Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast.

Chromosomal instability (CIN) drives cell-to-cell heterogeneity, and the development of genetic diseases, including cancer. Impaired homologous recombination (HR) has been implicated as a major driver of CIN, however, the underlying mechanism remains unclear. Using a fission yeast model system, we establish a common role for HR genes in suppressing DNA double-strand break (DSB)-induced CIN. Further, we show that an unrepaired single-ended DSB arising from failed HR repair or telomere loss is a potent driver of widespread CIN. Inherited chromosomes carrying a single-ended DSB are subject to cycles of DNA replication and extensive end-processing across successive cell divisions. These cycles are enabled by Cullin 3-mediated Chk1 loss and checkpoint adaptation. Subsequent propagation of unstable chromosomes carrying a single-ended DSB continues until transgenerational end-resection leads to fold-back inversion of single-stranded centromeric repeats and to stable chromosomal rearrangements, typically isochromosomes, or to chromosomal loss. These findings reveal a mechanism by which HR genes suppress CIN and how DNA breaks that persist through mitotic divisions propagate cell-to-cell heterogeneity in the resultant progeny.

Endothelial cell death after ionizing radiation does not impair vascular structure in mouse tumor models.

The effect of radiation therapy on tumor vasculature has long been a subject of debate. Increased oxygenation and perfusion have been documented during radiation therapy. Conversely, apoptosis of endothelial cells in irradiated tumors has been proposed as a major contributor to tumor control. To examine these contradictions, we use multiphoton microscopy in two murine tumor models: MC38, a highly vascularized, and B16F10, a moderately vascularized model, grown in transgenic mice with tdTomato-labeled endothelium before and after a single (15 Gy) or fractionated (5 × 3 Gy) dose of radiation. Unexpectedly, even these high doses lead to little structural change of the perfused vasculature. Conversely, non-perfused vessels and blind ends are substantially impaired after radiation accompanied by apoptosis and reduced proliferation of their endothelium. RNAseq analysis of tumor endothelial cells confirms the modification of gene expression in apoptotic and cell cycle regulation pathways after irradiation. Therefore, we conclude that apoptosis of tumor endothelial cells after radiation does not impair vascular structure.

Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer.

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α-positive (ERα+) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer, and is regulated by hypoxia both in vitro and in vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ERα, but it became predominantly a hypoxia-inducible factor 1α (HIF-1α)-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1α and ERα overlap in SNAT2's cis-regulatory elements. In addition, the down-regulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia. Overexpression of SNAT2 in vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ERα inhibition, in hypoxia, or when glutamine levels were low. SNAT2 up-regulation in vivo caused complete resistance to antiestrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlated with hypoxia profiles and worse outcome in patients given antiestrogen therapies. Our findings show a switch in the regulation of SNAT2 between ERα and HIF-1α, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.

Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.

BACKGROUND: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy. METHODS: Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment. RESULTS: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation. CONCLUSIONS: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations. CLINICAL TRIAL REGISTRATION: NCT01266486.

Segmentation of DNA using simple recurrent neural network.

We report the discovery of strong correlations between protein coding regions and the prediction errors when using the simple recurrent network to segment genome sequences. We are going to use SARS genome to demonstrate how we conduct training and derive corresponding results. The distribution of prediction error indicates how the underlying hidden regularity of the genome sequences and the results are consistent with the finding of biologists: predicated protein coding features of SARS genome. This implies that the simple recurrent network is capable of providing new features for further biological studies when applied on genome studies. The HA gene of influenza A subtype H1N1 is also analyzed in a similar way.

Impact of Using the Intelligent Physical Health Measurement System on Active Aging: A Survey in Taiwan.

BACKGROUND: In Taiwan, the Chiayi City Government and Industrial Development Bureau of the Ministry of Economic Affairs have worked together to promote smart health management in the community and encourage people to use the intelligent physical health measurement system (IPHMS) with Smart Body Health Measuring Machine. Volunteers help participants in the community to use the IPHMS to ensure that measurements are taken correctly. OBJECTIVES: This study aimed to explore volunteers' satisfaction with using the IPHMS and the effects of the measurement service on the participants' measurement behavior intention, and further explore the impact on their active aging. METHODS: This study used a paper questionnaire to survey both the participants of the measurement service and the community volunteers from March to April 2021. A total of 180 valid responses were collected. RESULTS: The sociodemographic information showed that the volunteers were mostly female, were aged over 61 years old, had received junior college education, had spent less than 3-6 years in community service, and had 6 months to 1 year of measured service experience. Additionally, the participants of the measurement service were mostly female, were aged over 61 years old, had received below middle school education, had spent less than 1-3 years in community service, and spent an average of 5 days in the community each week. Our results showed that the information quality (ß = 0.352, p < 0.001) and system quality (ß = 0.701, p < 0.001) had significant effects on volunteers' satisfaction of using the IPHMS. Subjective norms had significant effects on participants' perceived disease threat (ß = 0.347, p < 0.001) and behavior intention of management service (ß = 0.701, p < 0.001); furthermore, behavior intention had significant effects on their social participation for active aging (ß = 0.430, p < 0.05). CONCLUSIONS: Improving the system and information quality is likely to improve volunteers' satisfaction with the system. Active aging factors only affect social participation, which represents the measurement services promote for social interaction mostly.

