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1.  Breast cancer and fertility preservation 
Fertility and sterility  2011;95(5):1535-1543.
To review the benefits of adjuvant systemic therapy given to women with breast cancer of reproductive age, its effects on fertility, and options for fertility preservation.
Publications relevant to fertility preservation and breast cancer were identified through a PubMed database search.
Most women who develop invasive breast cancer under age 40 will be advised to undergo adjuvant chemotherapy with or without extended antihormonal therapy to reduce the risk of recurrence and death from breast cancer. Adjuvant chemotherapy particularly with alkylating agents such as cyclophosphamide is gonadotoxic and markedly accelerates the rate of age-related ovarian follicle loss. Although loss of fertility is an important issue for young cancer survivors, there is often little discussion about fertility preservation before initiation of adjuvant therapy. Greater familiarity with prognosis and effects of different types of adjuvant therapy on the part of infertility specialists and fertility preservation options such cryopreservation of embryos, oocytes, and ovarian tissue on the part of oncologists would facilitate these discussions. Establishment of rapid fertility consultation links within cancer survivorship programs can help ensure that every young woman who is likely to undergo gonadotoxic cancer treatment is counseled about the effects of therapy and options available to her to increase the likelihood of childbearing after cancer treatment.
PMCID: PMC3939612  PMID: 21272867
Breast cancer; fertility preservation; embryo cryopreservation; oocyte cryopreservation; ovarian tissue cryopreservation; ovarian transplantation; GnRH agonist; chemotherapy; cancer survivorship
2.  Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma 
Cancer research  2012;73(2):885-896.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2′-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), along with increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
PMCID: PMC3548986  PMID: 23204224
5.  Atrial natriuretic peptide is negatively regulated by microRNA-425 
The Journal of Clinical Investigation  2013;123(8):3378-3382.
Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.
PMCID: PMC3726159  PMID: 23867623
6.  Fertility considerations in young women with hematological malignancies 
The need for practice guidelines for fertility preservation in young women with hematological malignancies has been increased. To develop recommendations, publications relevant to fertility preservation and hematological cancers were identified through a PubMed database search and reviewed systematically, focusing on the effects of oncological treatments on fertility as well as on the efficacy, feasibility and risks of existing fertility preservation methods.
PMCID: PMC3370036  PMID: 22614159
Hematological malignancy; Fertility; Fertility preservation; Chemotherapy; Lymphoma; Leukemia, cancer
7.  Assessment of long term endocrine function after transplantation of frozen-thawed human ovarian tissue to the heterotopic site: 10 year longitudinal follow-up study 
To assess the longevity of ovarian grafts in five cancer patients who underwent heterotopic autotransplantation of frozen-thawed ovarian tissue.
Five cancer survivors underwent heterotopic ovarian transplantation between 2001and 2011. Stored ovarian tissue (for 1–10 years) was rapidly thawed and transplanted into the space between the rectus sheath and the rectus muscle (8–20 cortical sections per patient). Endocrine function was assessed by monthly blood tests (FSH, LH, E2, progesterone and testosterone) and ultrasound after transplantation. The monitoring was continued until the cessation of endocrine function by consecutive blood tests (E2 < 20 pg/ml; FSH ≥ 35 IU/L).
Endocrine function was restored in all patients between 12–20 weeks after transplantation. Four patients required the second transplantation one to two years after the first transplantation. The duration of endocrine function after the second transplantation was much longer (9 months–84 months). The longest duration of endocrine function was seen in a woman who underwent ovarian transplantation in 2003 and 2004 after radiotherapy for cervical cancer. Even more than seven years after transplantation, endocrine function has not ceased (FSH 9.5, E2 108, on July 1, 2011). Of note, this patient underwent three IVF cycles in 2004 which resulted in four embryos.
Long-term endocrine function lasting for seven years can be established with heterotopic transplantation of cryobanked human ovarian tissue. Re-establishment of long-term endocrine function after ovarian transplantation will benefit young cancer survivors with premature ovarian failure.
