Chronic Undernutrition in Ovine Twin Pregnancies Abolishes Differences in Birth Weight Due to Sex: An Evaluation of the Role of Nutritional and Antioxidant Supplementation.

In twin pregnancies of discordant sex, the male fetus grows larger than the female co-twin. Our study aimed to determine the effect of the sex of co-twins on lambs' birth weight in ovine pregnancies developed under natural undernourishment. Additionally, we investigated whether the nutritional and/or antioxidant supplementation provided to ewes during pregnancy could modulate the potential effects associated with the sex of co-twins. Ninety-six birth records of twin pregnancies of sheep grazing the natural Patagonian prairies were analyzed. The animals were divided into four groups: control (no supplementation), N (concentrate supplementation, 100% NRC), A (antioxidant supplementation), and NA (concentrate + antioxidant supplementation). Supplementation occurred from day 35 of gestation onwards until lambing. There were no differences in female or male birth weight in the control undernourished group. However, in group N, females or males with sex-discordant co-twins had a higher birth weight than did those with co-twins of the same sex. Group A males with female co-twins had a higher birth weight compared to males whose co-twins were also males. In NA lambs, males had a higher birth weight compared to females, regardless of their co-twin's sex. Therefore, chronic undernutrition abolished the differences in birth weight due to fetal sex. Restoring maternal nutrition or antioxidant supplementation tends to normalize birth weight and restore the differences between females and males. This effect is enhanced with the combined supplementation of concentrated food and antioxidants.

Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants.

Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo. This peptide may be of interest for the future development of therapeutic agents that ameliorate PTH1R malfunction.

Dynamic Expression of Follicle-Stimulating Hormone and Estrogen mRNA Receptors Associated with microRNAs 34a and -let-7c in Canine Follicles during the Estrous Cycle.

The genes encoding for estrogen receptor (ESR2) and follicle-stimulating hormone receptor (FSHR) play crucial roles in ovarian follicular development. This study aimed to determine the expression levels of miRNAs predicted against FSHR and ESR2 mRNAs in follicular cells related to their target genes during the estrous cycle in canines. Antral follicles were dissected from 72 ovaries following ovariohysterectomies. MiRNAs regulating FSHR and ESR2 genes were selected from miRNA databases, and mature miRNA and mRNA expression profiling was performed using real-time polymerase chain reaction (PCR). The best miRNA for each target gene was selected considering the quantitative PCR (qPCR) performance and target prediction probability, selecting only miRNAs with a binding p-value of 1.0, and choosing cfa-miR-34a and cfa-let-7c for FSHR and ESR2, respectively. The expression levels comparing the different phases of the estrous cycle were evaluated using ANOVA. Pearson correlations between the expression pattern of each miRNA and their target genes were performed. Each miRNA and its target genes were expressed in the granulosa cells in all estrous phases. FSHR remained low in anestrus and proestrus, increased (p < 0.05) to the highest level in estrus, and decreased (p < 0.05) in diestrus. ESR2 showed the same trend as FSHR, with the highest (p < 0.05) expression in estrus and the lowest (p < 0.05) in anestrus and proestrus. A tendency for an inverse relationship was observed between the expression of miR-34a and FSHR only in the anestrus phase, while an inverse correlation (r = -0.8) was found between miRNA-7c and ESR2 (p < 0.01). The expression profile of miR-34a and miR-let-7c and their predicted target genes of dog ovarian follicles throughout the estrous cycle observed in this study suggest a role in the transcriptional regulation of FSHR and ESR2, which is the first evidence of the involvement of these miRNAs in the canine follicular function.

Bovine adipose tissue-derived mesenchymal stem cells self-assemble with testicular cells and integrates and modifies the structure of a testicular organoids.

