The complex polyploid genome architecture of sugarcane.

Sugarcane, the world's most harvested crop by tonnage, has shaped global history, trade and geopolitics, and is currently responsible for 80% of sugar production worldwide1. While traditional sugarcane breeding methods have effectively generated cultivars adapted to new environments and pathogens, sugar yield improvements have recently plateaued2. The cessation of yield gains may be due to limited genetic diversity within breeding populations, long breeding cycles and the complexity of its genome, the latter preventing breeders from taking advantage of the recent explosion of whole-genome sequencing that has benefited many other crops. Thus, modern sugarcane hybrids are the last remaining major crop without a reference-quality genome. Here we take a major step towards advancing sugarcane biotechnology by generating a polyploid reference genome for R570, a typical modern cultivar derived from interspecific hybridization between the domesticated species (Saccharum officinarum) and the wild species (Saccharum spontaneum). In contrast to the existing single haplotype ('monoploid') representation of R570, our 8.7 billion base assembly contains a complete representation of unique DNA sequences across the approximately 12 chromosome copies in this polyploid genome. Using this highly contiguous genome assembly, we filled a previously unsized gap within an R570 physical genetic map to describe the likely causal genes underlying the single-copy Bru1 brown rust resistance locus. This polyploid genome assembly with fine-grain descriptions of genome architecture and molecular targets for biotechnology will help accelerate molecular and transgenic breeding and adaptation of sugarcane to future environmental conditions.

Combination of Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE) with sonographic and demographic characteristics in preoperative prediction of recurrence or progression of endometrial cancer.

OBJECTIVE: To evaluate the ability of demographic and sonographic variables and the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE) classification to predict preoperatively tumor recurrence or progression in women with endometrial cancer. METHODS: The study included 339 women with histologically confirmed endometrial cancer who underwent expert transvaginal ultrasound in a single center before surgery as part of the prospective International Endometrial Tumor Analysis 4 study or who were evaluated using the same protocol. The tumors were classified according to histotype, FIGO (International Federation of Gynecology and Obstetrics) grade and FIGO stage. In addition, molecular analysis was performed for classification into the four ProMisE subtypes: polymerase-ϵ exonuclease domain mutations (POLE EDM), mismatch repair proteins deficiency (MMR-D), protein 53 wild type (p53 wt) and protein 53 abnormal (p53 abn). Demographic and preoperative sonographic characteristics, tumor recurrence or progression and survival were compared between the ProMisE subgroups. Cox regression analysis was used to identify prognostic factors associated with recurrence or progression, using univariable models to study crude associations and multivariable models to study adjusted associations. Logistic regression and receiver-operating-characteristics (ROC)-curve analysis were used to assess the predictive ability of the preoperative prognostic factors regarding recurrence or progression of cancer within 3 years after surgery, and to compare their predictive ability to that of the European Society for Medical Oncology (ESMO) preoperative (based on depth of myometrial invasion, histotype and grade) and postoperative (based on histotype, grade, surgical stage and lymphovascular space invasion) risk classifications. In a separate subanalysis, cases were stratified according to ProMisE p53 abn status (present vs absent) and sonographic tumor size (anteroposterior (AP) diameter < 2 cm vs ≥ 2 cm). RESULTS: Median follow-up time from surgery was 58 months (interquartile range, 48-71 months; range, 0-102 months). Recurrence or progression of cancer occurred in 51/339 (15%) women, comprising 14% of those with MMR-D, 8% of those with POLE EDM, 9% of those with p53 wt and 45% of those with p53 abn ProMisE subtype. On multivariable analysis, age, waist circumference, ProMisE subtype and tumor extension and AP diameter on ultrasound were associated with tumor recurrence or progression. A multivariable model comprising ProMisE subtype, age, waist circumference and sonographic tumor extension and size (area under the ROC curve (AUC), 0.89 (95% CI, 0.85-0.93)) had comparable ability to predict tumor recurrence/progression to that of a multivariable model comprising histotype, grade, age, waist circumference and sonographic tumor extension and size (AUC, 0.88 (95% CI, 0.83-0.92)), and better predictive ability than both the preoperative (AUC, 0.74 (95% CI, 0.67-0.82); P < 0.01) and postoperative (AUC, 0.79 (95% CI, 0.72-0.86); P < 0.01) ESMO risk classifications. Women with a combination of non-p53 abn subtype and tumor size < 2 cm (164/339 (48%)) had a very low risk (1.8%) of tumor recurrence or progression. CONCLUSIONS: The combination of demographic characteristics, sonographic findings and ProMisE subtype had better preoperative predictive ability for tumor recurrence or progression than did the ESMO classification, supporting their use in the preoperative risk stratification of women with endometrial cancer. The combination of p53 status with ultrasound tumor size has the potential to identify preoperatively a large group of women with a very low risk of recurrence or progression. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. - Legal Statement: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Validation of ultrasound strategies to assess tumor extension and to predict high-risk endometrial cancer in women from the prospective IETA (International Endometrial Tumor Analysis)-4 cohort.

