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Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure and highly resistant to chemotherapy, potentially due to upregulated expression of the pro-survival proteins, BCL2/BCL-XL/MCL-1. Using clinically-relevant models of MPM we show that patient-derived primary MPM cell lines andex-vivo3D tumour explants are highly resistant to apoptosis induced by the BCL2/BCL-XL inhibitor, ABT-737. Importantly, we discover that 2-deoxyglucose (2DG), a glycolytic inhibitor, can sensitize MPM cells to ABT-737 and show this correlates with loss of the pro-survival protein, MCL-1. siRNA knockdown of MCL-1 (MCL-1 KD) combined with ABT-737 induced BAX/BAK-dependent, but BIM/PUMA-independent apoptosis, mimicking 2DG/ABT-737 treatment. MCL-1 KD/ABT-737 induced mitochondrial cytochromecrelease and caspase-independent inhibition of mitochondrial respiration. Moreover, we observed a hitherto unreported caspase-dependent cleavage of glycolytic enzymes and subsequent inhibition of glycolysis. 2DG inhibited ERK/STAT3 activity, decreased MCL-1 mRNA and protein levels, with concurrent activation of AKT, which limited loss of MCL-1 protein. However, co-treatment with a specific AKT inhibitor, AZD5363, and 2DG/ABT-737 potently induced cell death and inhibited clonogenic cell survival, while in MPM 3D tumour explants MCL-1 protein expression decreased significantly following 2DG or 2DG/AZD5363 treatment. Notably, a similar synergy was observed in MPM cell lines and MPM 3D tumour explants using ABT-737 in combination with the recently developed MCL-1 inhibitor, S63845. Importantly, our study provides a mechanistic explanation for the chemoresistance of MPM and highlights how this can be overcome by a combination of metabolic reprogramming and/or simultaneous targeting of MCL-1 and BCL-2/BCL-XL using BH3-mimetics.

Dysregulated mitochondrial fusion and fission has been implicated in the pathogenesis of numerous diseases. We have identified a novel function of the p53 family protein TAp73 in regulating mitochondrial dynamics. TAp73 regulates the expression of Optic atrophy 1, a protein responsible for controlling mitochondrial fusion, cristae biogenesis and electron transport chain function. Disruption of this axis results in a fragmented mitochondrial network and an impaired capacity for energy productionviaoxidative phosphorylation. Owing to the role of OPA1 in modulating cytochromecrelease, TAp73-/-cells also display an increased sensitivity to apoptotic cell death, e.g.,viaBH3-mimetics. We also show that the TAp73/OPA1 axis has functional relevance in the upper airway, where TAp73 expression is essential for multiciliated cell differentiation and function. Consistently, ciliated epithelial cells ofTrp73-/-(global p73 KO) mice display decreased expression of OPA1 and perturbations of the mitochondrial network, which may drive multiciliated cell loss. In support of this,Trp73andOPA1gene expression is decreased in COPD patients, a disease characterised by alterations in mitochondrial dynamics. We therefore highlight a potential mechanism involving the loss of p73 in COPD pathogenesis. This work also adds to the growing body of evidence for growth-promoting roles of TAp73 isoforms.

Engineered carbon nanotubes (CNT) are currently used in many industrial products. Multi-walled carbon nanotubes (MWCNT) exhibit unique physicochemical properties and due to their low density and small size are easily aerosolized, making workplace exposure a potential risk to human health. MWCNT are similar to Asbestos in terms of their high aspect-ratio and thus may pose an asbestos-like inhalation hazard, including sporadic pleural Mesothelioma. Mitsui-7 MWCNT (MWCNT-7) have been classified by IARC as a Group 2B carcinogen. Importantly, physicochemically-altered MWCNT synthesized with nitrogen (MWCNT-ND) have been found to elicit attenuated toxicity; however, their pathogenicity in the pleura is unknown. Using a mouse model of direct injection into the pleural cavity, we compared the molecular changes that occur at the mesothelium over 20-months following injection with an occupationally-relevant dose of MWCNT-7, MWCNT-ND, Asbestos or carbon black. When compared to Asbestos or MWCNT-7, mice injected with MWCNT-ND did not develop respiratory symptoms. In contrast, in cell lines established from pleural effusions from MWCNT-7 or Asbestos-exposed mice with pre-neoplastic lesions or tumours, Whole-Exome-Sequencing and RNASeq revealed common molecular changes in both lesions and tumours. This identified genes involved in driving progression of pleural inflammatory lesions to Mesothelioma, whereas pre-neoplastic lesion-derived cell lines allow dissection of the hazard mechanism of pathogenic fibres at the molecular level early in disease development and thus may help predict genotoxic potency in exposed human populations. Our data demonstrate that physicochemical alteration of MWCNT (e.g. synthesis with nitrogen) attenuates pathogenicity and may offer an alternative for use in industrial applications.

