Graphical abstract. Highlights ► RNA is a versatile substrate for encoding sensing, processing, and control functions. ► RNA switches detect molecular and environmental signals to modulate gene ...expression. ► RNA switches interface with endogenous gene networks to regulate cellular functions. ► Applications include environmental remediation and advanced medical interventions.
Receptor tyrosine kinase signaling cooperates with WNT/β-catenin signaling in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent ...activation of WNT/β-catenin by FGFR2, FGFR3, EGFR and TRKA kinases, which is independent of the PI3K/AKT pathway. Instead, this phenotype depends on ERK MAP kinase-mediated phosphorylation of WNT co-receptor LRP6 at Ser1490 and Thr1572 during its Golgi network-based maturation process. This phosphorylation dramatically increases the cellular response to WNT. Moreover, FGFR2, FGFR3, EGFR and TRKA directly phosphorylate β-catenin at Tyr142, which is known to increase cytoplasmic β-catenin concentration via release of β-catenin from membranous cadherin complexes. We conclude that signaling via ERK/LRP6 pathway and direct β-catenin phosphorylation at Tyr142 represent two mechanisms used by various receptor tyrosine kinase systems to activate canonical WNT signaling.
Much To Do About Frailty Berian, Julia R; Wolf, Joshua H; Kunitake, Hiroko
Diseases of the colon & rectum,
04/2022, Letnik:
65, Številka:
4
Journal Article
•Prostate intrafraction rotations are typically non-symmetrical about the pitch axis.•Observed rotations resulted in reduced PTV dose coverage for many patients.•CTV coverage was maintained for ...virtually all observed rotations.•Existing SBRT CTV–PTV margins sufficient to account for intrafraction rotations.
Accurate delivery of radiotherapy is critical to achieve optimal treatment outcomes. Interfraction translational IGRT is now standard, and intrafraction motion management is becoming accessible. Some platforms can report both translational and rotational movements in real time. This study aims to quantify the dosimetric impact of observed intrafraction rotation of the prostate measured using monitoring software.
A dose grid resampling algorithm was used to model the dosimetric impact of prostate rotations for 20 patients on a SBRT prostate clinical trial. Translations were corrected before and during treatment, but rotations were not. Real time rotation data were acquired using KIM and a cumulative histogram analysis performed. Prostate volumes were rotated by the range of observed angles and used to calculate DVH data.
The pitch axis had a higher range of observed rotations resulting in only 7 patients spending at least 90% of the beam on time across all fractions within rotation angles resulting in PTV D95% ≥36 Gy in this axis. The yaw and roll axes saw 17 and 15 patients respectively achieving this criterion. All but one of 20 patients exceeded CTV D98% ≥36 Gy for all observed rotation angles.
Current CTV–PTV margins do not result in compromised CTV dose coverage due to inter and intrafraction prostate rotations in the absence of other uncertainties. Reduced PTV dosing is due to the extremely conformal treatment delivery but is unlikely to be clinically deleterious. Prostate standard IGRT should continue to focus on correcting any observed translational movements. Margin reduction could be explored in conjunction with other uncertainties.
We validated the use of 3-D printed Shepard and Metzler-style shapes in a simultaneous cross-modal (vision & touch) mental rotation procedure. Participants compared a visually presented 3-D shape to ...a 3-D shape they could only feel to determine if the shapes were the same. Participant response time and error rate demonstrated the expected linear increase as the angular disparity of the 3-D printed shapes increased. We expect the freely available data and stimuli from the procedure will be useful to researchers studying both traditional mental rotation and cross-modality mental rotation with complex, highly adaptable, and easy to create shapes.
Patients with Crohn’s disease are particularly susceptible to preoperative frailty owing to the chronic nature of the illness and immunosuppressive therapy. The hypothesis in this study was that ...frailty would have a greater impact on postoperative outcome than age in older individuals with Crohn’s disease.
Data were obtained from the National Surgical Quality Improvement Program (NSQIP) from the years 2012 to 2018. Patients with Crohn’s disease who underwent a bowel resection were identified from diagnostic and procedure codes. Frailty was assessed using the 5-point Simplified Frailty Index (0–not frail, 5–most frail). Age was defined as an ordinal variable with 3 age ranges (18–64, 65–79, >80 years). Aggregate morbidity was classified according to the standard NSQIP definitions. Simplified Frailty Index was evaluated as a potential predictor of morbidity and mortality using covariate-adjusted logistic regression modeling.
A total of 9,023 patients underwent bowel resection for Crohn’s disease during the study period. Patient Simplified Frailty Index ranged from 0 to 3 (Simplified Frailty Index = 0, 82%; 1, 15%; 2, 2.5%; 3, 0.1%), and higher Simplified Frailty Index was associated with increased age (P < .01). In multivariate regression, a Simplified Frailty Index was significantly associated with postoperative morbidity (Simplified Frailty Index ≥ 2: odds ratio = 2.59, 95% confidence interval 1.84–3.63, P < .0001). In contrast, age was not found to be a significant predictor of morbidity when adjusted for Simplified Frailty Index and other covariates (P > .05).
