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BACKGROUND: Neoadjuvant Endocrine Therapy (NET) is seldom used in breast cancer management except in patients with several comorbidities or in elderly patients in which chemotherapy is not an option. Clinical response with NET is not typically achieved until after several months of treatment. In the NET setting, reduction of Ki67 (< 10%) after 2-4 weeks has been used as a predictor of positive response, but studies such as ALTERNATE have questioned this association. It remains uncertain whether a single gene or protein can adequately predict outcomes or inform how NET alters a variety of cancer genes and global tumor biology. This study evaluated the effect of short-term NET on the tumor genomics of patients with early-stage breast cancer (EBC) by comparing whole transcriptome gene expression changes in matched pre- and post-NET tumor samples. METHODS: In this single-institution FLEX substudy performed at Johns Hopkins, patients (n=30) with matched pre- and post-treatment specimens who received at least two weeks of NET between 2019 – 2021 were included. Premenopausal and male patients with breast cancer received Tamoxifen (n=10) and postmenopausal women received either Letrozole (n=10) or Exemestane (n=10). Limma R package was used for quantile normalization and differential gene expression analysis. Significant differentially expressed genes (DEGs) had a false discovery rate of < 0.05 and >2-fold change. Pathway enrichment analysis was performed using Reactome. For patients with available clinical information, changes in immunohistochemistry (IHC) between pre- and post-NET were quantified using absolute values, and the median percent change was reported, with significance assessed using the Wilcoxon test. The observational FLEX trial (NCT03053193) enrolls patients with EBC who have MammaPrint (MP) with or without BluePrint testing and consent to clinically annotated full transcriptome data collection. MammaPrint classifies tumors as having a Low Risk (LR) or High Risk (HR) of distant recurrence. BluePrint is a molecular subtyping assay, and together with MammaPrint, tumors are classified as Luminal A-Type (MP LR), Luminal B-Type (MP HR), HER2-Type, or Basal-Type. RESULTS: Transcriptional profiles between pre- and post-NET samples were distinct with short-term NET inducing 774 DEGs. The majority of significant DEGs (n=748) such as MGAT1, IQGAP3, and PRC1, which are associated with tumor aggressiveness and metastasis, were downregulated in post-NET samples. Upregulated genes in post-NET tumors, such as FOS, JUN, and EGR1, are involved in estrogen signaling and NF-κB pathways and are associated with better outcomes. Among the 30 patients, 7 (6 Luminal B and 1 Basal) remained MP HR and 16 remained MP LR (Luminal A) pre- and post-NET, 1 changed from LR (Luminal A) pre-NET to HR (Luminal B) post-NET, and 6 changed from HR (Luminal B) pre-NET to LR post-NET (Luminal A). The median percent change by IHC in matched pre- and post-NET tissue was 2.5% for estrogen receptor (ER) (range: 0-50%; p=0.750), 22% for progesterone receptor (PR) (range: 0-81%; p=0.097), and 9% for Ki67 (range: 0-43%; p=0.026). CONCLUSIONS: In this study, significant gene expression changes were discovered within a shorter timeframe than when clinical responses are usually observed in the NET setting. This could indicate biological complexity and diverse response pathways, which may be more informative when combined with a single IHC biomarker (ER/PR/Ki67). Results from this study should be confirmed using a larger cohort. Future studies will determine the significance of these DEGs and their impact on outcomes, and will further define gene expression changes by endocrine therapy type (tamoxifen versus aromatase inhibitors). ACKNOWLEDGMENTS: We would like to thank Lynn and Robert Downing for their generous support of our study. Citation Format: Mehran Habibi, Danijela Jelovac, Rima Couzi, Cesar Augusto Santa-Maria, Catherine Klein, Marissa White, Nivali Naik, Jennifer Wei, Yen Huynh, Architha Ellappalayam, Lisa E. Blumencranz, Erin B. Yoder, Patricia Dauer, Bas van der Baan, William Audeh. Impact of neoadjuvant endocrine therapy on tumor transcriptome in patients with early-stage breast cancer from the FLEX trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-02.