Peer reviewed: True, Malignant mesothelioma is an aggressive tumour of the pleura (MPM) or peritoneum with a clinical presentation at an advanced stage of the disease. Current therapies only marginally improve survival and there is an urgent need to identify new treatments. Carcinoma-associated fibroblasts (CAFs) represent the main component of a vast stroma within MPM and play an important role in the tumour microenvironment. The influence of CAFs on cancer progression, aggressiveness and metastasis is well understood; however, the role of CAF-derived extracellular vesicles (CAF-EVs) in the promotion of tumour development and invasiveness is underexplored. We purified CAF-EVs from MPM-associated cells and healthy dermal human fibroblasts and examined their effect on cell proliferation and motility. The data show that exposure of healthy mesothelial cells to EVs derived from CAFs, but not from normal dermal human fibroblasts (NDHF) resulted in activating pro-oncogenic signalling pathways and increased proliferation and motility. Consistent with its role in suppressing Yes-Associated Protein (YAP) activation (which in MPM is a result of Hippo pathway inactivation), treatment with Simvastatin ameliorated the pro-oncogenic effects instigated by CAF-EVs by mechanisms involving both a reduction in EV number and changes in EV cargo. Collectively, these data determine the significance of CAF-derived EVs in mesothelioma development and progression and suggest new targets in cancer therapy.

Rare-metal mineralization in aluminous granites (i.e. rare-metal granites, RMGs) is usually associated with high degree of magma fractionation, strong enrichment in fluxing elements (Li, B, P, and F), and the operation of both magmatic and hydrothermal processes. Experimental data have established the theoretical basis for melt- or fluid-driven rare-metal mineralization. To investigate these mechanisms in natural samples, this paper presents detailed textural and compositional variations for zoned micas and rare-metal minerals from rocks of the Late Jurassic Yashan rare-metal granitic pluton, South China. This pluton preserves an evolutionary sequence from ore-barren rocks to those containing ores formed by Ta–Nb–Li mineralization during magmatic–hydrothermal processes. Three main units of the Yashan pluton are exposed: from bottom to top, these comprise protolithionite–muscovite granite (Unit I), Li-mica granite (Unit II), and topaz–lepidolite granite (Unit III), representing crystallization from successive magma batches from a deep-level magma chamber. The gradual decrease in Nb/Ta and K/Rb in both whole rocks and micas from units I to II to III illustrates fractionation within the magma chamber, accompanied by successive enrichment of incompatible elements in the residual melt. Furthermore, the strong enrichment of fluxing elements such as Li, P, and F in Unit III likely led to lower magma viscosity, which may have helped to expulse interstitial residual melt from the magma chamber. Zoned micas from the Yashan pluton are composed of Li-phengite or lepidolite inner cores and muscovite rims. Cores show increasing Li, F, and rare-metal elements from units I and II to Unit III, consistent with the trend of magmatic fractionation. In contrast, rims that formed in the residual hydrosilicate melt show marked decrease in F and rare metals (i.e. Li, Cs, Rb, Nb, Ta, Sn, and W). Chemical variations of the zoned micas and rare-metal minerals were used together with Rayleigh fractionation modeling calculations to reconstruct the contribution of melt–fluid immiscibility to the crystallization of rare metals, which took place via the combination of melts enriched in high-field-strength elements (e.g. Nb and Ta) and fluids enriched in mobile elements (e.g. Mn, Fe, W, and Cs). Strong fractionation of Nb and Ta, along with extreme enrichment of Ta, in RMGs is caused mainly by the crystallization of micas and columbite-group minerals, and also depends on the degree of fractional crystallization. The subsolidus alteration of micas by acidic fluids may have leached some Nb rather than Ta during chloritization, which could have partly contributed to the enrichment of rare metals and fractionation of Nb–Ta. It is concluded that magmatic–hydrothermal processes, including magmatic evolution and fluid exsolution, are critical for rare-metal enrichment and Nb–Ta fractionation in RMGs.

