysis to determine the optimal prognostic cut-off value for LLR (lactate dehydrogenase-to-lymphocyte ratio), neutrophil-to-lymphocyte ratio (NLR) and derived neutrophil-to-lymphocyte ratio (dNLR). Variable associated with OS were evaluated by univariate and multivariate analyses. 124 out of 248 patients were randomly selected as the internal validation cohort.ResultsBy univariate analysis, an age >60 years, Eastern Cooperative Oncology Group performance status (ECOG PS) >1, treatment with radiotherapy alone, high-risk groups of Memorial Sloan Kettering Cancer Center (MSKCC) score, NLR >4.74, dNLR >3.29, and LLR >166.8 were significantly associated with a worse OS. By multivariate analysis, the MSKCC score and LLR were confirmed as independent prognostic parameters for poorer OS. OS, however, was not significantly different between low- and intermediate-risk groups according to the MSKCC score, while LLR proved to be prognostically relevant and was thus used to develop a novel, effective three-tier PCNSL scoring system. Of 124 patients, 84 patients with survival data and LLR data were successfully validated by newly established PCNSL LLR scoring system.ConclusionsIn the present study, we demonstrate that a high LLR represents an independent unfavorable prognostic parameter in PCNSL patients which can be integrated into an effective prognostic model.

As an emerging class of hybrid complexes, donor–acceptor (D–A) hybrid heterostructures with advantages of both photoactive organic and inorganic components have provided an excellent platform for the fabrication of multifunctional photoactive materials. In this context, we have demonstrated three novel host–guest D–A hybrid heterostructures, {[Ln(BCEbpy)(H2O)4][CoIII(CN)6]·4H2O}n (1 (Eu), 2 (Dy), 3 (Sm)), based on the anionic Co(CN)63− and cationic coordination layers assembled from a viologen functionalized tecton and Ln(NO)3. Due to the introduction of an electron donor, CoIII(CN)63−, the unique hybrid exhibits a highly sensitive and reversible photochromic transformation from light-yellow to brown upon UV-Vis irradiation. More interestingly, accompanied with this photochromic process, hybrid 1 simultaneously possesses a photomodulated fluorescence behaviour. In addition, hybrid 1 shows high sensitivity and selectivity towards Cr2O72− anions with a fairly small LOD of ca. 9.6 × 10−6 M.

Metastases to the central nervous system (CNS) occur frequently in adults and their frequency increases with the prolonged survival of cancer patients. Patients with CNS metastases have short survival, and modern therapeutics, while effective for extra-cranial cancers, do not reduce metastatic burden. Tumor cells attract and reprogram stromal cells, including tumor-associated macrophages that support cancer growth by promoting tissue remodeling, invasion, immunosuppression and metastasis. Specific roles of brain resident and infiltrating macrophages in creating a pre-metastatic niche for CNS invading cancer cells are less known. There are populations of CNS resident innate immune cells such as: parenchymal microglia and non-parenchymal, CNS border-associated macrophages that colonize CNS in early development and sustain its homeostasis. In this study we summarize available data on potential roles of different brain macrophages in most common brain metastases. We hypothesize that metastatic cancer cells exploit CNS macrophages and their cytoprotective mechanisms to create a pre-metastatic niche and facilitate metastatic growth. We assess current pharmacological strategies to manipulate functions of brain macrophages and hypothesize on their potential use in a therapy of CNS metastases. We conclude that the current data strongly support a notion that microglia, as well as non-parenchymal macrophages and peripheral infiltrating macrophages, are involved in multiple stages of CNS metastases. Understanding their contribution will lead to development of new therapeutic strategies.

The ternary combination of CuI, lanthanide cations and electron-deficient viologen based organic tectons led to a donor–acceptor (D–A) hybrid heterostructural framework with a narrow energy gap. Thanks to the electron transfer between inorganic donors (cuprous iodide clusters) and organic acceptors (viologen based tectons), this unique hybrid framework exhibits enhanced photocatalytic activities towards the degradation of rhodamine B (RhB) in comparison with those of lanthanide cations and bulk CuI.

Lin28a has been found to enhance glucose uptake and insulin sensitivity. Lin28a alleviates cardiac dysfunction under various pathological conditions. However, the effects and underlying mechanisms of Lin28a on diabetic cardiomyopathy (DCM) are not well-understood. The aim of this study was to determine whether Lin28a protects against DCM and the potential mechanisms. Two to three days old mouse neonatal primary cardiomyocytes were randomized for treatment with adenoviruses harboring Lin28a and mammalian sterile 20-like kinase 1 (Mst1) short hairpin RNA, 48 hr before culturing in normal or high glucose medium. Cardiomyocyte apoptosis, autophagy, mitochondrial morphology, adenosine triphosphate content, and cytokine levels in the high glucose or normal conditions were observed between all groups. Either Lin28a overexpression or Mst1 knockdown alleviated mitochondrial ultrastructure impairment, decreased cytokine levels, inhibited apoptosis, and enhanced autophagy in primary neonatal mouse cardiomyocytes treated with high glucose. Importantly, the protective effects of Lin28a and Mst1 disappeared after treatment with 3-methyladenine, an autophagy inhibitor. Interestingly, in Mst1 knockdown cardiomyocytes, Lin28a overexpression failed to further enhance autophagy and alleviate high glucose-induced cardiomyocyte injury, which implies the protective roles of Lin28a counteracting high glucose-induced cardiomyocyte injury are dependent on Mst1 inhibition. Furthermore, co-immunoprecipitation and immunofluorescence double staining suggested that there were no direct interactions between Mst1 and Lin28a. Lin28a increased the expression of Akt, which inhibited the activation of Mst1-mediated apoptotic pathways.