Mesenchymal stem cells (MSC) display self-renewal and mesodermal differentiation potentials. These characteristics make them potentially useful for in vitro derivation of gametes, which may constitute experimental therapies for human and animal reproduction. Organoids provide a spatial support and may simulate a cellular niche for in vitro studies. In this study, we aimed at evaluating the potential integration of fetal bovine MSCs derived from adipose tissue (AT-MSCs) in testicular organoids (TOs), their spatial distribution with testicular cells during TO formation and their potential for germ cell differentiation. TOs were developed using Leydig, Sertoli, and peritubular myoid cells that were previously isolated from bovine testes (n = 6). Thereafter, TOs were characterized using immunofluorescence and Q-PCR to detect testicular cell-specific markers. AT-MSCs were labeled with PKH26 and then cultured with testicular cells at a concentration of 1 × 106 cells per well in Ultra Low Attachment U-shape bottom (ULA) plates. TOs formed by testicular cells and AT-MSCs (TOs + AT-MSCs) maintained a rounded structure throughout the 28-day culture period and did not show significant differences in their diameters. Conversely, control TOs exhibited a compact structure until day 7 of culture, while on day 28 they displayed cellular extensions around their structure. Control TOs had greater (P < 0.05) diameters compared to TOs + AT-MSCs. AT-MSCs induced an increase in proportion of Leydig and peritubular myoid cells in TOs + AT-MSCs; however, did not induce changes in the overall gene expression of testicular cell-specific markers. STAR immunolabelling detected Leydig cells that migrated from the central area to the periphery and formed brunches in control TOs. However, in TOs + AT-MSCs, Leydig cells formed a compact peripheral layer. Sertoli cells immunodetected using WT1 marker were observed within the central area forming clusters of cells in TOs + AT-MSCs. The expression of COL1A associated to peritubular myoids cells was restricted to the central region in TOs + AT-MSCs. Thus, during a 28-day culture period, fetal bovine AT-MSCs integrated and modified the structure of the TOs, by restricting formation of branches, limiting the overall increase in diameters and increasing the proportions of Leydig and peritubular myoid cells. AT-MSCs also induced a reorganization of testicular cells, changing their distribution and particularly the location of Leydig cells.

[Dietary and physical activity practices and preferences in children: An approach from school parliaments in educational public establishments]. / Prácticas y preferencias alimentarias y de actividad física en niños y niñas: Una aproximación desde los Parlamentos Escolares en establecimientos educacionales.

In Chile, overnutrition continues to increase, especially affecting children. Solving this public health problem requires the development of promotion and prevention strategies that consider the suggestions of the communities, especially those of the children themselves. OBJECTIVE: To know the opinions and suggestions of third and fourth-grade children from schools in the southern area of Santiago, Chile, regarding their eating practices and physical activity, as part of the FONDEF IT 1810016 project. SUBJECTS AND METHOD: Seven School Meetings were held in seven schools using a participatory qualitative methodology, collecting the opinions of 176 children regarding both their food and physical activity habits and preferences. RESULTS: The most consumed and preferred foods are those easy to prepare and highly available, such as bread, pasta, and milk. Foods that require preparation or are less available, such as fish, legumes, fruits, vegetables, and homemade preparations, are less consumed and have less preference. Regarding physical activities, video games and soccer stand out. Students propose increasing the hours of physical education and recesses and improving the availability and access to healthy foods in school environments as a solution strategy. CONCLUSIONS: School Meetings as a participatory strategy contribute to the joint generation of knowledge. The need to include communities as participants in health initiatives recognizes, through their role, children as subjects of rights.

Effect of progesterone on in vitro meiotic maturation of canine oocytes associated with Cx37 and Cx43 gene expression.

