Machine learning for predicting liver and/or lung metastasis in colorectal cancer: A retrospective study based on the SEER database.

OBJECTIVE: This study aims to establish a machine learning (ML) model for predicting the risk of liver and/or lung metastasis in colorectal cancer (CRC). METHODS: Using the National Institutes of Health (NIH)'s Surveillance, Epidemiology, and End Results (SEER) database, a total of 51265 patients with pathological diagnosis of colorectal cancer from 2010 to 2015 were extracted for model development. On this basis, We have established 7 machine learning algorithm models. Evaluate the model based on accuracy, and AUC of receiver operating characteristics (ROC) and explain the relationship between clinical pathological features and target variables based on the best model. We validated the model among 196 colorectal cancer patients in Beijing Electric Power Hospital of Capital Medical University of China to evaluate its performance and universality. Finally, we have developed a network-based calculator using the best model to predict the risk of liver and/or lung metastasis in colorectal cancer patients. RESULTS: 51265 patients were enrolled in the study, of which 7864 (15.3 %) had distant liver and/or lung metastasis. RF had the best predictive ability, In the internal test set, with an accuracy of 0.895, AUC of 0.956, and AUPR of 0.896. In addition, the RF model was evaluated in the external validation set with an accuracy of 0.913, AUC of 0.912, and AUPR of 0.611. CONCLUSION: In this study, we constructed an RF algorithm mode to predict the risk of colorectal liver and/or lung metastasis, to assist doctors in making clinical decisions.

Prevotella copri exhausts intrinsic indole-3-pyruvic acid in the host to promote breast cancer progression: inactivation of AMPK via UHRF1-mediated negative regulation.

Emerging evidence has revealed the novel role of gut microbiota in the development of cancer. The characteristics of function and composition in the gut microbiota of patients with breast cancer patients has been reported, however the detailed causation between gut microbiota and breast cancer remains uncertain. In the present study, 16S rRNA sequencing revealed that Prevotella, particularly the dominant species Prevotella copri, is significantly enriched and prevalent in gut microbiota of breast cancer patients. Prior-oral administration of P. copri could promote breast cancer growth in specific pathogen-free mice and germ-free mice, accompanied with sharp reduction of indole-3-pyruvic acid (IPyA). Mechanistically, the present of excessive P. copri consumed a large amount of tryptophan (Trp), thus hampering the physiological accumulation of IPyA in the host. Our results revealed that IPyA is an intrinsic anti-cancer reagent in the host at physiological level. Briefly, IPyA directly suppressed the transcription of UHRF1, following by the declined UHRF1 and PP2A C in nucleus, thus inhibiting the phosphorylation of AMPK, which is just opposite to the cancer promoting effect of P. copri. Therefore, the exhaustion of IPyA by excessive P. copri strengthens the UHRF1-mediated negative control to inactivated the energy-controlling AMPK signaling pathway to promote tumor growth, which was indicated by the alternation in pattern of protein expression and DNA methylation. Our findings, for the first time, highlighted P. copri as a risk factor for the progression of breast cancer.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Toxicity and detoxification of T-2 toxin in poultry.

This review summarizes the updated knowledge on the toxicity of T-2 on poultry, followed by potential strategies for detoxification of T-2 in poultry diet. The toxic effects of T-2 on poultry include cytotoxicity, genotoxicity, metabolism modulation, immunotoxicity, hepatotoxicity, gastrointestinal toxicity, skeletal toxicity, nephrotoxicity, reproductive toxicity, neurotoxicity, etc. Cytotoxicity is the primary toxicity of T-2, characterized by inhibiting protein and nucleic acid synthesis, altering the cell cycle, inducing oxidative stress, apoptosis and necrosis, which lead to damages of immune organs, liver, digestive tract, bone, kidney, etc., resulting in pathological changes and impaired physiological functions of these organs. Glutathione redox system, superoxide dismutase, catalase and autophagy are protective mechanisms against oxidative stress and apoptosis, and can compensate the pathological changes and physiological functions impaired by T-2 to some degree. T-2 detoxifying agents for poultry feeds include adsorbing agents (e.g., aluminosilicate-based clays and microbial cell wall), biotransforming agents (e.g., Eubacterium sp. BBSH 797 strain), and indirect detoxifying agents (e.g., plant-derived antioxidants). These T-2 detoxifying agents could alleviate different pathological changes to different degrees, and multi-component T-2 detoxifying agents can likely provide more comprehensive protection against the toxicity of T-2.