Objective Less than half of eligible Chinese rural women have been screened for breast and cervical cancer. The objective of this study was to describe individual-level reasons for attending or not attending ‘two cancers’ screening using Andersen's Behavioral Model of Health Services Use. Study design Cross-sectional study. Methods The study sample was from the Health Services Survey in 2013 in Jiangsu, China. A total of 6520 rural women aged 36–65 years answered the questions on ‘two cancers’ screening participation and were included in the final analysis, which consisted of univariate and multivariate logistic regression. Results In the results of multivariate logistic regression, factors significantly associated with having ‘two cancers’ screening included educational level (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.65–0.92), per capita household income (OR = 0.65, 95% CI = 0.58–0.73), availability of female medical faculty in township facilities (OR = 0.35, 95% CI = 0.28–0.42), quality of life (OR = 0.72, 95% CI = 0.58–0.90), being nulliparous (OR = 3.21, 95% CI = 1.96–5.26), and multiparous (OR = 1.91, 95% CI = 1.68–2.16). Conclusion To reduce inadequate screening service utilization of breast and cervical cancer in rural areas, efforts should be made not only to target the vulnerable rural women with lower income, lower educational level, and lower health conditions but also to further improve access to female primary-care providers. Strategies are also urgently needed to focus on nulliparous and multiparous women.

Gastrointestinal probiotics play an important role in maintaining intestinal bacteria homeostasis. They might benefit people with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), which remains a global health challenge. However, there is a controversy regarding the efficacy of probiotics for the treatment of AIDS. This study systematically reviewed the evidence of the effects of existing probiotic interventions on AIDS and sought to provide information on the role of probiotics in the treatment of HIV/AIDS patients. A meta-analysis of studies identified by screening multiple databases was performed using a fixed-effects model in Review Manager 5.2 software. The meta-analysis showed that probiotics could reduce the incidence of AIDS-related diarrhea (RR = 0.60 (95% CI: 0.44–0.82), p = 0.001). The short-term use of probiotics (supplementation duration shorter than 30 days) did not reduce the incidence of diarrhea (RR = 0.76 (95% CI: 0.51–1.14), p = 0.19), while the long-term use of probiotics (supplementation duration longer than 30 days) reduced diarrhea (RR = 0.47 (95% CI: 0.29–0.76), p = 0.002). Probiotics had no effect on CD4 cell counts in HIV/AIDS patients (MD = 21.24 (95% CI: −12.95–55.39), p = 0.22). Our data support that probiotics were associated with an obvious reduction in AIDS-related diarrhea, which indicates the need for additional research on this potential preventive strategy for AIDS.

Objective To investigate the predictive value of hyperhomocysteinaemia (HHcy) for obstructive coronary artery disease (CAD) in an Asian population in northern China. Methods This retrospective study enrolled patients at their first cardiac assessment and assigned them to an obstructive CAD group or a non-obstructive CAD group according to the coronary angiography results. HHcy was defined as a homocysteine (Hcy) level > 15 µmol/l. Results This study enrolled 2987 participants: 1172 in the non-obstructive CAD group and 1815 in the obstructive CAD group. Hcy level in the obstructive CAD group was significantly higher than in the non-obstructive CAD group. The proportion of patients with HHcy in the obstructive CAD group was significantly greater than in the non-obstructive CAD group. Multivariate logistic regression analysis demonstrated that HHcy was independently correlated with obstructive CAD in both young (aged ≤ 55 years) and old patients (aged > 55 years). HHcy showed a higher sensitivity (93.1%), specificity (86.1%) and accuracy (90.0%) for obstructive CAD. The odds ratio for HHcy was 84.2. The Kappa value (0.8) showed substantial agreement between obstructive CAD and HHcy. Conclusions HHcy was associated with obstructive CAD and may be a potentially independent risk factor for obstructive CAD with good predictive value.

Immune checkpoint blockade (ICB) has become a standard treatment for non-small cell lung cancer (NSCLC). However, most patients with NSCLC do not benefit from these treatments. Abnormal vasculature is a hallmark of solid tumors and is involved in tumor immune escape. These abnormalities stem from the increase in the expression of pro-angiogenic factors, which is involved in the regulation of the function and migration of immune cells. Anti-angiogenic agents can normalize blood vessels, and thus transforming the tumor microenvironment from immunosuppressive to immune-supportive by increasing the infiltration and activation of immune cells. Therefore, the combination of immunotherapy with anti-angiogenesis is a promising strategy for cancer treatment. Here, we outline the current understanding of the mechanisms of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) signaling in tumor immune escape and progression, and summarize the preclinical studies and current clinical data of the combination of ICB and anti-angiogenic drugs in the treatment of advanced NSCLC.