Progesterone (P4) concentrations in canines are exceptionally high in the periovulatory period. However, the mechanisms by which P4 modulates final oocyte development in dogs remain to be characterized. The aim of this study was to evaluate the effect of P4 on meiotic development related to the gene expression of connexin 37 (Cx37) and connexin 43 (Cx43) in the canine cumlus oocyte complexes (COCs). COCs were isolated from 120 canine ovaries after a routine ovariohysterectomy. In each experiment, groups of COCs retrieved from the antral follicles were subjected to in vitro maturation (IVM) for 72 h without (control) or with P4 (50 µg/mL and 100 µg/mL) or the P4 receptor antagonist, aglepristone (RU534 at 1 µM and 10 µM). Some of the COCs recovered (from each group) after 72 h of IVM were subjected to meiotic evaluation; the remaining COCs, and those not subjected to IVM, were used to analyze the gene expression of Cx37 and Cx43 by qPCR. The results were evaluated using ANOVA. The addition of P4 increased (P < 0.05) the meiotic development compared to that in the control or aglepristone groups. The highest (P < 0.05) percentage of oocytes in the MII stage was observed upon P4 supplementation. In contrast, the highest percentage (P < 0.05) of oocytes arrested in the GV stage and the lowest (P < 0.05) percentages in the MII stage were observed for COCs cultured with aglepristone. Although a significant decrease in the mRNA levels of both connexins was observed after culturing, no effect on Cx37 and Cx43 gene expression was observed when exogenous P4 was added compared to those of the control group. However, COCs cultured with aglepristone exhibited higher (P < 0.05) expression of Cx37 and Cx43 than COCs in the control IVM-group, regardless of the concentration. In conclusion, our results suggest that a high dosage of P4 during IVM enhances the nuclear maturation of canine oocytes without altering the gene expression levels of Cx37 and Cx43. However, the increase in their expression upon treatment with a P4 antagonist indicates an in vivo role for this hormone in the endogenous modulation of both Cx37 and Cx43.

Qualitative Findings From a Survey on Patient Experiences and Satisfaction with Lung Cancer Screening.

BACKGROUND: To reveal successes and potential limitations of the lung cancer screening program, we conducted a survey that included both quantitative and open-ended questions to measure patient experiences and satisfaction with screening. METHODS: We report on the five open-ended items related to barriers to returning for screening, experience with other cancer prevention screenings, positive and negative experiences, and suggestions for improving future appointments. The open-ended responses were analyzed using constant comparison method and inductive content analysis. RESULTS: Respondents (182 patients, 86% response rate for open-ended questions) provided generally positive comments about their lung cancer screening experience. Negative comments were related to desire for more information about results, long wait times for results, and billing issues. Suggestions for improvements included: scheduling on-line appointments and text or email reminders, lower costs, and responding to uncertainty about eligibility criteria. CONCLUSION: Findings provide insights about patient experiences and satisfaction with lung cancer screening which is important given low uptake. Ongoing patient-centered feedback may improve the lung cancer screening experience and increase follow-up screening rates.

Association of physical activity, muscular strength, and obesity indicators with self-concept in Chilean children.

Introduction: Objectives: the present study examined the association of physical activity, muscular strength, and obesity indicators with self-concept in Chilean children. Methods: this cross-sectional study included 1078 Chilean children (mean age: 9.1 years [standard deviation: 1.1]; 598 boys). Physical activity was evaluated using the Physical Activity Questionnaire for Older Children. Upper and lower limb strength was evaluated using a digital dynamometer and standing long jump performance, respectively. The general strength index was calculated based on z-score values. Obesity indicators used were height, weight, body mass index, and body fat. The self-concept test was used to determine the academic, social, emotional, family, physical self-concept dimensions and total self-concept of children. Results: the mean total self-concept was 3.3 (standard deviation: 0.5). Physical activity was associated with academic (ß: 0.32; p = 0.03), social (ß: 0.24; p = 0.04), family (ß: 0.13; p = 0.01), physical (ß: 0.46; p = 0.01) self-concept dimensions and total self-concept (ß: 0.22; p = 0.01), regardless of sex and age. Upper limb strength and general strength index were negatively associated with academic self-concept dimensions (ß: -0.02; p = 0.01 and ß: -0.13; p = 0.02) and total self-concept (ß: -0.04; p = 0.01). Body weight and body mass index were negatively associated with academic (ß: -0.01; p = 0.01 and ß: -0.01; p = 0.02) and physical self-concept dimensions (ß: -0.03; p = 0.03). Conclusions: these findings suggest that physical activity is positively related with self-concept. Thus, physical activity and self-percept must be considered as an essential social cognitive perspective to provide suitable mental health in children.

