Chromosome-scale genome assembly of the tropical abalone (Haliotis asinina).

Abalone (family Haliotidae) are an ecologically and economically significant group of marine gastropods that can be found in tropical and temperate waters. To date, only a few Haliotis genomes are available, all belonging to temperate species. Here, we provide the first chromosome-scale abalone genome assembly and the first reference genome of the tropical abalone Haliotis asinina. The combination of PacBio long-read HiFi sequencing and Dovetail's Omni-C sequencing allowed the chromosome-level assembly of this genome, while PacBio Isoform sequencing across five tissue types enabled the construction of high-quality gene models. This assembly resulted in 16 pseudo-chromosomes spanning over 1.12 Gb (98.1% of total scaffolds length), N50 of 67.09 Mb, the longest scaffold length of 105.96 Mb, and a BUSCO completeness score of 97.6%. This study identified 25,422 protein-coding genes and 61,149 transcripts. In an era of climate change and ocean warming, this genome of a heat-tolerant species can be used for comparative genomics with a focus on thermal resistance. This high-quality reference genome of H. asinina is a valuable resource for aquaculture, fisheries, and ecological studies.

Top 20 EGFR+ NSCLC Clinical and Translational Science Papers That Shaped the 20 Years Since the Discovery of Activating EGFR Mutations in NSCLC. An Editor-in-Chief Expert Panel Consensus Survey.

The year 2024 is the 20th anniversary of the discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential "cure" in early-stage EGFR+ NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most EGFR+ NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described "discoveries" of activating EGFR mutations (del19, L858R, exon 20 insertions, and "uncommon" mutations) were published. To commemorate this 20th anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered "honorable mention" and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as "syllabus" for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25th anniversay of the discovery EGFR mutations (i.e. top 25 papers on the 25 years since the discovery of activating EGFR mutations).

To Crush or Not to Crush: Administering Dabrafenib and Trametinib Through a Nasogastric Tube in a Critically Ill Patient With Nonsmall Cell Lung Cancer - A Case Report and Review of Literature of Targeted Therapies Given Through Enteral Feeding Tubes.

Up to 71% of lung cancer patients admitted to the ICU are newly diagnosed. The decision to initiate cancer directed treatments in lung cancer patients admitted to the ICU remains complex. For those with identified oncogene driver mutations, targeted therapies with rapid and high response rates are attractive treatment options. However, mechanically ventilated patients face additional barriers in which enteral tube administration of oral therapies may require tablets or capsules to be crushed or opened and diluted. Data on the pharmacodynamics and pharmacokinetics of this alternative route of administration are often very limited. Here we describe the first case report of an intubated patient with newly diagnosed NSCLC who was successfully treated with opened dabrafenib capsules and crushed trametinib tablets administered through a nasogastric tube. We also provide a review of the existing literature on feeding tube administration of commonly used tyrosine kinase inhibitors in lung cancer. Tyrosine kinase inhibitors administered through feeding tubes can lead to a clinically meaningful recovery in critically ill patients.

Genomic evidence for West Antarctic Ice Sheet collapse during the Last Interglacial.

The marine-based West Antarctic Ice Sheet (WAIS) is considered vulnerable to irreversible collapse under future climate trajectories, and its tipping point may lie within the mitigated warming scenarios of 1.5° to 2°C of the United Nations Paris Agreement. Knowledge of ice loss during similarly warm past climates could resolve this uncertainty, including the Last Interglacial when global sea levels were 5 to 10 meters higher than today and global average temperatures were 0.5° to 1.5°C warmer than preindustrial levels. Using a panel of genome-wide, single-nucleotide polymorphisms of a circum-Antarctic octopus, we show persistent, historic signals of gene flow only possible with complete WAIS collapse. Our results provide the first empirical evidence that the tipping point of WAIS loss could be reached even under stringent climate mitigation scenarios.

Programmed Cell Death Protein 1 Inhibitors and MET Targeted Therapies in NSCLC With MET Exon 14 Skipping Mutations: Efficacy and Toxicity as Sequential Therapies.

