Health-promotion interventions targeting multiple behaviors: A meta-analytic review of general and behavior-specific processes of change.

Although health-promotion interventions that recommend changes across multiple behavioral domains are a newer alternative to single-behavior interventions, their general efficacy and their mechanisms of change have not been fully ascertained. This comprehensive meta-analysis (6,878 effect sizes from 803 independent samples from 364 research reports, N = 186,729 participants) examined the association between the number of behavioral recommendations in multiple-behavior interventions and behavioral and clinical change across eight domains (i.e., diet, smoking, exercise, HIV [Human Immunodeficiency Virus] prevention, HIV testing, HIV treatment, alcohol use, and substance use). Results showed a positive, linear effect of the number of behavioral recommendations associated with behavioral and clinical change across all domains, although approximately 87% of the samples included between 0 and 4 behavioral recommendations. This linear relation was mediated by improvements in the psychological well-being of intervention recipients and, in several domains (i.e., HIV, alcohol use, and drug use), suggested behavioral cuing. However, changes in information, motivation, and behavioral skills did not mediate the impact of the number of recommendations on behavioral and clinical change. The implications of these findings for theory and future intervention design are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Polymorphic residues in HLA-B that mediate HIV control distinctly modulate peptide interactions with both TCR and KIR molecules.

Immunogenetic studies have shown that specific HLA-B residues (67, 70, 97, and 156) mediate the impact of HLA class I on HIV infection, but the molecular basis is not well understood. Here we evaluate the function of these residues within the protective HLA-B∗5701 allele. While mutation of Met67, Ser70, and Leu156 disrupt CD8+ T cell recognition, substitution of Val97 had no significant impact. Thermal denaturation of HLA-B∗5701-peptide complexes revealed that Met67 and Leu156 maintain HLA-peptide stability, while Ser70 and Leu156 facilitate T cell receptor (TCR) interactions. Analyses of existing structures and structural models suggested that Val97 mediates HLA-peptide binding to inhibitory KIR3DL1 molecules, which was confirmed by experimental assays. These data thereby demonstrate that the genetic basis by which host immunity impacts HIV outcomes occurs by modulating HLA-B-peptide stability and conformation for interaction with TCR and killer immunoglobulin receptor (KIR) molecules. Moreover, they indicate a key role for epitope specificity and HLA-KIR interactions to HIV control.

Screening and diagnosis of cardiovascular disease using artificial intelligence-enabled cardiac magnetic resonance imaging.

Cardiac magnetic resonance imaging (CMR) is the gold standard for cardiac function assessment and plays a crucial role in diagnosing cardiovascular disease (CVD). However, its widespread application has been limited by the heavy resource burden of CMR interpretation. Here, to address this challenge, we developed and validated computerized CMR interpretation for screening and diagnosis of 11 types of CVD in 9,719 patients. We propose a two-stage paradigm consisting of noninvasive cine-based CVD screening followed by cine and late gadolinium enhancement-based diagnosis. The screening and diagnostic models achieved high performance (area under the curve of 0.988 ± 0.3% and 0.991 ± 0.0%, respectively) in both internal and external datasets. Furthermore, the diagnostic model outperformed cardiologists in diagnosing pulmonary arterial hypertension, demonstrating the ability of artificial intelligence-enabled CMR to detect previously unidentified CMR features. This proof-of-concept study holds the potential to substantially advance the efficiency and scalability of CMR interpretation, thereby improving CVD screening and diagnosis.

2-(3-Indolyl)acetamides and their oxazoline analogues: Anticancer SAR study.

We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both series of compounds and found that the 2-naphthyl is a preferred group at C-2 of the indole in the amide series, whereas the tetralin moiety is favorable in the same location in the oxazoline series. Overall, three compounds in the amide series have GI50 values as low as 0.2-0.3 µM and the results clearly indicate that the N-hydroxyl group is not necessary for high potency in vitro.

Identification of CDKN3 as a Key Gene that Regulates Neuroblastoma Cell Differentiation.

