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A 7-tungstabicyclo[4.3.0]nonane complex forms slowly upon addition of cyclohexene to the ethylene complex, W(NAr)(OSiPh3)2(C2H4), at 22 °C. A single-crystal X-ray study showed its structure to be closest to a square pyramid (τ = 0.23). At 22 °C, loss of cyclohexene or ring contraction of the 7-tungstabicyclo[4.3.0]nonane complex is slow. Above ∼80 °C, cyclohexene is ejected to give W(NAr)(OSiPh3)2(C2H4), but a sufficient amount of 7-tungstabicyclo[4.3.0]nonane complex remains in the presence of cyclohexene and the ring contracts to yield methylenecyclohexane and a methylidene complex or ethylene and a cyclohexylidene complex. Other complexes that have been observed include an 8-tungstabicyclo[4.3.0]nonane complex formed from 1,7-octadiene, a 7-tungstabicyclo[4.2.0]octane complex (formed from a methylidene complex and cyclohexene), and a methylenecyclohexane complex. 13C-Labeling studies show that the exo-methylene group in methylenecyclohexane and the α positions in the 8-tungstabicyclo[4.3.0]nonane come from ethylene. An alternative ring contraction of a tungstacyclopentane made from two molecules of cyclohexene cannot be excluded when concentrations of ethylene are low. A cyclohexylidene complex could also form from two cyclohexenes via a newly proposed "alkyl/allyl" mechanism. The results reported here are the first experimental confirmations that a tungstacyclopentane can ring-contract thermally at a substituted WCα position to form a tungstacyclobutane and therefore metathesis-active alkylidenes.

Abstract Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.

High-grade glioma is an aggressive cancer that occurs naturally in pet dogs. Canine high-grade glioma (cHGG) is treated with radiation, chemotherapy or surgery, but has no curative treatment. Within the past eight years, there have been advances in our imaging and histopathology standards as well as genetic charactereization of cHGG. However, there are only three cHGG cell lines publicly available, all of which were derived from astrocytoma and established using methods involving expansion of tumour cells in vitro on plastic dishes. In order to provide more clinically relevant cell lines for studying cHGG in vitro, the goal of this study was to establish cHGG patient-derived lines, whereby cancer cells are expanded in vivo by injecting cells into immunocompromized laboratory mice. The cells are then harvested from mice and used for in vitro studies. This method is the standard in the human field and has been shown to minimize the acquisition of genetic alterations and gene expression changes from the original tumour. Through a multi-institutional collaboration, we describe our methods for establishing two novel cHGG patient-derived lines, Boo-HA and Mo-HO, from a high-grade astrocytoma and a high-grade oligodendroglioma, respectively. We compare our novel lines to G06-A, J3T-Bg, and SDT-3G (traditional cHGG cell lines) in terms of proliferation and sensitivity to radiation. We also perform whole genome sequencing and identify an NF1 truncating mutation in Mo-HO. We report the characterization and availability of these novel patient-derived lines for use by the veterinary community.

Detailed γ-ray spectroscopy of the exotic neon isotope 28Ne has been performed for the first time using the one-neutron removal reaction from 29Ne on a liquid hydrogen target at 240 MeV/nucleon. Based on an analysis of parallel momentum distributions, a level scheme with spin-parity assignments has been constructed for 28Ne and the negative-parity states are identified for the first time. The measured partial cross sections and momentum distributions reveal a significant intruder p-wave strength providing evidence of the breakdown of the N=20 and N=28 shell gaps. Only a weak, possible f-wave strength was observed to bound final states. Large-scale shell-model calculations with different effective interactions do not reproduce the large p-wave and small f-wave strength observed experimentally, indicating an ongoing challenge for a complete theoretical description of the transition into the island of inversion along the Ne isotopic chain.