Background This study evaluates the effectiveness of continuous glucose monitoring (CGM) in diabetes patients who were on routine dialysis. Methods Literature search was conducted in electronic databases and studies were selected by following precise eligibility criteria. Random-effects meta-analyses were performed to estimate a) correlations of CGM with other indicators including glycated hemoglobin A1c (HbA1c), glycated albumin and mean amplitude of glucose excursions (MAGE), and b) mean differences (MDs) in CGM and MAGE values between dialysis and off-dialysis days or during vs before dialysis. Results There was a good correlation between CGM and self-monitoring of blood glucose values (r=0.837 [95% confidence interval (CI): 0.67, 0.92]. Correlation coefficient between CGM and HbA1c was 0.523 [95% CI: 0.422, 604] in diabetes patients on dialysis and 0.592 [95% CI: 0.354, 0.757] in diabetes patients without renal failure. Correlation coefficient between CGM and glycated albumin in diabetes patients on dialysis was 0.544 [95% CI: 0.254, 0.744]. Average CGM and MAGE values on dialysis day were not significantly different from those of offdialysis day in diabetes patients (MDs: -0.40 millimole/liter (mmol/L) [95% CI: -1.06, 0.26]; p=0.23) and MAGE 0.50 mmol/L [95% CI: -0.01, 1.00]; p=0.05, respectively). Compared to predialysis values, average CGM and MAGE values were significantly lower during dialysis in diabetes patients (MDs: -2.11 mmol/L [95% CI: -3.25, -0.97]; p=0.0003 and MAGE -2.24 mmol/L [95% CI: -3.99, -0.50]; p=0.01, respectively). Conclusions CGM is an efficient method of glycemic monitoring in diabetes patients on dialysis. CGM had similar correlations with HbA1c and glycated albumin.

Despite the in vitro usage of CRISPR/Cas12a system in fluorescent biosensors has made remarkable achievements, many challenges such as poor biological delivery, insufficient sensitivity, and uncontrollable initiation compel them hard to conduct in vivo analysis. Thus, we propose here some fruitful sensing concepts. First, the multiple biomolecular components of CRISPR/Cas12a system are collectively carried by MnO

Owing to their favorable design flexibility and eminent signal amplification ability, DNA nanomachine-supported biosensors have provided an attractive avenue for intracellular fluorescence imaging, especially for DNA walkers. However, this promising option not only suffers from poor controllability but also needs to be supplied with additional driving forces on account of the frequent employment of metal ion-dependent DNAzymes. Aiming at overcoming these obstacles, we introduce some fruitful solutions. On one hand, innovative light-activated walking behavior induced by a photocleavage mode is established on the surfaces of gold nanoparticles, and such a photoselective sensing system can be perfectly prevented from pre-activating during the intracellular delivery process and made to achieve target identification only under irradiation using a moderate ultraviolet light source. On the other hand, this light-switchable sensing frame is encapsulated within a dissociable metal-organic framework (ZIF-8) to facilitate endocytosis and ensure sufficient internal cofactors (Zn2+) to realize a self-driven pattern in the acidic environment of the cell lysosome. Based on the abovementioned efforts, the newly constructed autonomous three-dimensional DNA walkers present satisfactory sensitivity (a limit of detection of down to 19.4 pM) and specificity (even distinguishing single-base changes) toward a model biomarker (microRNA-21). More importantly, the sensing method allows determination of the variations in targets in living cancer cells with exceptional precision and efficiency, offering a powerful assay platform for intracellular imaging.