PMCID: PMC3370050  PMID: 22492223
Fertility preservation; Ovarian transplantation; Heterotopic transplantation; Endocrine function; Cancer; Cryopreservation; Ovarian tissue
8.  Fertility preservation in young women with breast cancer 
When a young woman is diagnosed with breast cancer, there is often a sense of urgency by the patient and her providers to initiate treatment. This article provides guidelines for incorporating the discussion of fertility preservation with newly diagnosed young women with breast cancer.
PMCID: PMC3370052  PMID: 22614158
Fertility preservation; Breast cancer; Chemotherapy; Cancer; Survivorship; Oocyte cryopreservation; Embryo cryopreservation; Ovarian tissue cryopreservation; Ovarian stimulation; Infertility
9.  Rodent Estrous Cycle Response to Incomplete Spinal Cord Injury, Surgical Interventions, and Locomotor Training 
Behavioral Neuroscience  2011;125(6):996-1002.
Estrous cycle disruption after spinal cord injury (SCI) in female rats is a common phenomenon. It remains unknown, however, if the aberrant estrous cycle is a result of an injury to the spinal cord itself or due to the general stress associated with surgical interventions. We addressed this issue by determining estrous cyclicality in female rats after a spinal cord hemisection (HX), implantation of EMG wires into selected hindlimb muscles, and/or injections of tracer dyes into the spinal cord. Since it is known that aerobic exercise can enhance the recovery of locomotor function in rodents with an incomplete SCI, we also determined if locomotor training positively impacts the disrupted estrous cycle after a HX. Estrous cycle assessments were made during a 5-8 week period in 27 female rats before and after HX, EMG, and/or dye injection surgeries and in HX rats that recovered spontaneously or underwent locomotor training. Our results show that estrous cyclicality was disrupted (cycle length >5 days) in approximately 76%, 46%, and 50% of the rats after HX, EMG, and dye injection surgeries, respectively. The cyclicality, however, was disrupted for a longer period after HX than after EMG or dye injection surgeries. Furthermore, estrous cycle mean length was shorter in the trained than non-trained HX group. These results suggest that estrous cycle disruption after a major SCI is a consequence of both the direct injury to the spinal cord and to the associated stress. Moreover, moderate aerobic exercise initiated early after a spinal cord HX returns the duration of the estrous cycle towards normal.
PMCID: PMC3361964  PMID: 22122153
spinal cord injury; surgical intervention; EMG surgery; estrous cycle; rodents
10.  Krüppel-like Factor 5 is Important for Maintenance of Crypt Architecture and Barrier Function in Mouse Intestine 
Gastroenterology  2011;141(4):1302-1313.e6.
Background & Aims
Krüppel-like factor 5 (KLF5) is transcription factor that is expressed by dividing epithelial cells of the intestinal epithelium. KLF5 promotes proliferation in vitro and in vivo and is induced by mitogens and various stress stimuli. To study the role of KLF5 in intestinal epithelial homeostasis, we examined the phenotype of mice with conditional deletion of Klf5 in the gut.
Mice were generated with intestinal-specific deletion of Klf5 (Vil-Cre;Klf5fl/fl).
Morphological changes in the small intestine and colon were examined by immunohistochemistry, immunoblotting, and real-time PCR.
Klf5 mutant mice were born at a normal Mendelian ratio but had high mortality compared to controls. Complete deletion of Klf5 from the intestinal mucosa resulted in neonatal lethality that corresponded with an absence of epithelial proliferation. Variegated intestinal-specific deletion of Klf5 in adult mice resulted in morphological changes that included a regenerative phenotype, impaired barrier function, and inflammation. Adult mutant mice exhibited defects in epithelial differentiation and migration. These changes were associated with reduced expression of Cdx 1, Cdx2, and Eph and ephrin signaling proteins. Concomitantly, Wnt signaling to β-catenin was reduced. Proliferation in regenerative crypts was associated with increased expression of the progenitor cell marker Sox9.
