Correction: Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

[This corrects the article DOI: 10.1371/journal.pone.0140310.].

Epidemiological investigation of foot-and-mouth disease outbreaks in a Vietnamese bear rescue centre.

Foot-and-mouth disease (FMD) outbreaks affecting Asiatic black bears (Ursus thibetanus) and a Malayan sun bear (Helarctos malayanus) were previously reported in 2011 in two housing facilities at a Vietnamese bear rescue centre. In this study, demographic data of all animals housed in the centre at the time of the outbreaks (n = 79) were collected. Blood samples drawn from 23 bears at different timepoints were tested for FMDV-specific antibodies targeting using a non-structural protein (NSP) ELISA and by virus neutralisation test (VNT). The relationship between seroconversion and clinical signs was explored and epidemic curves and transmission diagrams were generated for each outbreak, where FMD cases were defined as animals showing FMD clinical signs. Outbreak-specific attack rates were 18.75 and 77.77%, with corresponding basic reproduction numbers of 1.11 and 1.92, for the first and second outbreaks, respectively. Analyses of risk factors showed that after adjusting for sex there was strong evidence for a decrease in odds of showing clinical signs per year of age. All samples collected from bears before the outbreak tested negative to NSP and VNT. All cases tested positive to VNT following onset of clinical signs and remained positive during the rest of the follow up period, while only 6 out of 17 cases tested positive to NSP after developing clinical signs. Six animals without clinical signs were tested post outbreaks; five seroconverted using VNT and three animals were seropositive using NSP ELISA. This study provides initial epidemiological parameters of FMD in captive bears, showing that FMDV is easily spread between bears in close proximity and can cause clinical and subclinical disease, both of which appear to induce rapid and long-lasting immunity.

Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

The dual role of a highly structured RNA (the S fragment) in the replication of foot-and-mouth disease virus.

Secondary and tertiary RNA structures play key roles in genome replication of single-stranded positive sense RNA viruses. Complex, functional structures are particularly abundant in the untranslated regions of picornaviruses, where they are involved in initiation of translation, priming of new strand synthesis and genome circularization. The 5' UTR of foot-and-mouth disease virus (FMDV) is predicted to include a c. 360 nucleotide-long stem-loop, termed the short (S) fragment. This structure is highly conserved and essential for viral replication, but the precise function(s) are unclear. Here, we used selective 2' hydroxyl acetylation analyzed by primer extension (SHAPE) to experimentally determine aspects of the structure, alongside comparative genomic analyses to confirm structure conservation from a wide range of field isolates. To examine its role in virus replication in cell culture, we introduced a series of deletions to the distal and proximal regions of the stem-loop. These truncations affected genome replication in a size-dependent and, in some cases, host cell-dependent manner. Furthermore, during the passage of viruses incorporating the largest tolerated deletion from the proximal region of the S fragment stem-loop, an additional mutation was selected in the viral RNA-dependent RNA polymerase, 3Dpol. These data suggest that the S fragment and 3Dpol interact in the formation of the FMDV replication complex.

CX-5461 Preferentially Induces Top2α-Dependent DNA Breaks at Ribosomal DNA Loci.

While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous work demonstrating that the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 elicits a non-canonical DNA damage response and our discovery of a critical role for Topoisomerase 2α (Top2α) in the initiation of Pol I-dependent transcription. Here, we identify Top2α as a mediator of CX-5461 response in the murine Eµ-Myc B lymphoma model whereby sensitivity to CX-5461 is dependent on cellular Top2α expression/activity. Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs.

Impact of Marijuana Use on Lung Health.

The widespread use of marijuana in the context of increasing legalization has both short- and long-term health implications. Although various modes of marijuana use-smoked, vaped, or ingested-may lead to a wide scope of potential systemic effects, we focus here on inhalational use of marijuana as the most common mode with the lung as the organ that is most directly exposed to its effects. Smoked marijuana has been associated with symptoms of chronic bronchitis and histopathologic changes in airway epithelium, but without consistent evidence of long-term decline in pulmonary function. Its role in immunomodulation, both for risk of infection and protection against a hyperinflammatory host response to infection, has been suggested in animal models and in vitro without conclusive extrapolation to humans. Marijuana smoke contains carcinogens like those found in tobacco, raising concern about its role in lung cancer, but evidence is mixed and made challenging by concurrent tobacco use. Vaping may offer a potential degree of harm reduction when compared with smoking marijuana with reduction of exposure to several toxins, including carbon monoxide, and reduction in chronic respiratory symptoms. However, these potential benefits are counterbalanced by risks including vaping-associated lung injury, potentially more intense drug exposure, and other yet not well-understood toxicities. As more states legalize marijuana and the federal government considers changing this from a Schedule I to a Schedule III controlled substance, we anticipate an increase in prospective medical studies concerning the risks related to marijuana use. This review is based on currently available data concerning the impact of inhaled marijuana on lung health.

