NF1 is a tumor suppressor gene and its protein product, neurofibromin, is a negative regulator of the RAS pathway. NF1 is one of the top driver mutations in sporadic breast cancer such that 27 % of ...breast cancers exhibit damaging NF1 alterations. NF1 loss-of-function is a frequent event in the genomic evolution of estrogen receptor (ER)+ breast cancer metastasis and endocrine resistance. Individuals with Neurofibromatosis type 1 (NF) – a disorder caused by germline NF1 mutations – have an increased risk of dying from breast cancer 1–4. NF-related breast cancers are associated with decreased overall survival compared to sporadic breast cancer. Despite numerous studies interrogating the role of RAS mutations in tumor metabolism, no study has comprehensively profiled the NF1-deficient breast cancer metabolome to define patterns of energetic and metabolic reprogramming. The goals of this investigation were (1) to define the role of NF1 deficiency in estrogen receptor-positive (ER+) breast cancer metabolic reprogramming and (2) to identify potential targeted pathway and metabolic inhibitor combination therapies for NF1-deficient ER + breast cancer.
We employed two ER+ NF1-deficient breast cancer models: (1) an NF1-deficient MCF7 breast cancer cell line to model sporadic breast cancer, and (2) three distinct, Nf1-deficient rat models to model NF-related breast cancer 1. IncuCyte proliferation analysis was used to measure the effect of NF1 deficiency on cell proliferation and drug response. Protein quantity was assessed by Western Blot analysis. We then used RNAseq to investigate the transcriptional effect of NF1 deficiency on global and metabolism-related transcription. We measured cellular energetics using Agilent Seahorse XF-96 Glyco Stress Test and Mito Stress Test assays. We performed stable isotope labeling and measured U–13C-glucose and U–13C-glutamine metabolite incorporation and measured total metabolite pools using mass spectrometry. Lastly, we used a Bliss synergy model to investigate NF1-driven changes in targeted and metabolic inhibitor synergy.
Our results revealed that NF1 deficiency enhanced cell proliferation, altered neurofibromin expression, and increased RAS and PI3K/AKT pathway signaling while constraining oxidative ATP production and restricting energetic flexibility. Neurofibromin deficiency also increased glutamine influx into TCA intermediates and dramatically increased lipid pools, especially triglycerides (TG). Lastly, NF1 deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis.
NF1 deficiency drives metabolic reprogramming in ER+ breast cancer. This reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion, and these metabolic changes introduce novel metabolic-to-targeted inhibitor synergies.
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•NF1 deficiency drives metabolic reprogramming in ER + breast cancer.•NF1-driven metabolic reprogramming is characterized by OXPHOS constraints, glutamine TCA influx, and lipid pool expansion.•NF1-deficient ER + breast cancer cells have increased sensitivity to combined RAS and triglyceride synthesis inhibitors.
ABSTRACT
Plants endure environmental stressors via adaptation and phenotypic plasticity. Studying these mechanisms in seagrasses is extremely relevant as they are important primary producers and ...functionally significant carbon sinks. These mechanisms are not well understood at the tissue level in seagrasses. Using RNA-seq, we generated transcriptome sequences from tissue of leaf, basal leaf meristem and root organs of Posidonia australis, establishing baseline in situ transcriptomic profiles for tissues across a salinity gradient. Samples were collected from four P. australis meadows growing in Shark Bay, Western Australia. Analysis of gene expression showed significant differences between tissue types, with more variation among leaves than meristem or roots. Gene ontology enrichment analysis showed the differences were largely due to the role of photosynthesis, plant growth and nutrient absorption in leaf, meristem and root organs, respectively. Differential gene expression of leaf and meristem showed upregulation of salinity regulation processes in higher salinity meadows. Our study highlights the importance of considering leaf meristem tissue when evaluating whole-plant responses to environmental change.
This article has an associated First Person interview with the first author of the paper.
Background:
Few authors have directly compared multiple types of lateralizing calcaneal osteotomies (LCOs) in terms of their ability to achieve deformity correction. The aim of this research was to ...use a digital model of a varus hindfoot to compare 4 different LCOs in terms of deformity correction and amount of tuberosity lateralization required. The authors hypothesis was that osteotomies involving a wedge resection would achieve greater correction with less lateralization.
