Eco-evolutionary Guided Pathomic Analysis to Predict DCIS Upstaging.

Cancers evolve in a dynamic ecosystem. Thus, characterizing cancer's ecological dynamics is crucial to understanding cancer evolution and can lead to discovering novel biomarkers to predict disease progression. Ductal carcinoma in situ (DCIS) is an early-stage breast cancer characterized by abnormal epithelial cell growth confined within the milk ducts. Although there has been extensive research on genetic and epigenetic causes of breast carcinogenesis, none of these studies have successfully identified a biomarker for the progression and/or upstaging of DCIS. In this study, we show that ecological habitat analysis of hypoxia and acidosis biomarkers can significantly improve prediction of DCIS upstaging. First, we developed a novel eco-evolutionary designed approach to define habitats in the tumor intra-ductal microenvironment based on oxygen diffusion distance in our DCIS cohort of 84 patients. Then, we identify cancer cells with metabolic phenotypes attributed to their habitat conditions, such as the expression of CA9 indicating hypoxia responding phenotype, and LAMP2b indicating a hypoxia-induced acid adaptation. Traditionally these markers have shown limited predictive capabilities for DCIS upstaging, if any. However, when analyzed from an ecological perspective, their power to differentiate between indolent and upstaged DCIS increased significantly. Second, using eco-evolutionary guided computational and digital pathology techniques, we discovered distinct spatial patterns of these biomarkers and used the distribution of such patterns to predict patient upstaging. The patterns were characterized by both cellular features and spatial features. With a 5-fold validation on the biopsy cohort, we trained a random forest classifier to achieve the area under curve(AUC) of 0.74. Our results affirm the importance of using eco-evolutionary-designed approaches in biomarkers discovery studies in the era of digital pathology by demonstrating the role of eco-evolution dynamics in predicting cancer progression.

Tepilamide Fumarate as a Novel Potentiator of Virus-Based Therapy.

Oncolytic virotherapy, using viruses such as vesicular stomatitis virus (VSVΔ51) and Herpes Simplex Virus-1 (HSV-1) to selectively attack cancer cells, faces challenges such as cellular resistance mediated by the interferon (IFN) response. Dimethyl fumarate (DMF) is used in the treatment of multiple sclerosis and psoriasis and is recognized for its anti-cancer properties and has been shown to enhance both VSVΔ51 and HSV-1 oncolytic activity. Tepilamide fumarate (TPF) is a DMF analog currently undergoing clinical trials for the treatment of moderate-to-severe plaque psoriasis. The aim of this study was to evaluate the potential of TPF in enhancing the effectiveness of oncolytic viruses. In vitro, TPF treatment rendered 786-0 carcinoma cells more susceptible to VSVΔ51 infection, leading to increased viral replication. It outperformed DMF in both increasing viral infection and increasing the killing of these resistant cancer cells and other cancer cell lines tested. Ex vivo studies demonstrated TPF's selective boosting of oncolytic virus infection in cancer cells without affecting healthy tissues. Effectiveness was notably high in pancreatic and ovarian tumor samples. Our study further indicates that TPF can downregulate the IFN pathway through a similar mechanism to DMF, making resistant cancer cells more vulnerable to viral infection. Furthermore, TPF's impact on gene therapy was assessed, revealing its ability to enhance the transduction efficiency of vectors such as lentivirus, adenovirus type 5, and adeno-associated virus type 2 across various cell lines. This data underscore TPF's potential role in not only oncolytic virotherapy but also in the broader application of gene therapy. Collectively, these findings position TPF as a promising agent in oncolytic virotherapy, warranting further exploration of its therapeutic potential.

Fluorescently Tagged Verticillium dahliae to Understand the Infection Process on Cotton (Gossypium hirsutum) and Weed Plant Species.

