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1.
Nature ; 580(7803): 355-359, 2020 04.
Article in English | MEDLINE | ID: mdl-32296188

ABSTRACT

Quantum computation requires many qubits that can be coherently controlled and coupled to each other1. Qubits that are defined using lithographic techniques have been suggested to enable the development of scalable quantum systems because they can be implemented using semiconductor fabrication technology2-5. However, leading solid-state approaches function only at temperatures below 100 millikelvin, where cooling power is extremely limited, and this severely affects the prospects of practical quantum computation. Recent studies of electron spins in silicon have made progress towards a platform that can be operated at higher temperatures by demonstrating long spin lifetimes6, gate-based spin readout7 and coherent single-spin control8. However, a high-temperature two-qubit logic gate has not yet been demonstrated. Here we show that silicon quantum dots can have sufficient thermal robustness to enable the execution of a universal gate set at temperatures greater than one kelvin. We obtain single-qubit control via electron spin resonance and readout using Pauli spin blockade. In addition, we show individual coherent control of two qubits and measure single-qubit fidelities of up to 99.3 per cent. We demonstrate the tunability of the exchange interaction between the two spins from 0.5 to 18 megahertz and use it to execute coherent two-qubit controlled rotations. The demonstration of 'hot' and universal quantum logic in a semiconductor platform paves the way for quantum integrated circuits that host both the quantum hardware and its control circuitry on the same chip, providing a scalable approach towards practical quantum information processing.

2.
Asian Journal of Andrology ; (6): 324-331, 2019.
Article in English | WPRIM (Western Pacific) | ID: wpr-1009676

ABSTRACT

To assess safety of the no-flip ShangRing male circumcision technique and to determine clinical course and safety of spontaneous detachment (i.e., allowing the device to fall off), we conducted a case series of no-flip ShangRing circumcision combined with a randomized controlled trial of removal 7 days postcircumcision versus spontaneous detachment at two health facilities in Kenya. The primary outcome was the safety of the no-flip technique based on moderate and severe adverse events (AEs) during the procedure and through 42-day follow-up. A main secondary outcome was clinical course and safety of spontaneous detachment. Two hundred and thirty males 10 years and older underwent no-flip circumcision; 114 randomized to 7-day removal and 116 to spontaneous detachment. All circumcisions were successfully completed. Overall 5.3% (6/114) of participants in the 7-day group and 1.7% (2/116) in the spontaneous group had an AE; with no differences when compared to the 3% AE rate in historical data from African studies using the original flip technique (P = 0.07 and P = 0.79, respectively). Overall 72.4% (84/116) of participants in the spontaneous group wore the ShangRing until it detached. Among the remaining (27.6%; 32/116), the ring was removed, primarily at the participants' request, due to pain or discomfort. There was no difference in AE rates (P = 0.169), visit day declared healed (P = 0.324), or satisfaction (P = 0.371) between randomization groups. The median time to detachment was 14.0 (IQR: 7-21, range: 5-35) days. The no-flip technique and spontaneous detachment are safe, effective, and acceptable to boys and men 10 years and older. Phimosis and penile adhesions do not limit successful ShangRing circumcision with the no-flip technique.


Subject(s)
Adolescent , Adult , Child , Humans , Male , Middle Aged , Young Adult , Circumcision, Male/methods , Kenya , Patient Satisfaction , Treatment Outcome , Wound Healing
3.
Nature ; 555(7698): 633-637, 2018 03 29.
Article in English | MEDLINE | ID: mdl-29443962

ABSTRACT

Now that it is possible to achieve measurement and control fidelities for individual quantum bits (qubits) above the threshold for fault tolerance, attention is moving towards the difficult task of scaling up the number of physical qubits to the large numbers that are needed for fault-tolerant quantum computing. In this context, quantum-dot-based spin qubits could have substantial advantages over other types of qubit owing to their potential for all-electrical operation and ability to be integrated at high density onto an industrial platform. Initialization, readout and single- and two-qubit gates have been demonstrated in various quantum-dot-based qubit representations. However, as seen with small-scale demonstrations of quantum computers using other types of qubit, combining these elements leads to challenges related to qubit crosstalk, state leakage, calibration and control hardware. Here we overcome these challenges by using carefully designed control techniques to demonstrate a programmable two-qubit quantum processor in a silicon device that can perform the Deutsch-Josza algorithm and the Grover search algorithm-canonical examples of quantum algorithms that outperform their classical analogues. We characterize the entanglement in our processor by using quantum-state tomography of Bell states, measuring state fidelities of 85-89 per cent and concurrences of 73-82 per cent. These results pave the way for larger-scale quantum computers that use spins confined to quantum dots.