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Purpose: Recent work points out a role of B7H3, a member of the B7-family of costimulatory proteins, in conveying immunosuppression and enforced invasiveness in a variety of tumor entities. Glioblastoma is armed with effective immunosuppressive properties resulting in an impaired recognition and ineffective attack of tumor cells by the immune system. In addition, extensive and diffuse invasion of tumor cells into the surrounding brain tissue limits the efficacy of local therapies. Here, 4IgB7H3 is assessed as diagnostic and therapeutic target for glioblastoma.Experimental Design: To characterize B7H3 in glioblastoma, we conduct analyses not only in glioma cell lines and glioma-initiating cells but also in human glioma tissue specimens.Results: B7H3 expression by tumor and endothelial cells correlates with the grade of malignancy in gliomas and with poor survival. Both soluble 4IgB7H3 in the supernatant of glioma cells and cell-bound 4IgB7H3 are functional and suppress natural killer cell–mediated tumor cell lysis. Gene silencing showed that membrane and soluble 4IgB7H3 convey a proinvasive phenotype in glioma cells and glioma-initiating cells in vitro. These proinvasive and immunosuppressive properties were confirmed in vivo by xenografted 4IgB7H3 gene silenced glioma-initiating cells, which invaded significantly less into the surrounding brain tissue in an orthotopic model and by subcutaneously injected LN-229 cells, which were more susceptible to natural killer cell–mediated cytotoxicity than unsilenced control cells.Conclusions: Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma. Clin Cancer Res; 18(1); 105–17. ©2011 AACR.

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The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

A delay in breast cancer treatment is associated with inferior survival outcomes; however, no clear guidelines exist defining the appropriate time frame from diagnosis to definitive treatment of breast cancer. A multidisciplinary approach for breast cancer treatment can minimize the time from diagnosis to first treatment. We hypothesized single-day multidisciplinary clinic (MDC) may accelerate the time to first treatment on complex breast cancer cases at our institution. We identified patients who were treated at Johns Hopkins for stage II or III breast cancer, who were at least 18 years of age, and were seen in a new single-day MDC with coordination between two or three specialties or by specialists from varying disciplines on different days (IDC). Patients who initiated treatment between May 2015 (initiation of MDC clinic) and December 2017 were included in our study. A total of 296 patient records were reviewed independently. The mean (SD) patient age was 55 (13) years. The median time to first neoadjuvant chemotherapy (NACT) was significantly reduced for patients seen in the MDC (12.7 days), compared to those seen at the IDC (24.4 days, logrank p

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

RESUMEN: Introduccion: La valoracion particular de sitios severamente comprometidos, involucra considerar los tiempos necesarios de cicatrizacion, asi como evidencia actual en terminos de biomateriales y tecnicas quirurgicas con el fin de lograr un tratamiento exitoso. Material y metodo: Paciente sexo femenino, 28 anos, asiste por dolor e infeccion en diente 2.1 al Postitulo de Periodoncia UDD. Se observa defecto extenso y lesion que compromete tanto las tablas oseas vestibular como palatina. El tratamiento consistio en: exodoncia y regeneracion osea, instalacion del implante 6 meses despues de la exodoncia y cirugia de conexion 7 meses despues mas injerto de tejidos blandos. Resultados: El tratamiento de defectos combinados (tejidos duros y blandos), asociados a procesos infecciosos de larga data, mediante rehabilitacion implanto soportada puede ser muy predecible y exitoso en la medida que se respeten los tiempos de regeneracion de diferentes estructuras.