Introduction: NSCLC with MET exon 14 skipping mutation (METex14) is associated with poor outcomes. Integration of novel targeted therapies is challenging because of barriers in testing and drug access. We, therefore, sought to characterize the treatment patterns, outcomes, and emerging issues of treatment sequencing in patients with METex14-mutant NSCLC. Methods: We reviewed all NSCLC cases with METex14 alterations between 2014 and 2020 across four Canadian cancer centers. Demographics, disease characteristics, systemic therapy, overall response rates (ORRs), survival, and toxicity were summarized. Results: Among 64 patients with METex14-mutant NSCLC, the median overall survival was 23.1 months: 127.0 months in stage 1, 27.3 months in resected stage 2 and 3, and 16.6 months in unresectable stage 3 or 4 disease, respectively. In patients with advanced disease, 22% were too unwell for systemic treatment. MET tyrosine kinase inhibitors (TKIs) were administered to 28 patients with an ORR of 33%, median progression-free survival of 2.7 months, and 3.8 months for selective TKIs. Programmed cell death protein-1 (PD-1) inhibitors were given to 25 patients-the ORR was 44% and progression-free survival was 10.6 months. No responses were seen with subsequent MET TKIs after initial TKI treatment. Grade 3 or higher toxicities occurred in 64% of patients who received MET TKI after PD-1 inhibitors versus 8% in those who did not receive PD-1 inhibitors. Conclusions: Many patients with advanced METex14 NSCLC were too unwell to receive treatment. PD-1 inhibitors seem effective as an initial treatment, although greater toxicity was seen with subsequent MET TKIs. Thus, timely testing for METex14 skipping and initial therapy are imperative to improving patient survival.

Spotlight on Small-Cell Lung Cancer and Other Lung Neuroendocrine Neoplasms.

Lung neuroendocrine neoplasms (NENs) encompass a spectrum of neoplasms that are subdivided into the well-differentiated neuroendocrine tumors comprising the low- and intermediate-grade typical and atypical carcinoids, respectively, and the poorly differentiated, high-grade neuroendocrine carcinomas including large-cell neuroendocrine carcinomas and small-cell lung carcinoma (SCLC). Here, we review the current morphological and molecular classifications of the NENs on the basis of the updated WHO Classification of Thoracic Tumors and discuss the emerging subclassifications on the basis of molecular profiling and the potential therapeutic implications. We focus on the efforts in subtyping SCLC, a particularly aggressive tumor with few treatment options, and the recent advances in therapy with the adoption of immune checkpoint inhibitors in the frontline setting for patients with extensive-stage SCLC. We further highlight the promising immunotherapy strategies in SCLC that are currently under investigation.

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer.

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD + degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD + . Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE: Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

Genomic insights of evolutionary divergence and life history innovations in Antarctic brittle stars.

Understanding the drivers of evolutionary innovation provides a crucial perspective of how evolutionary processes unfold across taxa and ecological systems. It has been hypothesised that the Southern Ocean provided ecological opportunities for novelty in the past. However, the drivers of innovation are challenging to pinpoint as the evolutionary genetics of Southern Ocean fauna are influenced by Quaternary glacial-interglacial cycles, oceanic currents and species ecology. Here we examined the genome-wide single nucleotide polymorphisms of the Southern Ocean brittle stars Ophionotus victoriae (five arms, broadcaster) and O. hexactis (six arms, brooder). We found that O. victoriae and O. hexactis are closely-related species with interspecific gene flow. During the late Pleistocene, O. victoriae likely persisted in a connected deep water refugium and in situ refugia on the Antarctic continental shelf and around Antarctic islands; O. hexactis persisted exclusively within in situ island refugia. Within O. victoriae, contemporary gene flow linking to the Antarctic Circumpolar Current, regional gyres and other local oceanographic regimes was observed. Gene flow connecting West and East Antarctic islands near the Polar Front was also detected in O. hexactis. A strong association was detected between outlier loci and salinity in O. hexactis. Both O. victoriae and O. hexactis are associated with genome-wide increase in alleles at intermediate-frequencies; the alleles associated with this peak appear to be species specific, and these intermediate-frequency variants are far more excessive in O. hexactis. We hypothesise that the peak in alleles at intermediate frequencies could be related to adaptation in the recent past, linked to evolutionary innovations of increase in arm number and a switch to brooding from broadcasting, in O. hexactis.

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

Squamous cell lung cancer: Current landscape and future therapeutic options.