BackgroundDifficult facemask ventilation is perilous in children whose tracheas are difficult to intubate. We hypothesised that certain physical characteristics and anaesthetic factors are associated with difficult mask ventilation in paediatric patients who also had difficult tracheal intubation.MethodsWe queried a multicentre registry for children who experienced "difficult" or "impossible" facemask ventilation. Patient and case factors known before mask ventilation attempt were included for consideration in this regularised multivariable regression analysis. Incidence of complications, and frequency and efficacy of rescue placement of a supraglottic airway device were also tabulated. Changes in quality of mask ventilation after injection of a neuromuscular blocking agent were assessed.ResultsThe incidence of difficult mask ventilation was 9% (483 of 5453 patients). Infants and patients having increased weight, being less than 5th percentile in weight for age, or having Treacher-Collins syndrome, glossoptosis, or limited mouth opening were more likely to have difficult mask ventilation. Anaesthetic induction using facemask and opioids was associated with decreased risk of difficult mask ventilation. The incidence of complications was significantly higher in patients with "difficult" mask ventilation than in patients without. Rescue placement of a supraglottic airway improved ventilation in 71% (96 of 135) of cases. Administration of neuromuscular blocking agents was more frequently associated with improvement or no change in quality of ventilation than with worsening.ConclusionsCertain abnormalities on physical examination should increase suspicion of possible difficult facemask ventilation. Rescue use of a supraglottic airway device in children with difficult or impossible mask ventilation should be strongly considered.

PurposeAlpelisib is a PI3K alpha (PI3Kα)-selective inhibitor approved for the treatment of hormone receptor-positive/HER2-negative (HR+/HER2-) PIK3CA-mutated advanced breast cancer (ABC) based on the SOLAR-1 trial, which defined 11 substitutions in exons 7, 9, and 20 in PIK3CA (SOLAR1m). We report alpelisib effectiveness for ABC harboring SOLAR1m, as well as other pathogenic PIK3CA mutations (OTHERm) using comprehensive genomic profiling (CGP).Experimental designA total of 33,977 tissue and 1,587 liquid biopsies were analyzed using hybrid capture-based CGP covering the entire coding sequence of PIK3CA. Clinical characteristics and treatment history were available for 10,750 patients with ABC in the deidentified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB).ResultsPIK3CAm were detected in 11,767/33,977 (35%) of tissue biopsies, including 2,300 (7%) samples with OTHERm and no SOLAR1m. Liquid biopsy had 77% sensitivity detecting PIK3CAm, increasing to 95% with circulating tumor DNA fraction ≥2%. In patients with HR+/HER2- ABC and PIK3CAm receiving alpelisib/fulvestrant (ALP+FUL; n = 182) or fulvestrant alone (FUL; n = 119), median real-world progression-free survival (rwPFS) was 5.9 months on ALP+FUL [95% confidence interval (CI): 5.1-7.4] versus 3.1 months on FUL (95% CI: 2.7-3.7; P < 0.0001). In patients with OTHERm, median rwPFS was 4.0 months on ALP+FUL (95% CI: 2.8-10.1) versus 2.5 months on FUL (95% CI: 2.2-3.7; P = 0.0054).ConclusionsCGP detects diverse PIK3CAm in a greater number of patients with ABC than PCR hotspot testing; 20% of patients with PIK3CAm do not have SOLAR1m. These patients may derive benefit from alpelisib. See related commentary by Tau and Miller, p. 989.

Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies. Co-alteration landscapes were largely similar across KRAS mutations but distinct from KRAS wild-type, though differences were observed in some tumor types for tumor mutational burden, PD-L1 expression, microsatellite instability, and other mutational signatures. Prognosis of KRAS-mutant versus other genomic cohorts of lung, pancreatic, and colorectal cancer were assessed using a real-world clinicogenomic database. As specific KRAS inhibitors and combination therapeutic strategies are being developed, genomic profiling to understand co-alterations and other biomarkers that may modulate response to targeted or immunotherapies will be imperative.