Deletion of Klf5 in the gut epithelium of mice demonstrated that KLF5 maintains epithelial proliferation, differentiation, and cell positioning along the crypt radial axis. Morphological changes that occur with deletion of Klf5 are associated with disruption of canonical Wnt signaling and increased expression of Sox9.
PMCID: PMC3186863  PMID: 21763241
intestinal homeostasis; gastrointestinal development; genetics; GI tract
11.  Recommendations for fertility preservation in patients with lymphoma, leukemia, and breast cancer 
Fertility issues should be addressed to all patients in reproductive age before cancer treatment. In men, cryopreservation of sperm should be offered to all cancer patients in reproductive age regardless of the risk of gonadal failure. In women, the recommendation of fertility preservation should be individualized based on multiple factors such as the urgency of treatment, the age of the patient, the marital status, the regimen and dosage of cancer treatment.
PMCID: PMC3370045  PMID: 22648282
Fertility preservation; Cancer; Lymphoma; Leukemia; Breast cancer; Chemotherapy; Ovarian tissue cryopreservation; Oocyte cryopreservation; Primary ovarian insufficiency; Cancer survival; Gonadal failure; GnRH agonist; Fertility
12.  Krüppel-Like Factor 5 Protects Against Dextran Sulfate Sodium-Induced Colonic Injury by Promoting Epithelial Repair in Mice 
Gastroenterology  2010;140(2):540-549.e2.
Krüppel-like factor 5 (KLF5) is a transcription factor that promotes proliferation; is highly expressed in dividing crypt cells of the gastrointestinal epithelium and is induced by various stress stimuli. We sought to determine the role of KLF5 in colonic inflammation and recovery by studying mice with dextran sulfate sodium (DSS)-induced colitis.
Wild-type (WT) and Klf5+/− mice were given DSS in the drinking water to induce colitis. For recovery experiments, mice were given normal drinking water for 5 days after DSS administration. The extent of colitis was determined using established clinical and histological scoring systems. Immunohistochemical and immunoblotting analyses were used to examine proliferation, migration, and expression of the epidermal growth factor receptor (EGFR).
Klf5 expression was increased in colonic tissues of WT mice given DSS; induction of Klf5 was downstream of mitogen-activated protein kinase signaling. In DSS-induced colitis, Klf5+/− mice exhibited greater sensitivity to DSS than WT mice, with significantly higher clinical and histological colitis scores. In recovery experiments, Klf5+/− mice showed poor recovery, with continued weight loss and higher mortality than WT mice. Klf5+/− mice from the recovery period had reduced epithelial proliferation and cell migration at sites of ulceration compared to WT mice; these reductions correlated with reduced expression of EGFR.
Epithelial repair is an important aspect of recovery from DSS-induced colitis.
The transcription factor KLF5 regulates mucosal healing through its effects on epithelial proliferation and migration.
PMCID: PMC3031670  PMID: 21078320
inflammatory bowel disease; animal model; inflammatory response; mouse
14.  Polarization of Tumor-Associated Neutrophil (TAN) Phenotype by TGF-β: “N1” versus “N2” TAN 
Cancer cell  2009;16(3):183-194.
TGF-β blockade significantly slows tumor growth through many mechanisms, including activation of CD8+ T-cells and macrophages. Here, we show that TGF-β blockade also increases neutrophil-attracting chemokines resulting in an influx of CD11b+/Ly6G+ tumor-associated neutrophils (TAN) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of pro-inflammatory cytokines. Accordingly, following TGF-β blockade, depletion of these neutrophils significantly blunts anti-tumor effects of treatment and reduces CD8+ T-cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8+ T-cells intra-tumorally. Together, these data suggest that TGF-β within the tumor microenvironment induces a population of TAN with a pro-tumor phenotype. TGF-β blockade results in the recruitment and activation of TAN with an anti-tumor phenotype.