We report the case of letrozole-induced radiation recall dermatitis (RRD) in a patient with a remote history of radiation therapy. There is only one previously known case of RRD triggered by letrozole in a patient with a recent (

Objective To determine if a standardized intervention process for Category II fetal heart rates (FHRs) with significant decels (SigDecels) would improve neonatal outcome and to determine the impact on mode of delivery rates. Study Design Patients with Category II FHRs from six hospitals were prospectively managed using a standardized approach based on the presence of recurrent SigDecels. Maternal and neonatal outcomes were compared between pre- (6 months) and post-(11 months) implementation. Neonatal outcomes were: 5-minute APGAR scores of Results Post implementation there were 8,515 eligible deliveries, 3,799 (44.6%) were screened, and 361 (9.5%) met criteria for recurrent SigDecels. Compliance with the algorithm was 97.8%. The algorithm recommended delivery in 68.0% of cases. Relative to pre-implementation, 5-minute APGAR score of Conclusion Standardized management of recurrent SigDecels reduced the rate of 5-minute APGAR scores of

BAP GEAPSI; International audience; Small non-coding RNAs are versatile riboregulators that control gene expression at the transcriptional or post-transcriptional level, governing many facets of plant development. Here we present evidence for the existence of a 24 nt small RNA (named small1) that is complementary to the 3' UTR of OCL1 (Outer Cell Layer1), the founding member of the maize HD-ZIP IV gene family encoding plant-specific transcription factors that are mainly involved in epidermis differentiation and specialization. The biogenesis of small1 depends on DICER-like 3 (DCL3), RNA-dependent RNA polymerase 2 (RDR2) and RNA polymerase IV, components that are usually required for RNA-dependent DNA-methylation. Unexpectedly, GFP sensor experiments in transient and stable transformation systems revealed that small1 may regulate its target at the post-transcriptional level, mainly through translational repression. This translational repression is attenuated in an rdr2 mutant background in which small1 does not accumulate. Our experiments further showed the possible involvement of a secondary stem-loop structure present in the 3' UTR of OCL1 for efficient target repression, suggesting the existence of several regulatory mechanisms affecting OCL1 mRNA stability and translation.

Summary Once-weekly administration of bortezomib has reduced bortezomib-induced peripheral neuropathy without affecting response rates, but this has only been demonstrated prospectively in three- and four- drug combinations. We report a phase II trial of alternate dosing and schedule of bortezomib and dexamethasone in newly diagnosed multiple myeloma patients who are not eligible for or refused autologous stem cell transplantation. Bortezomib 1·6 mg/m2 intravenously was given once-weekly for six cycles, together with dexamethasone 40 mg on the day of and day after bortezomib. Fifty patients were enrolled; 58% did not require any dose modification. The majority of patients had multiple co-morbidities, including cardiovascular (76%) and renal insufficiency (54%), and the median number of medications prior to enrollment was 13. Of all evaluable patients, the overall response rate was 79% and at least 45% had at least a very good partial response. The median time to first response was 1·3 months (range, 0·25–2·4 months). The progression-free and overall survivals were 8 months and 46·5 months, respectively. Twenty-four percent developed worsening neuropathy. We conclude that alternate dosing and scheduling of bortezomib and dexamethasone is both safe and effective for management of newly diagnosed multiple myeloma in frail patients. (ClinicalTrials.gov number, NCT01090921).

The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling for hereditary cancer syndromes and risk management recommendations for patients who are diagnosed with a syndrome. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer. The NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. The NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding risk management for carriers of moderately penetrant genetic mutations associated with breast and/or ovarian cancer.

During the past few years, several genetic aberrations that may contribute to increased risks for development of breast and/or ovarian cancers have been identified. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian focus specifically on the assessment of genetic mutations in BRCA1/BRCA2, TP53, and PTEN, and recommend approaches to genetic testing/counseling and management strategies in individuals with these mutations. This portion of the NCCN Guidelines includes recommendations regarding diagnostic criteria and management of patients with Cowden Syndrome/PTEN hamartoma tumor syndrome.

