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Abstract Introduction KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. Methods We contrasted tumor development between Kras G12C and Kras G12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of Kras G12C and Kras G12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRAS G12C or KRAS G12D -mutant NSCLC. Results KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Conclusions Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.

Abstract NASH is characterized by hepatic lipid accumulation and inflammation; and JMJD2B—a histone demethylase—upregulation has been linked to its progression. Pirfenidone (PFD) is an antifibrotic agent with anti-inflammatory and antioxidant effects recognized to decrease NASH symptoms. Herein, our aim was to investigate PFD-induced epigenetics mechanisms involving JMJD2B and histone modifications in experimental NASH. Male C57BL/6J mice were fed with normo-diet, or high fat/carbohydrate diet (HF) for 16 weeks. A HF-subgroup was treated with PFD 300 mg/kg/d from week 8th to the end of protocol. Insulin tolerance test and liver and fat histological and biochemical analyses were carried out. Hepatic transcriptome was examined. Liver proteins were studied by western blot (WB) and Chromatin immunoprecipitation. In vitro, lipotoxicity was induced in HepG2 cells and proteins were evaluated using WB. Molecular docking was used to explore binding of PFD to JMJD2B. Mice treated with PFD reduced weight gain, epididymal fat and inflammatory nodules, and steatosis in liver tissue, as well as, improved biochemical test. PFD modified the expression of Jmjd2b, Pparg, Fasn and Srebp1, and restored JMJD2B protein and H3K9me3 repressive mark, both in animal and cell models. PFD increased hepatic enrichment of H3K9me2 and H3K9me3 at the promoter region of Fasn and Srebp1, and Pparg. In HepG2 cells, PFD reduced lipid vacuole accumulation. In silico, PFD interacted with JMJD2B catalytic site. PFD is an epigenetic regulator modifying JMJD2B activity, resulting in reduced NASH traits.

Abstract Minimal residual disease (MRD) assessment is a known surrogate marker for survival in multiple myeloma (MM). Here, we present a single institution’s experience assessing MRD by NGS of Ig genes and the long-term impact of depth of response as well as clonal diversity on the clinical outcome of a large population of MM patients; 482 MM patients at the University of California, San Francisco (UCSF) diagnosed from 2008 to 2020 were analyzed retrospectively. MRD assessment was performed by NGS. PFS curves were plotted by the Kaplan–Meier method. In the newly diagnosed group, 119 of 304, achieved MRD negativity at the level of 10−6 at least once. These patients had a prolonged PFS versus patients who were persistently MRD positive at different levels (p > 0.0001). In the relapsed disease group, 64 of 178 achieved MRD negativity at 10−6, and PFS was prolonged versus patients who remained MRD positive (p = 0.03). Three categories of MRD dynamics were defined by artificial intelligence: (A) patients with ≥3 consistently MRD negative samples, (B) patients with continuously declining but detectable clones, and (C) patients with either increasing or a stable number of clones. Groups A and B had a more prolonged PFS than group C (p

IntroductionT cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection.MethodsHere, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides. Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared “public” T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells.ResultsCollectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3–7 = 85.1% [95% CI = 79.9–89.7]; Day 8–14 = 94.8% [90.7–98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1–98.3]).DiscussionThe approaches described in this work provide detailed insights into the adaptive immune response to SARS-CoV-2 infection, and they have potential applications in clinical diagnostics, vaccine development, and monitoring.

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This article offers Ancestral Computing for Sustainability (ACS) to dismantle the logics of settler colonialism that affect accessibility, identities, and epistemologies of computer science education (CSE). ACS centers Indigenous epistemologies in researching CSE across four public universities in the United States. This paper describes Ancestral Computing for Sustainability and explores reflections of two students engaging as researchers in ACS inquiry. Drawing on Indigenous methodologies and Participatory Action Research, they share their reflections as co-researchers in ACS through storywork. These critical reflections include their relationship to computing, observations of the interdependent work within ACS, ethics and sustainability, and their experiences within the focus groups. The article ends with recommendations for furthering ACS as a decolonial approach that centers Indigenous epistemologies in CSE. Recommendations for CSE education include Ancestral Knowledge Systems and adding sustainability as a topic within computing education pathways and building student-faculty relationships based on trust is recommended to foster students' academic and personal growth within CSE education and research.