We conducted a high-content screening (HCS) in neuroblastoma BE(2)-C cells to identify cell cycle regulators that control cell differentiation using a library of siRNAs against cell cycle-regulatory genes. We discovered that knocking down expression of cyclin dependent kinase inhibitor 3 (CDKN3) showed the most potent effect in inducing neurite outgrowth, the morphological cell differentiation marker of neuroblastoma cells. We then demonstrated that CDKN3 knockdown increased expression of neuroblastoma molecular differentiation markers, neuron specific enolase (NSE), ßIII-tubulin and growth associated protein 43 (GAP43). We further showed that CDKN3 knockdown reduced expression of cell proliferation markers Ki67 and proliferating cell nuclear antigen (PCNA), and reduced colony formation of neuroblastoma cells. More importantly, we observed a correlation of high tumor CDKN3 mRNA levels with poor patient survival in the investigation of public neuroblastoma patient datasets. In exploring the mechanisms that regulate CDKN3 expression, we found that multiple strong differentiation-inducing molecules, including miR-506-3p and retinoic acid, down-regulated CDKN3 expression. In addition, we found that N-Myc promoted CDKN3 expression at the transcriptional level by directly binding to the CDKN3 promoter. Furthermore, we found that CDKN3 and two additional differentiation-regulating cell cycle proteins identified in our HCS, CDC6 and CDK4, form an interactive network to promote expression of each other. In summary, we for the first time discovered the function of CDKN3 in regulating neuroblastoma cell differentiation and characterized the transcriptional regulation of CDKN3 expression by N-Myc in neuroblastoma cells. Our findings support that CDKN3 plays a role in modulating neuroblastoma cell differentiation and that overexpression of CDKN3 may contribute to neuroblastoma progression.

Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR.

The effectiveness of chimaeric antigen receptor (CAR) T cell therapies for solid tumours is hindered by difficulties in the selection of an effective target antigen, owing to the heterogeneous expression of tumour antigens and to target antigen expression in healthy tissues. Here we show that T cells with a CAR specific for fluorescein isothiocyanate (FITC) can be directed against solid tumours via the intratumoural administration of a FITC-conjugated lipid-poly(ethylene)-glycol amphiphile that inserts itself into cell membranes. In syngeneic and human tumour xenografts in mice, 'amphiphile tagging' of tumour cells drove tumour regression via the proliferation and accumulation of FITC-specific CAR T cells in the tumours. In syngeneic tumours, the therapy induced the infiltration of host T cells, elicited endogenous tumour-specific T cell priming and led to activity against distal untreated tumours and to protection against tumour rechallenge. Membrane-inserting ligands for specific CARs may facilitate the development of adoptive cell therapies that work independently of antigen expression and of tissue of origin.

Molecular basis of differential HLA class I-restricted T cell recognition of a highly networked HIV peptide.

Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which the presenting HLA allele contributes to this process is unknown. Here we examine the CTL response to QW9, a highly networked epitope presented by the disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust targeting of QW9 in persons expressing either allele, T cell receptor (TCR) cross-recognition of the naturally occurring variant QW9_S3T is consistently reduced when presented by HLA-B53 but not by HLA-B57. Crystal structures show substantial conformational changes from QW9-HLA to QW9_S3T-HLA by both alleles. The TCR-QW9-B53 ternary complex structure manifests how the QW9-B53 can elicit effective CTLs and suggests sterically hindered cross-recognition by QW9_S3T-B53. We observe populations of cross-reactive TCRs for B57, but not B53 and also find greater peptide-HLA stability for B57 in comparison to B53. These data demonstrate differential impacts of HLAs on TCR cross-recognition and antigen presentation of a naturally arising variant, with important implications for vaccine design.

Case Report: A Child With Omental Infarction.

BACKGROUND: Omental infarction (OI) is a rare cause of acute abdominal pain, which is benign and self-limited. It is diagnosed by imaging. The etiology of OI is either idiopathic or secondary and due to torsion, trauma, hypercoagulability, vasculitis, or pancreatitis. CASE REPORT: Here, we present a case of OI in a child with acute severe right upper quadrant pain. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Correct diagnosis of OI via imaging can prevent unnecessary surgery.

From patterns to patients: Advances in clinical machine learning for cancer diagnosis, prognosis, and treatment.

