Twenty-five years of research on the effects of exercise training in breast cancer survivors:A systematic review of the literature

AIM:To investigate the role of exercise training the past 25 years on major physiological-psychological outcomes studied thus far in this patient population.METHODS:Pub Med, Medline Plus, the Cochrane Library, Web of Science, SportD iscus, Embase, Scorpus, and Google Scholar were searched from September to November 2013 to identify exercise training studies that used objective measurements of fitness and/or patient reported outcomes assessed pre and post-exercise training with statistical analyses performed in at least one of the following outcome measurements:Cardiorespiratory function, body composition, muscular strength, fatigue, depression, and overall quality of life. Five reviewers independently identified the studies that met the criteria for the review and discrepancies were resolved by consensus among all authors.RESULTS:Fifty-one studies were included in this review with 5 from the period between 1989-1999, 11 from 2000-2006, and 35 from 2007-2013. The evolution of study designs changed from aerobic only exercise training interventions(1989-1999), to a combination of aerobic and resistance training(2000-2006), to studies including an arm of resistance training or examining the effects of resistance training as the main mode of exercise(2007-2013). Overall, the benefits of exercise showed improvements in cardiorespiratory function, body composition, strength, and patient reported outcomes including fatigue, depression, and quality of life.CONCLUSION:Exercise training appears to be safe for most breast cancer patients and improvements in physiological, psychological, and functional parameters can be attained with regular participation in moderate intensity exercise.

Patient Participation in Communication about Treatment Decision-Making for Localized Prostate Cancer during Consultation Visits

Objectives: To describe the communication behaviors of patients and physicians and patient par-ticipation in communication about treatment decision-making during consultation visits for local-ized prostate cancer (LPCa). Methods: This is a secondary analysis of data from 52 men enrolled in the usual care control group of a randomized trial that focused on decision-making for newly diagnosed men with LPCa. We analyzed the patient-physician communication using the transcribed audio-recordings of real-time treatment consultations and a researcher-developed coding tool, including codes for communication behaviors (information giving, seeking, and clarifying/ verifying) and contents of clinical consultations (health histories, survival/mortality, treatment options, treatment impact, and treatment preferences). After qualitative content analysis, we categorized patient participation in communication about treatment-related clinical content, including “none” (content not discussed);“low” (patient listening only);“moderate” (patient providing information or asking questions);and “high” (patient providing information and asking questions). Results: Physicians mainly provided information during treatment decision consultations and patients frequently were not active participants in communication. The participation of patients with low and moderate cancer risk typically was: 1) “moderate and high” in discussing health histories;2) “low” in discussing survival/mortality;3) “low and moderate” in discussing treatment options;4) “none and low” in discussing treatment impacts;and 5) “low” in discussing treatment preferences. Conclusions: Findings suggest opportunities for increasing patient participation in communication about treatment decision-making for LPCa during clinical consultations.

Gene therapy for cancer: novel approaches

Utilization of gene therapy approaches for cancertreatment requires either that the transferred genegains access to the great majority of the tumor cells orthat gene transfer results in a cytotoxic effect that willkill a large number of tumor cells that do not directlyreceive the gene of interest. The latter effect can beachieved by the transfer into tumors of

Impact of community-based exercise program participation on aerobic capacity in women with and without breast cancer