OBJECTIVES: To compare the performance of ultrasound measurements and subjective ultrasound assessment (SA) in detecting deep myometrial invasion (MI) and cervical stromal invasion (CSI) in women with endometrial cancer, overall and according to whether they had low- or high-grade disease separately, and to validate published measurement cut-offs and prediction models to identify MI, CSI and high-risk disease (Grade-3 endometrioid or non-endometrioid cancer and/or deep MI and/or CSI). METHODS: The study comprised 1538 patients with endometrial cancer from the International Endometrial Tumor Analysis (IETA)-4 prospective multicenter study, who underwent standardized expert transvaginal ultrasound examination. SA and ultrasound measurements were used to predict deep MI and CSI. We assessed the diagnostic accuracy of the tumor/uterine anteroposterior (AP) diameter ratio for detecting deep MI and that of the distance from the lower margin of the tumor to the outer cervical os (Dist-OCO) for detecting CSI. We also validated two two-step strategies for the prediction of high-risk cancer; in the first step, biopsy-confirmed Grade-3 endometrioid or mucinous or non-endometrioid cancers were classified as high-risk cancer, while the second step encompassed the application of a mathematical model to classify the remaining tumors. The 'subjective prediction model' included biopsy grade (Grade 1 vs Grade 2) and subjective assessment of deep MI or CSI (presence or absence) as variables, while the 'objective prediction model' included biopsy grade (Grade 1 vs Grade 2) and minimal tumor-free margin. The predictive performance of the two two-step strategies was compared with that of simply classifying patients as high risk if either deep MI or CSI was suspected based on SA or if biopsy showed Grade-3 endometrioid or mucinous or non-endometrioid histotype (i.e. combining SA with biopsy grade). Histological assessment from hysterectomy was considered the reference standard. RESULTS: In 1275 patients with measurable lesions, the sensitivity and specificity of SA for detecting deep MI was 70% and 80%, respectively, in patients with a Grade-1 or -2 endometrioid or mucinous tumor vs 76% and 64% in patients with a Grade-3 endometrioid or mucinous or a non-endometrioid tumor. The corresponding values for the detection of CSI were 51% and 94% vs 50% and 91%. Tumor AP diameter and tumor/uterine AP diameter ratio showed the best performance for predicting deep MI (area under the receiver-operating characteristics curve (AUC) of 0.76 and 0.77, respectively), and Dist-OCO had the best performance for predicting CSI (AUC, 0.72). The proportion of patients classified correctly as having high-risk cancer was 80% when simply combining SA with biopsy grade vs 80% and 74% when using the subjective and objective two-step strategies, respectively. The subjective and objective models had an AUC of 0.76 and 0.75, respectively, when applied to Grade-1 and -2 endometrioid tumors. CONCLUSIONS: In the hands of experienced ultrasound examiners, SA was superior to ultrasound measurements for the prediction of deep MI and CSI of endometrial cancer, especially in patients with a Grade-1 or -2 tumor. The mathematical models for the prediction of high-risk cancer performed as expected. The best strategies for predicting high-risk endometrial cancer were combining SA with biopsy grade and the subjective two-step strategy, both having an accuracy of 80%. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Ultrasound characteristics of endometrial cancer as defined by International Endometrial Tumor Analysis (IETA) consensus nomenclature: prospective multicenter study.