4.
Asian Journal of Andrology ; (6): 576-580, 2018.
Article in English | WPRIM (Western Pacific) | ID: wpr-1009628

ABSTRACT

Microsurgical longitudinal intussusception vasoepididymostomy (LIVE) has been widely used to treat epididymal obstructive azoospermia since 2004. Although the deferential vasculature plays an important role in supplying blood to the testis and epididymis, little attention has been paid to the potential benefits of sparing the deferential vessels during the anastomosis in LIVE. This study aimed to evaluate the efficacy and safety of deferential vessel-sparing LIVE in humans. From December 2013 to December 2015, 69 azoospermic men with epididymal obstruction due to a genital infection, trauma, or idiopathic factors underwent deferential vessel-sparing LIVE in the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. The outcomes of these patients were analyzed retrospectively. The mean age was 31.1 years for men and 28.3 years for their partners. Fifty-nine (85.5%, 59/69) men were followed up after surgery for approximately 16 months. Patency was noted and confirmed by semen analysis (>10 000 sperm/ml) in 83.1% (49/59) of men. The natural pregnancy rate was 40.7% (24/59) by the end of the study, with 87.5% (21/24) of these natural pregnancies achieved within 12 months after surgery. No severe adverse events or complications were observed. In this study, we present a novel technique for sparing the deferential vessels during LIVE. The preliminary outcomes show this technique to be safe with favorable patency and pregnancy rates.


Subject(s)
Adolescent , Adult , Female , Humans , Male , Pregnancy , Young Adult , Azoospermia/surgery , Epididymis/surgery , Follow-Up Studies , Organ Sparing Treatments/methods , Postoperative Complications/epidemiology , Pregnancy Rate , Retrospective Studies , Semen Analysis , Testis/surgery , Treatment Outcome , Urogenital Surgical Procedures/methods , Vas Deferens/surgery
5.
National Journal of Andrology ; (12): 579-288, 2018.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-689716

ABSTRACT

In the past two decades, with the rapid development of assisted reproductive technology and particularly the technological advances in male infertility microsurgery, many obstructive azoospermia-related infertile couples can now acquire the chances of natural pregnancy via reconstruction of the seminal tract. This article highlights the latest advances in surgical reconstruction of the seminal tract for the treatment of obstructive azoospermia, such as the application of laparoscopic and robotic techniques, with a discussion on microsurgical epididymal sperm aspiration and preservation, potential use of absorbable sutures or the bio-suture tape for microsurgical anastomosis in the management of obstructive azoospermia.


Subject(s)
Female , Humans , Male , Pregnancy , Azoospermia , General Surgery , Infertility, Male , General Surgery , Laparoscopy , Microsurgery , Methods , Reproductive Techniques, Assisted , Robotic Surgical Procedures , Seminal Vesicles , General Surgery , Sperm Retrieval , Sutures
6.
Breast Cancer Res Treat ; 166(1): 277-287, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28730340

ABSTRACT

PURPOSE: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. METHODS: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). RESULTS: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00-2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). CONCLUSIONS: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/mortality , Cytochrome P-450 CYP2D6/genetics , Genotype , Polymorphism, Genetic , Adult , Aged , Alleles , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Pharmacogenomic Variants , Prognosis , Survival Analysis , Tamoxifen/therapeutic use , Treatment Outcome
7.
Bone Marrow Transplant ; 50(8): 1110-8, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25961767

ABSTRACT

Caregivers of patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCT) serve a pivotal role in patient care but experience high stress, anxiety and depression as a result. We theorized that stress management adapted for allo-HSCT caregivers would reduce distress compared with treatment as usual (TAU). Of 267 consecutive caregivers of allo-HSCT patients approached, 148 (mean=53.5 years, 75.7% female) were randomized to either psychosocial intervention (i=74) or TAU (n=74). Eight one-on-one stress management sessions delivered across the 100-day post-transplant period focused on understanding stress, changing role(s) as caregiver, cognitive behavioral stress management, pacing respiration and identifying social support. Primary outcomes included perceived stress (psychological) and salivary cortisol awakening response (CAR) (physiological). Randomized groups were not statistically different at baseline. Mixed models analysis of covariance (intent-to-treat) showed that intervention was associated with significantly lower caregiver stress 3 months post transplant (mean=20.0, 95% confidence interval (95% CI)=17.9-22.0) compared with TAU (mean=23.0, 95% CI=21.0-25.0) with an effect size (ES) of 0.39 (P=0.039). Secondary psychological outcomes, including depression and anxiety, were significantly reduced with ESs of 0.46 and 0.66, respectively. Caregiver CAR did not differ from non-caregiving controls at baseline and was unchanged by intervention. Despite significant caregiving burden, this psychosocial intervention significantly mitigated distress in allo-HSCT caregivers.