Background: With the continuous large-scale development of the COVID-19 vaccine, the acceptance of vaccination and its influencing factors at the individual level have become crucial to stemming the pandemic. This study aims to explore the factors that influence the acceptance of the COVID-19 vaccine among international college students. Methods: The target population constituted international students pursuing various degrees in Jiangsu Province through an online cross-sectional study. A cluster random sampling was performed using a self-administered questionnaire. The Health Belief Model and Knowledge, Attitude/Beliefs, and Practice Theory served as the underlying theories to understanding the factors that influence vaccine acceptance. Results: We received 330 responses. About 36.4% intended to accept the vaccine. The acceptance varied across respondents’ place of residence, program of study, continent of origin, knowledge, susceptibility, severity, benefits, and cues to action (p &lt, 0.05). A multivariable logistics regression revealed cues to action (p &lt, 0.001), the perception of COVID-19 vaccination benefits (p = 0.002), and the perception of barriers (p &lt, 0.001) that were associated with vaccine acceptance. Conclusions: The acceptance of the COVID-19 vaccine was low among international students. The correct and comprehensive beliefs of the target groups regarding the benefits and barriers of the vaccination must be raised. Various effective social strategies must be adopted to trigger the intention of COVID-19 vaccination. The study findings will inform the decisions of public health campaigners, aimed at reducing vaccine hesitation when the COVID-19 vaccine is widely available.

Background: Kounis syndrome is an allergy-related acute coronary syndrome that is induced by various pharmacological and environmental factors. Given that many clinicians are not aware of this condition, many cases may be underdiagnosed. We report a case of type II Kounis syndrome induced by phloroglucinol.Case Summary: A 52-year-old man with pre-existing coronary artery stenosis presented with a 30-min history of chest pain and erythematous rash after intramuscular administration of phloroglucinol. An electrocardiogram demonstrated ST-segment elevation in leads II, III and aVF. Emergency coronary angiography revealed severe stenosis in the distal right coronary artery. Intravascular ultrasound showed plaque rupture and thrombosis, and the minimum lumen area was 3.0 mm2. A 3.5 × 38 mm stent was implanted in the distal right coronary artery. Troponin I levels were elevated. A diagnosis of type II Kounis syndrome induced by phloroglucinol was made, and the condition manifested as acute ST-segment elevation myocardial infarction.Conclusions: Clinicians should be aware of Kounis syndrome as a possible diagnosis in a patient who presents with chest pain and allergic manifestations given that an increasing number of triggers are being reported.

Background: The COVID-19 outbreak in China has created multiple stressors that threaten individuals' mental health, especially among public health workers (PHW) who are devoted to COVID-19 control and prevention work. This study aimed to investigate the prevalence of mental help-seeking and associated factors among PHW using Andersen's Behavioral Model of Health Services Use (BMHSU).Methods: A cross-sectional survey was conducted among 9,475 PHW in five provinces across China between February 18 and March 1, 2020. The subsample data of those who reported probable mental health problems were analyzed for this report (n = 3,417). Logistic and hierarchical regression analyses were conducted to examine the associations of predisposing, enabling, need, and COVID-19 contextual factors with mental health help-seeking.Results: Only 12.7% of PHW reported professional mental help-seeking during the COVID-19 outbreak. PHW who were older, had more days of overnight work, received psychological training, perceived a higher level of support from the society, had depression and anxiety were more likely to report mental help-seeking (ORm range: 1.02–1.73, all p < 0.05) while those worked in Centers for Disease Control and Prevention were less likely to seek help (ORm = 0.57, p < 0.01). The belief that mental health issues were not the priority (64.4%), lack of time (56.4%), and shortage of psychologists (32.7%) were the most frequently endorsed reasons for not seeking help.Conclusions: The application of BMHSU confirmed associations between some factors and PHW's mental health help-seeking. Effective interventions are warranted to promote mental health help-seeking of PHW to ameliorate the negative impact of mental illness and facilitate personal recovery and routine work.

BACKGROUND: Gallbladder cancer (GBC) is a highly aggressive biliary epithelial malignancy. The median survival time of GBC patients was less than 1 year. Tumor invasion and metastasis are the major cause of high mortality of GBC patients. However, the molecular mechanisms involved in GBC metastases are still unclear. METHODS: We performed 10X genomics single-cell RNA sequencing (scRNA-seq) on GBC liver metastasis tissue to evaluate the characteristics of the GBC liver metastasis microenvironment. RESULTS: In this study, 8 cell types, a total of 7,788 cells, including T cells, B cells, malignant cells, fibroblasts, endothelial cells, macrophages, dendritic cells (DCs), and mast cells were identified. Malignant cells displayed a high degree of intratumor heterogenicity, while neutrophils were found to promote GBC cell proliferation, migration, and invasion. Furthermore, cytotoxic cluster of differentiation (CD8(+)) T cells became exhausted and CD4(+) regulatory T cells (Tregs) exhibited immunosuppressive characteristics. Macrophages played an important role in the tumor microenvironment (TME). We identified three distinct macrophage subsets and emergent M2 polarization. We also found that cancer-associated fibroblasts exhibited heterogeneity and may be associated with GBC metastasis. CONCLUSIONS: Although preliminary in nature, our study provides a landscape view at the single-cell level. These results offer a unique perspective into understanding the liver metastasis of GBC.