Introducción: Objetivos: el presente estudio examinó la asociación de indicadores de actividad física, fuerza muscular y obesidad con el autoconcepto en niños chilenos. Métodos: este estudio transversal incluyó a 1078 niños chilenos (edad media: 9,1 años [desviación estándar: 1,1]; 598 niños). La actividad física se evaluó mediante el Physical Activity Questionnaire for Older Children. La fuerza de los miembros superiores e inferiores se evaluó utilizando un dinamómetro digital y el rendimiento en salto de longitud de pie. El índice de fuerza general se calculó en base a los valores de z-score. Los indicadores de obesidad utilizados fueron altura, peso, índice de masa corporal y grasa corporal. Se utilizó el test de autoconcepto para determinar las dimensiones académicas, social, emocional, familiar, físico y autoconcepto total. Resultados: la muestra total presento un autoconcepto promedio de 3,3 (desviación estándar: 0,5). La actividad física se asocio con autoconcepto académico (ß: 0,32; p = 0,03), social (ß: 0,24; p = 0,04), familiar (ß: 0,13; p = 0,01), físico (ß: 0,46; p = 0,01) y total (ß: 0,22; p = 0,01). La fuerza muscular de miembros superiores y el índice general de fuerza se asociaran negativamente con al autoconcepto académico (ß: -0,02; p = 0,01 y ß: -0,13; p = 0,02) y total (ß: -0,04; p = 0,01). Mientras que el peso corporal e índice de masa corporal se asociaron negativamente con autoconcepto académico (ß: -0,01; p = 0,01 y ß: -0,01; p = 0,02) y físico (ß: -0,03; p = 0,03). Conclusiones: estos hallazgos sugieren que la actividad física se relaciona positivamente con el autoconcepto. Así, la actividad física y la autopercepción deben ser consideradas como una perspectiva cognitiva social imprescindible para proporcionar una adecuada salud mental en los niños.

Oxidative Stress and Fetal Growth Restriction Set Up Earlier in Undernourished Sheep Twin Pregnancies: Prevention with Antioxidant and Nutritional Supplementation.

Hypoxemia and oxidative stress, resulting in intrauterine growth restriction (IUGR) in undernourished twin sheep pregnancies, has been described in near-term studies. Our aim was to evaluate if the counteractive effects of maternal nutritional or antioxidant supplementation on the fetal redox status were evident before the accelerated fetal growth phase. Forty twin-bearing ewes grazing on natural Patagonian prairie were randomly assigned to four groups (n = 10 each; P: control ewes consuming mainly natural pasture; P+A: pasture plus antioxidants; P+C: pasture plus concentrate; P+A+C: pasture plus antioxidants and concentrate). Daily herbal antioxidants were supplemented in a feedstuff concentrate as a premix from day 35 until day 100 of gestation, when fetal venous cord blood samples and biometric measurements were obtained via cesarean section. The fetuses from group P were clearly hypoxemic. An analysis of variance showed that maternal antioxidant supplementation showed a trend of increased PO2, SatHb, and Ht, effects not observed in P+C fetuses. Antioxidants decreased the fetal MDA concentration (p < 0.05). Fetal TAC was increased by the antioxidants and concentrate (p < 0.05). Antioxidant supplementation showed a trend to increase fetal body weight but not biometry. The results suggest that negative effects of oxidative stress occur earlier than the overt growth arrest, and the maternal administration of antioxidants may constitute a good nutritional strategy for the early prevention of IUGR.

Actions of Parathyroid Hormone Ligand Analogues in Humanized PTH1R Knockin Mice.

Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related protein (PTHrP) ligands and analogues for their pharmacologic activities and potential therapeutic utility toward diseases of bone and mineral ion metabolism. Divergence, however, in the amino acid sequences of rodent and human PTH receptors (rat and mouse PTH1Rs are 91% identical to the human PTH1R) can lead to differences in receptor-binding and signaling potencies for such ligands when assessed on rodent vs human PTH1Rs, as shown by cell-based assays in vitro. This introduces an element of uncertainty in the accuracy of rodent models for performing such preclinical evaluations. To overcome this potential uncertainty, we used a homologous recombination-based knockin (KI) approach to generate a mouse (in-host strain C57Bl/6N) in which complementary DNA encoding the human PTH1R replaces a segment (exon 4) of the murine PTH1R gene so that the human and not the mouse PTH1R protein is expressed. Expression is directed by the endogenous mouse promoter and hence occurs in all biologically relevant cells and tissues and at appropriate levels. The resulting homozygous hPTH1R-KI (humanized) mice were healthy over at least 10 generations and showed functional responses to injected PTH analog peptides that are consistent with a fully functional human PTH1R in target bone and kidney cells. The initial evaluation of these mice and their potential utility for predicting behavior of PTH analogues in humans is reported here.