Methods:
A weightbearing computed tomographic scan of a patient with a varus hindfoot deformity was used to construct a 3-dimensional digital model of the hindfoot, preserving weightbearing alignment. Four different LCOs were modeled: a standard oblique osteotomy, a Dwyer osteotomy, a modified Dwyer osteotomy involving lateralization in addition to wedge resection, and a Malerba Z-type osteotomy with wedge resection and lateralization. Incremental corrections were performed with each osteotomy type, and amount of correction was assessed with a vertical hindfoot angle and measurement of the lateral translation of the most inferior aspect of the calcaneus. Calcaneal length and osteotomy contact surface area were also measured.
Results:
The modified Dwyer osteotomy led to the greatest improvements in the vertical hindfoot angle and lateral translation, followed by the Malerba osteotomy. The standard and Malerba osteotomies allowed the most preservation of calcaneal length; the Malerba and Dwyer osteotomies had the greatest contact surface area.
Conclusion:
LCOs that involve wedge resection as well as lateralization were able to achieve the greatest correction of hindfoot varus.
Clinical Relevance:
For the surgical treatment of cavovarus foot deformities, osteotomies with wedge resection in addition to lateralization enable more powerful correction.
Background:
To date, no study has assessed fulfillment of patients’ expectations after foot and ankle surgery. This study aimed to validate a method of assessing expectation fulfillment in foot/ankle ...patients postoperatively.
Methods:
Preoperatively, patients completed the expectations survey, consisting of 23 questions for domains including pain, ambulation, daily function, exercise, and shoe wear. At 2 years postoperatively, patients answered how much improvement they received for each item cited preoperatively. A fulfillment proportion (FP) was calculated as the amount of improvement received versus the amount of improvement expected. The FP ranges from 0 (no expectations fulfilled), to between 0 and 1 (expectations partially fulfilled), to 1 (expectations met), to greater than 1 (expectations surpassed). Receiver operating characteristic (ROC) curves and areas under the curve (AUCs) with 95% confidence intervals (CIs) were used to compare the expectations survey to other outcome surveys, including Foot and Ankle Outcome Score, improvement, overall fulfillment, Delighted-Terrible scale, and satisfaction.
Results:
Of the 271 patients (mean age 55.4 years, mean BMI 27.5, 65% female), 34% had expectations surpassed (FP >1), 4% had expectations met, 58% had expectations partially fulfilled (FP between 0 and 1), and 5% had no expectations met. The mean FP was 0.84 ± 0.41 (range 0-3.13), indicating partially fulfilled expectations. FP correlated significantly with all outcome measures (P ≤ .007). FP was associated most closely with satisfaction (r = 0.66 95% CI 0.57-0.75; AUC = 0.92 95% CI 0.88-0.96; P < .001) and improvement (r = 0.73 95% CI 0.64-0.81; AUC = 0.94 95% CI 0.91-0.96; P < .001). Based on the associations with satisfaction and improvement outcomes, a clinically important proportion of expectations fulfilled is 0.68, with sensitivity 0.85-0.90 and specificity 0.84-0.86.
Conclusion:
The proportion of expectations fulfilled is a novel patient-centered outcome that correlated with validated outcome measures. The expectations survey may be used by surgeons to counsel patients preoperatively and also to assess patients’ results postoperatively.
Level of Evidence:
Level II, prospective comparative series.
Optimal care for persons with multiple chronic conditions (MCC) requires primary and specialty care continuity, access to multiple providers, social risk assessment, and self-management support. The ...COVID-19 pandemic abruptly changed primary care delivery to increase reliance on telehealth and virtual care. We report on the experiences of individuals with MCC and their family caregivers on managing their health and receiving health care during the initial pandemic.
Semistructured qualitative interviews with 30 patients (19 English speaking, 11 Spanish speaking) plus 9 accompanying care partners, who had 2+ primary care encounters between March 1, 2020, and November 30, 2020, 2+ chronic conditions, and 1 or more self-reported social risks. Questions focused on access to and experiences with care, roles for care partners, and self-management during the first 6 months of the pandemic.