Phosphoglycerate kinase 1 (PGK1), a critical component of the glycolytic pathway, relates to the development of various cancers. However, the mechanisms of PGK1 inhibition and physiological significance of PGK1 inhibitors in cancer cells are unclear. Long non-coding RNAs (lncRNAs) play a vital role in tumor growth and progression. Here, we identify a lncRNA LINC00926 that negatively regulates PGK1 expression and predicts good clinical outcome of breast cancer. LINC00926 downregulates PGK1 expression through the enhancement of PGK1 ubiquitination mediated by E3 ligase STUB1. Moreover, hypoxia inhibits LINC00926 expression and activates PGK1 expression largely through FOXO3A. FOXO3A/LINC00926/PGK1 axis regulates breast cancer glycolysis, tumor growth, and lung metastasis both in vitro and in vivo. In breast cancer patients, LINC00926 expression is negatively correlated with PGK1 and positively correlated with FOXO3A expression. Our work established FOXO3A/LINC00926/PGK1 as a critical axis to regulate breast cancer growth and progression. Targeting PGK1 or supplement of LINC00926 or FOXO3A could be potential therapeutic strategies in breast cancer.

The incorporation of photochromic moieties into coordination polymers is of particular interest because it can endow them with various switching functions such as electrical conductivity, luminescence, and magnetism. In this context, a viologen ligand as a photochromic moiety was incorporated into 3d-4f heterobimetallic hexacyanoferrates, resulting in three novel 3-D photochromic complexes with different metal cations, namely {[Ln(BCEbpy) M(CN)6 (H2O)4]·2H2O}n (denoted as CoDy, CoEu, and FeDy, Ln = Dy, Eu; M = Fe, Co, H2BCEbpy·2Br = N,N'-bis(carboxymethyl)-4,4'-bipyridinium dibromide). And the photoresponsive mechanism has been well discussed based on the solid UV-vis, IR, ESR, photoluminescence, and magnetism data. Moreover, accompanying the photochromic process, these unique complexes exhibit different photomagnetic behaviors upon UV-vis irradiation at RT because of the different ferromagnetic coupling interactions between photogenerated radicals and lanthanide cations.

Despite advances in treatment, the prognosis for glioma patients remains poor. Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) protein family, plays an important role in controlling oncogene expression and genome stability. In recent years, numerous BRD4 inhibitors have entered clinical trials and achieved exciting results in tumor treatment. Recent clinical studies have shown that BRD4 expression in glioma is significantly higher than in the adjacent normal brain tissue. BRD4 inhibitors effectively penetrate the blood-brain barrier and target glioma tumor tissues but have little effect on normal brain tissues. Thus, BRD4 is a target for the treatment of glioma. In this study, we discuss the progress in the use of BRD4 inhibitors for glioma treatment, their mechanism of action, and their broad potential clinical application., Graphical abstract, BRD4, a member of BET protein family, has been implicated in cell proliferation, invasion, self-renewal, apoptosis, and cell cycle arrest through multiple pathways. Thus, inhibition of BRD4 seems a prospective therapy. In this review, we discuss the progress of BRD4 inhibitors in glioma treatment and their broad potential clinical application.

The prognosis of melanoma patients is highly variable due to multiple factors conditioning immune response and driving metastatic progression. In this study, we have correlated the expression of immune-related lncRNAs with patient survival, developed a prognostic model, and investigated the characteristics of immune response in the diverse groups. The gene expression profiles and prognostic information of 470 melanoma patients were downloaded from TCGA database. Significantly predictive lncRNAs were identified by multivariate Cox regression analyses, and a prognostic model based on these variables was constructed to predict survival. Kaplan-Meier curves were plotted to estimate overall survival. The predictive accuracy of the model was evaluated by the area under the ROC curve (AUC). Principal component analysis was used to observe the distribution of immune-related genes. CIBERSORT and ESTIMATE were used to evaluate the composition of immune cells and the immune microenvironment. Eight immune-related lncRNAs were determined to be prognostic by multivariate COX regression analysis. The patient scores were calculated and divided into high- and low-risk groups. The model could effectively predict the prognosis in patients of different stages. The AUC of the model is 0.784, which was significantly higher than that of the other variables. There were significant differences in the distribution of immune-related genes between two groups; the immune score and immune function enrichment score were higher in the low risk group.