Background: Although cancer outcomes have improved in recent decades, substantial disparities by race, ethnicity, income, and education persist. Increasingly, patient navigation services are demonstrating success in improving cancer detection, treatment, and care and in reducing cancer health disparities. To advance progress in developing patient navigation programs, extensive descriptions of each component of the program must be made available to researchers and health service providers. Objective: We sought to describe the components of a patient navigation program designed to improve cancer screening based on informed decision making on cancer screening and cancer treatment services among predominantly Black older adults in Baltimore City. Methods: A community-academic participatory approach was used to develop a patient navigation program in Baltimore, Maryland. The components of the patient navigation system included the development of a community academic (advisory) committee (CAC); recruitment and selection of community health workers (CHWs)/navigators and supervisory staff, initial training and continuing education of the CHWs/navigators, and evaluation of CHWs/navigators. The study was approved by the Johns Hopkins Bloomberg School of Public Health Institutional Review Board. Conclusions: The incorporation of community-based participatory research principles into each facet of this patient navigation program facilitated the attainment of the intervention's objectives. This patient navigation program successfully delivered cancer navigation services to 1,302 urban Black older adults. Appropriately recruited, selected and trained CHWs monitored by an experienced supervisor and investigators are the key elements in a patient navigation program. This model has the potential to be adapted by research and health service providers.

Hypertensive disorders of pregnancy result in significant maternal morbidity and mortality. State and national guidelines have been proposed to increase treatment of patients with hypertensive emergencies or critically elevated blood pressures. There are limited data available to assess the impact of these recommendations on maternal morbidity.The purpose of this prospective quality improvement project was to determine if maternal morbidity would be improved using a standardized approach for treatment of critically elevated blood pressures.In all, 23 hospitals participated in this project. Treatment recommendations included the use of an intravenous blood pressure medication and magnesium sulfate when there was a sustained blood pressure of ≥160 mm Hg systolic and/or ≥110 mm Hg diastolic. Compliance with the metric recommendations was monitored based on the number of patients treated with an intravenous blood pressure medication, use of magnesium sulfate, and if they received a timely postpartum follow-up appointment. The metric was scored as all or none; missing any of the 3 metric components was considered noncompliant. From January through June 2015 baseline data were collected and hospitals were made aware that ongoing monitoring of compliance would begin in July 2015 through June 2016. The primary outcomes were composite metric compliance, the incidence of eclampsia per 1000 births, and severe maternal morbidity.During the 18 months of this study there were 69,449 births. Within this population, 2034 met criteria for a critically elevated blood pressure, preeclampsia, or superimposed preeclampsia with severe features. Of this group, 1520 had a sustained critical blood elevation. Initial compliance with treatment recommendations was low (50.5%) and increased to90% after April 2016 (P.001). Compliance with utilization of intravenous blood pressure medication increased by 33.2%, from a baseline of 57.1-90.3% (P.01) during the last 6 months of monitoring. Compliance with utilization of magnesium sulfate increased by 10.8%, from a baseline of 85.4-96.2% (P.01). The incidence of eclampsia declined by 42.6% (1.15 ± 0.15/1000 to 0.62 ± 0.09/1000 births). Severe maternal morbidity decreased by 16.7% from 2.4 ± 0.10% to 2.0 ± 0.15% (P.01).We noted 3 important findings: (1) compliance with state and national treatment guidelines is low without monitoring; (2) high levels of compliance can be achieved in a relatively short period of time; and (3) early intervention with intravenous blood pressure medication and magnesium sulfate for verified sustained critical maternal blood pressures resulted in a significant reduction in the rate of eclampsia and severe maternal morbidity. The reduction in the rate of eclampsia could only partially be attributed to the increase in the use of magnesium sulfate, suggesting an additive or synergistic effect of the combined treatment of an antihypertensive medication and magnesium sulfate on the rate of eclampsia and severe maternal morbidity.

Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma-initiating cells have been proposed to be more resistant to radiochemotherapy and responsible for recurrence. Here, established stem cell markers and stem cell attributed characteristics such as self-renewal capacity and tumorigenicity have been profiled in primary glioblastoma cultures to predict radiosensitivity. Furthermore, the sensitivity to radiotherapy of different subpopulations within a single primary glioblastoma culture was analyzed by a flow cytometric approach using Nestin, SRY (sex-determining region Y)-box 2 (SOX2) and glial fibrillary acidic protein. The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1 cell adhesion molecule, CD133, Nestin, and pleiomorphic adenoma gene-like 2 inversely correlated with radioresistance in regard to the clonogenic potential. Only CD44 protein expression correlated positively with radioresistance. In terms of proliferation, Nestin protein expression and Musashi1, pleiomorphic adenoma gene-like 2, and CD133 mRNA levels are inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in the cancer genome atlas glioblastoma collective. SOX2 expressing subpopulations exist within single primary glioblastoma cultures. These subpopulations predominantly form the proliferative pool of the primary cultures and are sensitive to irradiation. Thus, profiling of established stem cell markers revealed a surprising result. Except CD44, the tested stem cell markers showed an inverse correlation between expression and radioresistance. Markers used to define glioma-initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or - resistance, but a SOX-2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity.

Wood-pastures are among the oldest land-use types in Europe and have high ecological and cultural importance. They are under rapid decline all over Europe because of changes in land use, tree cutting, and lack of regeneration. In this study we characterized the structure, condition and threats of wood-pastures in a traditional rural region in Romania. Forty-two wood-pastures were surveyed, as well as 15 forest sites for comparison. All wood-pasture sites were described via four groups of variables: condition, management, site, and landscape context. Forest sites were dominated by Hornbeam ( Carpinus betulus ) and Beech ( Fagus sylvatica ), whereas wood-pastures were dominated by Oak ( Quercus sp.) and various species of fruit trees. Most wood-pastures contained trees classified as ‘ancient’ but no such trees were found in forests. The proportion of dead trees was positively related to forest cover within 300 m around the wood-pasture. Models that included management, site and landscape-related variables best explained the prelevance of Oak, Beech, Hornbeam and Pear trees in wood-pastures. Large oaks and hornbeams were more likely to be dead or affected by uncontrolled pasture burning than small oaks and other tree species. Our results show that ancient wood-pastures are common in this rural region, and they may be more common in Eastern Europe than previously thought. There is an urgent need for research, legal recognition and conservation management of wood-pastures as distinct landscape elements for their cultural, ecological and agricultural importance.

To determine if ciprofloxacin therapy alters the response to warfarin treatment, 36 adult patients attending three university-affiliated outpatient anticoagulation clinics randomly received a 12-day course of ciprofloxacin (750 mg twice daily) and a 12-day course of placebo; each course was separated by a 2-week washout period. Prothrombin times (PTs), concentrations of S-warfarin and R-warfarin (the isomers of warfarin), and concentrations of clotting factors II and VII were determined three times weekly for 9 weeks. By day 12 of ciprofloxacin therapy, concentrations of S-warfarin remained unchanged compared with those after placebo therapy, but R-warfarin concentrations increased significantly (1.15 times those after placebo therapy; P = .001); concentrations of clotting factors II and VII decreased (0.903 and 0.872 times those after placebo therapy, respectively, P < or = .020). The mean PT ratio after 12 days of ciprofloxacin therapy increased slightly (1.032 times that after placebo therapy; P = .057), but no patient had bleeding or a change in PT that required alteration in warfarin or ciprofloxacin therapy. We conclude that warfarin therapy is not a contraindication to the use of ciprofloxacin.