Verticillium wilt is a soil-borne disease caused by distinct vegetative compatibility groups (VCG) of the fungus Verticillium dahliae. Defoliating (VCG 1A) and non-defoliating (VCG 2A) pathotypes of V. dahliae have contributed to yield losses of cotton production in Australia. To study the virulence and the infection process of V. dahliae on cotton, two isolates, one representing each VCG, have been transformed with fluorescent protein genes. The transformants maintained their ability to infect the host, and both strains were observed to move through the plant vasculature to induce wilt symptoms. Furthermore, virulence testing suggests that the cotton V. dahliae strains can endophytically colonise common weed plant species found in the Australian landscape, and that is contrasted by their ability to infect and colonise native tobacco plants. The fluorescently labelled strains of V. dahliae not only allowed us to gain a thorough understanding of the infection process but also provided a method to rapidly identify recovered isolates from host colonisation studies.

Awake Combined Spinal Caudal Anesthesia for Longer-Duration Urologic Surgery in Infants: A Case Series.

Awake combined spinal caudal anesthesia has been used as an anesthetic technique for longer-duration infraumbilical surgeries in infants. Literature on the safety and feasibility of this technique is limited. We share our experience with 27 infants undergoing longer-duration urologic surgery using awake combined spinal and caudal anesthesia without the use of systemic sedatives or inhalational agents. We describe our technique, safety considerations, and details surrounding the optimal timing of caudal catheter activation for prolongation of surgical anesthesia.

Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes.

Patients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival. Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology and mechanisms that couple T2D to TNBC outcomes are poorly understood. Here we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72h). EMT, proliferation and angiogenesis were elevated in IR vs. control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis. Significance: IR adipocyte exosomes modify TME, increase EMT and promote metastasis to distant organs, likely through miRNA pathways. We suggest metabolic diseases such as T2D reshape the TME, promoting metastasis and decreasing survival. Therefore, TNBC patients with T2D should be closely monitored for metastasis, with metabolic medications considered.

Outcomes Following Surgical Fixation of Distal Radius Fractures in Patients With Chronic Kidney Disease.

Purpose: Moderate-to-severe chronic kidney disease (CKD, stages III-IV) and end-stage renal disease (ESRD or CKD stage V) are known to be independent risk factors for fragility fracture. Altered bone and mineral metabolism contributes to greater complications and mortality rates in the setting of fractures, although most existing literature is limited to hip fractures. We hypothesized that patients with moderate-to-severe CKD or ESRD would have greater complication rates after surgical treatment of distal radius fractures compared with those without CKD. Methods: We retrospectively identified all patients at a level 1 trauma center between 2008 and 2018 who had a diagnosis of stage III-IV CKD or ESRD at the time of operative fixation of a distal radius fracture. We recorded demographic data, comorbidities, and surgical complications. Data for readmissions within 90 days and 1-year mortality were collected. A 2:1 sex-matched control group without CKD who underwent distal radius fixation was selected for comparison, with age-adjusted analysis. Results: A total of 32 patients with CKD (78.1% CKD stage III/IV, 21.9% ESRD) and 62 without CKD were identified. The mean age was 67 ± 12 years in the CKD group and 55 ± 15 years in the control group. The CKD group had a higher Charlson Comorbidity Index (5.7 vs 2.0). Surgical complication rate in the CKD group was 12.5% (12.0% CKD III/IV; 14.3% ESRD). Neither early nor late surgical complication rates were statistically different from those in patients without CKD. Reoperation rate as well as 30- and 90-day readmission rates were similar between groups. Overall, 1-year mortality was greater in the CKD group (9.4% vs 0%). Conclusions: Surgical complications and readmission rates are similar in patients with and without CKD after distal radius fracture fixation. However, 1-year mortality rate is significantly higher after distal radius fixation in patients with moderate-to-severe CKD or ESRD. Type of study/level of evidence: Prognostic IIIa.

Outcomes Following Surgical Fixation of Upper Extremity Fractures in Patients with Chronic Kidney Disease.