Anesthetic Considerations for Carbon Dioxide Emboli in Patients with Obesity - A Case Report.

Gas embolization is a rare but potentially deadly complication of any laparoscopic surgery. There has only been one other report of gas emboli in patients undergoing bariatric surgery. We present a case of gas embolization in a young female patient undergoing Roux-en-Y gastric bypass. Onset of gas embolus was identified by a dramatic drop in End Tidal Carbon Dioxide (ETCO2) followed by drops in blood pressure, heart rate, and oxygen saturation over the following 15 minutes before the patient was stabilized and transferred to the ICU. The surgery was completed three days later without incident, and extensive hepatomegaly was identified. A discussion on pre-operative evaluation, special considerations, and acute management of gas embolization in patients with obesity ensues. We highlight the emerging Jain's point for insufflation, the potential for ultrasound-guided Verres needle insertion, and the paucity of literature evaluating the risk, incidence, and outcomes of gas embolization in patients with obesity.

EstroGene2.0: A multi-omic database of response to estrogens, ER-modulators, and resistance to endocrine therapies in breast cancer.

Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing drugs and to develop new ER-modulators. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed substantial diversity in response to different classes of ER-modulators including SERMs, SERDs, SERCA and LDD/PROTAC. Notably, endocrine resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signaling, which is recapitulated clinically. Furthermore, dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of genome-edited versus ectopic overexpression model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.

Association of bronchial disease on CT imaging and clinical definitions of chronic bronchitis in a single-center COPD phenotyping study.

INTRODUCTION: Chronic Bronchitis (CB) represents a phenotype of chronic obstructive pulmonary disease (COPD). While several definitions have been used for diagnosis, the relationship between clinical definitions and radiologic assessment of bronchial disease (BD) has not been well studied. The aim of this study was to evaluate the relationship between three clinical definitions of CB and radiographic findings of BD in spirometry-defined COPD patients. METHODS: A cross-sectional analysis was performed from a COPD phenotyping study. It was a prospective observational cohort. Participants had spirometry-defined COPD and available chest CT imaging. Comparison between CB definitions, Medical Research Council (CBMRC), St. George's Respiratory Questionnaire (CBSGRQ), COPD Assessment Test (CBCAT) and CT findings were performed using Cohen's Kappa, univariate and multivariate logistic regressions. RESULTS: Of 112 participants, 83 met inclusion criteria. Demographics included age of 70.1 ± 7.0 years old, predominantly male (59.0 %), 45.8 ± 30.8 pack-year history, 21.7 % actively smoking, and mean FEV1 61.5 ± 21.1 %. With MRC, SGRQ and CAT definitions, 22.9 %, 36.6 % and 28.0 % had CB, respectively. BD was more often present in CB compared to non-CB patients; however, it did not have a statistically significant relationship between any of the CB definitions. CBSGRQ had better agreement with radiographically assessed BD compared to the other two definitions. CONCLUSION: Identification of BD on CT was associated with the diagnoses of CB. However, agreement between imaging and definitions were not significant, suggesting radiologic findings of BD and criteria defining CB may not identify the same COPD phenotype. Research to standardize imaging and clinical methods is needed for more objective identification of COPD phenotypes.

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting.

OBJECTIVE: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. RESULTS: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. CONCLUSIONS: Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.

A hot-Jupiter progenitor on a super-eccentric retrograde orbit.

Giant exoplanets orbiting close to their host stars are unlikely to have formed in their present configurations1. These 'hot Jupiter' planets are instead thought to have migrated inward from beyond the ice line and several viable migration channels have been proposed, including eccentricity excitation through angular-momentum exchange with a third body followed by tidally driven orbital circularization2,3. The discovery of the extremely eccentric (e = 0.93) giant exoplanet HD 80606 b (ref. 4) provided observational evidence that hot Jupiters may have formed through this high-eccentricity tidal-migration pathway5. However, no similar hot-Jupiter progenitors have been found and simulations predict that one factor affecting the efficacy of this mechanism is exoplanet mass, as low-mass planets are more likely to be tidally disrupted during periastron passage6-8. Here we present spectroscopic and photometric observations of TIC 241249530 b, a high-mass, transiting warm Jupiter with an extreme orbital eccentricity of e = 0.94. The orbit of TIC 241249530 b is consistent with a history of eccentricity oscillations and a future tidal circularization trajectory. Our analysis of the mass and eccentricity distributions of the transiting-warm-Jupiter population further reveals a correlation between high mass and high eccentricity.