Bioactive Phytoconstituents as Potent Inhibitors of Tyrosine-Protein Kinase Yes (YES1): Implications in Anticancer Therapeutics.

Tyrosine-protein kinase Yes (YES1) belongs to the Tyrosine-protein kinase family and is involved in several biological activities, including cell survival, cell-cell adhesion, cell differentiation, and cytoskeleton remodeling. It is highly expressed in esophageal, lung, and bladder cancers, and thus considered as an attractive drug target for cancer therapy. In this study, we performed a virtual screening of phytoconstituents from the IMPPAT database to identify potential inhibitors of YES1. Initially, the molecules were retrieved on their physicochemical properties following the Lipinski rule of five. Then binding affinities calculation, PAINS filter, ADMET, and PASS analyses followed by an interaction analysis to select safe and clinically better hits. Finally, two compounds, Glabrene and Lupinisoflavone C (LIC), with appreciable affinities and a specific interaction towards the AlphaFold predicted structure of YES1, were identified. Their time-evolution analyses were carried out using an all-atom molecular dynamics (MD) simulation, principal component analysis, and free energy landscapes. Altogether, we propose that Glabrene and LIC can be further explored in clinical settings to develop anticancer therapeutics targeting YES1 kinase.

Computational Insights of Unfolding of N-Terminal Domain of TDP-43 Reveal the Conformational Heterogeneity in the Unfolding Pathway.

TDP-43 proteinopathies is a disease hallmark that characterizes amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The N-terminal domain of TDP-43 (NTD) is important to both TDP-43 physiology and TDP-43 proteinopathy. However, its folding and dimerization process is still poorly characterized. In the present study, we have investigated the folding/unfolding of NTD employing all-atom molecular dynamics (MD) simulations in 8 M dimethylsulfoxide (DMSO) at high temperatures. The MD results showed that the unfolding of the NTD at high temperature evolves through the formation of a number of conformational states differing in their stability and free energy. The presence of structurally heterogeneous population of intermediate ensembles was further characterized by the different extents of solvent exposure of Trp80 during unfolding. We suggest that these non-natives unfolded intermediate ensembles may facilitate NTD oligomerization and subsequently TDP-43 oligomerization, which might lead to the formation of irreversible pathological aggregates, characteristics of disease pathogenesis.

The central nervous system can directly regulate breast cancer progression and blockage by quercetin.

BACKGROUND: Neuroinflammation involving the central nervous system (CNS), such as depression, is associated with a significantly increased risk of cancer and cancer-specific mortality due to breast cancer. It is of great significance to learn about the regulatory process of CNS in breast cancer progression. METHODS: We established a depressive MMTV-PyVT mouse model. The expression levels of neurotransmitters in the serum of depression animal models were assessed by enzyme-linked immunosorbent assay (ELISA). Changes of the microglia cells in the mice's brains were evaluated by immunofluorescence and reverse transcription-polymerase chain reaction (RT-PCR). Breast cancer progression was assessed by immunohistochemistry (IHC) analysis. To further investigate the mechanism by which ant-depressant drugs disrupt breast cancer progression, protein sequencing and network pharmacology were applied to identify related targets. Furthermore, we used conditioned medium from BV-2 microglia to culture breast cancer cells and treated the cells with quercetin at different concentrations; cell viability was assessed by the MTT assay. RESULTS: Our results show a possible regulatory target between neuroinflammation in the CNS and development of breast cancer, along with the reversal effect of quercetin on breast cancer progression. CONCLUSIONS: Chronic stress may be an indicator of breast cancer and that quercetin could be an effective treatment for breast cancer patients with chronic stress.

Acupuncture for Breast Cancer: A Systematic Review and Meta-Analysis of Patient-Reported Outcomes.