Prevalence and co-occurrence of lifestyle risk factors for non-communicable diseases according to sociodemographic characteristics among adults Chilean residents.

To examine the prevalence and co-occurrence of lifestyle risk factors for non-communicable diseases (NCDs) according to sociodemographic characteristics in Chilean residents. A cross-sectional study based on data from 5995 adults from the Chilean National Health Survey. The lifestyle risk factors included were physical inactivity, tobacco consumption, alcohol consumption, low fruits and vegetable consumption, and overweight/obesity. The most frequent risk factor was overweight/obesity (75.6%), followed by alcohol consumption (74.8%), low fruits and vegetable consumption (51.7%), physical inactivity (36.3%), and tobacco consumption (27.9%). Only 1.0% of the participants did not present any risk factor, while 9.6%, 30.4%, 34.0%, 20.3%, and 4.7% accumulated one, two, three, four, and five risk factors. Men (OR 1.56; 95% CI 1.18; 2.04), people who have secondary education (OR 1.59; 95% CI 1.20; 2.10), and those with lower household income (OR 1.39; 95% CI 1.09; 1.59) had higher odds of three or more risk factors. Associations were inverse for older adults (OR 0.57; 95% CI 0.41; 0.79) and rural geographic areas (OR 0.77; 95% CI 0.67; 0.89). The prevalence of risk factors for NCDs is fairly high in Chilean residents. Interventions may need to target these co-occurrences rather than emphasizing individual risk factors for NCDs. Interventions could further consider these co-occurrences as a potential target for population stratification.

Lifestyle Habits and Health Indicators in Migrants and Native Schoolchildren in Chile.

In Chile, the migrant population has increased in the last years. Migrants adopt behaviors of this new culture, which can have an effect on their health. Contradictory results regarding differences between migrant and native children have been reported. The aim of this study was to explore the associations between nationality with health indicator and lifestyle habits among schoolchildren in Chile. A cross-sectional and observational study with a non-probabilistic sample was conducted in 1033 children (86.4% Chilean and 13.6% migrant) from second to fourth grade of seven public schools from low-income municipalities from the Metropolitan Region, Chile. Anthropometric measurements (weight, height, waist circumference, triceps and subscapular folds), handgrip strength, and standing long jump measurements, physical activity, self-esteem and food guidelines accomplishments were determined. Migrant children presented lower body mass index (BMI), Z-BMI, body fat% and waist circumference values; and higher handgrip strength, standing long jump, and more satisfactory compliance with food guidelines than natives (p < 0.05). No significant difference for physical activity and self-esteem was observed. In the adjusted models, migrants presented lower odds for overweight/obesity, risk of abdominal obesity, low handgrip strength and unsatisfactory food guidelines accomplishment in all models (p < 0.05). The nutritional and muscular fitness of migrant children was better than that of the Chilean ones.

Inactividad física versus sedentarismo: análisis de la Encuesta Nacional de Salud de Chile 2016-2017

Background: Physical inactivity and sedentariness are independent risk factors for mortality. Physical inactivity is defined as engaging in insufficient moderate/vigorous physical activity (i.e. not meeting the WHO's recommendations). Sedentariness is defined according to sedentary behavior; evidence suggests that > 8 h/d could serve to consider a person as sedentary. The Chilean National Health Survey 2016-2017 (NHS), using a single question (Question-NHS), considered as "sedentary" those who did not engage in sports or physical activity for ≥ 30 min, ≥ 3 times/wk. Thus, it attempted to estimate sedentariness without considering sedentary behavior. Aim: To determine the prevalence of physical inactivity and sedentariness in Chile, and to contrast such results with the Question-NHS. Material and Methods: We analyzed data from 5564 participants of the 2016-2017 NHS, aged ≥ 18 years. The Global Physical Activity Questionnaire was used to determine moderate/vigorous physical activity and sedentary behavior. We defined physical inactivity as having 8 h/d of sedentary behavior. Results: The prevalences [95% confidence intervals] of physical inactivity and sedentariness were 32% [29-34] and 6% [5-7] respectively, while 3% [2-4] were both physically inactive and sedentary. The Question-NHS classified 88% [86-89] as "sedentary", but among them, 35% were physically inactive and 6% were sedentary. Conclusions: One third of adults are inactive, one out of ten is sedentary, and one out of twenty is inactive and sedentary. The Question-NHS overestimates the population at risk.

Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion.

The sodium-phosphate cotransporter NPT2a plays a key role in the reabsorption of filtered phosphate in proximal renal tubules, thereby critically contributing to phosphate homeostasis. Inadequate urinary phosphate excretion can lead to severe hyperphosphatemia as in tumoral calcinosis and chronic kidney disease (CKD). Pharmacological inhibition of NPT2a may therefore represent an attractive approach for treating hyperphosphatemic conditions. The NPT2a-selective small-molecule inhibitor PF-06869206 was previously shown to reduce phosphate uptake in human proximal tubular cells in vitro. Here, we investigated the acute and chronic effects of the inhibitor in rodents and report that administration of PF-06869206 was well tolerated and elicited a dose-dependent increase in fractional phosphate excretion. This phosphaturic effect lowered plasma phosphate levels in WT mice and in rats with CKD due to subtotal nephrectomy. PF-06869206 had no effect on Npt2a-null mice, but promoted phosphate excretion and reduced phosphate levels in normophophatemic mice lacking Npt2c and in hyperphosphatemic mice lacking Fgf23 or Galnt3. In CKD rats, once-daily administration of PF-06869206 for 8 weeks induced an unabated acute phosphaturic and hypophosphatemic effect, but had no statistically significant effect on FGF23 or PTH levels. Selective pharmacological inhibition of NPT2a thus holds promise as a therapeutic option for genetic and acquired hyperphosphatemic disorders.

Patterns of racial/ethnic disparities in baseline health-related quality of life and relationship with overall survival in patients with colorectal cancer.

PURPOSE: Racial disparities are evident in colorectal cancer (CRC) prognosis with black patients experiencing worse outcomes than Hispanics and whites, yet mediators of these disparities are not fully known. The aim of this study is to identify variables that contribute to racial/ethnic disparities in health-related quality of life (HR-QoL) and overall survival in CRC. METHODS: Using SF-12 questionnaires, we assessed HR-QoL in 1132 CRC patients by calculating their physical (PCS) and mental composite summary (MCS) scores. Associations between poor PCS/MCS and sociodemographic factors were estimated and survival differences were identified by race/ethnicity. RESULTS: Hispanic patients who never married were at greater risk of poor PCS (OR 2.69; 95% CI 1.11-6.49; P = 0.028) than were currently married patients. College education was associated with a decreased risk of poor PCS in Hispanic and white, but not black, patients. Gender was significantly associated with poor MCS among white patients only. CRC patients who reported a poor PCS or MCS had poor survival, with differences in median survival times (MSTs) by race. The effect of PCS was strongest in white CRC patients with a difference in overall MST of > 116 months between those with favorable versus poor physical HR-QoL. Black patients who reported poor Physical and Mental HR-QoL showed significant risk of a poor outcome. CONCLUSION: These findings suggest that racial/ethnic disparities in CRC survival may be related to differences in HR-QoL. Identified mediators of HR-QoL could supplement current CRC management strategies to improve patients' survival.

Survey of Principal Investigators in Biobanking: Knowledge, Attitudes, and Research Behaviors About Transgender and Gender-Diverse Patients.