Hypoxia-induced SETX links replication stress with the unfolded protein response.

Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.

A Stress Relief App Intervention for Newly Employed Nursing Staff: Quasi-Experimental Design.

BACKGROUND: Most newly employed nurses have limited practical experience, lack problem-solving abilities, and have low resistance to stress, and therefore often opt to resign from the nursing profession. OBJECTIVE: This study aimed to assess the effectiveness of a stress relief app (SR_APP) to monitor the stress levels of newly employed nurses. METHODS: We conducted a quasi-experiment to assess changes in stress levels of newly employed nurses at a case hospital, in which the experimental group used the SR_APP and the control group did not. In-depth interviews were conducted to reveal insights regarding their stress. The app usage experiences of experimental group members were assessed via a questionnaire. RESULTS: All the participants appreciated the experiment and were interested to know more about managing their stress. The experimental group members showed significant differences in heart rate variability scores before and after using the SR_APP, and they reported high levels of intention to use and satisfaction with regard to the SR_APP. CONCLUSIONS: The SR_APP can be effective in helping newly employed nurses to manage their stress.

Guidelines for using sigQC for systematic evaluation of gene signatures.

With the increased use of next-generation sequencing generating large amounts of genomic data, gene expression signatures are becoming critically important tools for the interpretation of these data, and are poised to have a substantial effect on diagnosis, management, and prognosis for a number of diseases. It is becoming crucial to establish whether the expression patterns and statistical properties of sets of genes, or gene signatures, are conserved across independent datasets. Conversely, it is necessary to compare established signatures on the same dataset to better understand how they capture different clinical or biological characteristics. Here we describe how to use sigQC, a tool that enables a streamlined, systematic approach for the evaluation of previously obtained gene signatures across multiple gene expression datasets. We implemented sigQC in an R package, making it accessible to users who have knowledge of file input/output and matrix manipulation in R and a moderate grasp of core statistical principles. SigQC has been adopted in basic biology and translational studies, including, but not limited to, the evaluation of multiple gene signatures for potential clinical use as cancer biomarkers. This protocol uses a previously obtained signature for breast cancer metastasis as an example to illustrate the critical quality control steps involved in evaluating its expression, variability, and structure in breast tumor RNA-sequencing data, a different dataset from that in which the signature was originally derived. We demonstrate how the outputs created from sigQC can be used for the evaluation of gene signatures on large-scale gene expression datasets.

Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer.

BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

Molecular targets for anti-oxidative protection of green tea polyphenols against myocardial ischemic injury.

Ischemic heart disease is the leading cause of death worldwide. An improved understanding of the mechanisms involved in myocardial injury would allow intervention downstream in the pathway where certain drugs including natural products could be efficiently applied to target the end effectors of the cell death pathway. Green tea polyphenols (GTPs) have potent anti-oxidative capabilities, which may account for their beneficial effects in preventing oxidative stress associated with ischemia injury. Although studies have provided convincing evidence to support the protective effects of GTPs in cardiovascular system, the potential end effectors that mediate cardiac protection are only beginning to be addressed. Proteomics analyses widely used to identify the protein targets for many cardiovascular diseases have advanced the discovery of the signaling mechanism for GTPs-mediated cardio-protection. This review focuses on putative triggers, mediators, and end effectors for the GTPs-mediated cardio-protection signaling pathways engaged in myocardial ischemia crisis, allowing a promising natural product to be used for ameliorating oxidative stress associated with ischemic heart diseases.

Group factor analysis for Alzheimer's disease.

For any neuroimaging study in an institute, brain images are normally acquired from healthy controls and patients using a single track of protocol. Traditionally, the factor analysis procedure analyzes image data for healthy controls and patients either together or separately. The former unifies the factor pattern across subjects and the latter deals with measurement errors individually. This paper proposes a group factor analysis model for neuroimaging applications by assigning separate factor patterns to control and patient groups. The clinical diagnosis information is used for categorizing subjects into groups in the analysis procedure. The proposed method allows different groups of subjects to share a common covariance matrix of measurement errors. The empirical results show that the proposed method provides more reasonable factor scores and patterns and is more suitable for medical research based on image data as compared with the conventional factor analysis model.

Structural complexity of DNA sequence.

In modern bioinformatics, finding an efficient way to allocate sequence fragments with biological functions is an important issue. This paper presents a structural approach based on context-free grammars extracted from original DNA or protein sequences. This approach is radically different from all those statistical methods. Furthermore, this approach is compared with a topological entropy-based method for consistency and difference of the complexity results.

Manifold construction based on local distance invariance.

This paper presents a distance invariant manifold that preserves the neighborhood relations among data patterns. All patterns have their corresponding cells in the manifold space. The constellation of neighborhood cells closely resembles that of patterns. The manifold is invariant under the translation, rotation and scale of the pattern coordinates. The neighborhood relations among cells are adjusted and improved in each iteration according to the reduction of the distance preservation energy.

A web-based breastfeeding education program.

Two Web-based breastfeeding programs were developed to provide new parents with necessary information on proper breastfeeding techniques. One version was plain text and the other version combined text with graphics. The computer was viewed as a valuable learning tool. The breastfeeding program that contained graphics was preferred over the text-only program. Educators are encouraged to use Web-based graphic programs to provide breastfeeding education to new parents.