Squamous cell lung cancers (lung squamous cell carcinomas [LUSCs]) are associated with high mortality and a lack of therapies specific to this disease. Although recurrent molecular aberrations are present in LUSCs, efforts to develop targeted therapies against receptor tyrosine kinases, signaling transduction, and cell cycle checkpoints in LUSCs were met with significant challenges. The present therapeutic landscape focuses on epigenetic therapies to modulate the expression of lineage-dependent survival pathways and undruggable oncogenes. Another important therapeutic approach is to exploit metabolic vulnerabilities unique to LUSCs. These novel therapies may synergize with immune checkpoint inhibitors in the right therapeutic context. For example, the recognition that alterations in KEAP1-NFE2L2 in LUSCs affected antitumor immune responses created unique opportunities for targeted, metabolic, and immune combinations. This article provides a perspective on how lessons learned from the past influence the current therapeutic landscape and opportunities for future drug development for LUSCs.

Immunotherapy in non-small cell lung cancer: Past, present, and future directions.

Many decades in the making, immunotherapy has demonstrated its ability to produce durable responses in several cancer types. In the last decade, immunotherapy has shown itself to be a viable therapeutic approach for non-small cell lung cancer (NSCLC). Several clinical trials have established the efficacy of immune checkpoint blockade (ICB), particularly in the form of anti-programmed death 1 (PD-1) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies and anti-programmed death 1 ligand (PD-L1) antibodies. Many trials have shown progression free survival (PFS) and overall survival (OS) benefit with either ICB alone or in combination with chemotherapy when compared to chemotherapy alone. The identification of biomarkers to predict response to immunotherapy continues to be evaluated. The future of immunotherapy in lung cancer continues to hold promise with the development of combination therapies, cytokine modulating therapies and cellular therapies. Lastly, we expect that innovative advances in technology, such as artificial intelligence (AI) and machine learning, will begin to play a role in the future care of patients with lung cancer.

Emerging biological archives can reveal ecological and climatic change in Antarctica.

Anthropogenic climate change is causing observable changes in Antarctica and the Southern Ocean including increased air and ocean temperatures, glacial melt leading to sea-level rise and a reduction in salinity, and changes to freshwater water availability on land. These changes impact local Antarctic ecosystems and the Earth's climate system. The Antarctic has experienced significant past environmental change, including cycles of glaciation over the Quaternary Period (the past ~2.6 million years). Understanding Antarctica's paleoecosystems, and the corresponding paleoenvironments and climates that have shaped them, provides insight into present day ecosystem change, and importantly, helps constrain model projections of future change. Biological archives such as extant moss beds and peat profiles, biological proxies in lake and marine sediments, vertebrate animal colonies, and extant terrestrial and benthic marine invertebrates, complement other Antarctic paleoclimate archives by recording the nature and rate of past ecological change, the paleoenvironmental drivers of that change, and constrain current ecosystem and climate models. These archives provide invaluable information about terrestrial ice-free areas, a key location for Antarctic biodiversity, and the continental margin which is important for understanding ice sheet dynamics. Recent significant advances in analytical techniques (e.g., genomics, biogeochemical analyses) have led to new applications and greater power in elucidating the environmental records contained within biological archives. Paleoecological and paleoclimate discoveries derived from biological archives, and integration with existing data from other paleoclimate data sources, will significantly expand our understanding of past, present, and future ecological change, alongside climate change, in a unique, globally significant region.

Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy.

Type I interferons (IFN-Is) are central regulators of anti-tumor immunity and responses to immunotherapy, but they also drive the feedback inhibition underlying therapeutic resistance. In the present study, we developed a mass cytometry approach to quantify IFN-I-stimulated protein expression across immune cells and used multi-omics to uncover pre-therapy cellular states encoding responsiveness to inflammation. Analyzing peripheral blood cells from multiple cancer types revealed that differential responsiveness to IFN-Is before anti-programmed cell death protein 1 (PD1) treatment was highly predictive of long-term survival after therapy. Unexpectedly, IFN-I hyporesponsiveness efficiently predicted long-term survival, whereas high responsiveness to IFN-I was strongly associated with treatment failure and diminished survival time. Peripheral IFN-I responsive states were not associated with tumor inflammation, identifying a disconnect between systemic immune potential and 'cold' or 'hot' tumor states. Mechanistically, IFN-I responsiveness was epigenetically imprinted before therapy, poising cells for differential inflammatory responses and dysfunctional T cell effector programs. Thus, we identify physiological cell states with clinical importance that can predict success and long-term survival of PD1-blocking immunotherapy.

PD-L1 assessment in cytology samples predicts treatment response to checkpoint inhibitors in NSCLC.