BACKGROUND Evidence for exercise as an efficacious strategy to improve aerobic capacity of breast cancer survivors(BCS)has come largely from intervention studies conducted in laboratory settings.There is an increasing need to translate to community-type settings,but the efficacy of those interventions using gold standard evaluation is not well-established.AIM To investigate whether similar improvement in aerobic capacity(maximal oxygen consumption[VO2])measured with gold standard testing can be achieved through a community-based setting in BCS.METHODS A peak cardiopulmonary exercise test(VO2peak),6-min walk test(6MWT),and timed up and go test(TUG)were assessed pre-and post-16 wk of progressive intensity aerobic and strength training exercise at a community center.RESULTS The sample consisted of 31 early BCS(<1 year since treatment completion)and 15 controls(CTLs).Both groups significantly improved VO2peak(+1.2 mL/kg/min;P=0.030),6MWT(+35 meters;P<0.001),and TUG(-0.44 s;P<0.01)following training.Both groups improved peak cycling power during the cardiopulmonary exercise test with BCS improving by+10 watts more than the CTLs(P=0.020).Average exercise attendance was 71%(34 of 48 possible days),but compliant days averaged only 60%of total days for aerobic,and<40%for strength in both groups.CONCLUSION Community-based exercise programs can be an effective strategy to improve aerobic capacity and physical function for early-stage BCS but potentially not to the same extent observed in laboratory-based randomized controlled trials.Further research is needed to explore barriers and facilitators of exercise engagement in community-based centers to maximize training benefits for adults with cancer.

More evidence intratumoral DHT synthesis drives castration-resistant prostate cancer

Again-of-function stabilizing somatic mutation in 3β-hydroxysteroiddehydrogenase type 1 （3βHSDI, HSD3B1） was reported in castration-resistant prostate cancer. The A-C nucleotide polymorphism replaced asparagine-367 with threonine （3βHSD1-N367T） as a homozygous somatic mutation in a subset of castration-resistant prostate cancers by loss of heterozygosity of the wild-type allele. Increased stability of 3[HSD I-N367T was associated with decreased ubiquitin-mediated degradation and higher levels of dihydrotestosterone （DHT）. The studies suggest that genetic instability in castration-resistant prostate cancer favors the more stable 313HSD I-N367T mutant that contributes to drug resistance. A somatic mutation in a steroid metabolic enzyme required for DHT synthesis provides further support for intratumoral androgen synthesis contributing to prostate cancer progression.

Competing risks of death in younger and older postmenopausal breast cancer patients

AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death. METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival(P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival(P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific(Br Ca) and other cause(OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1(IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-OH vitamin D were associated with(1) all cause mortality, and if so; and(2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447(82%) < 70 years and 120(18%) ≥ 70 years. There were 170 deaths: 106(62.3%) BrC a; 55(32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9(5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrC a and OC deaths were not significantly different by treatment arm(P = 0.40): tamoxifen patients experienced 50 BrC a and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 Br Ca and 23 OC deaths. Proportionately more deaths(P = 0.004) were from BrC a for patients< 70 years, where 70% of deaths were due to Br Ca, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index(BMI)(P = 0.02). Higher pathologic T and N were associated with more BrC a deaths(P < 0.0001 and 0.002, respectively). The cumulative hazard plot for Br Ca and OC mortality indicated the concurrent accrual of both types of death throughout followup, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality(P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC(P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrC a mortality(respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrC a mortality(P = 0.002); there was weak evidence that, lower C-peptide(P = 0.08) was associated with less BrC a mortality, while higher BMI(P = 0.01) was associated with worse OC mortality.CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.

Comparative study of breast cancer in Mexican and Mexican-American women

Breast cancer is the number one cause of can- cer deaths among Hispanic women in the United States, and in Mexico, it recently became the primary cause of cancer deaths. This malign- nancy represents a poorly understood and un- derstudied disease in Hispanic women. The ELLA Binational Breast Cancer Study was es- tablished in 2006 as a multi-center study to as- sess patterns of breast tumor markers, clinical characteristics, and their risk factors in women of Mexican descent. We describe the design and implementation of the ELLA Study and provide a risk factor comparison between women in the U.S. and those in Mexico based on a sample of 765 patients (364 in the U.S. and 401 in Mexico). Compared to women in Mexico, U.S. women had significantly (p < 0.05) lower parity (3.2 vs. 3.9 mean live births) and breastfeeding rates (57.5% vs. 80.5%), higher use of oral contraceptives (60.7% vs. 50.1%) and hormone replacement therapy (23.3% vs. 7.6%), and higher family history of breast cancer (15.7% vs. 9.0%). Re- sults show that differences in breast cancer risk factor patterns exist between Mexico and U.S. women. We provide lessons learned from the conduct of our study. Binational studies are an important step in understanding disease pat- terns and etiology for women in both countries.

