Ingesting protein-containing supplements and foods provides essential amino acids (EAA) necessary to increase muscle and whole-body protein synthesis (WBPS). Large variations exist in the EAA ...composition of supplements and foods, ranging from free-form amino acids to whole protein foods. We sought to investigate how changes in peripheral EAA after ingesting various protein and free amino acid formats altered muscle and whole-body protein synthesis. Data were compiled from four previous studies that used primed, constant infusions of L-(ring-
H
)-phenylalanine and L-(3,3-
H
)-tyrosine to determine fractional synthetic rate of muscle protein (FSR), WBPS, and circulating EAA concentrations. Stepwise regression indicated that max EAA concentration (EAAC
; R
= 0.524,
< 0.001), EAAC
(R
= 0.341,
< 0.001), and change in EAA concentration (ΔEAA; R = 0.345,
< 0.001) were the strongest predictors for postprandial FSR, Δ (change from post absorptive to postprandial) FSR, and ΔWBPS, respectively. Within our dataset, the stepwise regression equation indicated that a 100% increase in peripheral EAA concentrations increases FSR by ~34%. Further, we observed significant (
< 0.05) positive (R = 0.420-0.724) correlations between the plasma EAA area under the curve above baseline, EAAC
, ΔEAA, and rate to EAAC
to postprandial FSR, ΔFSR, and ΔWBPS. Taken together our results indicate that across a large variety of EAA/protein-containing formats and food, large increases in peripheral EAA concentrations are required to drive a robust increase in muscle and whole-body protein synthesis.
Inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSIs) has been proposed as a molecularly targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL). However, GSIs seem to have ...limited antileukemic activity in human T-ALL and are associated with severe gastrointestinal toxicity resulting from inhibition of NOTCH signaling in the gut. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid sensitivity and co-treatment with glucocorticoids inhibited GSI-induced gut toxicity. Thus, combination therapies with GSIs plus glucocorticoids may offer a new opportunity for the use of anti-NOTCH1 therapies in human T-ALL.
The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with ...CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL.
Display omitted
•T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma•Cxcl12 deletion in vascular endothelial, but not perivascular, cells suppresses disease•Cxcr4 deletion in T-ALL cells after disease onset inhibits leukemia progression•CXCR4 antagonism suppresses human T-ALL in a primary xenograft model
Pitt et al. identify a T cell acute lymphoblastic leukemia (T-ALL) niche and show that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Importantly, targeting CXCL12 or its receptor CXCR4 expressed in T-ALL cells reduces tumor growth in murine T-ALL and xenograft models.
Nutritional status is a strong predictor of postoperative outcomes and is recognized as an important component of surgical recovery programs. Adequate nutritional consumption is essential for ...addressing the surgical stress response and mitigating the loss of muscle mass, strength, and functionality. Especially in older patients, inadequate protein can lead to significant muscle atrophy, leading to a loss of independence and increased mortality risk. Current nutritional recommendations for surgery primarily focus on screening and prevention of malnutrition, pre-surgical fasting protocols, and combating post-surgical insulin resistance, while recommendations regarding macronutrient composition and timing around surgery are less established. The goal of this review is to highlight oral nutrition strategies that can be implemented leading up to and following major surgery to minimize atrophy and the resultant loss of functionality. The role of carbohydrate and especially protein/essential amino acids in combating the surgical stress cascade and supporting recovery are discussed. Practical considerations for nutrient timing to maximize oral nutritional intake, especially during the immediate pre- and post- surgical periods, are also be discussed.
Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 ...glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.
