Deep Q-networks with web-based survey data for simulating lung cancer intervention prediction and assessment in the elderly: a quantitative study

Background Lung cancer screening and intervention might be important to help detect lung cancer early and reduce the mortality, but little was known about lung cancer intervention strategy associated with intervention effect for preventing lung cancer. We employed Deep Q-Networks (DQN) to respond to this gap. The aim was to quantitatively predict lung cancer optimal intervention strategy and assess intervention effect in aged 65 years and older (the elderly). Methods We screened lung cancer high risk with web-based survey data and conducted simulative intervention. DQN models were developed to predict optimal intervention strategies to prevent lung cancer in elderly men and elderly women separately. We assessed the intervention effects to evaluate the optimal intervention strategy. Results Proposed DQN models quantitatively predicted and assessed lung cancer intervention. DQN models performed well in five stratified groups (elderly men, elderly women, men, women and the whole population). Stopping smoking and extending quitting smoking time were optimal intervention strategies in elderly men. Extending quitting time and reducing smoked cigarettes number were optimal intervention strategies in elderly women. In elderly men and women, the maximal reductions of lung cancer incidence were 31.81% and 24.62% separately. Lung cancer incidence trend was deduced from the year of 1984 to 2050, which predicted that the difference of lung cancer incidence between elderly men and women might be significantly decreased after thirty years quitting time. Conclusions We quantitatively predicted optimal intervention strategy and assessed lung cancer intervention effect in the elderly through DQN models. Those might improve intervention effects and reasonably prevent lung cancer.

Long Non-Coding RNA Neighbor of BRCA1 Gene 2: A Crucial Regulator in Cancer Biology

Long non-coding RNAs (lncRNAs) are involved in fundamental biochemical and cellular processes. The neighbor of BRCA1 gene 2 (NBR2) is a long intergenic non-coding RNA (lincRNA) whose gene locus is adjacent to the tumor suppressor gene breast cancer susceptibility gene 1 (BRCA1). In human cancers, NBR2 expression is dysregulated and correlates with clinical outcomes. Moreover, NBR2 is crucial for glucose metabolism and affects the proliferation, survival, metastasis, and therapeutic resistance in different types of cancer. Here, we review the precise molecular mechanisms underlying NBR2-induced changes in cancer. In addition, the potential application of NBR2 in the diagnosis and treatment of cancer is also discussed, as well as the challenges of exploiting NBR2 for cancer intervention.

Role of MRI in diagnosing the primary site of origin in indeterminate cases of uterocervical carcinomas: a systematic review and meta-analysis

Objective: To perform a literature review assessing role of MRI in predicting origin of indeterminate uterocervical carcinomas with emphasis on sequences and imaging parameters. Methods: Electronic literature search of PubMed was performed from its inception until May 2020 and PICO model used for study selection; population was female patients with known/clinical suspicion of uterocervical cancer, intervention was MRI, comparison was by histopathology and outcome was differentiation between primary endometrial and cervical cancers. Results: Eight out of 9 reviewed articles reinforced role of MRI in uterocervical primary determination. T2 and Dynamic contrast were the most popular sequences determining tumor location, morphology, enhancement, and invasion patterns. Role of DWI and MR spectroscopy has been evaluated by even fewer studies with significant differences found in both apparent diffusion coefficient values and metabolite spectra. The four studies eligible for meta-analysis showed a pooled sensitivity of 88.4% (95% confidence interval 70.6 to 96.1%) and a pooled specificity of 39.5% (95% confidence interval 4.2 to 90.6%). Conclusions: MRI plays a pivotal role in uterocervical primary determination with both conventional and newer sequences assessing important morphometric and functional parameters. Socioeconomic impact of both primaries, different management guidelines and paucity of existing studies warrants further research. Prospective multicenter trials will help bridge this gap. Meanwhile, individual patient database meta-analysis can help corroborate existing data. Advances in knowledge: MRI with its classical and functional sequences helps in differentiation of the uterine ‘cancer gray zone’ which is imperative as both primary endometrial and cervical tumors have different management protocols.

The Role of ARID1A in Tumors: Tumor Initiation or Tumor Suppression?

Genes encoding subunits of SWItch/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling complexes are collectively mutated in 20% of all human cancers, among which the AT-rich interacting domain−containing protein 1A (ARID1A, also known as BAF250a, B120, C1orf4, Osa1) that encodes protein ARID1A is the most frequently mutated, and mutations in ARID1A have been found in various types of cancer. ARID1A is thought to play a significant role both in tumor initiation and in tumor suppression, which is highly dependent upon context. Recent molecular mechanistic research has revealed that ARID1A participates in tumor progression through its effects on control of cell cycle, modulation of cellular functions such as EMT, and regulation of various signaling pathways. In this review, we synthesize a mechanistic understanding of the role of ARID1A in human tumor initiation as well as in tumor suppression and further discuss the implications of these new discoveries for potential cancer intervention. We also highlight the mechanisms by which mutations affecting the subunits in SWI/SNF complexes promote cancer.

