AlphaFold[1]has turned everyone into a structural biologist.No need for knowledge of Fourier transforms or spectral density,driven by artificial intelligence(AI),all one needs to do is enter the primary structure of a...AlphaFold[1]has turned everyone into a structural biologist.No need for knowledge of Fourier transforms or spectral density,driven by artificial intelligence(AI),all one needs to do is enter the primary structure of a folded protein,and out pops a tertiary structure nearly as good as one from an experiment-based structure.展开更多
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 ...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.展开更多
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 (LPC...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.展开更多
The tumor suppressor p53 transactivates the expression of multiple genes to exert its multifaceted functions and ultimately maintains genome stability.Thus,cancer cells develop various mechanisms to diminish p53 expre...The tumor suppressor p53 transactivates the expression of multiple genes to exert its multifaceted functions and ultimately maintains genome stability.Thus,cancer cells develop various mechanisms to diminish p53 expression and bypass the cell cycle checkpoint.In this study,we identified the gene encoding RNAbinding protein cytoplasmic polyadenylation element-binding protein 2(CPEB2)as a p53 target.In turn,CPEB2 decreases p53 messenger RNA stability and translation to fine-tune p53 level.Specifically,we showed that CPEB2 binds the cytoplasmic polyadenylation elements in the p5330-untranslated region,and the RNA recognition motif and zinc finger(ZF)domains of CPEB2 are required for this binding.Furthermore,we found that CPEB2 was upregulated in renal cancer tissues and promotes the renal cancer cell proliferation and migration.The oncogenic effect of CPEB2 is partially dependent on negative feedback regulation of p53.Overall,we identify a novel regulatory feedback loop between p53 and CPEB2 and demonstrate that CPEB2 promotes tumor progression by inactivating p53,suggesting that CPEB2 is a potential therapeutic target in human renal cancer.展开更多
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 willkil...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展开更多
Cytokines play an essential role in governing the overall immune response toward cancer.Recently,the role of IL-12 family cytokines in dictating immune response toward cancer has been well appreciated.1 IL-23 is one o...Cytokines play an essential role in governing the overall immune response toward cancer.Recently,the role of IL-12 family cytokines in dictating immune response toward cancer has been well appreciated.1 IL-23 is one of such heterodimeric cytokines belonging to the IL-12 family cytokine,composed of p19 and p40 subunits.2 The role of IL-23 in regulating tumorigenesis is controversial.In some cancer settings,IL-23 activates the effector immune system and has antitumorigenic functions;on the other hand,it can support immune regulatory response and favor tumor growth.3 In this issue of Asian Journal of Andrology,Liu et al.4 reported the novel functions of IL-23,a cytokine that regulates both innate and adaptive immune cells;especially,it is well known to maintain Th17 cell phenotype in prostate cancer.Prostate cancer is one of the utmost challenging tumor types and is the most common cancer in men,and one man in eight will be diagnosed with prostate cancer.展开更多
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...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.展开更多
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-36...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.展开更多
Dear Editor, Prostate cancer （PCa） is the most frequently diagnosed male cancer in Western countries, and the number of PCa patients is also rapidly increasing in ]apan.1,2 Simultaneously, androgen deprivation ther...Dear Editor, Prostate cancer （PCa） is the most frequently diagnosed male cancer in Western countries, and the number of PCa patients is also rapidly increasing in ]apan.1,2 Simultaneously, androgen deprivation therapy （ADT） has also been increasingly used in PCa patients in recent years2-5 However, the long-term use of ADT is associated with a variety of pivotal adverse events, including diabetes, anemia, osteoporosis, serum lipid profile changes, and cardiovascular disease （CVD）.1,2 Higher low-density lipoprotein cholesterol （LDL-C） and/or lower high-density lipoprotein cholesterol （HDL-C） are well-established risk factors for CVD, and control of their levels has been an important goal in the treatment and prevention of CVD.6,7 Recently, another alternative parameter, the LDL-C to HDL-C （L/H） ratio, has been reported to be strongly associated with CVD and is thought to be a better predictor of future CVD than LDL-C alone. Closely monitoring serum lipid profile, including the L/H ratio changes affected by ADT, is a key to preventing CVD in PCa patients. Moreover, we previously suggested that a higher L/H ratio might have an impact on the development of arterial stiffness after ADT administration,r Although some cutoff points of the L/H ratio have been reported in clinical use, it has been suggested that thrombosis can occur when the L/H ratio increases to around 2.5 or more in East Asian populations.6 The aim of the present study was to investigate the changes in serum lipid profile and to identify the clinical factors associated with an increased L/H ratio in PCa patients who received ADT.展开更多
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 ...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.展开更多
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 understo...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.展开更多