Maternal mortality in the United States has increased unabated for the past 20 years. Maternal morbidity is also affecting an increasingly large number of women in the United States. A number of national and state organizations have recommend the use of maternal early warning tools as a method to combat this problem. There are limited data suggesting that the use of these types of clinical assessment tools can reduce maternal morbidity.We sought to determine if maternal morbidity could be reduced with the implementation of a clinical pathway-specific Maternal Early Warning Trigger (MEWT) tool.The tool was developed internally and prospectively implemented as a pilot project in 6 of 29 hospitals within a large hospital system. The primary goal was early assessment and treatment of patients suspected of clinical deterioration. The tool addressed the 4 most common areas of maternal morbidity: sepsis, cardiopulmonary dysfunction, preeclampsia-hypertension, and hemorrhage. To be considered positive, triggers needed to be sustained for20 minutes and were defined as severe (single abnormal value): maternal heart rate (HR)130 beats/min (bpm), respiratory rate30/min, mean arterial pressure55 mm Hg, oxygen saturation90%, or nurse concern; or nonsevere (required 2 abnormal values): temperature38 or36°C, blood pressure160/110 or85/45 mm Hg, HR110 or50 bpm, respiratory rate24 or10/min, oxygen saturation93%, fetal HR160 bpm, altered mental status, or disproportionate pain. Within each group, recommended management or assessment was also provided. Outcome measures were Centers for Disease Control and Prevention (CDC)-defined severe maternal morbidity, composite maternal morbidity, and intensive care unit (ICU) admissions. Two time intervals were used to analyze the effect of the MEWT tool: a 24-month baseline control period and a 13-month MEWT study period. To determine that the findings noted were not simply changes that would have occurred without the utilization of the early warning tool, we also compared a control population from nonpilot sites during the same baseline and 13-month time periods.There were 36,832 deliveries at the pilot sites (24,221 pre- and 12,611 post-MEWT testing) and 146,359 at the nonpilot sites (95,718 pre- and 50,641 post-MEWT testing) during the 2 study time periods. Use of the MEWT tool resulted in significant reductions in CDC severe maternal morbidity (P0.01) and composite morbidity (P0.01). ICU admissions were unchanged. At nonpilot sites CDC severe maternal morbidity, composite morbidity, and ICU admissions were unchanged between baseline and the post-MEWT testing time period.The use of the MEWT tool in this study, designed to address 4 of the most common causes of maternal morbidity, as well as provide assessment and management recommendations, resulted in significant improvement in maternal morbidity. The variation in hospital delivery services at the pilot sites suggests that this maternal early warning tool would be suitable for use in the majority of maternity centers in the United States.

Transcription factors of the plant-specific homeodomain leucine zipper IV (HD-ZIP IV) family have been found from moss to higher plants, and several family members have been associated with epidermis-related expression and/or function. In maize (Zea mays), four of the five characterized HD-ZIP IV family members are expressed specifically in the epidermis, one contributes to trichome development, and target genes of another one are involved in cuticle biosynthesis. Assessing the phylogeny, synteny, gene structure, expression, and regulation of the entire family in maize, 12 novel ZmHDZIV genes were identified in the recently sequenced maize genome. Among the 17 genes, eight form homeologous pairs duplicated after the split of maize and sorghum (Sorghum bicolor), whereas a fifth duplication is shared with sorghum. All 17 ZmHDZIV genes appear to be derived from a basic module containing seven introns in the coding region. With one possible exception, all 17 ZmHDZIV genes are expressed and show preferential expression in immature reproductive organs. Fourteen of 15 ZmHDZIV genes with detectable expression in laser-dissected tissues exhibit a moderate to very strong expression preference for the epidermis, suggesting that at least in maize, the majority of HD-ZIP IV family members may have epidermis-related functions. Thirteen ZmHDZIV genes carry conserved motifs of 19 and 21 nucleotides in their 3′ untranslated region. The strong evolutionary conservation and the size of the conserved motifs in the 3′ untranslated region suggest that the expression of HD-ZIP IV genes may be regulated by small RNAs.