ABSTRACT: The present systematic review and meta-analysis was undertaken to evaluate the effects of acupuncture in women with breast cancer (BC), focusing on patient-reported outcomes (PROs). METHODS: A comprehensive literature search was carried out for randomized controlled trials (RCTs) reporting PROs in BC patients with treatment-related symptoms after undergoing acupuncture for at least four weeks. Literature screening, data extraction, and risk bias assessment were independently carried out by two researchers. RESULTS: Out of the 2, 524 identified studies, 29 studies representing 33 articles were included in this meta-analysis. At the end of treatment (EOT), the acupuncture patients' quality of life (QoL) was measured by the QLQ-C30 QoL subscale, the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), the Functional Assessment of Cancer Therapy-General/Breast (FACT-G/B), and the Menopause-Specific Quality of Life Questionnaire (MENQOL), which depicted a significant improvement. The use of acupuncture in BC patients lead to a considerable reduction in the scores of all subscales of the Brief Pain Inventory-Short Form (BPI-SF) and Visual Analog Scale (VAS) measuring pain. Moreover, patients treated with acupuncture were more likely to experience improvements in hot flashes scores, fatigue, sleep disturbance, and anxiety compared to those in the control group, while the improvements in depression were comparable across both groups. Long-term follow-up results were similar to the EOT results. CONCLUSIONS: Current evidence suggests that acupuncture might improve BC treatment-related symptoms measured with PROs including QoL, pain, fatigue, hot flashes, sleep disturbance and anxiety. However, a number of included studies report limited amounts of certain subgroup settings, thus more rigorous, well-designed and larger RCTs are needed to confirm our results.

Physicians' attitudes towards reproduction in young patients with early breast cancer in China.

BACKGROUND: As more young patients with breast cancer undergo treatments and obtain good prognoses, the issue of postoperative reproduction in breast cancer patients has attracted more attention. METHODS: We conducted a prospective, cross-sectional survey of 2000 breast cancer-associated physicians using a 24-items questionnaire adapted from prior guides. Then we used a multivariable linear regression model to confirm independent associations between the propensity of physicians' attitudes toward reproduction and physicians' specific demographic characteristics. RESULTS: A total of 911/1249 (72.93%) eligible physicians completed the questionnaire. Regarding the most concerning topic of whether breast cancer patients could conceive, 65 (7.1%) physicians having low and 457 (50.2%) physicians having high propensity for recommending reproduction. For ductal carcinoma in situ (DCIS) after surgery and radiotherapy, 599 (65.8%) physicians did not agree with the recommendation to conceive. 231 (25.4%) highly agree with the recommendation of reproduction for 2 years after surgery in invasive breast cancer patients with lymph nodes-negative. Only 140 (15.4%) physicians did not agree with the recommendation for 5 years after surgery in invasive breast cancer patients with lymph nodes-positive. A total of 861 (94.5%) physicians stated that they advised the patients to consult experts from other disciplines, such as gynecology, oncology, genetic and psychology disciplines. In multivariable analysis, more positive attitude toward reproduction was significantly associated with male, more than 11 times of participating in academic forum on breast cancer, 1-2 times of consulting about reproduction problems after breast cancer surgery per outpatient service and more than 11 min spending on solving the problem about reproduction in early breast cancer. CONCLUSION: This study showed that attitudes towards reproduction of young breast cancer patients from physicians in China. Physicians had a high propensity for recommending reproduction. Compared with the two reproduction guidelines recommendation when to reproduce in different circumstances for breast cancer patients, physicians from China remained a relatively conservative attitude. Most physicians advised the patients to consult experts from other disciplines, such as gynecology, oncology, genetic and psychology disciplines.

Positive acceleration adaptive training attenuates gastric ischemia-reperfusion injury through COX-2 and PGE2 expression.

The mechanism involved in the effects of positive acceleration adaptive training (PAAT) on gastric ischemia-reperfusion injury (GI-RI) has not been fully characterized. The aim of the present study was to investigate the effects of PAAT in attenuating GI-RI in a rat model. The inflammatory factor and caspase-3 levels were measured using ELISA kits. A western blot assay was used to analyze tumor necrosis factor-α (TNF)-α, tumor necrosis factor receptor 1 (TNFR1), tumor necrosis factor-related apoptosis inducing ligand (TRAIL), death receptor (DR) 4, DR5, cyclooxygenase (COX)-2, COX-1 and prostaglandin E2 (PGE2) protein expression levels. It was revealed that PAAT could alleviate GI-RI and inflammatory factor levels in a rat model. PAAT suppressed TNF-α and TNFR1 protein expression levels, inhibited TRAIL, DR4, DR5, COX-2 and PGE2 protein expression levels; however, it did not have an effect on COX-1 protein expression in the model of GI-RI. The data indicated that the effects of PAAT attenuated GI-RI through the downregulation of COX-2 and PGE2 expression.

Signal reconstruction of the slow wave and spike potential from electrogastrogram.