Purpose: Moderate to severe (stage III-IV) chronic kidney disease (CKD) and end stage renal disease (ESRD) have been shown to be independent risk factors for sustaining a fragility fracture. High rates of complications and mortality are associated with fracture fixation in patients with CKD, but existing literature is limited. It is unknown how CKD stage III-IV or ESRD affects outcomes in upper-extremity fractures. We hypothesize that patients with CKD stage III-IV or ESRD will have high complication rates after surgical fixation of upper extremity fractures. Methods: We identified all patients between 2008 and 2018 who underwent operative fixation of an upper extremity fracture proximal to the distal radius with a diagnosis of CKD stage III-IV or ESRD at the time of injury. Those with an acute kidney injury at the time of injury or a history of a kidney transplant were excluded. Demographics, medical complications, and surgical complications were collected retrospectively. Data on readmissions within 90 days and mortality within 1 year were also collected. Results: Thirty-five patients were identified. Three patients had ESRD. Fractures included two clavicle, twelve proximal humerus, one humeral shaft, ten distal humerus, five olecranon, two ulnar shaft, one radial shaft, and two both-bone forearm fractures. In total, 91.4% of fractures were closed injuries. Surgical complications occurred in 40% of patients. The reoperation rate was 11.4%, and all cases of reoperation involved hardware removal. The all-cause 90-day readmission rate was 34.3%. The 1-year mortality rate was 8.6%. Conclusions: Surgical complications occurred in 40% of patients with CKD stage III-IV or ESRD who underwent fixation for an upper extremity fracture. It is important to counsel these patients regarding their high risk for complications. Further research is needed to investigate and identify how to mitigate risk. Type of study/level of evidence: Prognostic IV.

Predictors of Substance Use Initiation by Early Adolescence.

OBJECTIVE: Substance use initiation during early adolescence is associated with later development of substance use and mental health disorders. This study used various domains to predict substance use initiation, defined as trying any nonprescribed substance (e.g., alcohol, tobacco, cannabis), by age 12, using a large longitudinal data set. METHODS: Substance-naive youths from the Adolescent Brain Cognitive Development Study (ages 9-10; N=6,829) were followed for 3 years. A total of 420 variables were examined as predictors of substance use initiation, using a penalized logistic regression with elastic net; domains spanned demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, culture and environment, hormones, neurocognitive functioning, and structural neuroimaging. RESULTS: By age 12, 982 (14.4%) children reported substance initiation, with alcohol being the most common. Models with only self-report predictors had similar prediction performance to models adding hormones, neurocognitive factors, and neuroimaging predictors (AUCtest=0.66). Sociodemographic factors were the most robust predictors, followed by cultural and environmental factors, physical health factors, and parenting behaviors. The top predictor was a religious preference of Mormon (coefficient=-0.87), followed by a religious preference for Jewish (coefficient=0.32), and by Black youths (coefficient=-0.32). CONCLUSIONS: Sociodemographic variables were the most robust predictors of substance use initiation. Adding resource-intensive measures, including hormones, neurocognitive assessment, and structural neuroimaging, did not improve prediction of substance use initiation. The application of these large-scale findings in clinical settings could help to streamline and tailor prevention and early intervention efforts.

Combination radiofrequency ablation and vertebral cement augmentation for spinal metastatic tumors: A systematic review and meta-analysis of safety and treatment outcomes.

Background: The treatment of spine metastases continues to pose a significant clinical challenge, requiring the integration of multiple therapeutic modalities to address the multifactorial aspects of this disease process. Radiofrequency ablation (RFA) and vertebral cement augmentation (VCA) are 2 less invasive modalities compared to open surgery that have emerged as promising strategies, offering the potential for both pain relief and preservation of vertebral stability. The utility of these approaches, however, remains uncertain and subject to ongoing investigation.This systematic review and meta-analysis evaluates the available evidence and synthesize the results of studies that have investigated the combination of RFA and VCA for the treatment of spinal metastases, with the goal of providing a comprehensive and up-to-date assessment of the efficacy and safety of this therapeutic approach. Methods: A literature search was conducted using the electronic databases PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus from their inception to May 4th, 2022 in accordance with PRISMA guidelines. Studies were included if they met the following criteria: 1) spine metastases treated with RFA in combination with VCA, 2) available data on at least one outcome (i.e., pain palliation, complications, local tumor control), 3) prospective or retrospective studies with at least 10 patients, and 4) English language. Meta-analyses were conducted in R (R Foundation for Statistical Computing; Vienna, Austria), using the meta package. Results: In the 25 included studies, a total of 947 patients (females=53.9%) underwent RFA + VCA for spinal metastatic tumors. Out of 1,163 metastatic lesions, the majority were located in the lumbar region (585/1,163 [50.3%]) followed by thoracic (519/1,163 [44.6%]), sacrum (39/1,163 [3.4%]), and cervical (2/1,163 [0.2%]). 48/72 [66.7%] metastatic lesions expanded into the posterior elements. Preoperative pathologic vertebral fractures were identified in 115/176 [65.3%] patients. Between pre-procedure pain scores and postprocedure pain scores, average follow-up (FU) was 4.41±2.87 months. Pain scores improved significantly at a short-term FU (1-6 months), with a pooled mean difference (MD) from baseline of 4.82 (95% CI, 4.48-5.16). The overall local tumor progression (LTP) rate at short-term FU (1-6 months) was 5% (95% CI, 1%-8%), at mid-term FU (6-12 months) was 22% (95% CI, 0%-48%), and at long-term FU (>12 months) was 5% (95% CI, 0%-11%). The pooled incidence of total complications was 1% (95% CI, 0%-1%), the most frequent of which were transient radicular pain and asymptomatic cement extravasation. Conclusions: The findings of this meta-analysis reveal that the implementation of RFA in conjunction with VCA for the treatment of spinal metastatic tumors resulted in a significant short-term reduction of pain, with minimal total complications. The LTP rate was additionally low. The clinical efficacy and safety of this technique are established, although further exploration of the long-term outcomes of RFA+VCA is warranted.