Machine learning (ML) is increasingly used in clinical oncology to diagnose cancers, predict patient outcomes, and inform treatment planning. Here, we review recent applications of ML across the clinical oncology workflow. We review how these techniques are applied to medical imaging and to molecular data obtained from liquid and solid tumor biopsies for cancer diagnosis, prognosis, and treatment design. We discuss key considerations in developing ML for the distinct challenges posed by imaging and molecular data. Finally, we examine ML models approved for cancer-related patient usage by regulatory agencies and discuss approaches to improve the clinical usefulness of ML.

"Nothing to lose and the possibility of gaining": a qualitative study on the feasibility and acceptability of registry-based randomised controlled trials among cancer patients and clinicians.

BACKGROUND: Randomised controlled trials (RCTs) are considered the "gold standard" for evaluating the effectiveness of interventions in clinical research. However, conventional RCTs are typically complex, expensive, and have narrow eligibility criteria, which limits generalisability. Registry-based randomised controlled trials (RRCTs) are an alternative approach that integrates the internal validity of an RCT with the external validity of a clinical registry by recruiting real-world patients and leveraging an existing registry platform for data collection. As RRCT is a novel research design, there has been limited research on the feasibility and acceptability of RRCTs from the patients' and trial team's perspectives. This study aims to explore patients', clinicians', and study coordinators' perspectives towards participation in and conduct of oncology RRCTs in Australia. METHODS: Thirty-seven semi-structured interviews were conducted with 15 cancer patients, 15 clinicians, and 7 study coordinators. Interviews were audio-recorded and transcribed verbatim. The data were analysed using thematic analysis. RESULTS: Three overarching themes were identified: (1) enablers and barriers to recruitment and enrolment of patients in RRCTs, (2) experiences of patients participating in RRCTs, and (3) recommendations for the implementation of future RRCTs. For patients, altruism and "trust in the clinician" were key reasons to participate in a RRCT. For clinicians and clinical trial coordinators, the RRCT study design was perceived as "simple and straightforward" but "less exciting" than RCTs. Competition from commercially sponsored RCTs poses challenges for investigator-led RRCTs recruitment, particularly if eligible patient numbers are low. There were limited impacts on patients' treatment experiences and clinicians' clinical workflow given that the RRCTs explored different standards of care. Recommendations to improve the enrolment of patients in RRCTs included generating greater buy-in from clinicians by increasing awareness of RRCTs via education initiatives and broader promotion of the "selling point" of RRCTs and providing monetary compensation to hospitals for enrolling patients. CONCLUSIONS: Whilst patients, clinicians, and study coordinators were generally supportive of RRCTs, several barriers to effective RRCT implementation in oncology were identified. Developing strategies to increase acceptance of the methodology by clinicians will help enhance the uptake of RRCTs in Australia and internationally.

Dysplastic hips demonstrate increased joint translation at higher body mass index.

OBJECTIVE: To determine which radiographic measures used to define the severity of hip dysplasia are associated with hip joint translation and to investigate relationships between position, body mass index, and joint translation. MATERIALS AND METHODS: This is a cross-sectional retrospective study evaluating 10 validated radiographic measures of dysplasia on weight-bearing AP pelvis and supine 45-degree bilateral Dunn radiographs of 93 young adults with symptomatic hip dysplasia presenting to a single academic institution between October 2016 and May 2019. We determined the difference between standing and supine measurements for each hip and the correlation of each measure with the patient's body mass index. RESULTS: Femoral head extrusion index was 2.49% lower on supine X-ray (p = 0.0020). Patients with higher body mass index had higher center gap distance (p = 0.0274), femoral head extrusion (p = 0.0170), and femoral head lateralization (p = 0.0028) when standing. They also had higher Tönnis angle (pstanding = 0.0076, psupine = 0.0121) and lower lateral center-edge angle (pstanding = 0.0196, psupine = 0.0410) in both positions. The difference in femoral head lateralization between standing and supine positions increased with higher body mass index (p = 0.0081). CONCLUSION: Translation of the hip joint with position change is demonstrated by decreased femoral head extrusion index on supine X-ray. Patients with higher body mass index had more dysplastic hips, as measured by five of six radiographic outcomes of dysplasia, and experienced more translation with weight-bearing, reflected by increased femoral head lateralization.

Screening for CD19-specific chimaeric antigen receptors with enhanced signalling via a barcoded library of intracellular domains.