OBJECTIVES/GOALS: This work aims to explore how citizen science serves as a transformative frame work to bridge scientific knowledge, focusing on its potential to enhance transdisciplinary learning in artificial intelligence (AI) biomedical and clinical sciences by facilitating near-peer mentoring. METHODS/STUDY POPULATION: Our group of eight friends comprise a multicultural and multidisciplinary cohort including students from the USA, Philippines, Indonesia, and Guatemala pursuing PhD degrees in electrical and computer engineering, epidemiology, physics, and MD, PharmD, and DMD degrees. We engage in shared online courses, collaborative projects, and abstract submissions. Employing our collective knowledge, we design interactive learning experiences, support each other’s initiatives, and collaboratively develop lectures and presentations. We in tend to expand collaborations in biomedical AI education while fostering principles of experiential and collaborativelearning, constructivism, and authentic inquiry. RESULTS/ANTICIPATED RESULTS: Our recent successes include submittedconference abstracts on data science and AI education in pharmacy and the facilitation of a guest lecture in health informatics. Additionally, we are currently collaborating on seven biomedical machine learning projects in radio frequency engineering, aiming for conference submissions. Moving forward, our goal is to expand our group, support the formation of similar communities, and promote data science and AI literacy in biomedical and clinical contexts. We aspire to extend this knowledge to families, classmates, and eventually patients, facilitating a broader understanding of the role of AI in healthcare. DISCUSSION/SIGNIFICANCE: We believe diverse expertise and pedagogical theories can help demonstrate the potential of citizen science to democratize scientific experience. By nurturing collaborative networks our efforts aim to bridge gaps between disciplines and enhance the broader public’s understanding of AI in healthcare.

Case summary A 5-month-old male castrated domestic shorthair cat was evaluated for acute onset of emesis. Abdominal radiographs identified a suspected colonic foreign body and abdominal-focused assessment with sonography for trauma, triage and tracking (AFAST) evaluation revealed a large amount of peritoneal effusion. Cytology of the peritoneal effusion was consistent with a septic exudate. An exploratory celiotomy identified a ruptured ileocecocolic mass and a resection and anastomosis was performed. No foreign material was identified and histopathology confirmed that the ruptured mass was a colonic duplication cyst. Recurrent septic peritonitis was diagnosed based on cytologic evaluation of fluid from a silicone bulb reservoir of a closed suction drain. No abnormalities were surgically identified, the cat recovered without complication, was discharged at 7 days postoperatively and has continued to remain healthy 8 months after surgical intervention. Relevance and novel information To our knowledge, this is the first known instance of a histopathologically confirmed non-communicating colonic duplication cyst causing septic peritonitis in the veterinary literature.

ABSTRACT: Non-typhoidal Salmonella infection is a significant health and economic burden in poultry industry. Developing an oral vaccine to induce robust mucosal immunity in the intestines of birds, especially cross protection against different Salmonella serotypes is challenging. Therefore, a potent oral vaccine platform that can mitigate different serotypes of Salmonella is warranted for the poultry industry. We reported earlier that the Salmonella enteritidis (SE) immunogenic outer membrane proteins (OMPs) and flagellin (FLA) entrapped in mannose chitosan nanoparticles (OMPs-FLA-mCS NPs) administered prime-boost (d-3 and 3-wk later) by oral inoculation elicits mucosal immunity and reduces challenge SE colonization by over 1 log10 CFU in birds. In this study, we sought to evaluate whether the SE antigens containing OMPs-FLA-mCS NPs vaccine induces cross-protection against Salmonella typhimurium (ST) in broilers. Our data indicated that the OMPs-FLA-mCS NPs vaccine induced higher cross-protective antibody responses compared to commercial Poulvac ST vaccine (contains a modified-live ST bacterium). Particularly, OMPs-FLA-mCS-NP vaccine elicited OMPs and FLA antigens specific increased production of secretory IgA and IgY antibodies in samples collected at both post-vaccination and post-challenge timepoints compared to commercial vaccine group. Notably, the vaccine reduced the challenge ST bacterial load by 0.8 log10 CFU in the cecal content, which was comparable to the outcome of Poulvac ST vaccination. In conclusion, our data suggested that orally administered OMPs-FLA-mCS-NP SE vaccine elicited cross protective mucosal immune responses against ST colonization in broilers. Thus, this candidate vaccine could be a viable option replacing the existing both live and killed Salmonella vaccines for birds.