Exposure to asbestos causes pathological changes in the pleural cavity, including malignant mesothelioma (MPM). Length-dependent retention of asbestos fibres in the pleural cavity is crucial for disease development. Chronic inflammation induced by biopersistent asbestos fibres plays a key role in carcinogenesis. Engineered CarbonNanoTubes (CNT) are similar to long-fibre asbestos (LFA) in terms of their high aspect-ratio and thus may pose an asbestos-like inhalation hazard, with evidence from our laboratory and others showing the carcinogenic potential of Long-CNT. Asbestos-induced MPM is diagnosed most commonly at late stage; as a result, little is known about the genetic or epigenetic aberrations occurring in pre-malignant pleural lesions and whether they align with deletions/mutations commonly found in end-stage asbestos-exposed patient tumours. Using a mouse model of direct injection into the pleural cavity, we compared the molecular changes that occur at the mesothelium following injection with an occupationally-relevant dose of Long-CNT or LFA over 20-months. We show a common molecular signature induced by Long-CNT and LFA throughout disease progression eventually leading to the development of sporadic MPM. DNA methylation, gene expression profiles, as well as specific genes are similarly altered in the presence of Long-CNT and LFA, at matched longitudinal exposure times. For the first time, these data uncover the Adverse Outcome Pathway (AOP) from initial Long-CNT exposure through to induction of pre-neoplastic lesions and the development of sporadic pleural mesothelioma, replicating the pathogenesis of end-stage asbestos-induced human disease. This reinforces concerns that high aspect-ratio CNT may pose an asbestos-like hazard, including sporadic malignant mesothelioma.

Funder: Libor Fund grant from the UK Department of Health, by the British Lung Foundation and by the Asmarley Foundation, Funder: UK Medical Research Council, Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

BackgroundThis research aimed to investigate the tasks performed by Coronavirus Disease 2019(COVID-19) prevention and control management teams at primary healthcare (PHC) facilities during COVID-19 pandemic across the mainland China.MethodsAn online survey was performed and COVID-19 prevention and control management teams at PHC facilities were invited to participate in this research. The top 7 most important tasks in the three different periods of COVID-19 containment were selected and ranked. Participations of tasks were surveyed.ResultsA total of 998 valid responses (an effective rate of 99.11%) were collected. The respondents were divided into Group A (≤5 respondents within each PHC facility, n1 = 718) and Group B (> 5 respondents within each PHC facility, n2 = 280). The consensus was selected from top 7 most important tasks including screening at travel centers/intervals and screening at entry centers, at-home/centralized quarantine management, transferring, pre-examination/triage and fever sentinel surveillance clinic/fever clinic. Pre-examination/triage and fever sentinel surveillance clinic/fever clinic works became more significant in the regular prevention and control period. Adjusted analysis found that team members of Group A with a college, undergraduate college and graduate school educational background were less involved in pre-examination/triage works (aOR: 0.28; 95%CI: 0.09-0.86,P = 0.026; aOR: 0.30; 95%CI: 0.10-0.90,P = 0.031; aOR: 0.21; 95%CI: 0.05-0.82,P = 0.024). Those who were over the median age were twice more likely to be engaged in managing fever sentinel surveillance of clinic/fever clinic visitors (aOR: 2.18; 95%CI: 1.16-4.08,P = 0.015). Those being specialized in nursing and other specialties were less likely to participate in fever sentinel surveillance of clinic/fever clinic works (aOR: 0.44; 95%CI: 0.24-0.81,P = 0.009; aOR: 0.30; 95%CI: 0.16-0.58,P < 0.001). Those came from central and western China were less likely to participate in centralized quarantine management (aOR: 0.61; 95%CI: 0.38-0.98,P = 0.042; aOR: 0.64; 95%CI: 0.42-0.97,P = 0.037). Team members came from central and western China were twice less likely to participate in screening at travel centers/intervals (aOR: 1.75; 95%CI: 1.14-2.70,P = 0.011; aOR: 1.63; 95%CI: 1.07-2.48,P = 0.024).ConclusionIn mainland China, team members of COVID-19 prevention and control at PHC facilities are mainly responsible for screening, quarantine, transferring and monitoring during the COVID-19 pandemic. Pre-examination/triage and the fever sentinel surveillance clinic/fever clinic were gradually valued. Team members with lower educational background are competent in pre-examination/triage works, but more experienced general practitioners are more likely to be in charge of fever sentinel surveillance clinic/fever clinics work. The necessity of COVID-19 prevention and control management teams to participate in screening at travel centers/intervals is subjected to further discussions.