Subject(s)
Caregivers , Hematopoietic Stem Cell Transplantation/psychology , Social Support , Stress, Psychological/therapy , Adult , Aged , Aged, 80 and over , Allografts , Female , Humans , Male , Middle Aged , Stress, Psychological/metabolism
8.
Clin Pharmacol Ther ; 98(2): 205-15, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25968989

ABSTRACT

Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric [1-17 years], and adult [28-80 years]; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g., hsa-miR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n = 10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.


Subject(s)
Aging/genetics , Liver/metabolism , MicroRNAs/genetics , Pharmacogenetics , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Aging/metabolism , Biotransformation/genetics , Child , Child, Preschool , Cluster Analysis , Computational Biology , Gene Expression Profiling/methods , Gene Expression Regulation, Developmental , Gene Expression Regulation, Enzymologic , Humans , Infant , MicroRNAs/metabolism , Middle Aged
9.
Afr J Paediatr Surg ; 11(4): 287-92, 2014.
Article in English | MEDLINE | ID: mdl-25323175

ABSTRACT

BACKGROUND: There is paucity of data regarding the morbidity and mortality of rigid bronchoscopy in children for foreign body (FB) retrieval from India. The aim was to audit data regarding anaesthetic management of rigid bronchoscopy in children and associated morbidity and mortality. MATERIALS AND METHODS: Hospital records of all patients below 18 years of age undergoing rigid bronchoscopy for suspected FB aspiration (FBA) between January 1, 2002 and December 31, 2011 were audited to assess their demographic profile, anaesthetic management, complications, and postoperative outcomes. The children were divided into early and late diagnosis groups depending on whether they presented to the hospital within 24 hours of FBA, or later. RESULTS: One hundred and forty children, predominantly male (75%), with an average age of 1-year and 8 months, presented to our hospital for rigid bronchoscopy during the study period. Majority of children presented in the late diagnosis group (59.29% vs. 40.71%). The penetration syndrome was observed in 22% of patients. Majority of patients aspirated an organic FB (organic: Inorganic FB = 3:1), with peanuts being the most common (49.28%). A significantly higher number of children presented with cough (P = 0.0001) and history of choking (P = 0.0022) in the early diagnosis group and crepitations (P = 0.0011) in the late diagnosis group. Major complications included cardiac arrest (2.1%), pneumothorax (0.7%), and laryngeal oedema (9.3%). The average duration of hospitalization in our series was 3.08 ± 0.7 days. CONCLUSIONS: Foreign body aspiration causes considerable morbidity, especially when diagnosis is delayed.


Subject(s)
Foreign Bodies/diagnosis , Foreign Bodies/mortality , Foreign Bodies/surgery , Respiratory Aspiration , Bronchoscopy , Early Diagnosis , Female , Humans , India/epidemiology , Infant , Length of Stay/statistics & numerical data , Male , Postoperative Complications , Retrospective Studies
10.
Oncogene ; 33(46): 5379-90, 2014 Nov 13.
Article in English | MEDLINE | ID: mdl-24240679

ABSTRACT

Myeloproliferative neoplasms (MPNs) such as chronic myelogenous (CML) and chronic myelomonocytic leukemias (CMML) are frequently induced by tyrosine kinase oncogenes. Although these MPNs are sensitive to tyrosine kinase inhibitors such as imatinib, patients often relapse upon withdrawal of therapy. We used a model of MPN, which is induced by co-expression of the oncoproteins HIP1/PDGFßR (H/P) and AML1/ETO from their endogenous loci, to examine the mechanisms of disease development and recurrence following imatinib withdrawal. Although the MPN displayed a full hematologic response to imatinib, 100% of the diseased mice relapsed upon drug withdrawal. MPN persistence was not due to imatinib resistance mutations in the H/P oncogene or massive gene expression changes. Within 1 week of imatinib treatment, more than 98% of gene expression changes induced by the oncogenes in isolated hematopoietic stem and progenitor cells (lineage(-)Sca-1(+)c-Kit(+) immunophenotype) normalized. Supplementation of imatinib with granulocyte colony-stimulating factor or arsenic trioxide reduced MPN-initiating cell frequencies and the combination of imatinib with arsenic trioxide cured a large fraction of mice with MPNs. In contrast, no mice in the imatinib-treated control cohorts were cured. These data suggest that treatment with a combination of arsenic trioxide and imatinib can eliminate refractory MPN-initiating cells and reduce disease relapse.