Participants experienced substantial changes in care delivery. The most commonly reported changes were a shift to more virtual relative to in-person care and shifting roles for care partners. Changes fostered new perspectives on self-management and an appreciation of personal resilience and self-reliance. Virtual care was an acceptable complement to in-person care, though not a substitute for periodic in-person visits. It was more acceptable for English speakers and with a usual provider.
New models of care delivery that recognize patient and family resilience and resourcefulness, emphasize provider continuity, and combine virtual and in-person care may support self-management for individuals with MCC and social needs.
Background:
Various factors may affect differences between patient and surgeon expectations. This study aimed to assess associations between patient-reported physical and mental status, ...patient-surgeon communication, and musculoskeletal health literacy with differences in patient and surgeon expectations of foot and ankle surgery.
Methods:
Two hundred two patients scheduled to undergo foot or ankle surgery at an academic hospital were enrolled. Preoperatively, patients and surgeons completed the Hospital for Special Surgery Foot & Ankle Surgery Expectations Survey. Patients also completed Patient-Reported Outcomes Measurement Information System (PROMIS) scores in Physical Function, Pain Interference, Pain Intensity, Depression, and Global Health. Patient-surgeon communication and musculoskeletal health literacy were assessed via the modified Patients’ Perceived Involvement in Care Scale (PICS) and Literacy in Musculoskeletal Problems (LiMP) questionnaire, respectively.
Results:
Greater differences in patient and surgeon overall expectations scores were associated with worse scores in Physical Function (P = .003), Pain Interference (P = .001), Pain Intensity (P = .009), Global Physical Health (P < .001), and Depression (P = .009). A greater difference in the number of expectations between patients and surgeons was associated with all of the above (P ≤ .003) and with worse Global Mental Health (P = .003). Patient perceptions of higher surgeons’ partnership building were associated with a greater number of patient than surgeon expectations (P = .017). There were no associations found between musculoskeletal health literacy and differences in expectations.
Conclusion:
Worse baseline patient physical and mental status and higher patient perceptions of provider partnership building were associated with higher patient than surgeon expectations. It may be beneficial for surgeons to set more realistic expectations with patients who have greater disability and in those whom they have stronger partnerships with. Further studies are warranted to understand how modifications in patient and surgeon interactions and patient health literacy affect agreement in expectations of foot and ankle surgery.
Level of Evidence:
Level II, prospective comparative series.
BACKGROUND
Information comparing characteristics of patients who do and do not pick up their prescriptions is sparse, in part because adherence measured using pharmacy claims databases does not ...include information on patients who never pick up their first prescription, that is, patients with primary non-adherence. Electronic health record medication order entry enhances the potential to identify patients with primary non-adherence, and in organizations with medication order entry and pharmacy information systems, orders can be linked to dispensings to identify primarily non-adherent patients.
OBJECTIVE
This study aims to use database information from an integrated system to compare patient, prescriber, and payment characteristics of patients with primary non-adherence and patients with ongoing dispensings of newly initiated medications for hypertension, diabetes, and/or hyperlipidemia.
DESIGN
This is a retrospective observational cohort study.
PARTICIPANTS (OR PATIENTS OR SUBJECTS)
Participants of this study include patients with a newly initiated order for an antihypertensive, antidiabetic, and/or antihyperlipidemic within an 18-month period.
MAIN MEASURES
Proportion of patients with primary non-adherence overall and by therapeutic class subgroup. Multivariable logistic regression modeling was used to investigate characteristics associated with primary non-adherence relative to ongoing dispensings.
KEY RESULTS
The proportion of primarily non-adherent patients varied by therapeutic class, including 7% of patients ordered an antihypertensive, 11% ordered an antidiabetic, 13% ordered an antihyperlipidemic, and 5% ordered medications from more than one of these therapeutic classes within the study period. Characteristics of patients with primary non-adherence varied across therapeutic classes, but these characteristics had poor ability to explain or predict primary non-adherence (models c-statistics = 0.61–0.63).