PMCID: PMC2754404  PMID: 19732719
tumor immunology; immunosuppression; TGFβ; tumor associated macrophages; Tumor associated neutrophils; lung cancer; mesothelioma
15.  HLA genotyping in the international Type 1 Diabetes Genetics Consortium 
Clinical Trials (London, England)  2010;7(1_supplement):S75-S87.
Background Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers.
Purpose In this article, we present the operational strategy of training, classification, reporting, and quality control of HLA genotyping in four laboratories on three continents over nearly 5 years.
Methods Methods to standardize HLA genotyping at eight loci included: central training and initial certification testing; the use of uniform reagents, protocols, instrumentation, and software versions; an automated data transfer; and the use of standardized nomenclature and allele databases. We implemented a rigorous and consistent quality control process, reinforced by repeated workshops, yearly meetings, and telephone conferences.
Results A total of 15,246 samples have been HLA genotyped at eight loci to four-digit resolution; an additional 6797 samples have been HLA genotyped at two loci. The genotyping repeat rate decreased significantly over time, with an estimated unresolved Mendelian inconsistency rate of 0.21%. Annual quality control exercises tested 2192 genotypes (4384 alleles) and achieved 99.82% intra-laboratory and 99.68% inter-laboratory concordances.
Limitations The chosen genotyping platform was unable to distinguish many allele combinations, which would require further multiple stepwise testing to resolve. For these combinations, a standard allele assignment was agreed upon, allowing further analysis if required.
Conclusions High-resolution HLA genotyping can be performed in multiple laboratories using standard equipment, reagents, protocols, software, and communication to produce consistent and reproducible data with minimal systematic error. Many of the strategies used in this study are generally applicable to other large multi-center studies.
PMCID: PMC2917849  PMID: 20595243
16.  Systemic Blockade of Transforming Growth Factor-β (TGF-β) Signaling Augments the Efficacy of Immunogene Therapy 
Cancer research  2008;68(24):10247-10256.
Locally-produced TGF-β promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This paper explores the potential for increased efficacy when combining immunotherapies with TGF-β suppression using the TGF-β type I receptor kinase inhibitor, SM16. Adenovirus expressing IFNβ (Ad.IFNβ) was injected intratumorally once in established subcutaneous AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a K-ras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing HPV-E7 (Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine-expression and cell populations were measured in tumors and spleens by real time-PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.INFβ increased the number of intratumoral leukocytes (including macrophages, NK cells, and CD8+ cells) and increased the percentage of T-cells expressing the activation marker CD25. SM16 also augmented the anti-tumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8+ T cells in the spleens, but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-β signaling pathway augments the anti-tumor effects of Ad.INFβ immune-activating or Ad.E7 vaccination therapy. The addition of TGF-β blocking agents in clinical trials of immunotherapies may increase efficacy.
PMCID: PMC2637471  PMID: 19074893
tumor immunology; immunosuppression; TGFβ; tumor associated macrophages; cytokines; lung cancer; mesothelioma; tumor vaccine; interferon-β
17.  Comparison of Maturation, Fertilization, Development, and Gene Expression of Mouse Oocytes Grown In Vitro and In Vivo 
Purpose: To investigate the difference of in vitro and in vivo grown oocytes, we compared maturation, fertilization, development, and maternal gene expression from both in vitro and in vivo grown mouse oocytes.
Methods: The preantral follicles isolated from 12-day-old mice were cultured on Transwell-COL membrane inserts. After culture, maturation, fertilization, and developmental rates were assessed. RT-PCR (reverse transcription—polymerase chain reaction) was performed to examine the expression of β-actin, GDF-9, and IGF-II in matured oocytes.