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 transcri...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.展开更多
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...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.展开更多
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 examin...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.展开更多
In eukaryotes, crossovers together with sister chromatid cohesion maintain physical association between homologous chromosomes, ensuring accurate chromosome segregation during meiosis I and resulting in exchange of ge...In eukaryotes, crossovers together with sister chromatid cohesion maintain physical association between homologous chromosomes, ensuring accurate chromosome segregation during meiosis I and resulting in exchange of genetic information between homologues. The Arabidopsis PTD （Parting Dancers） gene affects the level of meiotic crossover formation, but its functional relationships with other core meiotic genes, such as AtSP011-1, AtRAD51, and AtMSH4, are unclear; whether PTD has other functions in meiosis is also unknown. To further analyze PTD function and to test for epistatic relationships, we compared the meiotic chromosome behaviors ofAtspoll-1 ptd and Atrad51 ptd double mutants with the relevant single mutants. The results suggest that PTD functions downstream of AtSP011-1 and AtRAD51 in the meiotic recombination pathway. Furthermore, we found that meiotic defects in rck pM and Atmsh4 ptd double mutants showed similar meiotic phenotypes to those of the relevant single mutants, providing genetic evidences for roles of PTD and RCK in the type I crossovers pathway. Moreover, we employed a pollen tetrad-based fluorescence method and found that the meiotic crossover frequencies in two genetic intervals were significantly reduced from 6.63% and 22.26% in wild-type to 1.14% and 6.36%, respectively, in the ptd^2 mutant. These results revealed new aspects of PTD function in meiotic crossover formation.展开更多
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 phenylbor...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.展开更多
Post-translational protein modification, including phosphorylation, is generally quick and reversible, facilitating rapid biologic adjustments to altered cellular physiologic demands. In addition to protein phosphoryl...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.展开更多
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 ...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.展开更多
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 appli...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.展开更多
基金supported by the U.S.National Natural Science Foundation(CHE-2203505 and MCB-2335137).
文摘AlphaFold[1]has turned everyone into a structural biologist.No need for knowledge of Fourier transforms or spectral density,driven by artificial intelligence(AI),all one needs to do is enter the primary structure of a folded protein,and out pops a tertiary structure nearly as good as one from an experiment-based structure.
文摘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.
文摘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.
基金supported by grants from the National Natural Science Foundation of China(81972377,82025027,31301131,81972723)the Science and Technology Project of Xuzhou(KC19064)+1 种基金the Social Development Project of Jiangsu Province(BE2019644)the Natural Science Foundation of the Jiangsu Higher Education Institutions(18KJA320012)。
文摘The tumor suppressor p53 transactivates the expression of multiple genes to exert its multifaceted functions and ultimately maintains genome stability.Thus,cancer cells develop various mechanisms to diminish p53 expression and bypass the cell cycle checkpoint.In this study,we identified the gene encoding RNAbinding protein cytoplasmic polyadenylation element-binding protein 2(CPEB2)as a p53 target.In turn,CPEB2 decreases p53 messenger RNA stability and translation to fine-tune p53 level.Specifically,we showed that CPEB2 binds the cytoplasmic polyadenylation elements in the p5330-untranslated region,and the RNA recognition motif and zinc finger(ZF)domains of CPEB2 are required for this binding.Furthermore,we found that CPEB2 was upregulated in renal cancer tissues and promotes the renal cancer cell proliferation and migration.The oncogenic effect of CPEB2 is partially dependent on negative feedback regulation of p53.Overall,we identify a novel regulatory feedback loop between p53 and CPEB2 and demonstrate that CPEB2 promotes tumor progression by inactivating p53,suggesting that CPEB2 is a potential therapeutic target in human renal cancer.
文摘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
文摘Cytokines play an essential role in governing the overall immune response toward cancer.Recently,the role of IL-12 family cytokines in dictating immune response toward cancer has been well appreciated.1 IL-23 is one of such heterodimeric cytokines belonging to the IL-12 family cytokine,composed of p19 and p40 subunits.2 The role of IL-23 in regulating tumorigenesis is controversial.In some cancer settings,IL-23 activates the effector immune system and has antitumorigenic functions;on the other hand,it can support immune regulatory response and favor tumor growth.3 In this issue of Asian Journal of Andrology,Liu et al.4 reported the novel functions of IL-23,a cytokine that regulates both innate and adaptive immune cells;especially,it is well known to maintain Th17 cell phenotype in prostate cancer.Prostate cancer is one of the utmost challenging tumor types and is the most common cancer in men,and one man in eight will be diagnosed with prostate cancer.