Subject(s)
Benzamides/pharmacology , Myeloproliferative Disorders/drug therapy , Neoplastic Stem Cells/drug effects , Piperazines/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenic Trioxide , Arsenicals/administration & dosage , Benzamides/administration & dosage , Blotting, Western , Bone Marrow Transplantation , Core Binding Factor Alpha 2 Subunit/genetics , Core Binding Factor Alpha 2 Subunit/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Disease Models, Animal , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Imatinib Mesylate , Mice, Inbred C57BL , Mice, Transgenic , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , Neoplasm Recurrence, Local , Neoplastic Stem Cells/metabolism , Oligonucleotide Array Sequence Analysis , Oxides/administration & dosage , Piperazines/administration & dosage , Pyrimidines/administration & dosage , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome
11.
National Journal of Andrology ; (12): 969-977, 2014.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-319584

ABSTRACT

Increasingly accumulated results from randomized controlled trials and other clinical studies have demonstrated that male circumcision reduces the risks of acquisition and transmission of HIV, HPV, HSV-2, and other sexually transmitted infections, and thus has a potential role in preventing cervical cancer, penile cancer and prostate cancer. The prevalence of male circumcision in China is currently less than 5%. The clinical evaluation studies and randomized controlled trials of the Shang Ring device showed excellent safety profiles, extremely high acceptability, and satisfaction among the participants and service providers in Africa and China. Given the recent recommendations by the World Health Organization and the Joint United Nations Program on HIV/AIDS (UNAIDS), voluntary medical male circumcision should be promoted in China at the national level as an important alternative intervention to reduce reproductive tract infections and prevent both males and females from reproductive tract cancers. More emphasis is required on the studies of the long-term health benefits of male circumcision in uro-andrology.


Subject(s)
Female , Humans , Male , China , Circumcision, Male , HIV Infections , Penile Neoplasms , Prevalence , Randomized Controlled Trials as Topic , Sexually Transmitted Diseases , Urinary Tract Infections , Uterine Cervical Neoplasms , World Health Organization
12.
National Journal of Andrology ; (12): 99-105, 2014.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-267970

ABSTRACT

Men with azoospermia or severe oligospermia (< 5 x 10(6)/ml) should have genetic testing to identify the reason for male infertility before treatment. Identification of obstructive azoospermia (OA) or non-obstructive azoospermia (NOA) is essential because genetic testing differs for OA (which has normal testicular function, testicular volume, and FSH) versus NOA (which has small, soft testes and increased FSH). Among patients with NOA, history and physical examination along with laboratory testing is required to choose genetic testing specifically for primary testicular failure or congenital hypogonadotropic hypogonadism (HH). Genetic testing options include cystic fibrosis transmembrane conductance regulator (CFTR) testing for men with OA due to congenital absence of the vas, while karyotype, Y chromosome microdeletions (YCMD), and other specific genetic tests may be indicated if patient has severe oligospermia or NOA. These genetic tests help to identify which patients may benefit from medical and/or surgical intervention. The most recent techniques for genetic analysis will improve diagnosis and management of male infertility.


Subject(s)
Humans , Male , Genetic Testing , Infertility, Male , Genetics , Oligospermia , Genetics
13.
National Journal of Andrology ; (12): 291-298, 2014.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-309719

ABSTRACT

HIV/STIs remain a major global public health problem. One of the global strategies for the prevention and control of HIV/STIs is to interrupt their transmission, which requires the public health methods based on scientific evidence and cost-effectiveness. The scale-up of male circumcision services in the priority countries of the HIV-prevention project in sub-Saharan Africa has been hampered by the scarcity of trained providers and relative technical difficulty of male circumcision techniques recommended by WHO and UNAIDS. Shang Ring is an innovative and disposable device for male circumcision, which has been safely used for over 600 000 males in China since 2006. Clinical studies of more than 3 000 cases of Shang Ring circumcision in China, Kenya, Zambia, and Uganda have demonstrated its safety, effectiveness, acceptability and ease of use. The most obvious advantages of Shang Ring include short procedure time (3-6 min), excellent postoperative cosmesis, low rate of complications, high acceptance by clients and providers, ease of use, and standardization for reliable performance. As an innovative technique, Shang Ring has a great potential for facilitating the safe and effective scale-up of circumcision services. This article comprehensively reviews the clinical studies of Shang Ring male circumcision in China and Africa.