BACKGROUND: Testing for tumor programmed death ligand-1 (PD-L1) expression was initially developed with histology specimens in non-small cell lung cancer (NSCLC). However, cytology specimens are widely used for primary diagnosis and biomarker studies in clinical practice. Limited clinical data exist on the predictiveness of cytology-derived PD-L1 scores for response to immune checkpoint inhibitor (ICI) therapy. METHODS: We reviewed all NSCLC specimens clinically tested at the University Health Network (UHN) for PD-L1 with 22C3pharmDx, from 01/2013 to 04/2021. Treatment outcomes in patients treated with single agent ICI therapy were reviewed and compared according to cytology- and histology-derived PD-L1 scores. RESULTS: We identified 494 and 1942 unique patients with cytology- and histology-derived tumor proportion scores, respectively, during the study period. Informative testing rates were 95 % vs 98 % for cytology and histology, respectively. Clinical data were available for 152 patients treated with single agent ICI: 61 cytology and 91 histology. Overall response rates (ORR) were similar for cytology and histology (36 % vs 34 %; p = 0.23), as well as median progression free survival (PFS) (4.9 vs 4.2 months; p = 0.99) and overall survival (23.4 vs 19.7 months; p = 0.99). The results remained similar even after adjusting for PD-L1 expression levels and line of ICI treatment (PFS HR 1.15; 95 %CI 0.78-1.70; p = 0.47). CONCLUSIONS: Treatment outcomes to single agent ICI based on cytology-derived PD-L1 scores were comparable to histology controls. Our results support PD-L1 biomarker testing on both cytology and histology specimens.

iRECIST and atypical patterns of response to immuno-oncology drugs.

With the advent of immunotherapy as one of the keystones of the treatment of our patients with cancer, a number of atypical patterns of response to these agents has been identified. These include pseudoprogression, where the tumor initially shows objective growth before decreasing in size, and hyperprogression, hypothesized to be a drug-induced acceleration of the tumor burden. Despite it being >10 years since the first immune-oncology drug was approved, neither the biology behind these paradoxical responses has been well understood, nor their incidence, identification criteria, predictive biomarkers, or clinical impact have been fully described. Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) guidelines have been published as a revision to the RECIST V.1.1 criteria for use in trials of immunotherapeutics, and the iRECIST subcommittee (of the RECIST Working Group) is working on elucidating these aspects, with data sharing a current major challenge to move forward with this unmet need in immuno-oncology.

Is the Southern Ocean ecosystem primed for change or at the cliff edge?

The Southern Ocean is experiencing unprecedented environmental risks and consequences from current climate change. It is unclear how the benthic fauna, which has largely evolved in isolation, will respond to future changes. Knowing how the benthic fauna persisted through repeated extreme glacial-interglacial cycles in the past provides a unique opportunity to inform future predictions. Right now, understanding and preserving current genetic diversity and connectivity between populations will give species the best chance to adapt.

Evolutionary innovations in Antarctic brittle stars linked to glacial refugia.

The drivers behind evolutionary innovations such as contrasting life histories and morphological change are central questions of evolutionary biology. However, the environmental and ecological contexts linked to evolutionary innovations are generally unclear. During the Pleistocene glacial cycles, grounded ice sheets expanded across the Southern Ocean continental shelf. Limited ice-free areas remained, and fauna were isolated from other refugial populations. Survival in Southern Ocean refugia could present opportunities for ecological adaptation and evolutionary innovation. Here, we reconstructed the phylogeographic patterns of circum-Antarctic brittle stars Ophionotus victoriae and O. hexactis with contrasting life histories (broadcasting vs brooding) and morphology (5 vs 6 arms). We examined the evolutionary relationship between the two species using cytochrome c oxidase subunit I (COI) data. COI data suggested that O. victoriae is a single species (rather than a species complex) and is closely related to O. hexactis (a separate species). Since their recent divergence in the mid-Pleistocene, O. victoriae and O. hexactis likely persisted differently throughout glacial maxima, in deep-sea and Antarctic island refugia, respectively. Genetic connectivity, within and between the Antarctic continental shelf and islands, was also observed and could be linked to the Antarctic Circumpolar Current and local oceanographic regimes. Signatures of a probable seascape corridor linking connectivity between the Scotia Sea and Prydz Bay are also highlighted. We suggest that survival in Antarctic island refugia was associated with increase in arm number and a switch from broadcast spawning to brooding in O. hexactis, and propose that it could be linked to environmental changes (such as salinity) associated with intensified interglacial-glacial cycles.