El presente estudio tiene como objetivo principal establecer valores referenciales que permitan categorizar los niveles de competencia motriz de estudiantes de entre 10 y 12 años, según sexo y edad. Participaron 1010 estudiantes (48,4% niñas) de 5° y 6° de primaria de 16 Centros de La Araucanía, Chile. Se utilizó la versión en español del test MOBAK 5-6. Para determinar valores referenciales se utilizó el procedimiento recomendado en la Batería MOBAK original, ordenando el puntaje de cada dimensión por Rango de Percentiles y valores T. También se presentan rangos para la categorización teórica de la competencia motriz. En los resultados de la dimensión de Control de Objetos, se encontraron diferencias según sexo a favor de los niños (p

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.

Background: Teclistamab is the first approved B-cell maturation antigen × CD3 bispecific antibody (BsAb) for the treatment of triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM), with weight-based dosing and the longest study follow-up of any BsAb in MM. In the pivotal phase 1/2 MajesTEC-1 study (NCT03145181/NCT04557098), teclistamab demonstrated rapid, deep, and durable responses (overall response rate [ORR], 63.0%; complete response or better [≥CR] rate, 46.1%; median duration of response [mDOR], 24 mo) and a low rate of discontinuations due to adverse events (AEs; 4.8%). This subgroup analysis of MajesTEC-1 reports the overall safety and efficacy of RRMM patients (pts) who received 2-3 prior lines of therapy vs. pts with 4 or more prior lines of therapies, with extended follow-up of 30 months. Methods: Pts received the recommended phase 2 dose (RP2D) of teclistamab (1.5 mg/kg QW) and could switch to Q2W dosing if in partial response or better after ≥4 cycles of therapy (phase 1) or in ≥CR for ≥6 mo (phase 2). The primary endpoint was ORR (assessed per IMWG 2016 criteria). AEs were graded per CTCAE v4.03. CRS and ICANS were graded per ASTCT. Safety was reported in the overall population and efficacy was evaluated in pts who received 2-3 prior lines of therapy (≤3 LoT) vs. pts who received more than 3 prior lines of therapies (> 3 LoT). Results: Of 165 pts who had received teclistamab as of Aug 2023, 26% (43/165) pts received ≤ 3 prior LoT and 74% (122/165) patients received > 3 prior LoT. Pts characteristics were similar between the groups, especially in terms of high-risk features. At 30.4 mo mFU, pts that received ≤3 prior LoT achieved an ORR of 74.4% with 60.5% of pts achieving ≥ CR [sCR 46.5% and CR 14%]. mPFS was 21.7 mo (95% CI, 13.8–NR), mDOR was 24.0 mo (95% CI, 14.0–NE) and median overall survival was not reached (95% CI, 18.3–NE). Pts who had > 3 prior LoT had an ORR of 59%, with 41% of pts achieving ≥CR [sCR 36.1% and CR 4.9%], mPFS was 9.7 mo (95% CI, 6.4–13.1), mDOR was 22.4 mo (95% CI, 14.9–NE) and median overall survival was 17.7 mo (95% CI, 12.2–29.7). In the overall population, hematologic AEs (any grade/grade 3/4) included neutropenia (72%/65%), anemia (55%/38%), thrombocytopenia (42%/23%), and lymphopenia (36%/35%). Infections occurred in 79% of pts (55% grade 3/4). Of grade 5 infections, 18/22 were due to COVID-19, reflecting study conduct during the COVID-19 pandemic. Onset of new grade ≥3 infections generally decreased over time, which aligned approximately with the median time of switch to Q2W dosing; other factors, such as increasing use of IVIG, may also contribute to this trend. AEs leading to dose reduction (n = 1) or discontinuation (n = 8; 5 due to infection) were infrequent. No new safety signals were reported. Conclusion: With the longest follow-up of any BsAb in MM, teclistamab continues to demonstrate deep and durable responses, especially in the subgroup of less heavily treated patients (≤3 prior LoT), which demonstrates even better PFS and complete response rates results than those patients in later lines of treatment (> 3 prior LOT). The safety profile of teclistamab remains consistent with that of BCMA-targeted bispecific therapies, with an important decrease in new onset of severe infections with time. Acknowledgments: This study was funded by Johnson & Johnson Innovative Medicine.