Using NMR-detected hydrogen-deuterium exchange to quantify protein stability in cosolutes,under crowded conditions in vitro and in cells

We review the use of nuclear magnetic resonance(NMR)spectroscopy to assess the exchange of amide protons for deuterons(HDX)in efforts to understand how high concentration of cosolutes,especially macromolecules,affect the equilibrium thermodynamics of protein stability.HDX NMR is the only method that can routinely provide such data at the level of individual amino acids.We begin by discussing the properties of the protein systems required to yield equilibrium thermodynamic data and then review publications using osmolytes,sugars,denaturants,synthetic polymers,proteins,cytoplasm and in cells.

Role of H3K27 methylation in the regulation of IncRNA expression

Once thought to be transcriptional noise, large non-coding RNAs （IncRNAs） have recently been demonstrated to be functional molecules. The cell-type-specific expression patterns of lncRNAs suggest that their transcription may be regulated epigenetically. Using a custom-designed microarray, here we examine the expression profile of IncRNAs in embryonic stem （ES） cells, lineage-restricted neuronal progenitor cells, and terminally differentiated fibroblasts. In addition, we also analyze the relationship between their expression and their promoter H3K4 and H3K27 methyla- tion patterns. We find that numerous lncRNAs in these cell types undergo changes in the levels of expression and promoter H3K4me3 and H3K27me3. Interestingly, lncRNAs that are expressed at lower levels in ES cells exhibit higher levels of H3K27me3 at their promoters. Consistent with this result, knockdown of the H3K27me3 methyltransferase Ezh2 results in derepression of these IncRNAs in ES cells. Thus, our results establish a role for Ezh2-mediated H3K27 methylation in lncRNA silencing in ES cells and reveal that lncRNAs are subject to epigenetic regulation in a similar manner to that of the protein-coding genes.

Coronavirus MHV-A59 infects the lung and causes severe pneumonia in C57BL/6 mice

It remains challenging to develop animal models of lung infection and severe pneumonia by severe acute respiratory syndrome coronavirus(SARS-CoV) and Middle East respiratory syndrome cornavirus(MERS-Co V) without high level of containment. This inevitably hinders understanding of virushost interaction and development of appropriate countermeasures. Here we report that intranasal inoculation of sublethal doses of murine coronavirus mouse hepatitis virus A-59(MHV-A59), a hepatic and neuronal tropic coronavirus, can induce acute pneumonia and severe lung injuries in C57BL/6 mice. Inflammatory leukocyte infiltrations, hemorrhages and fibrosis of alveolar walls can be observed 2-11 days after MHV-A59 infection. This pathological manifestation is associated with dramatical elevation of tissue IP-10 and IFN-γ and moderate increase of TNF-α and IL-1β, but inability of anti-viral type I interferon response. These results suggest that intranasal infection of MHV-A59 would serve as a surrogate mouse model of acute respiratory distress syndrome by SARS-CoV and MERS-CoV infections.

ACRIN数字化乳腺X线摄影筛查试验的放射医生Logistic回归模型分析

目的确定影响数字化乳腺X线摄影筛查试验（DMIST）中癌肿检出结果的因素。材料与方法此研究经学术审核委员会通过，符合健康医疗保险要求。7位影像医师复习DMIST癌肿病例的胶片硬拷贝（屏-片）和数字乳腺X线影像，并评价影响两种影像中病灶显示的因素。阅片者对数字化和屏一片影像的配对资料进行分级，采用两种多项式Logistic回归模型分析联合与浓缩显示的分级。

Correlation of Transcription of MALAT-1, a Novel Noncoding RNA, with Deregulated Expression of Tumor Suppressor p53 in Small DNA Tumor Virus Models