STUDY OBJECTIVE--The aim was to study the relationship between the level of alcohol consumption in pregnancy and craniofacial characteristics of the neonate. DESIGN--This was a prospective survey of a sample of pregnant women, stratified on prepregnancy level of alcohol consumption. SETTING--The study was carried out at the public antenatal clinic of Roubaix maternity hospital. PARTICIPANTS--During an eight month period, 684 women (89% of those eligible) were interviewed in a standardised way at their first antenatal clinic visit. Of these, all who were suspected of being alcoholic or heavy drinkers (at least 21 drinks per week) were selected for follow up, as was a subsample of light (0-6 drinks per week) and moderate (7-20 drinks per week) drinkers. Of 347 women selected in this way, 202 had their infants assessed by a standardised morphological examination. MEASUREMENTS AND AND MAIN RESULTS--Suggestive craniofacial characteristics of the infants, present either in isolation or in association with growth retardation ("fetal alcohol effects"), were compared in relation to maternal alcohol consumption (alcoholic 12%; heavy drinking 24%; moderate drinking 28%; light drinking 36%). No differences were found between light and moderate drinkers. Infants born to alcoholics had a greater number of craniofacial characteristics and the proportion with features compatible with fetal alcohol effects was higher. There was a similar trend for infants of heavy drinkers. Infants of heavy drinkers who had decreased their alcohol consumption during pregnancy had fewer craniofacial features. Infants of heavy smokers were also found to have increased numbers of craniofacial characteristics. CONCLUSIONS--Craniofacial morphology could be a sensitive indicator of alcohol exposure in utero. Altered morphology is usually considered specific for alcohol exposure, but the relation observed with smoking needs further exploration.

Certain beta-adrenoceptor-mediated functions seem to diminish with age; however, information on alpha-adrenoceptor-mediated function is sparse and often conflicting but overall suggests little age-related change. To assess an age-related alteration in the responsiveness to an alpha 1-adrenergic agonist and to estimate changes in the apparent affinity of the alpha 1-adrenoceptor for the antagonist prazosin, we infused phenylephrine into 12 healthy elderly subjects and 12 healthy young subjects before and after an oral dose of prazosin, and we compared the shift in the dose-response curves for the two groups. With this protocol we were unable to detect any age-related decline in sensitivity of the alpha-adrenoceptor to either agonist or antagonist. However, oral prazosin resulted in higher plasma concentrations and a consistently greater hypotensive effect in the elderly subjects than in the young subjects. We concluded that there was no difference in alpha 1-adrenoceptor sensitivity in the elderly persons, but that the kinetics of prazosin may be altered and that the response of the blood pressure to prazosin was increased because of the kinetic changes and possibly the physiologic changes associated with aging.

The plasma concentration and appearance rate of norepinephrine are increased in the elderly. A hypothesis to explain this observation is that the elderly have a diminished response of the α2-adrenoreceptor in the brainstem that modulates peripheral sympathetic tone. To evaluate the effect of age on α2-adrenoreceptor function, we studied 12 healthy elderly subjects and 12 healthy young volunteers and compared the decrease in plasma norepinephrine and blood pressure in response to increasing doses of orally administered clonidine. We found that, for the same plasma clonidine concentration, the blood pressure and plasma norepinephrine concentration fell equivalently in both groups. These data imply that the increased plasma norepinephrine and the elevated blood pressure in the healthy elderly population do not appear to be secondary to a decrease in α2-adrenergic response to an agonist in the central nervous system. Clinical Pharmacology and Therapeutics (1990) 47, 61–67; doi:10.1038/clpt.1990.9

UNC5H receptors (UNC5H1, UNC5H2, UNC5H3) are putative tumor suppressors whose expression is lost in numerous cancers. These receptors have been shown to belong to the so-called family of dependence receptors. Such receptors induce apoptosis when their ligand netrin-1 is absent, thus conferring a state of cellular dependence towards ligand presence. Along this line, these receptors may limit tumor progression because they induce the death of tumor cells that grow in settings of ligand unavailability. We show here that UNC5H receptors are localized to cholesterol-and sphingolipid-enriched membrane domains called lipid rafts. We then demonstrate that the lipid raft localization of UNC5H2 is required for the pro-apoptotic activity of unbound UNC5H2. We also propose that this lipid raft localization is probably mediated via the recruitment of adaptor protein(s) within the death domain of UNC5H2 but is not dependent on the post-translational modification by palmitoylation of UNC5H2 even though this palmitoylation is required for UNC5H2 pro-apoptotic activity. Moreover we show that the interaction of UNC5H2 with the downstream pro-apoptotic serine threonine kinase DAPk is dependent on both UNC5H2 lipid raft localization and palmitoylation. Thus, we propose that the UNC5H dependence receptors require lipid raft localization and palmitoylation to trigger apoptosis.