Subject(s)
Humans , Male , Africa , China , Circumcision, Male , Methods , HIV Infections
14.
National Journal of Andrology ; (12): 595-604, 2014.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-309668

ABSTRACT

Male infertility microsurgery represents the fastest growing sub-specialty in urology and clinical andrology over the past two decades. The importance of microsurgery for male infertility has risen as a part of the urologist's armamentarium in the medical and surgical management of male infertility. Despite the advances in male infertility microsurgery in China, the lack of standardized and well-organized training programs for male infertility microsurgery remains a serious problem affecting its development. In this article, Zhao and Peng have shared their experience with the learning curve of male infertility microsurgery at the Center for Male Reproductive Medicine and Microsurgery, Weill Medical College of Cornell University, which centers on how to pay attention to the details and basic principles of microsurgery. Male infertility microsurgery is physically, technically and mentally challenging, and must be first learned in the laboratory. Clinical success depends heavily upon appropriate training in a microsurgical laboratory. Good training can significantly reduce operation time and surgical errors as well as improve the quality of outcomes.


Subject(s)
Humans , Male , Andrology , Education , Infertility, Male , General Surgery , Microsurgery , Education
15.
Br J Cancer ; 109(9): 2331-9, 2013 Oct 29.
Article in English | MEDLINE | ID: mdl-24084768

ABSTRACT

BACKGROUND: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. METHODS: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. RESULTS: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ≥20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. CONCLUSION: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.


Subject(s)
Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast/drug effects , Adult , Aged , Aged, 80 and over , Androstadienes/therapeutic use , Aromatase/genetics , Breast/metabolism , Breast/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chemotherapy, Adjuvant/methods , Estrogens/metabolism , Female , Humans , Letrozole , Mammography/methods , Middle Aged , Nitriles/therapeutic use , Polymorphism, Single Nucleotide , Postmenopause/drug effects , Postmenopause/genetics , Postmenopause/metabolism , Prospective Studies , Triazoles/therapeutic use
16.
Ann Oncol ; 24(7): 1867-1873, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23508821

ABSTRACT

BACKGROUND: Beyond estrogen receptor (ER), there are no validated predictors for tamoxifen (TAM) efficacy and toxicity. We utilized a genome-wide cell-based model to comprehensively evaluate genetic variants for their contribution to cellular sensitivity to TAM. DESIGN: Our discovery model incorporates multidimensional datasets, including genome-wide genotype, gene expression, and endoxifen-induced cellular growth inhibition in the International HapMap lymphoblastoid cell lines (LCLs). Genome-wide findings were further evaluated in NCI60 cancer cell lines. Gene knock-down experiments were performed in four breast cancer cell lines. Genetic variants identified in the cell-based model were examined in 245 Caucasian breast cancer patients who underwent TAM treatment. RESULTS: We identified seven novel single-nucleotide polymorphisms (SNPs) associated with endoxifen sensitivity through the expression of 10 genes using the genome-wide integrative analysis. All 10 genes identified in LCLs were associated with TAM sensitivity in NCI60 cancer cell lines, including USP7. USP7 knock-down resulted in increasing resistance to TAM in four breast cancer cell lines tested, which is consistent with the finding in LCLs and in the NCI60 cells. Furthermore, we identified SNPs that were associated with TAM-induced toxicities in breast cancer patients, after adjusting for other clinical factors. CONCLUSION: Our work demonstrates the utility of a cell-based model in genome-wide identification of pharmacogenomic markers.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Drug Resistance, Neoplasm/genetics , Polymorphism, Single Nucleotide , Tamoxifen/analogs & derivatives , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Line, Tumor/drug effects , Clinical Trials as Topic , Drug Screening Assays, Antitumor , Estrogen Receptor alpha , Female , Gene Expression , Gene Knockdown Techniques , Genome-Wide Association Study , Humans , RNA, Small Interfering/genetics , Tamoxifen/pharmacology , Tamoxifen/therapeutic use , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Ubiquitin-Specific Peptidase 7
17.
Br J Radiol ; 85(1014): 682-96, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22253347

ABSTRACT

Pancreatic endocrine neoplasms are rare pancreatic tumours that may occur sporadically or as part of inherited syndromes such as multiple endocrine neoplasia-1 syndrome, von Recklinghausen disease, von Hippel-Lindau syndrome and tuberous sclerosis complex. Recent advances in the genetics and pathology of hereditary syndromes have provided valuable insights into the pathophysiology and biology of sporadic pancreatic endocrine neoplasms. Evolving molecular data on the biology of these neoplasms have the potential for diagnostic, therapeutic and prognostic use.