OBJECTIVE: To describe the sonographic features of endometrial cancer in relation to tumor stage, grade and histological type, using the International Endometrial Tumor Analysis (IETA) terminology. METHODS: This was a prospective multicenter study of 1714 women with biopsy-confirmed endometrial cancer undergoing standardized transvaginal grayscale and Doppler ultrasound examination according to the IETA study protocol, by experienced ultrasound examiners using high-end ultrasound equipment. Clinical and sonographic data were entered into a web-based database. We assessed how strongly sonographic characteristics, according to IETA, were associated with outcome at hysterectomy, i.e. tumor stage, grade and histological type, using univariable logistic regression and the c-statistic. RESULTS: In total, 1538 women were included in the final analysis. Median age was 65 (range, 27-98) years, median body mass index was 28.4 (range 16-67) kg/m2 , 1377 (89.5%) women were postmenopausal and 1296 (84.3%) reported abnormal vaginal bleeding. Grayscale and color Doppler features varied according to grade and stage of tumor. High-risk tumors, compared with low-risk tumors, were less likely to have regular endometrial-myometrial junction (difference of -23%; 95% CI, -27 to -18%), were larger (mean endometrial thickness; difference of +9%; 95% CI, +8 to +11%), and were more likely to have non-uniform echogenicity (difference of +7%; 95% CI, +1 to +13%), a multiple, multifocal vessel pattern (difference of +21%; 95% CI, +16 to +26%) and a moderate or high color score (difference of +22%; 95% CI, +18 to +27%). CONCLUSION: Grayscale and color Doppler sonographic features are associated with grade and stage of tumor, and differ between high- and low-risk endometrial cancer. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Endometrial intraepithelial neoplasia is associated with polyps and frequently has metaplastic change.

AIMS: Endometrial intraepithelial neoplasia (EIN) is a monoclonal precursor to endometrioid endometrial adenocarcinoma characterized by a geographic cluster of crowded glands with epithelial cytology altered relative to the background. It may demonstrate epithelial metaplastic changes, or arise within polyps, but the frequencies of these features as encountered in practice is unknown. The aim was to report the epithelial differentiation state and polyp context of 83 sequential EIN lesions diagnosed over a 2-year period. METHODS AND RESULTS: EIN is a rare lesion, seen in only 1.4% of endometrial biopsy specimens in a busy hospital-based practice. Of 83 EIN cases, 39 contained metaplastic changes (18% squamous morular, 14% tubal secretory and 5% each of secretory, mucinous or ciliated change). Endometrial polyps were more likely (odds ratio 5.2, P < 0.001) to occur in the endometrial biopsy specimens of women with EIN lesions (43.3%), compared with the background polyp rate (12.9%) of comparable specimens from the same patient population. CONCLUSIONS: Non-endometrioid differentiation and occurrence within polyps are frequent presentations of EIN lesions. Possible mechanisms of polyp association with EIN include: non-shedding of polyp tissue creating a shelter for persistence of pre-existing neoplastic glands, or promotion of premalignant glandular clones by unique polyp stroma.

Abnormal fragile histidine triad (FHIT) expression in advanced cervical carcinoma: a poor prognostic factor.