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no ‘druggable’ driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease., Treating malignant pleural mesothelioma (MpM) is challenging due to a lack of druggable genes, but other molecular features could be clinically useful. Here the authors profile mRNA translation dysregulation in MpM cell lines using polysome profiling, and identify mTORC1 and 2 as potential pharmacological targets.

To study the tensile mechanical properties of constant resistance bolts, the RFPA (Rock Failure Process Analysis) statics software is used to perform a uniaxial tensile test on a constant resistance bolt. The numerical test results show that the plastic strain value is 12 times the magnitude of the elastic strain. During plastic deformation, the fluctuation in the stress magnitude is relatively stable, indicating that the bolt has good constant resistance characteristics. The numerical test results are in good agreement with the laboratory test results of M.C. He, and the accuracy and reliability of the numerical test method are verified. Therefore, the RFPA software with coupled static-dynamic loading is further adopted to study the supporting effects of traditional bolts and constant resistance bolts under coupled static-dynamic loading. The numerical comparison of the test results show that the constant resistance bolts can effectively control the deformation amount and rate of the laneway surrounding rock, reduce the total and rate of increase in the accumulated acoustic emissions, decrease the stress on the units in the model and protect the stability of the laneway. This paper verifies that a constant resistance bolt has better impact resistance mechanical properties than those of a traditional bolt and provides an effective way to control rock burst and soft rock that is prone to large deformation damage.

Wound healing requires abundant nutrition and blood supply, thus angiogenesis is a vital stage in this process. Angiogenesis involves diverse kinds of immune cells, growth factors, cytokines and inhibitors. ADSCs, especially ADSCs cultured in hypoxic condition, are reported to be able to facilitate angiogenesis and promote wound healing process. Significant efforts have been made on the development of ADSCs-based therapies with wound-healing applications. Here the results showed that expression of Angiopoietin-2 (ANGPT2) in ADSCs was up-regulated in the hypoxic condition.

Background In fulfilling the COVID-19 containment, primary health care (PHC) facilities in China played an important role. We sought to investigate the exact tasks performed at the PHC facilities and the processes of COVID-19 prevention and control.Methods Semi-structured face-to-face interviews for primary care physicians (PCPs) and a simple survey for residents were conducted in the field survey. Based-on purposive stratified sampling, 32 PCPs were selected from 22 PHC facilities in Wuhan as a high-risk city, in Shanghai as medium-risk city and in Zunyi as low-risk city. In the field survey, semi-structured face-to-face interviews were conducted with PCPs to summarize the tasks of COVID-19 prevention and control at the PHC facilities. A simple survey was used to investigate the local residents’ awareness about COVID-19 prevention and control.Results In pre-outbreak period, the PHC facilities mainly engaged in storing medical supplies; in out-break period, they were responsible for screening, transferring, quarantine and treatment; in regular prevention and control period, attention was given to the employees and items of cold-chain & fresh food markets, etc. In Wuhan, PHC facilities focused on graded diagnoses and treatments of patients; in Shanghai, they were mainly engaged in at-home/centralized quarantine; in Zunyi, they focused on the screening of high-risk individuals. In urban areas, COVID-19 were more likely to be transmitted; in urban-rural areas, it was difficult to perform screening on the migrant populations; in rural areas, the risk was much lower. The community residents had satisfactory compliance with the preventive measures.Conclusion We identified differences in the prevention and control tasks performed at the PHC facilities in China. During the different phases of the pandemic, the tasks were adjusted depending on the gradually comprehensive understanding of COVID-19. Among the cities at different risk levels, screening, quarantine, transferring or treatment was chosen to be a priority accordingly. Located in different intra-city geographic locations at different risk levels, the PHC facilities conducted their own tasks accordingly. Additionally, compliance on the part of the local community residents could not be overemphasized in COVID-19 prevention and control.