Acidic microenvironment enhances MT1-MMP-mediated cancer cell motility through integrinβ1/cofilin/F-actin axis

Tumor acidic microenvironment is the main feature of many solid tumors. As a part of the tumor microenvironment, it has a profound impact on the occurrence and development of tumors. However, the research on how tumor cells sense the changes of the external microenvironment and how the intracellular subcellular structures transmit the signals from extracellular to intracellular is unclear. In this study, we identify that the acidic microenvironment enhances cancer cell motility, and the expression of membrane-anchored membrane type 1-matrix metalloproteinase is also associated with cell motility, which indicates more degradation of the ECM under the acidic microenvironment. Moreover, the expression of cofilin is low in the acidic microenvironment, and the F-actin filaments are distributed more along the cells. The cytoskeletal F-actin changes are consistent with the potential of a high-invasive phenotype. Further study reveals the upstream control of the signal transductions from extracellular to intracellular, that is, the integrin β1 functions to trigger the biological responses under the acidic microenvironment. Our results demonstrate that the acidic microenvironment enhances cancer cell motility through the integrin β1/cofilin/F-actin signal axis. This study clearly shows the scheme of the signal transmissions from extracellular to intracellular and further reveals the cytoskeletal roles for the contributions of cancer cell motility under acidic microenvironment, which provides new targets for cancer intervention from the biochemical and biophysical perspectives.

Inferred Ancestral Origin of Cancer Cell Lines Associates with Differential Drug Response

Disparities between risk, treatment outcomes and survival rates in cancer patients across the world may be attributed to socioeconomic factors. In addition, the role of ancestry is frequently discussed. In preclinical studies, high-throughput drug screens in cancer cell lines have empowered the identification of clinically relevant molecular biomarkers of drug sensitivity; however, the genetic ancestry from tissue donors has been largely neglected in this setting. In order to address this, here, we show that the inferred ancestry of cancer cell lines is conserved and may impact drug response in patients as a predictive covariate in high-throughput drug screens. We found that there are differential drug responses between European and East Asian ancestries, especially when treated with PI3K/mTOR inhibitors. Our finding emphasizes a new angle in precision medicine, as cancer intervention strategies should consider the germline landscape, thereby reducing the failure rate of clinical trials.

Pyroptosis at the forefront of anticancer immunity

Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two major contributors to poor therapeutic responses during cancer intervention. Pyroptosis, a lytic and inflammatory programmed cell death pathway distinct from apoptosis, has subsequently sparked notable interest among cancer researchers for its potential to be clinically harnessed and to address these problems. Recent evidence indicates that pyroptosis induction in tumor cells leads to a robust inflammatory response and marked tumor regression. Underlying its antitumor effect, pyroptosis is mediated by pore-forming gasdermin proteins that facilitate immune cell activation and infiltration through their release of pro-inflammatory cytokines and immunogenic material following cell rupture. Considering its inflammatory nature, however, aberrant pyroptosis may also be implicated in the formation of a tumor supportive microenvironment, as evidenced by the upregulation of gasdermin proteins in certain cancers. In this review, the molecular pathways leading to pyroptosis are introduced, followed by an overview of the seemingly entangled links between pyroptosis and cancer. We describe what is known regarding the impact of pyroptosis on anticancer immunity and give insight into the potential of harnessing pyroptosis as a tool and applying it to novel or existing anticancer strategies.

JFK Is a Hypoxia-Inducible Gene That Functions to Promote Breast Carcinogenesis

Many carcinomas feature hypoxia, a condition has long been associated with tumor progression and poor prognosis, as well as resistance to chemoradiotherapy. Here, we report that the F-box protein JFK promotes mammary tumor initiation and progression in MMTV-PyMT murine model of spontaneous breast cancer. We find that JFK is inducible under hypoxic conditions, in which hypoxia-inducible factor HIF-1α binds to and transcriptionally activates JFK in breast cancer cells. Consistently, analysis of public clinical datasets reveals that the mRNA level of JFK is positively correlated with that of HIF-1α in breast cancer. We show that JFK deficiency leads to a decrease in HIF-1α-induced glycolysis in breast cancer and sensitizes hypoxic breast cancer cells to ionizing radiation and chemotherapeutic treatment. These results indicate that JFK is an important player in hypoxic response, supporting the pursuit of JFK as a potential therapeutic target for breast cancer intervention.