Evidence-Based Performance Measures for Reconstruction after Skin Cancer Resection: A Multidisciplinary Performance Measure Set.

BACKGROUND: The American Society of Plastic Surgeons commissioned the multidisciplinary Performance Measure Development Work Group on Reconstruction after Skin Cancer Resection to identify and draft quality measures for the care of patients undergoing skin cancer reconstruction. Included stakeholders were the American Academy of Otolaryngology-Head and Neck Surgery, the American Academy of Facial Plastic and Reconstructive Surgery, the American Academy of Dermatology, the American Society of Dermatologic Surgery, the American College of Mohs Surgery, the American Society for Mohs Surgery, and a patient representative. METHODS: Two outcome measures and five process measures were identified. The outcome measures included the following: (1) patient satisfaction with information provided by their surgeon before their facial procedure, and (2) postprocedural urgent care or emergency room use. The process measures focus on antibiotic stewardship, anticoagulation continuation and/or coordination of care, opioid avoidance, and verification of clear margins. RESULTS: All measures in this report were approved by the American Society of Plastic Surgeons Quality and Performance Measures Work Group and Executive Committee, and the stakeholder societies. CONCLUSION: The work group recommends the use of these measures for quality initiatives, Continuing Medical Education, Continuous Certification, Qualified Clinical Data Registry reporting, and national quality reporting programs.

Patient-reported hip pain and function are worse among elite Nordic ski athletes competing in ski jumping versus Nordic combined: a cross-sectional analysis.

OBJECTIVES: Nordic ski athletes are at increased risk of developing hip pain and dysfunction secondary to femoroacetabular impingement syndrome (FAIS), but it is unclear whether hip symptomatology differs between ski jumping (SJ) and Nordic combined (NC) athletes. The purpose of this study was to compare patient-reported hip pain and dysfunction between elite Nordic ski athletes participating in SJ versus NC. METHODS: A cross-sectional study was conducted involving SJ and NC athletes who competed at the international and U.S. national levels during the 2021-2022 season. Subjects were excluded if they had hip surgery within two years prior to enrollment. Subjects were asked to undergo diagnostic workups for FAIS, including physical examination and plain radiographic imaging. Subjects were asked to complete a survey that collected information on athletic and training history and to complete the hip disability and osteoarthritis outcome score (HOOS). Demographics, athletic/training history, and HOOS sub-scores were compared between the SJ and NC groups using the Student's t-test, Wilcoxon rank-sum test, or Fisher's exact test, as appropriate. p-values < 0.05 were considered significant. RESULTS: Twenty-four athletes (13 SJ, 11 NC) were included in the study. There were no statistically significant differences in age, sex, BMI, or age of menarche between the two groups (all p â€‹> â€‹0.05). There were also no statistically significant differences in the number of prior sports participated in, total hours of participation in prior sports, or total hours of training in Nordic specialization (all p â€‹> â€‹0.05). Among the 18 athletes who underwent physical examination (9 SJ, 9 NC), there were no statistically significant inter-group differences in hip range of motion or incidence of positive impingement tests (all p â€‹> â€‹0.05). Among the 19 athletes who underwent imaging (9 SJ, 10 NC), there were no statistically significant inter-group differences in the incidence of cam or pincer morphology in at least one hip (all p â€‹> â€‹0.05). SJ athletes had statistically significantly worse HOOS sub-scores for hip symptoms and stiffness, hip function in sports/recreational activities, and hip-related quality of life compared to NC athletes (all p â€‹< â€‹0.05). CONCLUSION: Elite SJ athletes have worse self-reported hip function compared to elite NC athletes, despite comparable demographics, athletic history, and duration of ski training. LEVEL OF EVIDENCE: IV.