In order to improve the oil production in turnaround fracture well, the influence model of initial fracture on the stress field near the fracture is established, according to the reservoir stress field theory and production percolation theory of oil and gas well. The influence of reorientation fracture about the initial horizontal geostress difference, production pressure drop, reservoir permeability, fracture length and width are studied in turnaround fracture well. The impact of various factors on reorientation fracture is cleared by means of orthogonal experimental design and intuitive analysis method. Among several factors, initial horizontal geostress difference is the most important factor affecting the fracture reorientation, production pressure drop is the second place, reservoir permeability and fracture width are in the middle, and fracture length has the least effect on reorientation fracture. The research result given by this paper can provide a guidance for well and layer selection in turnaround fracture well.

Background: RSK4 is a member of the p90 Ribosomal S6 kinase family that promotes metastasis and chemoresistance in non-small cell lung cancer and its inhibition improves therapeutic outcome in in vivo and ex vivo models. Here, we show that RSK4 inhibition activates HIF-1alpha and also impacts glucose and glutamine metabolism in lung adenocarcinoma cells. Methods: RSK4 was downregulated in lung adenocarcinoma cells by RNA interference or CRISPR/Cas9 technology. Glycolytic rate assay and mitochondrial stress test were performed using the Seahorse XFe96 analyzer. ATP levels were determined by the CellTiter Glo assay. Intracellular metabolites were profiled by untargeted mass spectrometry and U-13C glutamine labelling. 3D spheroids viability was assessed by CellTiter Glo 3D assay with or without glycolysis inhibition using 2-deoxy-D-glucose (2DG) or glutaminase inhibition using 6-Diazo-5-oxo-L-norleucine (DON). Protein expression was determined by Western blotting. Results: RSK4 downregulation enhanced glycolysis, oxidative phosphorylation, and ATP production in A549 cells. The RSK4-silenced cells showed increased lactate production and glutamine consumption via reductive carboxylation. This sensitized RSK4-silenced cells to 2DG and DON treatments. Mechanistically, RSK4 knockdown upregulates HIF-1alpha in normoxia through decreased activation of PHD2, an enzymes that targets HIF-1alpha for degradation. Stabilization of HIF-1alpha resulted in increased transcription of HK2, the rate limiting enzyme of glycolysis, and GLS1, which hydrolyzes glutamine. Conclusion: RSK4 knockdown promotes a pseudo-hypoxic phenotype in lung adenocarcinoma cells characterized by increased glycolysis and enhanced glutamine utilization via reductive carboxylation. Targeting these changes potentiates the effects of RSK4 inhibition and may represent new therapeutic opportunities for this tumor type. Citation Format: Lucksamon Thamlikitkul, Peng Chai, Cristina Balcells Nadal, Rajat Roy, Xiao-Ming Sun, Marion MacFarlane, Hector Keun, Michael Seckl, Olivier Pardo. RSK4 inhibition promotes pseudo-hypoxic metabolic responses in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3037.

The traditional approaches to false discovery rate (FDR) control in multiple hypothesis testing are usually based on the null distribution of a test statistic. However, all types of null distributions, including the theoretical, permutation-based and empirical ones, have some inherent drawbacks. For example, the theoretical null might fail because of improper assumptions on the sample distribution. Here, we propose a null distribution-free approach to FDR control for multiple hypothesis testing in the case-control study. This approach, named