The gastric slow wave and the spike potential can correspondingly represent the rhythm and the intensity of stomach motility. Because of the filtering effect of biological tissue, electrogastrogram (EGG) cannot measure the spike potential on the abdominal surface in the time domain. Thus, currently the parameters of EGG adopted by clinical applications are only the characteristics of the slow wave, such as the dominant frequency, the dominant power and the instability coefficients. The limitation of excluding the spike potential analyses hinders EGG from being a diagnosis to comprehensively reveal the motility status of the stomach. To overcome this defect, this paper a) presents an EGG reconstruction method utilizing the specified signal components decomposed by the discrete wavelet packet transform, and b) obtains a frequency band for the human gastric spike potential through fasting and postprandial cutaneous EGG experiments for twenty-five human volunteers. The results indicate the lower bound of the human gastric spike potential frequency is 0.96±0.20 Hz (58±12 cpm), and the upper bound is 1.17±0.23 Hz (70±14 cpm), both of which have not been reported before to the best of our knowledge. As an auxiliary validation of the proposed method, synchronous serosa-surface EGG acquisitions are carried out for two dogs. The frequency band results for the gastric spike potential of the two dogs are respectively 0.83-0.90 Hz (50-54 cpm) and 1.05-1.32 Hz (63-79 cpm). They lie in the reference range 50-80 cpm proposed in previous literature, showing the feasibility of the reconstruction method in this paper.

Genetic predisposition of stroke: understanding the evolving landscape through meta-analysis.

Stroke, either ischemic or hemorrhagic, is the leading cause of death and morbidity worldwide. Identifying the risk factors is a prerequisite step for stroke prevention and treatment. It is believed that a major portion of the currently unidentified risk factors is of genetic origin. Consistent with this idea, numerous potential risk alleles for stroke have been reported, however, the genetic evidence so far is not conclusive. The major goal of this review is to update the current knowledge about the genetic predisposition to the common multifactorial stroke, and to provide a bird's-eye view of this fast moving field. We selectively review and meta-analyze the related English literatures in public domain (PubMed) from 2000 onward, including the original reports and meta-analyses, to evaluate the genetic risk factors of common multifactorial stroke. The results indicated that we reviewed and meta-analyzed original reports and existing meta-analyses that studied the genetic predisposition to the common multifactorial stroke. Some original reports and meta-analyses were specific for ischemic stroke and others were for hemorrhagic stroke only. We also evaluated the major evolving issues in this field and discussed the future directions. In conclusion, strong evidences suggest that genetic risk factors contribute to common multifactorial stroke, and many genetic risk genes have been implicated in the literatures. However, not a single risk allele has been conclusively approved.

[Effects of glutathione on plasma heat shock protein 70 of acute gastric mucosal injury in rats exposed to positive acceleration].

OBJECTIVE: To explore the change of plasma heat shock protein 70 (HSP70) in rats exposed to acute gastric mucosal injury under the condition of positive acceleration (+Gz) and elucidate the effects of glutathione (GSH) and the corresponding protective mechanisms. METHODS: A total of 40 male SD rats were randomly by computer randomization into 4 groups of ethanol control, +5 Gz value exposure, +10 Gz value exposure and GSH protection (n = 10 each). GSH protection group received adaptive feeding for 7 days and then an intraperitoneal injection of GSH for 3 consecutive days. All 4 groups fasted for 24 hours within 10 days, water deprivation for 12 hours and a gastric lavage of anhydrous ethanol (0.4 ml/100 g) for 1 hour, ethanol control group had no acceleration,+5 Gz value exposure group at + 5 Gz and the latter two groups respectively at +10 Gz for around 3 min.Each group underwent anesthesia of pentobarbital after centrifuge immediately. Abdominal aortic blood samples were collected and gastric tissues harvested for observation of mucosal injury. Mucosal damage index was calculated by the GUTH method. And the plasma content of HSP70 was measured by radioimmunoassay. RESULTS: (1) Gastric mucosa of each groups rats were injured. Damage was significantly reduced by GSH pretreatment, ethanol control group had less injury, the injury of +5 Gz value exposure group was aggravated compared with the control group (gastric mucosal injury index: 25.4 (14.0-30.0) vs 10.0 (9.2-13.9), P = 0.001); +10 Gz value exposure group mucosal injury was heaviest (47.2 (41.5-60.1)) . There were diffuse hyperemia, edema and erosion with a large area of bleeding spots and flat mucosal folds.It had statistically significant differences with the first two groups (all P < 0.01); GSH protection group was lightest at 9.5 (7.5-14.1). Compared with the +10 Gz value exposure group, mucosal damage was milder (P < 0.01).(2) The plasma levels of HSP70 of +5 Gz value exposure had no significant differences with the control and ethanol groups ((6.5 ± 0.5) ng/ml, P = 0.897); HSP70 plasma level ((5.9 ± 0.5) ng/ml) of +10 Gz value exposure was significantly lower than those of the first two groups (P = 0.018,0.014); GSH protection group ((7.0 ± 0.5) ng/ml) was significantly higher than the level of +10 Gz value exposure group (P < 0.01). CONCLUSIONS: +Gz exposure may cause the altered levels of plasma HSP70.High +Gz value exposure reduces its content and aggravates gastric mucosal injury. And glutathione reduces the injury of gastric mucosa through elevated plasma HSP70.