INTRODUCTION: Germline CHEK2 mutations are rare and have not been associated with increased risk of NSCLC. METHODS: We identified two sequential primary NSCLCs harboring distinct actionable driver alterations (EGFR E746 _S752 delinsV and CD74-ROS1) in a patient with NSCLC with a novel germline CHEK2 mutation S5fs∗54 (c.14_20delCGGATGT). We queried a genomic database of NSCLC samples profiled by plasma next-generation sequencing (Foundation Medicine Inc.) and performed a literature search of germline CHEK2 mutations in NSCLC. RESULTS: Of 6101 patients with unique NSCLC profiled by plasma next-generation sequencing, 53 cases (0.87%) of germline CHEK2 mutation were identified (male-to-female ratio, 49%:51%; median age = 75 y). The median allele frequency of CHEK2 was 49% (interquartile range: 49%-51%). Ten unique CHEK2 germline mutations were identified. Literature review identified 15 additional cases of germline CHEK2 mutations in NSCLC. Overall, a total of 70 CHEK2 germline mutations (21 unique CHEK2 alterations) were identified. Among these 70 CHEK2 germline mutations, 54.3% were amino acid substitutions (point mutation), 40.0% were frameshift mutations, and 5.7% were splice site mutations. Of these 70 total cases assessed, 29 (41.4%) potentially actionable driver alterations were identified with KRAS G12C mutation (27.6%) being the most common and KRAS G12A/C/D/R/S/V mutations together constituting 51.7% of these driver mutations. CONCLUSIONS: Germline CHEK2 mutations are rare in NSCLC. A large proportion of these cases harbor actionable driver alterations. The relationship between germline CHEK2 mutations and actionable driver alterations in NSCLC may be worth further investigation.

PURPOSE: Subset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date. PATIENTS AND METHODS: A total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB). RESULTS: Sixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi. CONCLUSION: Patients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

Internationally and in the UK universities are facing a crisis of student wellbeing. In this context, it is important to research the impact of the teaching and learning environment and experiences, including the relationships between students and staff, on student wellbeing. While separate pieces of research on students' wellbeing have addressed student and teacher perspectives on the role of learning experiences, we identified an opportunity to address the perspectives of both students and staff, including non-academics, in the same study. This study advances work on student wellbeing, recognising an interdependency between staff and student wellbeing. It adds to current research in identifying student-centred learning and assessment, intercultural awareness, international integration, and emotional intelligence as enablers of positive student wellbeing. The findings of this research also demonstrate the crucial role of the teacher-student relationship in impacting students' (and staff) wellbeing and suggest solutions and areas for development that reflect the complexity of the Higher Education environment in which they are located.

Summary: Background: The Paediatric Difficult Intubation Collaborative identified multiple attempts and persistence with direct laryngoscopy as risk factors for complications in children with difficult tracheal intubations and subsequently engaged in initiatives to reduce repeated attempts and persistence with direct laryngoscopy in children. We hypothesised these efforts would lead to fewer attempts, fewer direct laryngoscopy attempts and decrease complications. Methods: Paediatric patients less than 18 years of age with difficult direct laryngoscopy were enrolled in the Paediatric Difficult Intubation Registry. We define patients with difficult direct laryngoscopy as those in whom (1) an attending or consultant obtained a Cormack Lehane Grade 3 or 4 view on direct laryngoscopy, (2) limited mouth opening makes direct laryngoscopy impossible, (3) direct laryngoscopy failed in the preceding 6 months, and (4) direct laryngoscopy was deferred due to perceived risk of harm or poor chance of success. We used a 5:1 propensity score match to compare an early cohort from the initial Paediatric Difficult Intubation Registry analysis (August 6, 2012–January 31, 2015, 785 patients, 13 centres) and a current cohort from the Registry (March 4, 2017–March 31, 2023, 3925 patients, 43 centres). The primary outcome was first attempt success rate between cohorts. Success was defined as confirmed endotracheal intubation and assessed by the treating clinician. Secondary outcomes were eventual success rate, number of attempts at intubation, number of attempts with direct laryngoscopy, the incidence of persistence with direct laryngoscopy, use of supplemental oxygen, all complications, and severe complications. Findings: First-attempt success rate was higher in the current cohort (42% vs 32%, OR 1.5 95% CI 1.3–1.8, p

γ emission probabilities from unbound states in 78,80Se, populated by a neutron-transfer reaction (d,p) on 77,79Se nuclei in inverse kinematics, were measured by directly detecting reaction residues. Assuming the spin distribution at the respective excitation energy of the unbound state, the cross-sections of the 79Se(n,γ)80Se reaction were evaluated using the γ emission probabilities. The surrogate-ratio method with the experimental γ emission probabilities of 78,80Se was also employed to deduce the cross-sections of 79Se(n,γ) reaction by incorporating the theoretical evaluations of the neutron-capture reaction on the isomeric state in 77Se. Our two cross-sections are in good agreement with existing nuclear data compilations for the neutron-capture reaction on 79Se. The presented method contributes to the body of existing knowledge by providing approaches for determining the neutron capture cross-sections of radioactive nuclei at various neutron energies.