Frailty is a stronger predictor than age for morbidity in Crohn’s-related bowel resection. Functional assessments and vulnerability screening should be used to determine surgical candidacy rather than age alone.
Malnutrition has been associated with adverse surgical outcomes, but data regarding its impact specifically in rectal cancer are sparse. The goal of this study was to use national data to determine ...the effects of malnutrition on surgical outcomes in rectal cancer resection.
Data were obtained from the American College of Surgeons National Surgical Quality Initiative Program from the years 2012-2015. Patients were included on the basis of International Classification of Disease 9/10 and Current Procedural Terminology codes for rectal cancer and proctectomy. Malnutrition was defined as body mass index <18.5 kg/m2, weight loss >10% in 6 mo, or preoperative albumin <3.5 mg/dL. Associations between malnutrition and postoperative outcomes were assessed by the Student t-test and chi-square test. Multivariate regression models were constructed to adjust for potential confounders of the association between malnutrition and surgical outcomes.
Of the 9289 patients with primary rectal cancer who underwent resection, 1425 (15%) were in a state of malnutrition at the time of surgery. Patients with malnutrition had longer mean length of stay (LOS), and higher rates of 30-d mortality, wound infection, organ-space infection, sepsis, reoperation, prolonged LOS (>30 d), failure to wean off ventilator, renal failure, and cardiac arrest. With the exception of LOS, renal failure, and organ-space infection, malnutrition was still significantly associated with higher rates of these adverse outcomes after adjustment for confounders in multivariate regression models.
Malnutrition is a practical marker associated with a variety of adverse outcomes after rectal cancer surgery, and it represents a potential target for nutritional therapies to improve surgical outcomes.
•Increased odds of venous thromboembolism occurrence with increased frailty.•1.85-fold increase in venous thromboembolism odds for modified frailty index ≥3.•Frailty more strongly associated with ...venous thromboembolism than age.•Modified frailty index useful as venous thromboembolism risk stratification tool.
Curative surgery for ulcerative colitis can be subdivided into restorative (with pouch and anastomosis) and non-restorative operations. Restorative surgery in older adults is controversial, due to ...concerns about surgical risk and long-term functional outcome. The goal of this study is to compare 30-day outcomes for restorative and non-restorative surgery in older adults with ulcerative colitis.
Data were obtained from the American College of Surgeons National Surgical Quality Initiative Program from 2012-2018. Patients were included if they were >65 years old and had ulcerative colitis. Restorative and non-restorative surgeries were defined with procedure codes. Patient characteristics and adverse surgical outcomes were compared between restorative and non-restorative surgeries utilizing chi-square tests and Fisher's exact tests. Multivariate logistic regression models were constructed to evaluate the association of restorative versus non-restorative surgery with adverse surgical outcomes while adjusting for potential confounders.
Of 392 total patients, 95 had restorative and 297 had non-restorative surgery. Patients undergoing restorative surgery, compared to non-restorative surgery, were significantly younger (P<0.01), had lower incidences of steroid usage (P<0.001) and higher rates of readmission (P = 0.02). There were no differences in post-operative complications between the groups in both unadjusted analyses and covariate-adjusted regression analysis (P > 0.05).
In carefully selected older patients with ulcerative colitis, restorative surgery is associated with increased readmission, but otherwise similar rates of morbidity or mortality compared to non-restorative surgery. Data regarding postoperative functional outcome and quality of life are also needed to help select the most appropriate curative option for older adults.
Infection is the most important cause of treatment-related morbidity and mortality in pediatric patients treated for acute lymphoblastic leukemia (ALL). Although routine in adults with leukemia, ...antibacterial prophylaxis is controversial in pediatrics because of insufficient evidence for its efficacy or antibiotic choice and concerns about promoting antibiotic resistance and Clostridium difficile infection.
This was a single-center, observational cohort study of patients with newly diagnosed ALL, comparing prospectively collected infection-related outcomes in patients who received no prophylaxis, levofloxacin prophylaxis, or other prophylaxis during induction therapy on the total XVI study. A propensity score-weighted logistic regression model was used to adjust for confounders.
Of 344 included patients, 173 received no prophylaxis, 69 received levofloxacin prophylaxis, and 102 received other prophylaxis regimens. Patients receiving prophylaxis had longer duration of neutropenia. Prophylaxis reduced the odds of febrile neutropenia, likely bacterial infection, and bloodstream infection by ≥70%. Levofloxacin prophylaxis alone reduced these infections, but it also reduced cephalosporin, aminoglycoside, and vancomycin exposure and reduced the odds of C. difficile infection by >95%. No increase in breakthrough infections with antibiotic-resistant organisms was seen, but this cannot be excluded.
This is the largest study to date of antibacterial prophylaxis during induction therapy for pediatric ALL and the first to include a broad-spectrum fluoroquinolone. Prophylaxis prevented febrile neutropenia and systemic infection. Levofloxacin prophylaxis also minimized the use of treatment antibiotics and drastically reduced C. difficile infection. Although long-term antibiotic-resistance monitoring is needed, these data support using targeted prophylaxis with levofloxacin in children undergoing induction chemotherapy for ALL.
NCT00549848.
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