Despite numerous studies, questions remain about the evolutionary history of Ursidae and additional independent genetic markers were needed to elucidate these ambiguities. For this purpose, we sequenced ten nuclear genes for all the eight extant bear species. By combining these new sequences with those of four other recently published nuclear markers, we provide new insights into the phylogenetic relationships of the Ursidae family members. The hypothesis that the giant panda was the first species to diverge among ursids is definitively confirmed and the precise branching order within the Ursus genus is clarified for the first time. Moreover, our analyses indicate that the American and the Asiatic black bears do not cluster as sister taxa, as had been previously hypothesised. Sun and sloth bears clearly appear as the most basal ursine species but uncertainties about their exact relationships remain. Since our larger dataset did not enable us to clarify this last question, identifying rare genomic changes in bear genomes could be a promising solution for further studies.

BACKGROUND Germline mutations in the BRCA1 and BRCA2 genes are associated with an inherited predisposition to breast and ovarian carcinoma, and specific mutations in these genes are found at increased frequency in certain populations. The authors observed a repeated occurrence of the 185delAG mutation (BRCA1; also known as 187delAG) in a non-Jewish population that originated from the San Luis Valley in Colorado. METHODS This was a retrospective analysis of mutations that occur in non-Jewish Americans of Spanish ancestry from Colorado who were tested clinically for BRCA1 and BRCA2 genetic mutations using DNA sequencing. RESULTS Between August 1994 and December 2001, 19 Spanish/Latin American individuals from different families underwent genetic counseling and clinical genetic testing using direct DNA sequencing for mutations of the BRCA1 and BRCA2 genes. The results showed that 10 of 19 individuals had mutations or variants of BRCA1 or BRCA2, and 6 of 10 individuals (60%) carried the 185delAG mutation in BRCA1. All six families originated from the San Luis Valley in Colorado, indicated that they were of Spanish/Latin American ethnicity, and denied Jewish ancestry. CONCLUSIONS The 185delAG mutation is common in families of non-Jewish ancestry originating from the San Luis Valley in Colorado with hereditary breast/ovarian carcinoma, possibly due to a founder effect. Further investigation may lead to simplified genetic testing and may allow clinicians to serve this population better. The repeated occurrence of the 185delAG mutation in this specific population may have clinical and public health implications. Cancer 2003;98:597–602. © 2003 American Cancer Society. DOI 10.1002/cncr.11533

We evaluated the effect of age on the lipolytic response to intravenous infusion of isoproterenol in 12 elderly (age, >60 years) and 12 young (age, 21 to 34 years) volunteers to examine if there is alteration in innervated β-adrenergic responsiveness in tissues other than the heart. Lipolysis was evaluated by measuring the plasma concentrations of free fatty acids and glycerol. We also measured the plasma concentration of isoproterenol during infusion so that we could calculate comparable plasma isoproterenol concentrations to lipolytic responses in the two age groups. Our data show that, at equivalent infusion rates of isoproterenol, the two age groups achieved equivalent isoproterenol concentrations. The elderly had a higher concentration of free fatty acids but equivalent concentrations of glycerol as compared with the young subjects at equivalent isoproterenol plasma concentrations. However, our data were complicated by the fact that at the higher infusion rates of isoproterenol, the elderly showed a greater sympathetic stimulation than the young subjects as measured by plasma norepinephrine concentrations. Nonetheless, our data could not show that the elderly subjects were more resistant to β-adrenergic receptor–mediated stimulated lipolysis. Thus innervated β-adrenergic receptor hyporesponsiveness caused by aging may not necessarily extend to all organ systems. Clinical Pharmacology and Therapeutics (1994) 56, 210–216; doi:10.1038/clpt.1994.125