Sensitive MRD Detection from Lymphatic Fluid after Surgery in HPV-Associated Oropharyngeal Cancer.

PURPOSE: Our goal was to demonstrate that lymphatic drainage fluid (lymph) has improved sensitivity in quantifying postoperative minimal residual disease (MRD) in locally advanced human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) compared with plasma, and leverage this novel biofluid for patient risk stratification. EXPERIMENTAL DESIGN: We prospectively collected lymph samples from neck drains of 106 patients with HPV (+) OPSCC, along with 67 matched plasma samples, 24 hours after surgery. PCR and next-generation sequencing were used to quantify cancer-associated cell-free HPV (cf-HPV) and tumor-informed variants in lymph and plasma. Next, lymph cf-HPV and variants were compared with TNM stage, extranodal extension (ENE), and composite definitions of high-risk pathology. We then created a machine learning model, informed by lymph MRD and clinicopathologic features, to compare with progression-free survival (PFS). RESULTS: Postoperative lymph was enriched with cf-HPV compared with plasma (P < 0.0001) and correlated with pN2 stage (P = 0.003), ENE (P < 0.0001), and trial-defined pathologic risk criteria (mean AUC = 0.78). In addition, the lymph mutation number and variant allele frequency were higher in pN2 ENE (+) necks than in pN1 ENE (+) (P = 0.03, P = 0.02) or pN0-N1 ENE (-) (P = 0.04, P = 0.03, respectively). The lymph MRD-informed risk model demonstrated inferior PFS in high-risk patients (AUC = 0.96, P < 0.0001). CONCLUSIONS: Variant and cf-HPV quantification, performed in 24-hour postoperative lymph samples, reflects single- and multifeature high-risk pathologic criteria. Incorporating lymphatic MRD and clinicopathologic feature analysis can stratify PFS early after surgery in patients with HPV (+) head and neck cancer. See related commentary by Shannon and Iyer, p. 1223.

Outcomes of Humerus Nonunion Surgery in Patients With Initial Operative Fracture Fixation.

OBJECTIVES: To describe outcomes following humerus aseptic nonunion surgery in patients whose initial fracture was treated operatively and to identify risk factors for nonunion surgery failure in the same population. DESIGN: Retrospective case series. SETTING: Eight, academic, level 1 trauma centers. PATIENTS SELECTION CRITERIA: Patients with aseptic humerus nonunion (OTA/AO 11 and 12) after the initial operative management between 1998 and 2019. OUTCOME MEASURES AND COMPARISONS: Success rate of nonunion surgery. RESULTS: Ninety patients were included (56% female; median age 50 years; mean follow-up 21.2 months). Of 90 aseptic humerus nonunions, 71 (78.9%) united following nonunion surgery. Thirty patients (33.3%) experienced 1 or more postoperative complications, including infection, failure of fixation, and readmission. Multivariate analysis found that not performing revision internal fixation during nonunion surgery (n = 8; P = 0.002) and postoperative de novo infection (n = 9; P = 0.005) were associated with an increased risk of recalcitrant nonunion. Patient smoking status and the use of bone graft were not associated with differences in the nonunion repair success rate. CONCLUSIONS: This series of previously operated aseptic humerus nonunions found that more than 1 in 5 patients failed nonunion repair. De novo postoperative infection and failure to perform revision internal fixation during nonunion surgery were associated with recalcitrant nonunion. Smoking and use of bone graft did not influence the success rate of nonunion surgery. These findings can be used to give patients a realistic expectation of results and complications following humerus nonunion surgery. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

ACR Appropriateness Criteria® Breast Implant Evaluation: 2023 Update.