The immunostimulatory intracellular domains (ICDs) of chimaeric antigen receptors (CARs) are essential for converting antigen recognition into antitumoural function. Although there are many possible combinations of ICDs, almost all current CARs rely on combinations of CD3𝛇, CD28 and 4-1BB. Here we show that a barcoded library of 700,000 unique CD19-specific CARs with diverse ICDs cloned into lentiviral vectors and transduced into Jurkat T cells can be screened at high throughput via cell sorting and next-generation sequencing to optimize CAR signalling for antitumoural functions. By using this screening approach, we identified CARs with new ICD combinations that, compared with clinically available CARs, endowed human primary T cells with comparable tumour control in mice and with improved proliferation, persistence, exhaustion and cytotoxicity after tumour rechallenge in vitro. The screening strategy can be adapted to other disease models, cell types and selection conditions, and could be used to improve adoptive cell therapies and to expand their utility to new disease indications.

Medical Student Perspectives on the Ethics of Pelvic Exams Under Anesthesia: A Multi-Institutional Study✰.

OBJECTIVE: Pelvic examinations under anesthesia (EUAs) are routine components of gynecologic surgery and often used to educate students about female pelvic anatomy. This multi-institutional survey study aims to describe students' experiences with conducting educational pelvic EUAs and their attitudes around the ethics of informed consent for these exams. DESIGN: An anonymous survey of Likert and open-text response questions about institutions' practices around educational pelvic EUAs was sent to medical students. SETTING: Medical schools included Vanderbilt University School of Medicine, Indiana University School of Medicine, Emory University School of Medicine, University of New Mexico School of Medicine, Meharry Medical College, and Warren Alpert Medical School of Brown University. PARTICIPANTS: A total 305 medical students who had completed their obstetrics and gynecology (OB/GYN) clerkship between June 2019 and March 2020 filled out the survey (33% response rate). RESULTS: Overall, 84% of students performed at least 1 pelvic EUA during their clerkship. Of the 42% (142) of students that observed patient informed consent processes most or every time, 67% reported they never or rarely witnessed an explicit explanation that a medical student may perform a pelvic EUA. Analysis of open-text responses found that students wanted to uphold patient autonomy but felt they did not have the personal autonomy to object to performing pelvic EUAs that they believed were unconsented. They faced significant emotional distress when consent processes were at odds with their personal ethos and professional ethical norms. Students favored more standardized and explicit patient consent processes for educational pelvic EUAs. CONCLUSIONS: While students regularly perform pelvic EUAs, their involvement is inconsistently disclosed to patients, causing significant distress to students and risking erosion of students' attitudes about upholding patient autonomy and informed consent. Medical institutions must develop consistent, ethical, and patient-centered processes for trainee disclosure around pelvic EUAs.

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.

A Leucine Zipper Dimerization Strategy to Generate Soluble T Cell Receptors Using the Escherichia coli Expression System.

T cell-mediated adaptive immunity plays a key role in immunological surveillance and host control of infectious diseases. A better understanding of T cell receptor (TCR) recognition of pathogen-derived epitopes or cancer-associated neoantigens is the basis for developing T cell-based vaccines and immunotherapies. Studies on the interaction between soluble TCR α:ß heterodimers and peptide-bound major histocompatibility complexes (pMHCs) inform underlying mechanisms driving TCR recognition, but not every isolated TCR can be prepared in soluble form for structural and functional studies using conventional methods. Here, taking a challenging HIV-specific TCR as a model, we designed a general leucine zipper (LZ) dimerization strategy for soluble TCR preparation using the Escherichia coli expression system. We report details of TCR construction, inclusion body expression and purification, and protein refolding and purification. Measurements of binding affinity between the TCR and its specific pMHC using surface plasmon resonance (SPR) verify its activity. We conclude that this is a feasible approach to produce challenging TCRs in soluble form, needed for studies related to T cell recognition.

Cadmium exposure modulates the gut-liver axis in an Alzheimer's disease mouse model.