文摘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.
文摘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.
文摘Dear Editor, Prostate cancer （PCa） is the most frequently diagnosed male cancer in Western countries, and the number of PCa patients is also rapidly increasing in ]apan.1,2 Simultaneously, androgen deprivation therapy （ADT） has also been increasingly used in PCa patients in recent years2-5 However, the long-term use of ADT is associated with a variety of pivotal adverse events, including diabetes, anemia, osteoporosis, serum lipid profile changes, and cardiovascular disease （CVD）.1,2 Higher low-density lipoprotein cholesterol （LDL-C） and/or lower high-density lipoprotein cholesterol （HDL-C） are well-established risk factors for CVD, and control of their levels has been an important goal in the treatment and prevention of CVD.6,7 Recently, another alternative parameter, the LDL-C to HDL-C （L/H） ratio, has been reported to be strongly associated with CVD and is thought to be a better predictor of future CVD than LDL-C alone. Closely monitoring serum lipid profile, including the L/H ratio changes affected by ADT, is a key to preventing CVD in PCa patients. Moreover, we previously suggested that a higher L/H ratio might have an impact on the development of arterial stiffness after ADT administration,r Although some cutoff points of the L/H ratio have been reported in clinical use, it has been suggested that thrombosis can occur when the L/H ratio increases to around 2.5 or more in East Asian populations.6 The aim of the present study was to investigate the changes in serum lipid profile and to identify the clinical factors associated with an increased L/H ratio in PCa patients who received ADT.
基金Supported by the Canadian Cancer Society through a grant to the NCIC Clinical Trials Group from the Canadian Cancer Society Research InstituteNovartis provided the NCIC CTG MA.14 drug octreotide LAR
文摘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.
文摘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.
文摘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.
基金supported in part by grants from the Natural Science Foundation of China (30430640,31030031)the National Basic Research Program of MOST (2004BA519A61,2003CB514116,2006CB504300)Natural Science Foundation of China (31400765)
文摘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.
文摘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.
基金supported by funds from Fudan Universityfunds from Rijk Zwaan,the Netherlands,and the Biology Department and the Huck Institutes of the Life Sciences at the Pennsylvania State University in USA
文摘In eukaryotes, crossovers together with sister chromatid cohesion maintain physical association between homologous chromosomes, ensuring accurate chromosome segregation during meiosis I and resulting in exchange of genetic information between homologues. The Arabidopsis PTD （Parting Dancers） gene affects the level of meiotic crossover formation, but its functional relationships with other core meiotic genes, such as AtSP011-1, AtRAD51, and AtMSH4, are unclear; whether PTD has other functions in meiosis is also unknown. To further analyze PTD function and to test for epistatic relationships, we compared the meiotic chromosome behaviors ofAtspoll-1 ptd and Atrad51 ptd double mutants with the relevant single mutants. The results suggest that PTD functions downstream of AtSP011-1 and AtRAD51 in the meiotic recombination pathway. Furthermore, we found that meiotic defects in rck pM and Atmsh4 ptd double mutants showed similar meiotic phenotypes to those of the relevant single mutants, providing genetic evidences for roles of PTD and RCK in the type I crossovers pathway. Moreover, we employed a pollen tetrad-based fluorescence method and found that the meiotic crossover frequencies in two genetic intervals were significantly reduced from 6.63% and 22.26% in wild-type to 1.14% and 6.36%, respectively, in the ptd^2 mutant. These results revealed new aspects of PTD function in meiotic crossover formation.
基金financial support from National Key Research and Development Program(2017YFD0501403)National Natural Science Foundation of China(Nos.81872819)+4 种基金Natural Science Foundation of Jiangsu Province(No.BK20171390)supported by Double First-Rate construction plan of China Pharmaceutical University(CPU2018GY26)the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMZZCX201816)the National Science and Technology Major Project(2017ZX09101001)the financial support from Development Funds for Priority Academic Programs in Jiangsu Higher Education Institutions-Young Talent Program。
文摘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.
基金supported by NIH RO1 (No. AI49427) to Dr David S.Rubenstein
文摘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.
文摘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.
文摘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.