People living with HIV (PLWH) experience earlier onset of aging-related comorbidities compared to their counterparts without HIV. This paper lays out a theoretical model to explain why PLWH experience accelerated aging. Briefly, the model is structured as follows. PLWH experience disproportionately heavy burdens of psychosocial stress across the life course. This psychosocial stress increases risks for depressive symptoms and problematic substance use. Depressive symptoms and problematic substance use interfere with long-term adherence to antiretroviral therapy (ART). Lower ART adherence, in turn, exacerbates the elevated systemic inflammation stemming from HIV infection. This inflammation increases risks for aging-related comorbidities. Systemic inflammation also reduces connectivity in the brain's central executive network (CEN), a large-scale brain network that is critical for coping with stressful circumstances. This reduced capacity for coping with stress leads to further increases in depressive symptoms and problematic substance use. Together, these changes form a neuroimmune feedback loop that amplifies the impact of psychosocial stress on aging-related comorbidities. In this paper, I review the existing evidence relevant to this model and highlight directions for future research.

The nucleus Ne29 is situated at the border of the island of inversion. Despite significant efforts, no bound low-lying intruder f7/2 state, which would place Ne29 firmly inside the island of inversion, has yet been observed. Here, the first investigation of unbound states of Ne29 is reported. The states were populated in Ne30(p,pn) and Na30(p,2p) reactions at a beam energy of around 230 MeV/nucleon, and analyzed in terms of their resonance properties, partial cross sections, and momentum distributions. The momentum distributions are compared to calculations using the eikonal, direct reaction model, allowing ℓ assignments for the observed states. The lowest-lying resonance at an excitation energy of 1.48(4) MeV shows clear signs of a significant ℓ=3 component, giving first evidence for f7/2 single particle strength in Ne29. The excitation energies and strengths of the observed states are compared to shell-model calculations using the sdpf-u-mix interaction.

Abstract GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

This study focuses on the development and characterization of an intranasal vaccine platform using adjuvanted nanoparticulate delivery of swine influenza A virus (SwIAV). The vaccine employed whole inactivated H1N2 SwIAV as an antigen and STING-agonist ADU-S100 as an adjuvant, with both surface adsorbed or encapsulated in mannose–chitosan nanoparticles (mChit-NPs). Optimization of mChit-NPs included evaluating size, zeta potential, and cytotoxicity, with a 1:9 mass ratio of antigen to NP demonstrating high loading efficacy and non-cytotoxic properties suitable for intranasal vaccination. In a heterologous H1N1 pig challenge trial, the mChit-NP intranasal vaccine induced cross-reactive sIgA antibodies in the respiratory tract, surpassing those of a commercial SwIAV vaccine. The encapsulated mChit-NP vaccine induced high virus-specific neutralizing antibody and robust cellular immune responses, while the adsorbed vaccine elicited specific high IgG and hemagglutinin inhibition antibodies. Importantly, both the mChit-NP vaccines reduced challenge heterologous viral replication in the nasal cavity higher than commercial swine influenza vaccine. In summary, a novel intranasal mChit-NP vaccine platform activated both the arms of the immune system and is a significant advancement in swine influenza vaccine design, demonstrating its potential effectiveness for pig immunization.

PURPOSE: Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date. METHODS: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5 partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5/3 breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION: NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.