Long term rescue of Alzheimer's deficits in vivo by one-time gene-editing of App C-terminus.

Gene-editing technologies promise to create a new class of therapeutics that can achieve permanent correction with a single intervention. Besides eliminating mutant alleles in familial disease, gene-editing can also be used to favorably manipulate upstream pathophysiologic events and alter disease-course in wider patient populations, but few such feasible therapeutic avenues have been reported. Here we use CRISPR-Cas9 to edit the last exon of amyloid precursor protein (App), relevant for Alzheimer's disease (AD). Our strategy effectively eliminates an endocytic (YENPTY) motif at APP C-terminus, while preserving the N-terminus and compensatory APP-homologues. This manipulation favorably alters events along the amyloid-pathway - inhibiting toxic APP-ß-cleavage fragments (including Aß) and upregulating neuroprotective APP-α-cleavage products. AAV-driven editing ameliorates neuropathologic, electrophysiologic, and behavioral deficits in an AD knockin mouse model. Effects persist for many months, and no abnormalities are seen in WT mice even after germline App-editing; underlining overall efficacy and safety. Pathologic alterations in the glial-transcriptome of App-KI mice, as seen by single nuclei RNA-sequencing (sNuc-Seq), are also normalized by App C-terminus editing. Our strategy takes advantage of innate transcriptional rules that render terminal exons insensitive to nonsense-decay, and the upstream manipulation is expected to be effective for all forms of AD. These studies offer a path for a one-time disease-modifying treatment for AD.

Foot and Mouth Disease Vaccine Matching and Post-Vaccination Assessment in Abu Dhabi, United Arab Emirates.

Despite the annual vaccination of livestock against foot and mouth disease (FMD) in the United Arab Emirates (UAE), outbreaks of the disease continue to be reported. The effective control of field outbreaks by vaccination requires that the vaccines used are antigenically matched to circulating field FMD viruses. In this study, a vaccine matching analysis was performed using the two-dimensional virus neutralization test (VNT) for three field isolates belonging to the O/ME-SA/PanAsia-2/ANT-10 and O/ME-SA/SA-2018 lineages collected from different FMD outbreaks that occurred within the Abu Dhabi Emirate in 2021 affecting Arabian oryx (Oryx leucoryx), goat, and sheep. In addition, post-vaccination antibodies in sheep and goats were measured using solid-phase competitive ELISA (SPCE) for FMDV serotypes A and O at five months after a single vaccine dose and a further 28 days later after a second dose of the FMD vaccine. An analysis of vaccine matching revealed that five out of the six vaccine strains tested were antigenically matched to the UAE field isolates, with r1-values ranging between 0.32 and 0.75. These results suggest that the vaccine strains (O-3039 and O1 Manisa) included in the FMD vaccine used in the Abu Dhabi Emirate are likely to provide protection against outbreaks caused by the circulating O/ME-SA/PanAsia-2/ANT-10 and O/ME-SA/SA-2018 lineages. All critical residues at site 1 and site 3 of VP1 were conserved in all isolates, although an analysis of the VP1-encoding sequences revealed 14-16 amino acid substitutions compared to the sequence of the O1 Manisa vaccine strain. This study also reports on the results of post-vaccination monitoring where the immunization coverage rates against FMDV serotypes A and O were 47% and 69% five months after the first dose of the FMD vaccine, and they were increased to 81 and 88%, respectively, 28 days after the second dose of the vaccine. These results reinforce the importance of using a second booster dose to maximize the impact of vaccination. In conclusion, the vaccine strains currently used in Abu Dhabi are antigenically matched to circulating field isolates from two serotype O clades (O/ME-SA/PanAsia-2/ANT-10 sublineage and O/ME-SA/SA-2018 lineage). The bi-annual vaccination schedule for FMD in the Abu Dhabi Emirate has the potential to establish a sufficient herd immunity, especially when complemented by additional biosecurity measures for comprehensive FMD control. These findings are pivotal for the successful implementation of the region's vaccination-based FMD control policy, showing that high vaccination coverage and the wide-spread use of booster doses in susceptible herds is required to achieve a high level of FMDV-specific antibodies in vaccinated animals.

Reconstructive breast implant-related infections: Prevention, diagnosis, treatment, and pearls of wisdom.