The human Apolipoprotein E4 (ApoE4) variant is the strongest known genetic risk factor for Alzheimer's disease (AD). Cadmium (Cd) has been shown to impair learning and memory at a greater extent in humanized ApoE4 knock-in (ApoE4-KI) mice as compared to ApoE3 (common allele)-KI mice. Here, we determined how cadmium interacts with ApoE4 gene variants to modify the gut-liver axis. Large intestinal content bacterial 16S rDNA sequencing, serum lipid metabolomics, and hepatic transcriptomics were analyzed in ApoE3- and ApoE4-KI mice orally exposed to vehicle, a low dose, or a high dose of Cd in drinking water. ApoE4-KI males had the most prominent changes in their gut microbiota, as well as a predicted down-regulation of many essential microbial pathways involved in nutrient and energy homeostasis. In the host liver, cadmium-exposed ApoE4-KI males had the most differentially regulated pathways; specifically, there was enrichment in several pathways involved in platelet activation and drug metabolism. In conclusion, Cd exposure profoundly modified the gut-liver axis in the most susceptible mouse strain to neurological damage namely the ApoE4-KI males, evidenced by an increase in microbial AD biomarkers, reduction in energy supply-related pathways in gut and blood, and an increase in hepatic pathways involved in inflammation and xenobiotic biotransformation.

Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice.

Pten germline haploinsufficient (Pten+/-) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical-subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten+/- mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal "hard-wired" connectivity through enhancing synaptic plasticity. Thus, we reared Pten+/- mice and their wild-type littermates from weaning under either standard (4-5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9-10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten+/- mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten+/- mice and partially rescued increased repetitive behavior in Pten+/- males. We found that Pten+/- mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten+/- mice, possibly through normalizing the excitatory synaptic protein abundance.

Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia.

BACKGROUNDThe loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC.METHODSA human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion.RESULTSXenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs).CONCLUSIONThe elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.TRIAL REGISTRATIONClinicalTrials.gov (NCT03906253).FUNDINGNational Institutes of Health, Veterans Administration.

TAP AND INJECT VERSUS PARS PLANA VITRECTOMY FOR POSTPROCEDURAL ENDOPHTHALMITIS: A Meta-analysis.

PURPOSE: To compare the visual outcomes after prompt pars plana vitrectomy (PPV) with tap biopsy and intravitreal antimicrobial injection to treat postinjection and postsurgery endophthalmitis. METHODS: The Cochrane Central Register of Controlled Trials, Ovid MEDLINE, and Ovid Embase databases were searched for articles published between January 2010 and November 2020. Two independent reviewers selected articles and extracted data. We analyzed data in RevMan 5.3 and assessed methodological quality using the Cochrane ROBINS-I tool. The mean improvement in visual outcome was compared between PPV and intravitreal antimicrobial injection as a relative risk of improving ≥2 lines and a mean logarithm of the minimal angle of resolution difference in improvement. RESULTS: Fifteen retrospective case series (1,355 eyes), of which 739 eyes (55%) received intravitreal antimicrobial injection and 616 (45%) received PPV as initial treatment, were included. The overall relative risk of improving 2 or more lines in PPV in comparison with intravitreal antimicrobial injection was 1.04 (95% CI 0.88-1.23; P = 0.61; I2 = 0%) with a mean difference of 0.04 (95% CI -0.18 to 0.27; P = 0.69; I2 = 0%). The results stayed robust when subgroup analysis based on causative procedure for endophthalmitis was performed. CONCLUSION: Intravitreal antimicrobial injection is noninferior to PPV for the treatment of postcataract operation, postinjection, and post-PPV endophthalmitis.

Antitumor effects of iPSC-based cancer vaccine in pancreatic cancer.

Induced pluripotent stem cells (iPSCs) and cancer cells share cellular similarities and transcriptomic profiles. Here, we show that an iPSC-based cancer vaccine, comprised of autologous iPSCs and CpG, stimulated cytotoxic antitumor CD8+ T cell effector and memory responses, induced cancer-specific humoral immune responses, reduced immunosuppressive CD4+ T regulatory cells, and prevented tumor formation in 75% of pancreatic ductal adenocarcinoma (PDAC) mice. We demonstrate that shared gene expression profiles of "iPSC-cancer signature genes" and others are overexpressed in mouse and human iPSC lines, PDAC cells, and multiple human solid tumor types compared with normal tissues. These results support further studies of iPSC vaccination in PDAC in preclinical and clinical models and in other cancer types that have low mutational burdens.