Although metastasis-associated lung adenocarcinoma transcript (MALAT)-1 is known to be consistently upregulated in several epithelial malignancies, little is known about its function or regulation. We therefore examined the relationship between MALAT-1 expression and candidate modulators such as DNA tumor virus oncoproteins human papillomavirus (HPV)-16 E6 and E7, BK virus T antigen (BKVTAg), mouse polyoma virus middle T antigen (MPVmTAg) and tumor suppressor genes p53 and pRb. Using suppressive subtractive hybridization (SSH) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays, MALAT-1 was shown to be increased in viral oncongene-expressing salivary gland biopsies from humans and mice. The results also indicated that MALAT-1 transcripts and promoter activity were increased in vitro when viral oncongene-expressing plasmids were introduced into different cell types. These same viral oncogenes in addition to increasing MALAT-1 transcription have also been shown to inhibit p53 and/or pRb function. In p53 mutant or inactive cell lines MALAT-1 was also shown to be highly upregulated. We hypothesize that there is a correlation between MALAT-1 over-expression and p53 deregulation. In conclusion, we show that disruption of p53, by both polyoma and papilloma oncoproteins appear to play an important role in the up-regulation of MALAT-1. MALAT-1 might therefore represent a biomarker for p53 deregulation within malignancies.

A Combinative Assembly Strategy Inspired Reversibly Borate-Bridged Polymeric Micelles for Lesion-Specific Rapid Release of Anti-Coccidial Drugs

Stimuli-triggered drug delivery systems hold vast promise in local infection treatment for the site-specific targeting and shuttling of drugs.Herein,chitosan conjugates(SPCS)installed with sialic acid(SA)and phenylboronic acid(PBA)were synthesized,of which SA served as targeting ligand for coccidium and reversible-binding bridge for PBA.The enhanced drug-loading capacity of SPCS micelles was attributed to a combination assembly from hydrophobicity-driving and reversible borate bridges.The drug-loaded SPCS micelles shared superior biostability in upper gastrointestinal tract.After reaching the lesions,the borate bridges were snipped by carbohydrates under a higher pH followed by accelerated drug release,while SA exposure on micellar surface facilitated drug cellular internalization to eliminate parasites inside.The drugmicelles revealed an enhanced anti-coccidial capacity with a higher index of 185.72 compared with commercial preparation.The dual-responsive combination of physicochemical assembly could provide an efficient strategy for the exploitation of stable,safe and flexible anti-infectious drug delivery systems.

The role of intracellular protein O-glycosylation in cell adhesion and disease

Post-translational protein modification, including phosphorylation, is generally quick and reversible, facilitating rapid biologic adjustments to altered cellular physiologic demands. In addition to protein phosphorylation, other post-translational modifications have been identified. Intracellular protein O-glycosylation, the addition of the simple sugar O-linked N-acetylglucosamine （O-G1cNAc） to serine/threonine residues, is a relatively recently identified post-translational modification that has added to the complexity by which protein function is regulated. Two intracellular enzymes, O-GlcNAc transferase and O-GlcNAcase, catalyze the addition and removal, respectively, of O-GlcNAc to serine and threonine side-chain hydroxyl groups. Numerous proteins, including enzymes, transcription factors, receptors and structural proteins have been shown to be modified by intracellular O-glycosylation. In this review, the mechanism and relevance of O-GlcNAc protein modification are discussed in the context of cell adhesion and several representative diseases.

Novel immunotherapy approaches for metastatic urothelial and renal cell carcinoma

The treatment of metastatic renal cell carcinoma(RCC)and urothelial carcinoma(UC)remains a major challenge.Past research has implicated the immune system in tumor surveillance of both malignancies,leading to the application of immunotherapy agents for both cancers.Among them,the most promising agents are the checkpoint blockade drugs,such as antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4(CTLA-4),programmed death receptor 1(PD-1),and PD-1 ligand(PD-L1).In normal physiology,these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions,which is pivotal for maintaining self-tolerance.However,tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response,leading to disease progression and metastasis.Thus,there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC.To date,nivolumab(anti-PD-1)and atezolizumab(anti-PD-L1)have been approved for the treatment of metastatic RCC and UC,respectively.Despite these successes,challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach.In this report,we review existing data and research on immunotherapy in metastatic RCC and UC.