This paper applied mesoporous metal-organic frameworks (MOFs) of UiO-66 particles for pH-responsive doxorubicin (DOX) delivery and cancer treatment. Mesoporous structured UiO-66 MOFs were synthesized, and carboxymethylcellulose (CMC) was loaded for sensitive pH response and also as a linker to encapsulate the chemotherapeutic drug of DOX. The composite of UiO-66/CMC@DOX was synthesized, and the loading capacity was as high as 45 μg DOX per mg of the carrier. The structure and crystalization of the UiO-66 MOFs were determined by the Transmitting Electron Microscope (TEM) and x-ray diffraction methods, while the loading of CMC and DOX was inspected by Fourier Transform InfraRed (FT-IR) and UV–vis spectroscopy. The DOX release from UiO-66/CMC@DOX was tested under different pH at 37 °C. The DOX accumulative release could reach 78% under the pH of 5. A lower pH was more favorable for DOX release due to the CMC shrinking and higher DOX solubility in an acidic environment. The cytotoxicity study indicated that, under the DOX concentration of 4 μg ml−1, the A549 cell (Lung Carcinoma Cell Line) viability of UiO-66/CMC was 28%, which was lower than that from free DOX solution (47%). UiO-66 MOFs were demonstrated to be an efficient drug delivery carrier for chemotherapeutic drug and release.

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO–based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA–anthracycline for low-/intermediate-risk patients, or ATRA-ATO–anthracycline versus ATRA–anthracycline–cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of –5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI –0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan–Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA–chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Metastasis is the leading cause of cancer-related death. Surgery is a common intervention for most primary solid tumors; however, surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells. Currently, there are no effective interventions to prevent distant metastasis. Here, we show that HECTD3 deficiency in vascular endothelial cells (ECs) significantly reduces tumor metastasis in tumor resection metastasis, LPS-induced metastasis and MMTV-Neu metastasis models. HECTD3 depletion downregulates expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in mouse primary ECs and in human primary umbilical vein ECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo. We demonstrate that HECTD3 promotes stabilization and kinase activity of IKKα by ubiquitinating IKKα with K27- and K63-linked polyubiquitin chains at K296, increasing phosphorylation of histone H3 at Ser10 to promote NF-κB target gene transcription. IKKα kinase inhibitors prevented LPS-induced pulmonary metastasis. These findings reveal the promotional role of the HECTD3-IKKα axis in tumor hematogenous metastasis and provide a potential strategy for tumor metastasis prevention.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUThigh) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUThigh with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUThigh was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUThigh in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell–like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYOTP53/BCI.-2-targeted agents were investigated in DLBCI. cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining LNCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INICB057643, DS3032b and venetoclax to induce cellcycle arrest and apoptosis and to inhibit A KT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/1153 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2–targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/ BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. Implications: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.

Background: Public health workers at Chinese Center for Disease Control and Prevention (China CDC) and primary health care institutes (PHI) constitute one of the main workforces for implementing prevention and control measures to contain the COVID-19 epidemic, but their efforts and health status have not been well documented. We aimed to investigate the working conditions and health status of frontline public health workers in China during the epidemic. Methods: Between February 18 to March 1, 2020, we conducted a cross-sectional survey among 2,313 CDC workers and 4,004 PHI workers in five provinces across China experiencing different scales of COVID-19 epidemic. We interviewed all participants about their work conditions, roles, burdens, perceptions, mental health, and self-rated health using a self-constructed questionnaire and standardized measurements (i.e., Patient Health Questionnaire and General Anxiety Disorder scale). To examine the independent associations between working conditions and health outcomes, we used multivariate regression models controlling for potential confounders. Results: The prevalence of depression, anxiety, and poor self-rated health was 21.3%, 19.0%, and 9.8%, respectively, among public health workers (27.1%, 20.6% and 15.0% among CDC workers; and 17.5%, 17.9% and 6.8% among PHI workers). The majority (71.6%) participated in both field and non-field work and gave immense efforts. Nearly 20.0% have worked all night for more than 3 days and 45.3% had worked during the whole period of Chinese New Year. Three risk factors and two protective factors were found independently associated with all three health outcomes in our final multivariate models, including working all night for >3 days (ORm=1.67~1.75, pConclusions: Chinese public health workers gave immense efforts and personal sacrifices to curb the COVID-19 epidemic and were exposed to risk of mental health problems. Efforts should be taken to improve the working condition and health status of public health workers to maintain the morale and effectiveness of public health workers in the fight against the epidemic.