Background: The prognosis for patients (pts) with multiple myeloma (MM) who have high-risk (HR) cytogenetics is poor. In the phase 3 CARTITUDE-4 trial, ciltacabtagene autoleucel (cilta-cel) vs standard of care (SOC) significantly improved progression-free survival (PFS; p < 0.0001) in pts with relapsed and lenalidomide-refractory MM after 1–3 prior lines of therapy. Additionally, the proportion of pts with an overall response (OR) (85% vs 67%), complete response or better (≥CR; 73% vs 22%), and minimal residual disease (MRD) negativity rate (10–5; 61% vs 16%) was higher with cilta-cel vs SOC. Aims: To report the efficacy of cilta-cel vs SOC in pts with HR and standard-risk (SR) cytogenetics, including by type of cytogenetic abnormality from a post hoc subgroup analysis of CARTITUDE-4. Methods: Eligibility criteria for CARTITUDE-4 have been previously described. Pts in the cilta-cel arm underwent apheresis, received bridging therapy (pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd]), and then a single cilta-cel infusion (target dose, 0.75 × 106 CAR+ viable T cells/kg) 5–7 days after the start of lymphodepletion. The SOC arm received PVd or DPd until progressive disease. HR cytogenetics was defined as pts with ≥1 of the following cytogenetic abnormalities at baseline determined by fluorescence in situ hybridization: del(17p), t(4;14), t(14;16), or gain/amp(1q). SR cytogenetics was defined as pts without del(17p), t(4;14), t(14;16), or gain/amp(1q) at baseline. Efficacy analyses were assessed in the intent-to-treat population (all randomized pts) and are summarized descriptively. Results: In CARTITUDE-4, 394/419 pts were evaluable for cytogenetics and had non-missing data; of these, 255 pts had HR cytogenetics (cilta-cel, n = 123; SOC, n = 132) and 139 had SR cytogenetics (cilta-cel, n = 69; SOC, n = 70). At the data cutoff (Nov 1, 2022), median follow-up was 15.9 mo (range, 0.1–27.3). In pts with HR cytogenetics, median PFS was not reached (NR; 95% CI, 18.4–not estimable [NE]) with cilta-cel vs 10.3 mo (95% CI, 7.6–12.5) with SOC; 12-mo PFS rates were 76% vs 43%, respectively. Among pts with SR cytogenetics, median PFS was NR (95% CI, NE–NE) with cilta-cel vs 20.6 mo (95% CI, 11.2–NE) with SOC; 12-mo PFS rates were 77% vs 59%, respectively. In pts with HR cytogenetics, a greater proportion had an OR (85% vs 66%), ≥CR (73% vs 20%), and MRD negativity (105; 70% vs 14%) with cilta-cel vs SOC. Similarly, in pts with SR cytogenetics a greater proportion had an OR (86% vs 71%), ≥CR (74% vs 26%), and MRD negativity (105; 49% vs 19%) with cilta-cel vs SOC. [YfA[1] Efficacy in pts with t(14;16) was excluded because the small number of pts in the cilta-cel (n = 3) and SOC (n = 7) arms precludes meaningful analyses. Summary/Conclusions: A single infusion of cilta-cel demonstrated favorable efficacy outcomes vs SOC in lenalidomide-refractory MM pts who had HR and standard-risk disease, with generally consistent results across different cytogenetic abnormalities although sample sizes for some individual types were small. Of note, cilta-cel induced comparable OR, ≥CR, and MRD-negativity rates in pts with HR and standard-risk disease, supporting the role of cilta-cel as a potential new SOC in pts with lenalidomide-refractory MM after 1–3 prior lines of therapy. Acknowledgments: This study was funded by Janssen Research & Development, LLC and Legend Biotech USA Inc.

Abstract Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.