Concise review of machine perfusion in liver transplantation

With the advances and clinical growth in liver transplantation over the last four decades the focus on expanding deceased donor organs has been in need of scientific research.In the past ten years several researchers have looked at the domain of machine perfusion as it applies to deceased donor livers.The following review focuses on the clinical trials and recent advances that will likely have the earliest entrance into the clinical arena.

4-1BB-encoding CAR causes cell death via sequestration of the ubiquitin-modifying enzyme A20

CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor(CAR)molecules play a critical role in promoting sustained antitumor activity of CAR-T cells.However,the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored.In the current study,we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling.Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity,cell aggregation via ICAM-1 overexpression,and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway.Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.

The multiple faces of cGAS-STING in antitumor immunity:prospects and challenges

As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).This finally promotes the production of type I interferons(IFN-I)that is crucial for bridging innate and adaptive immunity.Recent evidence show that several antitumor therapies,including radiotherapy(RT),chemotherapy,targeted therapies and immunotherapies,activate the cGAS-STING pathway to provoke the antitumor immunity.In the last decade,the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry.However,up to now,none of STING agonists have been approved for clinical use.Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node(dLN),research on the optimal way to activate STING in tumor microenvironment(TME)appears to be a promising direction.Moreover,besides enhancing IFN-I signaling,the cGAS-STING pathway also plays roles in senescence,autophagy,apoptosis,mitotic arrest,and DNA repair,contributing to tumor development and metastasis.In this review,we summarize the recent advances on cGAS-STING pathway’s response to antitumor therapies and the strategies involving this pathway for tumor treatment.

Advances in the prerequisite and consequence of STING downstream signalosomes

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.Aside from recognizing pathogens through conserved motifs,these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed homeostasis.Upon binding external or self-derived DNA,a mobile sec-ondary messenger 2′3′-cyclic GMP-AMP(cGAMP)is produced by cGAS and in turn activates its adapter STING in the endo-plasmic reticulum(ER).Resting-state or activated STING protein isfinely restricted by multiple degradation machin-eries.The post-translational changes of the STING protein,along with the regulatory machinery ofthe secret routes,limit the onset,strength and sustention of STING signal.STING experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors,provoking the transcription activity of IRF3/IFN-I and NF-κB pathways,as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer,such as autophagy,NLRP3 inflamma-some,ER stress,and cell death.STING signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in tissues.Recent advances have established the vital role of STING in immune surveil-lance as well as tumorigenic process.This review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes,along with the underlying mechanisms of STING function in pathologies,providing therapeutic impli-cations for new approaches in hunt for the next generation of cancer immunotherapy base on STING.

The first human trial of CRISPR-based cell therapy clears safety concerns as new treatment for late-stage lung cancer

In a study recently published in Nature Medicine,Lu et al.examined the feasibility and safety of using CRISPR(Clustered Regularly Interspaced Short Palindromic Repeats)-engineered,patient-derived T cells to treat late-stage lung cancer.1 Gene-editing therapy holds great promise in treating a wide range of human diseases from cancer to genetic disorders.The introduction of the CRISPR technology,due to its simplicity and intrinsic programmability,2 has revolutionized the gene-editing field,and quickly surpasses both zinc-finger nuclease and transcription activator-like effector nuclease to become the method-of-choice for therapeutic gene editing.3 However,due to potential off-target effects,the safety of CRISPR-based therapy remains controversial.In a study recently published in Nature Medicine,1 Lu et al.examined the feasibility and safety of using CRISPR-engineered T cells to treat late-stage lung cancer.They demonstrated very low off-target editing rates and no severe treatment-related adverse events(AE),thus supporting its general safety for clinical use.