Implant-based reconstructions are increasingly utilized following mastectomy in the prevention and treatment of breast cancer. However, these implants are associated with a high rate of infection, which is a major complication that can lead to implant removal, delay in adjuvant radiation and chemotherapy, and increase in health care costs. Early clinical signs and symptoms of infection, such as erythema, warmth, and tenderness, are challenging to discern from expected postsurgical responses. Furthermore, when atypical features are present or the patient's condition does not improve on adequate antimicrobials, the clinician should be prompted to consider an alternative noninfectious etiology. Herein we highlight the key elements of the preventive, diagnostic, and multidisciplinary therapeutic approach to salvaging the infected breast implant; review several infectious disease mimickers; and provide many pearls of wisdom that the practicing clinician must be familiar with and be able to manage in an effective and successful manner.

Multi-institutional Protocol Guidance for Pediatric Photon-counting CT.

Performing CT in children comes with unique challenges such as greater degrees of patient motion, smaller and densely packed anatomy, and potential risks of radiation exposure. The technical advancements of photon-counting detector (PCD) CT enable decreased radiation dose and noise, as well as increased spatial and contrast resolution across all ages, compared with conventional energy-integrating detector CT. It is therefore valuable to review the relevant technical aspects and principles specific to protocol development on the new PCD CT platform to realize the potential benefits for this population. The purpose of this article, based on multi-institutional clinical and research experience from pediatric radiologists and medical physicists, is to provide protocol guidance for use of PCD CT in the imaging of pediatric patients.

Emerging Trends in the Prevalence of Military Medicine Interest Groups and Specialty Tracks at U.S. Medical Schools.

INTRODUCTION: A challenge confronting health care is the national physician shortage, notably impacting the DoD's recruitment of military physicians. To address this, the Health Professions Scholarship Program is annually awarded to medical students to facilitate their transition into the U.S. Armed Forces. There is a glaring absence of military medical education in civilian schools to accommodate the unique interests of these students. While medical schools have adapted with interest groups and specialty tracks, the current presence of military medicine interest groups (MMIGs) and military medicine specialty tracks (MMSTs) remains under-explored. This study aimed to (1) update the prevalence of MMIGs in U.S. medical institutions, (2) identify the presence of MMSTs, and (3) compare military medicine involvement between allopathic and osteopathic programs. METHODS: The study was approved for exempt status from the Kansas City University Institutional Review Board (study number 20,211,568-1). In a cross-sectional analysis, surveys were sent to 208 U.S. medical schools, with responses from student services or available public data from 200 institutions included in the final analysis. A secondary survey was sent to respondents who provided MMIG or MMST contacts. RESULTS: Results indicated that 62% (n = 124/200) of schools currently have an established MMIG, a modest growth from 56% (n = 70/125) in 2015 (p = .14). MMST prevalence, however, is minimal at 2.5% (5/200). Osteopathic institutions demonstrated a significantly greater engagement in military medicine education (88.7%) compared to allopathic schools (52.4%) (p < .001). CONCLUSION: This research underscores the need for comprehensive military medical training in medical schools to meet the interests and career aspirations of their students. Future studies should also evaluate the efficacy of MMIGs and MMSTs in preparing students for military medical roles.

Re-emergence of foot-and-mouth disease in the Republic of Korea caused by the O/ME-SA/Ind-2001e lineage.

The O/ME-SA/Ind-2001e foot-and-mouth disease virus (FMDV) lineage is a pandemic strain that has recently become dominant within East and Southeast Asia. During May 2023, this viral lineage spread to the Republic of Korea, where 11 outbreaks were detected on cattle and goat farms located in Cheongju and Jeungpyeong. Infected animals displayed typical FMD signs including vesicular lesions with drooling and anorexia. Molecular diagnostic testing and genetic analysis (VP1 sequencing) showed that the causative FMDVs belonged to the O/ME-SA/Ind-2001e lineage and shared the closest nucleotide identity (97.95-99.21%) to viruses that have been collected from Mongolia and South-East Asian countries. Phylogenetic analyses showed that these sequences were distinct to those collected from the previous Korean O/ME-SA/Ind-2001e lineage outbreaks in 2019, demonstrating that these cases are due to a new incursion of the virus into the country. Prompt implementation of emergency vaccination using antigenically matched serotype O vaccines (r1 value: 0.74-0.93), together with intensive active surveillance on farms surrounding the infected premises has successfully prevented further spread of FMD. These recent FMD outbreaks reinforce the importance of research to understand the risks associated with transboundary pathways in the region, in order to reduce the possibility of a further reintroduction of FMD into the Republic of Korea.