CONCLUSIONS
Primary non-adherence varies by therapeutic class. Healthcare delivery systems should pursue linking medication orders with dispensings to identify primarily non-adherent patients. We encourage conduct of research to determine interventions successful at decreasing primary non-adherence, as characteristics available from databases provide little assistance in predicting primary non-adherence.
The number of paralogs of proteins involved in translation initiation is larger in trypanosomes than in yeasts or many metazoan and includes two poly(A) binding proteins, PABP1 and PABP2, and four ...eIF4E variants. In many cases, the paralogs are individually essential and are thus unlikely to have redundant functions although, as yet, distinct functions of different isoforms have not been determined. Here, trypanosome PABP1 and PABP2 have been further characterised. PABP1 and PABP2 diverged subsequent to the differentiation of the Kinetoplastae lineage, supporting the existence of specific aspects of translation initiation regulation. PABP1 and PABP2 exhibit major differences in intracellular localization and distribution on polysome fractionation under various conditions that interfere with mRNA metabolism. Most striking are differences in localization to the four known types of inducible RNP granules. Moreover, only PABP2 but not PABP1 can accumulate in the nucleus. Taken together, these observations indicate that PABP1 and PABP2 likely associate with distinct populations of mRNAs. The differences in localization to inducible RNP granules also apply to paralogs of components of the eIF4F complex: eIF4E1 showed similar localization pattern to PABP2, whereas the localisation of eIF4E4 and eIF4G3 resembled that of PABP1. The grouping of translation initiation as either colocalizing with PABP1 or with PABP2 can be used to complement interaction studies to further define the translation initiation complexes in kinetoplastids.
Category:
Midfoot/Forefoot; Other
Introduction/ Purpose:
Cheilectomy of the first metatarsophalangeal joint (MTP) is employed as an early treatment option to alleviate pain and restore some motion in ...patients with hallux rigidus. A dorsal closing wedge osteotomy of the proximal phalanx (Moberg) is often added to the cheilectomy to theoretically increase functional range of motion of the MTP joint. While cheilectomy with Moberg (OCM) has traditionally been performed through an open dorsal incision exposing the entire joint, percutaneous cheilectomy (PC) has become increasingly popular due to smaller incisions, minimal pain, and quicker recovery; however, few studies have compared the PC to commonly practiced open techniques to determine if the PC could deliver similar outcomes. Therefore, we aimed to compare the patient reported outcomes of PC to open cheilectomy with Moberg osteotomy.
Methods:
This retrospective cohort study included 119 patients who underwent PC or OCM for a diagnosis of hallux rigidus. Patients were included if they were over 18 years old and had preoperative and minimum 1-year postoperative PROMIS scores. Patients were excluded if they had prior cheilectomy or any concomitant procedures on the ipsilateral forefoot. Patients were divided into two groups based on their procedures. Forty-eight patients were classified into the “percutaneous cheilectomy” group (mean age: 60 years) while 71 patients belonged to the “open cheilectomy with Moberg” group (mean age 54.2 years). Preoperative, minimum 1-year postoperative, and preoperative to postoperative change in PROMIS physical function, pain interference, pain intensity, global physical health, global mental health, and depression domains were analyzed between groups. Complications were also noted and compared.
Results:
Preoperatively, the OCM group demonstrated worse physical function, pain interference, pain intensity, and global physical health compared to the PC group. There were no significant differences in mental health-related domains.
Postoperatively, there were no significant differences in any PROMIS domain between groups (Table 1). Length of follow-up was 20.3 months in the PC group and 13.8 months for the OCM group (p <.001). While both groups experienced significant preoperative to postoperative improvement in physical function, pain interference, and pain intensity, in addition to global physical health for the OCM group, the degree of preoperative to postoperative improvement for the OCM group was significantly greater. There were no significant differences in complications between groups.
Conclusion:
While we found a greater degree of improvement in function and pain in the OCM group, postoperative scores were not different from the PC group. This implies that patients undergoing OCM had greater preoperative deficits in pain and function, and thus demonstrated greater improvements to end up with similar postoperative outcomes as the PC group. Therefore, since the percutaneous cheilectomy resulted in similar postoperative function and pain levels, it appears to deliver an adequate surgical treatment when compared to open cheilectomy with Moberg.
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