The FHIT gene is a candidate tumor suppressor gene that has been implicated in the development of cervical carcinoma. We hypothesized that abnormal Fhit expression might be a poor prognostic factor for patients with cervical cancer. The tumors from 59 high-risk patients (stage II-III) were evaluated for abnormal Fhit expression by immunohistochemical staining. Abnormal Fhit expression (absent or reduced) was noted in 66% of the specimens. There was no statistical difference with respect to stage, performance status, para-aortic node metastasis, completion of therapy, grade, race, age, and HIV status between the normal and abnormal Fhit expression groups. The 3-year survival for patients whose tumors displayed normal Fhit expression versus abnormal Fhit expression was 74% versus 37%, respectively. Univariate analysis demonstrated a difference in survival that was statistically significant for age <55 years versus > or =55 years (P = 0.015), normal Fhit expression versus abnormal Fhit expression (P = 0.015), and stage II versus stage III (P = 0.033). Multivariate analysis showed that abnormal Fhit expression was a poor prognostic factor (P = 0.015).

Radical vulvectomy with postoperative irradiation for vulvar cancer: therapeutic implications of a central block.

PURPOSE/OBJECTIVE: To report the long-term results of vulvectomy, node dissection, and postoperative nodal irradiation using a midline vulvar block in patients with node positive vulvar cancer. METHODS AND MATERIALS: From 1971 through 1992, 27 patients with carcinoma of the vulva and histologically involved inguinal lymph nodes were treated postoperatively with radiation therapy after radical vulvectomy and bilateral lymphadenectomy (n = 25), radical vulvectomy and unilateral lymphadenectomy (n = 1), or hemivulvectomy and bilateral lymphadenectomy (n = 1). Federation Internationale de Gynecologic et d'Obstetrique stages were III (n = 14), IVA (n = 8), and IVB (n = 5) squamous cell carcinoma. Inguinal lymph nodes were involved with tumor in all patients (average number positive = 4, range 1-15). Postoperative irradiation was directed at the bilateral groin and pelvic nodes (n = 19), unilateral groin and pelvic nodes (n = 6), or unilateral groin only (n = 1). These 26 patients had the midline blocked. In addition, one patient received irradiation to the entire pelvis and perineum. Doses ranged from 10.8 to 50.7 Gy (median 45.5) with all patients except 1 receiving > or = 42.0 Gy. RESULTS: Actuarial 5-year overall survival and disease-free survival estimates were 40% and 35%, respectively. Recurrences developed in 63% (17/27) of the patients at a median of 9 months from surgery (range 3 months to 6 years) and 15 of these have died; two patients with recurrences are surviving at 24 and 96 months after further surgery and radiation therapy. Central recurrences (under the midline block) were present in 13 of these 17 patients (76%), either as central only (n = 8), central and regional (n = 4), or central and distant (n = 1). Additionally, three patients developed regional recurrences and one patient developed a concurrent regional and distant relapse. One patient developed a squamous cell cancer of the anus under the midline block 54 months after the initial vulvar cancer and an additional patient developed transitional cell carcinoma of the ureter (outside the radiation field) 12 months after diagnosis. Factors associated with a decreased relapse-free survival included increasing Federation Internationale de Gynecologic et d'Obstetrique stage (p = 0.01) and invasion of the tumor into the subcutaneous (SC) fat or deep soft tissue (p = 0.05). Chronic lower extremity edema developed in four patients, but there have been no other complications. CONCLUSIONS: Radical vulvectomy has often been considered sufficient central treatment for vulvar carcinoma, with postoperative irradiation directed only to the nodes. Although designed to protect the radiosensitive vulva, use of a midline block in this series resulted in a 48% (13/27) central recurrence rate, much higher than the 8.5% rate previously reported with this technique. Routine use of the midline block should be abandoned and, instead, postoperative irradiation volumes should be tailored to the individual patient.

Nonlinear phase adjustment of selective excitation pulses.

A continuous transformation of an RF waveform with a modified Korteweg-de Vries equation or generalization can be used to adjust the phase behavior of a selective excitation pulse while preserving the magnitude behavior of the spin response. This transformation has applications in removing or adding to the nonlinear phase properties of a selected region.

Oncogenes in gynecologic oncology.