This document discusses the appropriate initial imaging in both asymptomatic and symptomatic patients with breast implants. For asymptomatic patients with saline implants, no imaging is recommended. If concern for rupture exists, ultrasound is usually appropriate though saline rupture is often clinically evident. The FDA recently recommended patients have an initial ultrasound or MRI examination 5 to 6 years after initial silicone implant surgery and then every 2 to 3 years thereafter. In a patient with unexplained axillary adenopathy with current or prior silicone breast implants, ultrasound and/or mammography are usually appropriate, depending on age. In a patient with concern for silicone implant rupture, ultrasound or MRI without contrast is usually appropriate. In the setting of a patient with breast implants and possible implant-associated anaplastic large cell lymphoma, ultrasound is usually appropriate as the initial imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Development and prospective validation of postoperative pain prediction from preoperative EHR data using attention-based set embeddings.

Preoperative knowledge of expected postoperative pain can help guide perioperative pain management and focus interventions on patients with the greatest risk of acute pain. However, current methods for predicting postoperative pain require patient and clinician input or laborious manual chart review and often do not achieve sufficient performance. We use routinely collected electronic health record data from a multicenter dataset of 234,274 adult non-cardiac surgical patients to develop a machine learning method which predicts maximum pain scores on the day of surgery and four subsequent days and validate this method in a prospective cohort. Our method, POPS, is fully automated and relies only on data available prior to surgery, allowing application in all patients scheduled for or considering surgery. Here we report that POPS achieves state-of-the-art performance and outperforms clinician predictions on all postoperative days when predicting maximum pain on the 0-10 NRS in prospective validation, though with degraded calibration. POPS is interpretable, identifying comorbidities that significantly contribute to postoperative pain based on patient-specific context, which can assist clinicians in mitigating cases of acute pain.

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, sensitizes cancer cells to VSVΔ51 oncolytic virotherapy.

The clinical efficacy of VSVΔ51 oncolytic virotherapy has been limited by tumor resistance to viral infection, so strategies to transiently repress antiviral defenses are warranted. Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor currently being tested in clinical trials for its antitumor potential. In this study, we demonstrate that pevonedistat sensitizes human and murine cancer cells to increase oncolytic VSVΔ51 infection, increase tumor cell death, and improve therapeutic outcomes in resistant syngeneic murine cancer models. Increased VSVΔ51 infectivity was also observed in clinical human tumor samples. We further identify the mechanism of this effect to operate via blockade of the type 1 interferon (IFN-1) response through neddylation-dependent interferon-stimulated growth factor 3 (ISGF3) repression and neddylation-independent inhibition of NF-κB nuclear translocation. Together, our results identify a role for neddylation in regulating the innate immune response and demonstrate that pevonedistat can improve the therapeutic outcomes of strategies using oncolytic virotherapy.

VIP interneurons in sensory cortex encode sensory and action signals but not direct reward signals.

Vasoactive intestinal peptide (VIP) interneurons in sensory cortex modulate sensory responses based on global exploratory behavior and arousal state, but their function during non-exploratory, goal-directed behavior is not well understood. In particular, whether VIP cells are activated by sensory cues, reward-seeking actions, or directly by reinforcement is unclear. We trained mice on a Go/NoGo whisker touch detection task that included a delay period and other features designed to separate sensory-evoked, action-related, and reward-related neural activity. Mice had to lick in response to a whisker stimulus to receive a variable-sized reward. Using two-photon calcium imaging, we measured ΔF/F responses of L2/3 VIP neurons in whisker somatosensory cortex (S1) during behavior. In both expert and novice mice, VIP cells were strongly activated by whisker stimuli and goal-directed actions (licking), but not by reinforcement. VIP cells showed somatotopic whisker tuning that was spatially organized relative to anatomical columns in S1, unlike lick-related signals which were spatially widespread. In expert mice, lick-related VIP responses were suppressed, not enhanced, when a reward was delivered, and the amount of suppression increased with reward size. This reward-related suppression was not seen in novice mice, where reward delivery was not yoked to licking. These results indicate that besides arousal and global state variables, VIP cells are activated by local sensory features and goal-directed actions, but not directly by reinforcement. Instead, our results are consistent with a role for VIP cells in encoding the expectation of reward associated with motor actions.