•AKT1 directly phosphorylates the NR3C1 glucocorticoid receptor protein•AKT-mediated S134 phosphorylation blocks nuclear translocation of NR3C1•PTEN loss and AKT1 activation induce glucocorticoid resistance in T-ALL•Pharmacologic inhibition of AKT1 reverses glucocorticoid resistance in T-ALL
As part of transition, transmasculine persons often use testosterone gender-affirming hormone therapy; however, there is limited data on its long-term effects. The impact of exogenous testosterone on ...uterine pathology remains unclear. While testosterone achieves amenorrhea in the majority of this population, persistence of abnormal uterine bleeding can be difficult to manage. Excess androgens in cisgender females are associated with pathologic uterine processes such as polycystic ovary syndrome, endometrial hyperplasia, or cancer. There are no guidelines for management of abnormal uterine bleeding or endometrial surveillance in this population.
The aim of this study was to describe the characteristics of uterine pathology after the initiation of testosterone in transmasculine persons.
A retrospective, multicenter case series was performed. Uterine pathology reports of transmasculine persons who received testosterone and subsequently underwent hysterectomy were reviewed. The endometrial phase and endometrial thickness were recorded.
A total of 94 subjects met search criteria. The mean age of participants was 30 ± 8.6 years, and the mean interval from initiation of testosterone to hysterectomy was 36.7 ± 36.6 months. Active endometrium was found in the majority of patients (n = 65; 69.1%). One patient had complex hyperplasia without atypia. There were no cases of endometrial cancer.
Despite amenorrhea in the majority of transmasculine persons on testosterone, endometrial activity persists with predominantly proliferative endometrium on histopathology. Individualized counseling for abnormal uterine bleeding is encouraged in this patient population.
Vaginoplasty Complications Ferrando, Cecile A
Clinics in plastic surgery,
07/2018, Letnik:
45, Številka:
3
Journal Article
Recenzirano
Complications after vaginoplasty surgery for the transgender woman exist. These adverse outcomes can be minor and easily treatable, whereas others are considered major events and require ongoing ...care. Adverse outcomes can be immediate or remote after surgery and include bleeding, hematoma, infection, delayed wound healing, neovaginal stenosis, visceral injury, and fistula. Patients may also experience pelvic floor disorders after surgery. Providers performing these surgeries and those providers caring for postoperative patients should be aware of the incidence of these complications and the treatment options that exist to manage them.
Uterus transplantation is the only known potential treatment for absolute uterine factor infertility. It offers a unique setting for the investigation of immunologic adaptations of pregnancy in the ...context of the pharmacologic-induced tolerance of solid organ transplants, thus providing valuable insights into the early maternal-fetal interface. Until recently, all live births resulting from uterus transplantation involved living donors, with only 1 prior birth from a deceased donor. The Cleveland Clinic clinical trial of uterus transplantation opened in 2015. In 2017, a 35 year old woman with congenital absence of the uterus was matched to a 24 year old parous deceased brain-dead donor. Transplantation of the uterus was performed with vaginal anastomosis and vascular anastomoses bilaterally from internal iliac vessels of the donor to the external iliac vessels of the recipient. Induction and maintenance immunosuppression were achieved and subsequently modified in anticipation of pregnancy 6 months after transplant. Prior to planned embryo transfer, ectocervical biopsy revealed ulceration and a significant diffuse, plasma cell–rich mixed inflammatory cell infiltrate, with histology interpreted as grade 3 rejection suspicious for an antibody-mediated component. Aggressive immunosuppressive regimen targeting both cellular and humoral rejection was initiated. After 3 months of treatment, there was no histologic evidence of rejection, and after 3 months from complete clearance of rejection, an uneventful embryo transfer was performed and a pregnancy was established. At 21 weeks, central placenta previa with accreta was diagnosed. A healthy neonate was delivered by cesarean hysterectomy at 34 weeks’ gestation. In summary, this paper highlights the first live birth in North America resulting from a deceased donor uterus transplant. This achievement underscores the capacity of the transplanted uterus to recover from a severe, prolonged rejection and yet produce a viable neonate. This is the first delivery from our ongoing clinical trial in uterus transplantation, including the first reported incidence of severe mixed cellular/humoral rejection as well as the first reported placenta accreta.
PDF