Summary Nuclear-erythroid-2-related factor 2 (Nrf2) is involved in the pathogenesis of different liver diseases. Herein, we first demonstrated that Nrf2 expression was diminished in nonalcoholic steatohepatitis (NASH) liver macrophages. In myeloid Nrf2-deficiency mice, aggravated liver steatosis and inflammation in high-fat-diet (HFD)-fed mice were observed compared with the chow-diet group. Moreover, the increasing inflammatory cytokines influenced the lipid metabolism in hepatocytes in vivo and in vitro. Further study showed Nrf2 regulated reactive-oxygen-species-mediated Hippo-yes-associated protein (YAP) signaling, which in turn modulated the NLRP3 inflammasome activation. Administration of YAP activator also significantly ablated the lipid accumulation and inhibited the NLRP3 activation in the Nrf2 deletion condition both in vitro and vivo. Overexpression Nrf2 in liver macrophages effectively alleviated steatohepatitis in wild-type mice fed with an HFD . Our data support that by modulating YAP-mediated NLRP3 inflammasome activity, macrophage Nrf2 slows down NASH progression., Graphical abstract, Highlights • Kupffer cells Nrf2 was downregulated in both human and mouse NASH livers • Myeloid Nrf2 deficiency aggravates liver steatosis and inflammation in HFD-induced NASH • Nrf2 controls the NLRP3 activation in a ROS-mediated Hippo-YAP signaling manner, Immunology; Physiology; Endocrine System Physiology; Human Metabolism

Glioblastoma (GBM) is a highly malignant and aggressive primary brain tumor mostly prevalent in adults and is associated with a very poor prognosis. Moreover, only a few effective treatment regimens are available due to their rapid invasion of the brain parenchyma and resistance to conventional therapy. However, the fast development of cancer immunotherapy and the remarkable survival benefit from immunotherapy in several extracranial tumor types have recently paved the way for numerous interventional studies involving GBM patients. The recent success of checkpoint blockade therapy, targeting immunoinhibitory proteins such as programmed cell death protein-1 and/or cytotoxic T lymphocyte-associated antigen-4, has initiated a paradigm shift in clinical and preclinical investigations, and the use of immunotherapy for solid tumors, which would be a potential breakthrough in the field of drug therapy for the GBM treatment. However clinical trial showed limited benefits for GBM patients. The main reason is drug resistance. This review summarizes the clinical research progress of immune checkpoint molecules and inhibitors, introduces the current research status of immune checkpoint inhibitors in the field of GBM, analyzes the molecular resistance mechanism of checkpoint blockade therapy, proposes corresponding re-sensitive strategies, and describes a reference for the design and development of subsequent clinical studies on immunotherapy for GBM.

Background: Follicular lymphoma is the second most frequent non-Hodgkin lymphoma (NHL) accounting for 20-25% of NHL cases in western countries. Although it has an indolent character, progressive disease or relapse occurs within first two years following therapy initiation in ~20% of FL cases. Several somatic mutations were identified in genes of epigenetic regulation or other biological processes by sequencing of FL tumors. Current diagnostic and prognostic evaluations include invasive methodologies that may be less effective and more risky for the FL patients. Therefore, there is urgent need for development of non-invasive methods to improve diagnosis as well as risk stratification. Accumulating evidence has shown that circulating cell-free DNA (cfDNA) includes tumor-derived mutations in several cancer types; however, this possibility has not been comprehensively investigated in FL patients. Here we evaluated the potential diagnostic and prognostic value of cfDNA in FL cases by addressing the proportion by which cfDNA samples contains cancer-associated and prognosis-related mutations. Methods: Twenty FL cases with available clinic data were included in this study. Thirteen of these cases were symptomatic who were later treated with R-chemo whereas rest of the cases were asymptomatic who were in watchful-waiting. Plasma cfDNA, granulocyte DNA, and FFPE tumor tissue DNA samples were obtained from treatment-naive FL cases. A custom gene panel including exons and exon-intron boundaries of 110 FL-associated genes was constructed based on previously published studies for ultra-deep targeted sequencing. Paired-end sequencing of the captured regions were performed using a HiSeq system in Novogene, which generated 150 bp NGS reads. Targeted genomic regions were covered with > 1500X average effective sequencing depth for identification of somatic variants with low variant allele fractions (VAF). Variants present in cfDNA and tumor tissue DNA but not in patient-matched granulocyte DNA were identified with the GATK pipeline including the MuTect2 variant caller. Somatic variants associated with hematopoietic and lymphoid tissues in the COSMIC database were chosen for further analyses. The final high-confident list of variants was determined by visual investigation and through additional filtering of each variant using Integrative Genomics Viewer. Selected variants were cross-validated with Sanger sequencing. Survival analyses were performed with Survival and Survminer R packages. Results: Ultra-deep targeted sequencing revealed 91 somatic variants (71 missense, 12 nonsense, 4 indel, 4 splice site) in 31 genes included in the panel. Consistent with previous reports, the most frequently mutated genes were CREBBP (40%), BCL2 (30%), STAT6 (25%), EZH2 (20%), and CARD11 (20%). In symptomatic cases, 41.5% of the variants was present in both cfDNA and tumor tissue DNA, whereas 52.3% and 6.2% of them was present only in tumor tissue DNA or in cfDNA samples, respectively. In asymptomatic cases, 11.5% of the detected variants was present in both cfDNA and tumor tissue DNA, while 84.6% and 3.8% of them were in only tumor tissue DNA or cfDNA samples. Mutations previously reported to be associated with FL pathogenesis (e.g. KMT2D R2417*) were in the list of common variants observed in both cfDNA and tumor tissue DNA. We observed high Ki67 staining, elevated LDH levels, presence of BCL2 or CCND3 mutations to be significantly associated with progression-free survival (Figure 1A, B). Importantly, survival analysis by stratifying patients based on BCL2 mutations present only in cfDNA also predicted poor prognosis (Figure 1C). One of the FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in the cfDNA but not in tumor tissue DNA sample. Finally, we cross-validated the selected somatic variants with VAF >20% using Sanger sequencing, which showed 100% consistency with NGS results. Conclusions: Tumor tissue-derived mutations can be detected in most FL patients albeit to a lesser extent than those in DLBCL. Plasma cfDNA genotyping may be useful for improving diagnosis and prognosis especially in symptomatic FL patients. Given that some somatic mutations associated with disease progression are detected only in plasma cfDNA samples, cfDNA genotyping may be useful for choosing appropriate therapy for high-risk FL patients. Disclosures No relevant conflicts of interest to declare.