Advances in molecular biology have facilitated the recent investigation of gynecological malignancies. The presence of certain oncogenes within gynecological tumors indicates that transformation may be associated with genetic alteration of normal regulatory processes. This paper reviews several oncogenes that have been implicated in the transformation of gynecological tissues.

Cervical adenocarcinoma in situ: a systematic review of therapeutic options and predictors of persistent or recurrent disease.

The incidence of cervical adenocarcinoma in situ is increasing in frequency, and our limited knowledge about this lesion presents the physician with a therapeutic dilemma. Treatment for this lesion has included conservative therapy, large loop excision or cold-knife cone biopsy, or definitive therapy consisting of hysterectomy. But, rates of residual adenocarcinoma in situ after cone biopsy with negative margins vary from 0% to 40%, and residual disease rates as high as 80% have been noted when the margins are positive. Despite these recent data on follow-up after conservative therapy such as cone biopsy, it seems that this method is safe and gaining acceptance by many physicians and patients. However, the short follow-up duration and small number of patients limit the conclusions of many studies. The relative infrequency of this diagnosis has precluded extensive clinical experience with the natural history of this lesion.

Prediction of malignancy using transvaginal color flow Doppler in patients with gynecologic tumors.

Eighty-five patients referred to the Women's Cancer Center, University of Minnesota had transvaginal color flow Doppler performed to determine if pelvic malignancy could be predicted by blood flow assessment. Their mean age was 49 years (range 21-86 years). Thirty-five patients were subsequently found to have malignant tumors of the cervix, uterus or ovary. The presence of increased intratumoral blood flow as depicted by color flow Doppler had a sensitivity of 83%, specificity of 100%, positive predictive value (PPV) of 100% and negative predictive value (NPV) of 89% for malignancy. The mean intratumoral Pulsatility Index (PI) of the patients with malignant tumors was 0.81 (SD 0.24; range 0.3-1.2), which was significantly lower than for the benign group (P = 0.001). A PI of

Management of osteogenesis imperfecta in pregnancy. A case report.

Osteogenesis imperfecta (OI) is a metabolic disorder of connective tissue; it is typically characterized by blue sclera, bone fragility and deformity secondary to repetitive fractures. The severity of the disease in the infant cannot be predicted by the phenotypic presentation of the mother. We present a case report and review literature and discuss the prenatal diagnosis, evaluation criteria and guidelines for delivery.

Laser ablation of squamous cell carcinoma in situ of the anal canal. A case report.

A case of squamous cell carcinoma in situ of the anal canal was discovered incidentally during a hemorrhoidectomy in a man. The anal canal was evaluated by colposcopy prior to ablation of the lesion with a CO2 laser. To our knowledge, this technique has not been reported previously.

An analysis of drug abuse policies in teaching hospitals.

The Drug-Free Workplace Act of 1988 mandated written drug abuse policies for recipients of certain government grants and contracts. The literature has reported costly side effects of employee drug abuse such as decreased productivity and increased use of health benefits. Furthermore, litigation involving drug abuse policies has been increasingly won by employers. More than 90% of Fortune 1000 companies have adopted formal drug abuse policies. Using content analysis techniques, the current study examined the written substance abuse policies of 30 large American teaching hospitals. Results showed substantial variation in the style and content of the policies. In general, language used in the policies was vague. The study cites the potential use of strategic ambiguity in the development of the policies.

Managed care, cost-effectiveness, and rehabilitation: the case of HIV.

Because of its cost-effective approach to impairment and disability, rehabilitation therapy is uniquely positioned to assume a significant role in today's healthcare environment. As the cost of health care has become a major concern, both the government and the private insurance industry have turned toward rehabilitation services as resources for preventing more costly use of the healthcare system in the future. Although funding in the area of injury research scarce, funding for demonstrating the success of therapies for chronic illness such as HIV is more plentiful. In the case of HIV, rehabilitation nursing techniques and principles can be used as a model for reducing the substantial social costs of the disease. Specifically, rehabilitation nurses can assume a leadership role as service coordinators for HIV-positive patients. If rehabilitation nurses perform this role effectively and participate fully in research efforts aimed at measuring the success of rehabilitation therapy, their efforts have the potential of permanently raising the status of the rehabilitation nursing specialty.