Subject(s)
Diagnostic Imaging , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Humans , Magnetic Resonance Imaging , Multiple Endocrine Neoplasia Type 1/diagnosis , Multiple Endocrine Neoplasia Type 1/genetics , Tomography, X-Ray Computed , von Hippel-Lindau Disease/diagnosis , von Hippel-Lindau Disease/genetics
18.
Mol Endocrinol ; 26(2): 220-7, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22174377

ABSTRACT

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)ß phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3ß increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3ß-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3ß phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.


Subject(s)
Antineoplastic Agents, Hormonal/adverse effects , Glycogen Synthase Kinase 3/metabolism , Nuclear Receptor Coactivator 1/genetics , Tamoxifen/adverse effects , Amino Acid Sequence , Amino Acid Substitution , Antineoplastic Agents, Hormonal/therapeutic use , Bone Demineralization, Pathologic/chemically induced , Bone Demineralization, Pathologic/genetics , Bone Density/drug effects , Breast Neoplasms/prevention & control , Cell Line, Tumor , Clinical Trials as Topic , Female , Genetic Association Studies , Glycogen Synthase Kinase 3 beta , Humans , Molecular Sequence Data , Phosphorylation , Polymorphism, Single Nucleotide , Protein Processing, Post-Translational , Protein Stability , Receptors, Estrogen/agonists , Receptors, Estrogen/metabolism , Sequence Analysis, DNA , Tamoxifen/therapeutic use
19.
Cancer Chemother Pharmacol ; 68(4): 863-70, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21286719

ABSTRACT

PURPOSE: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. METHODS: In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. RESULTS: Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5' flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. CONCLUSIONS: This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.


Subject(s)
Adenocarcinoma/therapy , Cisplatin/administration & dosage , DNA-Binding Proteins/genetics , Esophageal Neoplasms/therapy , Glutathione S-Transferase pi/genetics , Adenocarcinoma/genetics , Adult , Aged , Antineoplastic Agents/administration & dosage , Combined Modality Therapy , Esophageal Neoplasms/genetics , Female , Genetic Variation , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Radiation Injuries
20.
National Journal of Andrology ; (12): 195-202, 2011.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-266191

ABSTRACT

Male circumcision can reduce men's risk of HIV infection from heterosexual intercourse by 60% and is therefore recommended as an important strategy for HIV prevention in Africa by WHO and UNAIDS. However, rapid expansion of male circumcision efforts could be greatly facilitated by a safer, more effective and acceptable male circumcision surgical technique or device. Shang Ring is a simple technique developed in China. It allows a circumcision to be completed with minimal bleeding, without suturing, and in only 3-5 min and reported complications are few. A standardized adult male circumcision surgical protocol utilizing the Shang Ring device was developed in 2008 in China. Several surgical training courses using this protocol were successfully held in 2009 and 2010 in China. A recent pilot clinical study of the Shang Ring was conducted to evaluate its safety and efficiency in Kenya in 2009. The results and acceptability among study participants were excellent and confirmed many of the advantages seen in the earlier Chinese studies from Wuhu, Ningbo and Xi'an, suggesting that the Shang Ring is safe for further studies in Africa, thus, could facilitate more rapid roll-out of adult male circumcision through task shifting, surgical efficiencies and better acceptability. Further international investigations of the Shang Ring technique have now been planned for Kenya and Zambia in 2011. Moreover, adult male circumcision utilizing the Shang Ring device is now being considered as ope of the potential candidate techniques to be used in the scale-up of adult male circumcision services for HIV prevention in WHO priority countries in Africa. This review article summarizes Shang Ring related clinical studies, seminars and surgical workshops, publications and presentations conducted between February 2008 and December 2010 in China, the United States and Africa.


Subject(s)
Humans , Male , Africa , Circumcision, Male , Methods , HIV Infections
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