Objectives: The study is performed to analyze the relationship between immune-related long non-coding RNAs (lncRNAs) and the prognosis of cervical cancer patients. We constructed a prognostic model and explored the immune characteristics of different risk groups.Methods: We downloaded the gene expression profiles and clinical data of 227 patients from The Cancer Genome Atlas database and extracted immune-related lncRNAs. Cox regression analysis was used to pick out the predictive lncRNAs. The risk score of each patient was calculated based on the expression level of lncRNAs and regression coefficient (β), and a prognostic model was constructed. The overall survival (OS) of different risk groups was analyzed and compared by the Kaplan–Meier method. To analyze the distribution of immune-related genes in each group, principal component analysis and Gene set enrichment analysis were carried out. Estimation of STromal and Immune cells in MAlignant Tumors using Expression data was performed to explore the immune microenvironment.Results: Patients were divided into training set and validation set. Five immune-related lncRNAs (H1FX-AS1, AL441992.1, USP30-AS1, AP001527.2, and AL031123.2) were selected for the construction of the prognostic model. Patients in the training set were divided into high-risk group with shorter OS and low-risk group with longer OS (p = 0.004); meanwhile, similar result were found in validation set (p = 0.013), combination set (p < 0.001) and patients with different tumor stages. This model was further confirmed in 56 cervical cancer tissues by Q-PCR. The distribution of immune-related genes was significantly different in each group. In addition, the immune score and the programmed death-ligand 1 expression of the low-risk group was higher.Conclusions: The prognostic model based on immune-related lncRNAs could predict the prognosis and immune status of cervical cancer patients which is conducive to clinical prognosis judgment and individual treatment.

Primary central nervous system lymphoma (PCNSL) is an aggressive cancer typically confined to the brain, eyes, leptomeninges and spinal cord, without evidence of systemic involvement. PCNSL remains a challenge for scientists and clinicians due to insufficient biological knowledge, a lack of appropriate animal models and validated diagnostic biomarkers. We summarize recent findings on genomic, transcriptomic and epigenetic alterations identified in PCNSL. These findings help to define pathobiology of the disease and delineate defects in B cell differentiation. Evidence from genomic and transcriptomic studies helps to separate PCNSL from other hematological malignancies, improves diagnostics and reveals new therapeutic targets for treatment. Discovery of the CNS lymphatic system may be instrumental in better understanding the origin of the disease. We critically assess the attempts to model PCNSL in rodents, and conclude that there is a lack of a genetic/transgenic model that adequately mimics pathogenesis of the disease. Contribution of the tumor microenvironment in tumorigenesis and aggressiveness of PCNSL remains understudied. Assessing heterogeneity of immune infiltrates, cytokine profiling and molecular markers, may improve diagnostics and put forward new therapeutic strategies.

Breast cancer is the most diagnosed cancer in women. It significantly impairs a patient's physical and mental health. Gut microbiota comprise the bacteria residing in a host's gastrointestinal tract. Through studies over the last decade, we now know that alterations in the composition of the gut microbiome are associated with protection against colonization by pathogens and other diseases, such as diabetes and cancer. This review focuses on how gut microbiota can affect breast cancer development through estrogen activity and discusses the types of bacteria that may be involved in the onset and the progression of breast cancer. We also describe potential therapies to curtail the risk of breast cancer by restoring gut microbiota homeostasis and reducing systemic estrogen levels. This review will further explore the relationship between intestinal microbes and breast cancer and propose a method to treat breast cancer by improving intestinal microbes. We aimed at discovering new methods to prevent or treat BC by changing intestinal microorganisms.

Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell communication, cell migration, invasion and metastasis, tumor angiogenesis, inflammatory and anti-cancer immune responses. Semaphorins comprise secreted and cell surface-exposed molecules and their receptors are mainly found in the Plexin and Neuropilin families, which are further implicated in a signaling network controlling the tumor microenvironment. Accumulating evidence indicates that semaphorins may be considered as novel clinical biomarkers for cancer, especially for the prediction of patient survival and responsiveness to therapy. Moreover, preclinical experimental studies have demonstrated that targeting semaphorin signaling can interfere with tumor growth and/or metastatic dissemination, suggesting their relevance as novel therapeutic targets in cancer; this has also prompted the development of semaphorin-interfering molecules for application in the clinic. Here we will survey, in diverse human cancers, the current knowledge about the relevance of semaphorin family members, and conceptualize potential lines of future research development in this field.

Transcriptome differences between Hodgkin's lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL), which are all derived from B cell, remained unclear. This study aimed to construct lymphoma-specific diagnostic models by screening lymphoma marker genes. Transcriptome data of HL, DLBCL, and MCL were obtained from public databases. Lymphoma marker genes were screened by comparing cases and controls as well as the intergroup differences among lymphomas. A total of 9 HL marker genes, 7 DLBCL marker genes, and 4 MCL marker genes were screened in this study. Most HL marker genes were upregulated, whereas DLBCL and MCL marker genes were downregulated compared to controls. The optimal HL-specific diagnostic model contains one marker gene (MYH2) with an AUC of 0.901. The optimal DLBCL-specific diagnostic model contains 7 marker genes (LIPF, CCDC144B, PRO2964, PHF1, SFTPA2, NTS, and HP) with an AUC of 0.951. The optimal MCL-specific diagnostic model contains 3 marker genes (IGLV3-19, IGKV4-1, and PRB3) with an AUC of 0.843. The present study reveals the transcriptome data-based differences between HL, DLBCL, and MCL, when combined with other clinical markers, may help the clinical diagnosis and prognosis.

Immune cells have an uncertain function during the progression of extranodal natural killer/T-cell lymphoma (ENKTL). The present study determined the distribution, phenotype, and clinical significance of B lymphocytes in ENKTL. Immunohistochemistry indicated high infiltration of CD20+ B lymphocytes in the tumour tissues of 40% of the patients, and that a high infiltration correlated with better overall survival. Moreover, B lymphocytes had an active mature phenotype in situ and suppressed the proliferation of ENKTL cells in vitro. These results suggest that tumour infiltration of CD20+ B lymphocytes may be a new prognostic indicator for patients with ENKTL.

Background The management of critically ill patients with coronavirus disease 2019 (COVID‐19), caused by a new human virus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is challenging. Recently, there have been several reports with inconsistent results after treatment with convalescent plasma (CP) on critically ill patients with COVID‐19, which was produced with a neutralizing antibody titer and tested in a P3 or P4 laboratory. However, due to the limitation of the conditions on mass production of plasma, most producers hardly had the capability to isolate the neutralizing antibody. Here, we report the clinical courses of three critically ill patients with COVID‐19 receiving CP treatments by total immunoglobulin G (IgG) titer collection. Methods Three patients with COVID‐19 in this study were laboratory confirmed to be positive for SARS‐CoV‐2, with radiographic and clinical features of pneumonia. CP was collected by total IgG titer of 160 (range, 200‐225 mL), and patients were transfused between 20 and 30 days after disease onset at the critical illness stage as a trial in addition to standard care. The clinical courses of these patients, including laboratory results and pulmonary functional and image studies after receiving convalescent plasma infusions, were reviewed. Results No therapeutic effect of CP was observed in any of the patients; instead, all three patients deteriorated and required extracorporeal membrane oxygenation treatment. A potential cytokine storm 4 hours after infusion of CP in Patient 2 was observed. No more patients were put on the trial of CP transfusion. Conclusions We recommend extreme caution in using CP in critically ill patients more than 2 weeks after the onset of COVID‐19 pneumonia.

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract (indolent GI T-LPD) is a benign neoplasm of CD4(+)or CD8(+)T cells that form primary tumors in the GI tract. Indolent GI T-LPD has recently been provisionally recognized as a distinct entity by the 2016 revision of the WHO classification of lymphoid neoplasms. Appropriate diagnosis of these cases is challenging as they may be misdiagnosed as T cell lymphoma that has an aggressive clinical course. Consequently, aggressive therapeutic approaches were usually chosen to treat these cases with no obvious benefit for most of the patients and potential side effects. Moreover, inflammatory diseases of the GI tract with similar symptoms may lead to misdiagnosis that leads to delays in administration of proper therapeutics against these cases. Therefore, it is of utmost importance to identify prognostic genetic biomarkers at the time of diagnosis for optimal medical care of these patients. TCR clonality analyses may not be useful for distinguishing these benign neoplasms from aggressive gastrointestinal T cell lymphomas; however, molecular genetic tests may prove useful as recurrentSTAT3-JAK2fusions, which may have diagnostic, prognostic or therapeutic value, have recently been identified. However, there is still lack of comprehensive information on the genetic and epigenetic factors associated with pathogenesis of indolent GI T-LPD. In this mini-review, we focus on the so far reported literature on indolent GI T-LPD cases, and discuss future directions for better differential diagnosis, risk stratification, and therapeutic target discovery with a special focus on the genetic and epigenetic alterations.