Immunohistochemistry for beta-catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature.

AIMS: Nuclear staining for beta-catenin by immunohistochemistry is being used increasingly to diagnose desmoid tumours (deep fibromatoses), especially where the differential diagnosis includes other abdominal spindle cell neoplasms. This study aimed to define the prevalence of beta-catenin positivity in desmoid tumours and other morphologically similar spindle cell neoplasms. METHOD AND RESULTS: Nuclear beta-catenin expression was evaluated by immunohistochemistry in 270 soft tissue tumours. Nuclear immunopositivity was detected in 80% of cases of sporadic desmoid fibromatosis (24/30) and in 67% of tumours in patients with familial adenomatous polyposis (8/12). Nuclear positivity was also present in 14/25 superficial fibromatoses (56%), 3/10 low-grade myofibroblastic sarcomas (30%), 5/23 solitary fibrous tumours (22%), 1/5 infantile fibrosarcomas (20%), 1/18 desmoplastic fibroblastomas (6%) and 1/21 gastrointestinal stromal tumours (5%). No nuclear immunoreactivity was present in neurofibromas (0/26), schwannomas (0/25), nodular fasciitis (0/19), leiomyosarcomas (0/16), inflammatory myofibroblastic tumours (0/12), fibromas of tendon sheath (0/9), lipofibromatoses (0/5), Gardner fibromas (0/4), calcifying aponeurotic fibromas (0/4) or fibromatosis colli (0/1). CONCLUSION: Nuclear staining for beta-catenin is supportive, but not definitive, of the diagnosis of desmoid fibromatosis. No significant difference in immunoreactivity was observed between sporadic and familial desmoid fibromatoses. beta-Catenin negativity does not preclude the diagnosis of fibromatosis.

Biomarker-assisted diagnosis of ovarian, cervical and pulmonary small cell carcinomas: the role of TTF-1, WT-1 and HPV analysis.

AIMS: Small cell carcinoma of the ovary, hypercalcaemic-type (SCCOH) is morphologically similar to small cell carcinomas from other sites. The aims of this study were to (i) determine if a biomarker panel would distinguish small cell carcinomas of the ovary, cervix (SCCCx) and lung (SCCLu) and (ii) potentially determine the histogenesis of SCCOH. METHODS AND RESULTS: Nine ovarian small cell carcinomas (seven hypercalcaemic type; two pulmonary type), eight SCCCx and 22 SCCLu were immunostained for thyroid transcription factor (TTF)-1, WT-1, p16, cKIT and OCT3/4; a subset of cases were tested for human papillomavirus (HPV). WT-1 was diffusely positive in 6/7 SSCOH versus two of 33 other small cell carcinomas (P

Currents and fields of thin conductors in rf saddle coils.

The current distribution on thin conductors and rf field homogeneity for rf coils is described theoretically. After a pedagogical introduction to the techniques and an exact solution for the current or an isolated strip conductor, this article describes current distribution and field uniformity for a variety of conventional and quadrature rf coil designs.

Donum Vitae on homologous interventions: is IVF-ET a less acceptable gift than "GIFT"?

Donum Vitae argues that, by failing to respect the connection between the conjugal act and procreation, in vitro fertilization-even in the homologous or "simple case", where both gametes come from a married couple and the resulting embryo is transferred to the wife-shows itself to be morally unacceptable. On the other hand, the document refers approvingly to other technological interventions which "facilitate" or "assist" the conjugal act in achieving its objective. Although none of the latter interventions are mentioned by name, the recently developed gamete intrafallopian transfer (GIFT) and certain associated techniques have found favor with many orthodox Roman Catholic thinkers, as well with some church authorities. The present article explores this situation in the Catholic moral tradition, and offers reasons for believing that, given relevantly similar conditions, if GIFT is morally acceptable so also is homologous IVF-ET.