RBP4 is produced mainly by hepatocytes. In type 2 diabetes and obesity, circulating RBP4 is increased and may act systemically to cause insulin resistance and glucose intolerance. Observations that ...adipocyte RBP4 mRNA increases in parallel with circulating RBP4 in these conditions, whereas liver RBP4 mRNA does not, led to a widely held hypothesis that elevated circulating RBP4 is a direct result of increased production by adipocytes. To test this, we generated mice with hepatocyte-specific deletion of RBP4 (liver RBP4 knockout or LRKO mice). Adipose tissue RBP4 expression and secretion remained intact in LRKO mice and increased as expected in the setting of diet-induced insulin resistance. However, circulating RBP4 was undetectable in LRKO mice. We conclude that adipocyte RBP4 is not a significant source of circulating RBP4, even in the setting of insulin resistance. Adipocyte RBP4, therefore, may have a more important autocrine or paracrine function that is confined within the adipose tissue compartment.
In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been ...significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease have continued to rise; from 1987 to 2014 there has been a 75% increase in cases and almost 300% increase in endometrial cancer deaths. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer with increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress.
The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Publications Committee, and the SGO board members prior to submission for publication.
The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines 1 using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.
•Advances in molecular pathology complement clinical management of endometrial cancer.•Increased estrogen exposure and genetic predisposition remain important risk factors•Judicious evaluation of abnormal bleeding and cancer referrals to gynecologic oncologists optimize management•Most patients benefit from minimally invasive surgery and tailored lymph node evaluation.•Risk stratification based on recent trials should influence adjuvant therapy decisions.
The use of aluminum (Al) alloys for additive manufacturing (AM) has recently gained significant attention, specifically in the aerospace industry. This has been resulting in introducing new high ...strength Al alloys that are more compatible with the AM processes. However, it is critical to investigate the structural integrity of these newly developed Al alloys prior to being deployed in safety-critical load-bearing applications. This study investigates and compares the microstructure, porosity, and fatigue behavior of five different contemporary Al alloys fabricated via a laser beam powder bed fusion (LB-PBF) AM process. Vertically and horizontally built specimens out of AlSi10Mg, Scalmalloy, QuesTek Al, AD1, and AlF357 are fabricated to capture any effects of build orientation on the structural integrity of these alloys. Despite the variation in micro-/defect-structure of vertical and horizontal specimens, no significant build orientation dependency is observed on fatigue behavior of AlSi10Mg, Scalmalloy, and AD1 alloys. However, AlF357 and QuesTek Al show some anisotropic behavior in the high cycle fatigue regime. Among the LB-PBF Al alloys investigated, Scalmalloy and AD1 are found to have the highest fatigue resistance ascribed to their superfine microstructure.
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•Build orientation effect on the fatigue behavior of LB-PBF Al alloys is studied.•Horizontal specimens have a higher defect density than the vertical counterparts.•Lack of fusion defects cause anisotropy in the fatigue behavior of QuesTek Al.•AlF357, despite its higher porosity, exhibits similar fatigue behavior to AlSi10Mg.•Scalmalloy has comparable fatigue behavior to AD1 regardless of its higher porosity.
Cycles of biologically relevant reactions are an alternative to an origin of life emerging from a steady state away from equilibrium. The cycles involve a rate at which polymers are synthesized and ...accumulate in microscopic compartments called protocells, and two rates in which monomers and polymers are chemically degraded by hydrolytic reactions. Recent experiments have demonstrated that polymers are synthesized from mononucleotides and accumulate during cycles of hydration and dehydration, which means that the rate of polymer synthesis during the dehydrated phase of the cycle is balanced (but not dominated) by the rate of polymer hydrolysis during the hydrated phase of the cycle. Furthermore, depurination must be balanced by the reverse process of repurination. Here we describe a computational model that was inspired by experimental results, can be generalized to accommodate other reaction parameters, and has qualitative predictive power.
Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant ...chemotherapy after chemoradiotherapy.
The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0–2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0–50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088.
Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years IQR 37 to 55; 663 72% were White, 121 13% were Black or African American, 53 6% were Asian, 24 3% were Aboriginal or Pacific islander, and 57 6% were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% 95% CI –6 to 7; hazard ratio 0·90 95% CI 0·70 to 1·17; p=0·81). In the safety population, the most common clinically significant grade 3–4 adverse events were decreased neutrophils (71 20% in the adjuvant chemotherapy group vs 34 8% in the chemoradiotherapy only group), and anaemia (66 18% vs 34 8%). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths.
Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting.
National Health and Medical Research Council and National Cancer Institute.
Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated ...radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four-field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient's perspective.