Genetic Mapping, Candidate Gene Identification and Marker Validation for Host Plant Resistance to the Race 4 of Fusarium oxysporum f. sp. cubense Using Musa acuminata ssp. malaccensis.

Fusarium wilt of banana is a devastating disease that has decimated banana production worldwide. Host resistance to Fusarium oxysporum f. sp. Cubense (Foc), the causal agent of this disease, is genetically dissected in this study using two Musa acuminata ssp. Malaccensis segregating populations, segregating for Foc Tropical (TR4) and Subtropical (STR4) race 4 resistance. Marker loci and trait association using 11 SNP-based PCR markers allowed the candidate region to be delimited to a 12.9 cM genetic interval corresponding to a 959 kb region on chromosome 3 of 'DH-Pahang' reference assembly v4. Within this region, there was a cluster of pattern recognition receptors, namely leucine-rich repeat ectodomain containing receptor-like protein kinases, cysteine-rich cell-wall-associated protein kinases, and leaf rust 10 disease-resistance locus receptor-like proteins, positioned in an interspersed arrangement. Their transcript levels were rapidly upregulated in the resistant progenies but not in the susceptible F2 progenies at the onset of infection. This suggests that one or several of these genes may control resistance at this locus. To confirm the segregation of single-gene resistance, we generated an inter-cross between the resistant parent 'Ma850' and a susceptible line 'Ma848', to show that the STR4 resistance co-segregated with marker '28820' at this locus. Finally, an informative SNP marker 29730 allowed the locus-specific resistance to be assessed in a collection of diploid and polyploid banana plants. Of the 60 lines screened, 22 lines were predicted to carry resistance at this locus, including lines known to be TR4-resistant, such as 'Pahang', 'SH-3362', 'SH-3217', 'Ma-ITC0250', and 'DH-Pahang/CIRAD 930'. Additional screening in the International Institute for Tropical Agriculture's collection suggests that the dominant allele is common among the elite 'Matooke' NARITA hybrids, as well as in other triploid or tetraploid hybrids derived from East African highland bananas. Fine mapping and candidate gene identification will allow characterization of molecular mechanisms underlying the TR4 resistance. The markers developed in this study can now aid the marker-assisted selection of TR4 resistance in breeding programs around the world.

Is it blur or is it texture? An analysis of computational blur and texture measures commonly used in medical image analysis.

Purpose: In this work, we endeavor to investigate how texture information may contribute to the response of a blur measure (BM) with motivation rooted in mammography. This is vital as the interpretation of the BM is typically not evaluated with respect to texture present in an image. We are particularly concerned with lower scales of blur (≤1 mm) as this blur is least likely to be detected but can still have a detrimental effect on detectability of microcalcifications. Approach: Three sets of linear models, where BM response was modeled as a linear combination of texture information determined by texture measures (TMs), were constructed from three different datasets of equal-blur-level images; one of computer-generated mammogram-like clustered lumpy background (CLB) images and two image sets derived from the Brodatz texture images. The linear models were refined by removing those TMs that are not significantly non-zero across all three datasets for each BM. We use five levels of Gaussian blur to blur the CLB images and assess the ability of the BMs and TMs to separate the images based on blur level. Results: We found that many TMs used frequently in the reduced linear models, mimicked the structure of the BMs that they modeled. Surprisingly, while none of the BMs could separate the CLB images across all levels of blur, a group of TMs could. These TMs occurred infrequently in the reduced linear models meaning that they rely on different information compared with that used by the BMs. Conclusion: These results confirm our hypothesis that BMs can be influenced by texture information in an image. That a subset of TMs performed better than all BMs on the blur classification problem with the CLB images further shows that conventional BMs may not be the optimal tool for blur classification in mammogram images.