Results: No difference in the nuclear maturation was detected between in vitro and in vivo grown oocytes, but the mean oocyte diameter of the in vitro group was smaller than that of the in vivo group. The fertilization rate was significantly lower in the in vitro group than in the in vivo group (p < 0.05). The capacities of in vitro grown oocyte to cleave and develop to blastocysts were significantly lower than those of the in vivo grown oocytes (p < 0.001). Moreover, blastocyst of in vitro group had fewer total cells than those of in vivo group (p < 0.05). In regards to the expression of genes in mature oocytes, growth differentiation factor-9 (GDF-9) expression was similar between the two groups, but β-actin was significantly reduced in the in vitro group compared to the in vivo group. Particularly, the expression of insulin-like growth factor II (IGF-II) was not found in the in vitro grown oocytes.
Conclusions: These results showed that in vitro grown oocytes did not have the same developmental capacity as in vivo grown oocytes. We assume that the aberrant expression of maternal-derived genes in the in vitro grown oocytes may cause the poor embryo viability.
PMCID: PMC3455184  PMID: 15526980
Gene expression; in vitro; maturation; mouse; preantral follicle
18.  Nondestructive analysis of urinary calculi using micro computed tomography 
BMC Urology  2004;4:15.
Micro computed tomography (micro CT) has been shown to provide exceptionally high quality imaging of the fine structural detail within urinary calculi. We tested the idea that micro CT might also be used to identify the mineral composition of urinary stones non-destructively.
Micro CT x-ray attenuation values were measured for mineral that was positively identified by infrared microspectroscopy (FT-IR). To do this, human urinary stones were sectioned with a diamond wire saw. The cut surface was explored by FT-IR and regions of pure mineral were evaluated by micro CT to correlate x-ray attenuation values with mineral content. Additionally, intact stones were imaged with micro CT to visualize internal morphology and map the distribution of specific mineral components in 3-D.
Micro CT images taken just beneath the cut surface of urinary stones showed excellent resolution of structural detail that could be correlated with structure visible in the optical image mode of FT-IR. Regions of pure mineral were not difficult to find by FT-IR for most stones and such regions could be localized on micro CT images of the cut surface. This was not true, however, for two brushite stones tested; in these, brushite was closely intermixed with calcium oxalate. Micro CT x-ray attenuation values were collected for six minerals that could be found in regions that appeared to be pure, including uric acid (3515 – 4995 micro CT attenuation units, AU), struvite (7242 – 7969 AU), cystine (8619 – 9921 AU), calcium oxalate dihydrate (13815 – 15797 AU), calcium oxalate monohydrate (16297 – 18449 AU), and hydroxyapatite (21144 – 23121 AU). These AU values did not overlap. Analysis of intact stones showed excellent resolution of structural detail and could discriminate multiple mineral types within heterogeneous stones.
Micro CT gives excellent structural detail of urinary stones, and these results demonstrate the feasibility of identifying and localizing most of the common mineral types found in urinary calculi using laboratory CT.
PMCID: PMC544194  PMID: 15596006
19.  Holmium Laser Enucleation of the Prostate (HoLEP): A Technical Update 
Holmium laser enucleation of the prostate (HoLEP) combined with mechanical morcellation represents the latest refinement of holmium:YAG surgical treatment for benign prostatic hyperplasia (BPH). Utilizing this technique, even the largest of glands can be effectively treated with minimal morbidity. The learning curve remains an obstacle, preventing more widespread adoption of this procedure. This paper provides an outline of the HoLEP technique as is currently used at two centers in hopes of easing the initial learning curve.
Technical considerations
Detailed descriptions of the major steps of the HoLEP procedure are provided with attention to critical steps such as identification of the surgical capsule, median and lateral lobe enucleation, and morcellation of enucleated tissue.
HoLEP is a promising alternative for the surgical treatment of BPH which allows complete removal of intact lobes of the prostate. Obstruction is relieved immediately with superior hemostasis, no risk of TUR syndrome, and a minimal hospital stay.
PMCID: PMC165416  PMID: 12818001
Benign prostatic hyperplasia; Holmium; Lasers

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