A real-time weighted-eigenvector MUSIC method for time-frequency analysis of electrogastrogram slow wave.

The surface electrogastrogram (EGG) records the electrical slow wave of the stomach noninvasively, whose frequency is a useful clinical indicator of the state of gastric motility. Estimators based on the periodogram method are widely adopted to obtain this parameter. But they are with a poor frequency domain resolution when the data window is short in time-frequency analysis, and have not taken full advantage of the slow wave model. We present a modified multiple signal classification (MUSIC) method for computing the frequency from surface EGG records, developing it into a real-time time-frequency analysis algorithm. Simulations indicate that the modified MUSIC method has better performance in resolution and precision in the sinusoid-like resultant signal frequency detecting than periodogram. Volunteer data tests show that the modified MUSIC method is stable and efficient for clinical applications, and reduces the danger of pseudo peaks for the diagnosis.

[Effects of acute hypobaric hypoxia on gastric emptying and intestinal propulsion: experiment with rats].

OBJECTIVE: To investigate the impact of acute hypobaric hypoxia on the gastrointestinal motility. METHODS: Eighty Wistar rats were randomly divided into 4 equal groups to be fed with (99)Tc(m)-labeled test food: ground level control group, put in the hypobaric chamber for 30 minutes; 3000 m simulated altitude group, exposed to the environment of simulated altitude of 3000 m for 30 minutes; 5000 m simulated altitude group, exposed to the environment of simulated altitude of 5000 m for 30 minutes; and mosapride + 5000 m simulated altitude group, fed with mosapride 2 mg/kg by perfusing stomach and fed with isotope-labeled test food 30 minutes later, and then exposed to 5000 m simulated altitude for 30 minutes. By the end of experiment the rats were killed, their stomachs were taken out to calculate the gastric emptying rate. Their intestine from pylorus to ileocecum was taken out to measure the intestinal propulsion function by using charcoal particle method. At the beginning and at the end of experiment abdominal arterial blood samples were collected to detect the plasma motilin and nitric oxide (NO) concentrations. RESULTS: The gastric emptying rate of the 5000 m simulated altitude group was 41% +/- 10%, significantly lower than that of the ground level group (62% +/- 12%, P < 0.01), and the charcoal transit rate of the 5000 m simulated altitude group was 37% +/- 8%, significantly lower than that of the ground level group (61% +/- 13%, P < 0.01). The gastric emptying rate and intestine propulsion rate of the 3000 m simulated altitude group were not significantly different from those of the ground level group. The gastric emptying rate of the mosapride + 5000 m simulated altitude group was 55% +/- 12%, significantly higher than that of the 5000 m simulated altitude group (P < 0.05), however, the intestine propulsion rate of the mosapride + 5000 m simulated altitude group was not significantly different from that of the 5000 m simulated altitude group (P > 0.05). The plasma motilin level of the 5000 m simulated altitude group was 88 pg/ml +/- 19 pg/ml, significantly lower than that of the ground level group (123 pg/ml +/- 28 pg/ml, P < 0.01), in contrast, the plasma NO level of the 5000 m simulated altitude group was 106 micromol/L +/- 24 micromol/L, significantly higher than that of the ground level group (80 micromol/L +/- 18 micromol/L, P < 0.01). CONCLUSION: Acute exposure to hypobaric hypoxia at the height of 5000 m inhibits the gastric emptying and intestinal propulsion. Mosapride may alleviate the inhibitory effect of hypobaric hypoxia on gastric emptying. Decrease of plasma motilin and elevation of NO level may be the main mechanism of inhibition of gastrointestinal motility by hypobaric hypoxia.