Hippocampal interneurons are a very diverse population of cells. Using single-cell quantitative PCR to analyze rat CA1 hippocampal interneurons, we quantified neuronal nicotinic acetylcholine ...receptor (nAChR) mRNA subunit expression and detailed possible nAChR subtype combinations for the α2, α3, α4, α5, α7, β2, β3, and β4 subunits. We also compared the expression detected in the stratum oriens and the stratum radiatum hippocampal layers. We show that the majority of interneurons in the CA1 of the rat hippocampus contain detectable levels of nAChR subunit mRNA. Our results highlight the complexity of the CA1 nAChR population. Interestingly, the α3 nAChR subunit is one of the highest expressed subunit mRNAs in this population, while the α4 is one of the least likely subunits to be detected in CA1 interneurons. The β2 nAChR subunit is the highest expressed beta subunit mRNA in these cells. In addition, Pearson's correlation coefficient values are calculated to identify significant differences between the nAChR subunit combinations expressed in the CA1 stratum oriens and the stratum radiatum. Statistical analysis also indicates that there are likely over 100 different nAChR subunit mRNA combinations expressed in rat CA1 interneurons. These results provide a valid avenue for identifying nAChR subtype targets that may be effective hippocampus-specific pharmacological targets.
In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been ...significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women.
This manuscript, Part II in a two-part series, includes specific recommendations on treatment of recurrent disease, post treatment surveillance and survivorship, considerations for younger women, and special situations. Part I covered histopathology and molecular pathology, risk factors, presentation and diagnostic approach, surgical approach and adjuvant therapy.
•Context of recurrence drives treatment options to include combination approaches.•Surveillance and survivorship should be tailored for endometrial cancer patients.•Fertility and ovarian preservation can be considered for select patients.•Primary radiation is reasonable for patients who are not surgical candidates.
To review our institutional outcomes of patients treated with radiation therapy (RT) for Graves' orbitopathy (GO), assess the role of orbital reirradiation, and identify prognostic factors of ...complete response (CR).
This is a retrospective review of 211 patients who presented with a diagnosis of GO and received RT between January 2000-2010. RT dose was 20 Gy in 10 fractions. Patient median age was 51 years (range, 15-84 years), median follow-up was 11 months (range, 1-88 months). Patient symptoms included any combination of proptosis (90.9%), extraocular muscle dysfunction (78.9%), soft tissue signs (68.4%), and diplopia (58.4%). Corticosteroids were used as first-line therapy in 20.6% of patients. Among those who achieved either CR or partial response (PR), prognostic factors were evaluated.
Stabilization of disease without recurrence was clinically achieved overall in 202 patients (96.7%). At the completion of RT, 176 patients (84.2%) reported a symptomatic improvement of pretreatment symptoms. CR of GO symptoms was achieved using multiple treatment modalities, including RT by 93 patients (44.5%), of which 32 patients received RT only. Corticosteroids were discontinued in 97.8% of patients who received them as initial therapy. Surgical intervention following radiotherapy was required for 144 (68.9%) of all patients. Fourteen patients received orbital reirradiation for persistent or recurrent symptoms. Five of these achieved a CR, and the other nine achieved disease stabilization but retained persistent ocular symptoms. Long-term side effects of RT included dry eyes (12%). Of the prognostic factors we investigated, only gender predicted CR, which was less common in men (33.9%) than in women (49.7%) p = 0.0471.
Orbital radiation for GO is an established treatment modality for patients. Orbital reirradiation is beneficial for patients who do not respond to initial RT or experience symptom recurrence without an apparent risk of increased morbidity.
Burn injury predisposes patients to significant psychological morbidity, including anxiety, depression, and posttraumatic stress. Adding to the burden of injury, patients often require transfer to ...specialized burn centers located far from home. We hypothesized that greater distances between a patient's home address and the treating burn center would increase the rate of postinjury anxiety and depression. From January 2021 to June 2023, patients who were admitted to our American Burn Association verified center and seen for posthospitalization follow-up were identified. Demographics, burn characteristics, and follow-up anxiety (Generalized Anxiety Disorder-7) and depression (Patient Health Questionnaire-2) screening scores were reviewed. Comparisons between patients with positive and negative screens were performed using univariate analysis followed by logistic regression. Linear regression was used to evaluate the relationship between distance to the burn center and incremental screening scores. Of the 272 patients identified, 35.6% and 27.9% screened positive for anxiety and depression, respectively. The distance to burn center was not greater among patients with positive screens. Likewise, no statistically significant linear relationship was found between distance to the burn center and incremental screening scores. Morphine milligram equivalents on the last day of hospitalization (P = .04) and a prior psychiatric history (P < .001) all predicted postinjury anxiety. Total body surface area burned (P = .02) and a prior psychiatric history (P = .02) predicted postinjury depression. The distance between a patient's home and the treating burn center does not alter anxiety and depression rates following burn injury, further supporting the transfer of patients to specialized centers.
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