ObjectiveTo characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET).BackgroundDBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely.MethodsA retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores.ResultsThe therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58).ConclusionActive DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

All animals except sponges produce mucus. Across the animal kingdom, this hydrogel mediates surface wetting, viscosity, and protection against microbes. The primary components of mucus hydrogels are mucins-high molecular weight O-glycoproteins that adopt extended linear structures. Glycosylation is integral to mucin function, but other characteristics that give rise to their advantageous biological activities are unknown. We postulated that the extended conformation of mucins is critical for their ability to block microbial virulence phenotypes. To test this hypothesis, we developed synthetic mucin mimics that recapitulate the dense display of glycans and morphology of mucin. We varied the catalyst in a ring-opening metathesis polymerization (ROMP) to generate substituted norbornene-derived glycopolymers containing either cis- or trans-alkenes. Conformational analysis of the polymers based on allylic strain suggested that cis- rather than trans-poly(norbornene) glycopolymers would adopt linear structures that mimic mucins. High-resolution atomic force micrographs of our polymers and natively purified Muc2, Muc5AC, and Muc5B mucins revealed that cis-polymers adopt extended, mucin-like structures. The cis-polymers retained this structure in solution and were more water-soluble than their trans-analogs. Consistent with mucin's linear morphology, cis-glycopolymers were more potent binders of a bacterial virulence factor, cholera toxin. Our findings highlight the importance of the polymer backbone in mucin surrogate design and underscore the significance of the extended mucin backbone for inhibiting virulence.

Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired ALK resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis detected in a patient with ALK-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple ALK mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments.

Background: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. Methods: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. Results: The lateral portion of the CTT had the highest activation at clinical settings (p

Abstract Background Unlike the injectable vaccines, intranasal lipid nanoparticle (NP)-based adjuvanted vaccine is promising to protect against local infection and viral transmission. Infection of ferrets with SARS-CoV-2 results in typical respiratory disease and pathology akin to in humans, suggesting that the ferret model may be ideal for intranasal vaccine studies. Results We developed SARS-CoV-2 subunit vaccine containing both Spike receptor binding domain (S-RBD) and Nucleocapsid (N) proteins (NP-COVID-Proteins) or their mRNA (NP-COVID-mRNA) and NP-monosodium urate adjuvant. Both the candidate vaccines in intranasal vaccinated aged ferrets substantially reduced the replicating virus in the entire respiratory tract. Specifically, the NP-COVID-Proteins vaccine did relatively better in clearing the virus from the nasal passage early post challenge infection. The immune gene expression in NP-COVID-Proteins vaccinates indicated increased levels of mRNA of IFNα, MCP1 and IL-4 in lungs and nasal turbinates, and IFNγ and IL-2 in lungs; while proinflammatory mediators IL-1β and IL-8 mRNA levels in lungs were downregulated. In NP-COVID-Proteins vaccinated ferrets S-RBD and N protein specific IgG antibodies in the serum were substantially increased at both day post challenge (DPC) 7 and DPC 14, while the virus neutralizing antibody titers were relatively better induced by mRNA versus the proteins-based vaccine. In conclusion, intranasal NP-COVID-Proteins vaccine induced balanced Th1 and Th2 immune responses in the respiratory tract, while NP-COVID-mRNA vaccine primarily elicited antibody responses. Conclusions Intranasal NP-COVID-Proteins vaccine may be an ideal candidate to elicit increased breadth of immunity against SARS-CoV-2 variants.

Abstract In this study, we report the clinicopathologic and genomic profiles of 891 patients with RET fusion driven advanced solid tumors. All patient samples were tested using a tissue-based DNA hybrid capture next generation sequencing (NGS) assay and a subset of the samples were liquid biopsies tested using a liquid-based hybrid capture NGS assay. RET fusions were found in 523 patients with NSCLC and in 368 patients with other solid tumors. The two tumor types with the highest number of RET fusion were lung adenocarcinoma and thyroid papillary carcinoma, and they had a prevalence rate 1.14% (455/39,922) and 9.09% (109/1199), respectively. A total of 61 novel fusions were discovered in this pan-tumor cohort. The concordance of RET fusion detection across tumor types among tissue and liquid-based NGS was 100% (8/8) in patients with greater than 1% composite tumor fraction (cTF). Herein, we present the clinicopathologic and genomic landscape of a large cohort of RET fusion positive tumors and we observed that liquid biopsy-based NGS is highly sensitive for RET fusions at cTF ≥1%.