PURPOSE: Biobanks usually do not collect transgender and gender-diverse (TGD) demographic information, hindering research on cancer risk and biological effects related to gender-affirming interventions. METHODS: In August 2019, 172 scientists involved in biobanking research at a single institution (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL) were invited to complete a survey measuring knowledge and attitudes about TGD health and research practices. Quantitative and qualitative analyses were performed. RESULTS: Among 47 respondents, there was high agreement (77%) regarding the importance of collecting TGD identities and histories of gender-affirming treatments with biospecimens, which was contrasted by low self-reported rates of respondents' biorepositories allowing for the entry of TGD identities (14.9%) and histories of gender-affirming interventions (8.5%). There was high interest in receiving education regarding the unique cancer health needs of TGD patients (74%), and knowledge questions yielded high percentages of "neutral" and "don't know or prefer not to answer" responses. After completing the survey, confidence in knowledge of health needs for TGD patients decreased significantly (48.9% were confident during the presurvey assessment v 36.2% in the postsurvey assessment; P < .001). Qualitative analysis of open-ended questions indicated overall support of TGD data inclusion in biobanks along with perceived barriers to inclusion of such data in biobanks. CONCLUSION: To our knowledge, this was the first study of researchers to assess knowledge, attitudes, and research practices regarding TGD patients. Overall, there was limited knowledge about TGD health and cancer needs and low rates of TGD demographic data collection but a high interest in receiving education regarding this community.

Novel Prognostic Models for Patients With Penile Carcinoma.

Although penile carcinoma is a rare malignancy, there is still an unmet need to identify prognostic factors associated with poor survival. In this study, we utilized demographic and clinical information to identify the most informative variables associated with overall survival in patients with penile cancer. From a full model including all covariates found to be statistically significant in univariable analyses, we identified a parsimonious reduced model containing tumor site (penis glans: hazard ratio [HR] = 0.48; 95% CI: 0.28-0.85 and penis not otherwise specified: HR = 0.45; 95% CI: 0.25-0.84), undetermined tumor differentiation (HR = 0.48; 95% CI: 0.27-0.86), and TNM stage III/IV (HR = 2.83; 95% CI: 1.68-4.75). When all of the covariates from the full model were subjected to classification and regression tree analysis, we identified 6 novel risk groups. Of particular interest, we found marriage was associated with substantial improvement in survival among men with the same stage and disease site. Specifically, among single/widowed/divorced men with TNM stage 0-II and prepuce/penis corpus/overlapping lesions had worse survival (5-year survival = 18.2%) versus married men (5-year survival = 62.5%). Since marital status is linked to social support, these findings warrant a deeper investigation into the relationships between disease prognosis and social support in patients with penile carcinoma.

Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause.

The PTH/PTHrP receptor (PTHR1) mediates the actions of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) by coupling this G protein-coupled receptor (GPCR) to the alpha-subunit of the heterotrimeric stimulatory G protein (Gsα) and thereby to the formation of cAMP. In growth plates, PTHrP-dependent activation of the cAMP/PKA second messenger pathway prevents the premature differentiation of chondrocytes into hypertrophic cells resulting in delayed growth plate closure. Heterozygous mutations in GNAS, the gene encoding Gsα, lead to a reduction in cAMP levels in growth plate chondrocytes that is sufficient to cause shortening of metacarpals and/or -tarsals, i. e. typical skeletal aspects of Albright's Hereditary Osteodystrophy (AHO). However, heterozygous mutations in other genes, including those encoding PTHrP, PRKAR1A, PDE4D, and PDE3A, can lead to similar or even more pronounced acceleration of skeletal maturation that is particularly obvious in hands and feet, and reduces final adult height. Genetic mutations other than those resulting in Gsα haploinsufficiency thus reduce intracellular cAMP levels in growth plate chondrocytes to a similar extent and thereby accelerate skeletal maturation.

An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia.

Jansen's metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in PTHR1. Ligand-independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turnover, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short stature, limb deformities, nephrocalcinosis, and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cell-based assays, we found that certain N-terminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, [Leu11 ,dTrp12 ,Trp23 ,Tyr36 ]-PTHrP(7-36)NH2 (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1-H223R allele of JMC in osteoblastic cells via the collagen-1α1 promoter (C1HR mice). We observed that after 2 weeks of twice-daily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, because it reduced the excess trabecular bone mass, bone marrow fibrosis, and levels of bone turnover markers in blood and urine. The overall findings provide proof-of-concept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths toward the first treatment option for this debilitating skeletal disorder. © 2019 American Society for Bone and Mineral Research.