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For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11and/or KEAP1tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1was the strongest genomic predictor of dual ICB efficacy—a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1and STK11alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+cytotoxic T cells, but relative sparing of CD4+effector subsets. Dual ICB potently engaged CD4+effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that—together with CD4+and CD8+T cells—contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11and/or KEAP1alterations.

Background: Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). Methods: This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m2(combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. Results: 18 pts were enrolled into the study—10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. Conclusion: DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

A cross-coupling reaction via the dehydrogenative route over heterogeneous solid atomic catalysts offers practical solutions toward an economical and sustainable elaboration of simple organic substrates. The current utilization of this technology is, however, hampered by limited molecular definition of many solid catalysts. Here, we report the development of Cu–M dual-atom catalysts (where M = Co, Ni, Cu, and Zn) supported on a hierarchical USY zeolite to mediate efficient dehydrogenative cross-coupling of unprotected phenols with amine partners. Over 80% isolated yields have been attained over Cu–Co–USY, which shows much superior reactivity when compared with our Cu1and other Cu–M analogues. This amination reaction has hence involved simple and non-forceful reaction condition requirements. The superior reactivity can be attributed to (1) the specifically designed bimetallic Cu–Co active sites within the micropore for “co-adsorption–co-activation” of the reaction substrates and (2) the facile intracrystalline (meso/micropore) diffusion of the heterocyclic organic substrates. This study offers critical insights into the engineering of next-generation solid atomic catalysts with complex reaction steps.

This paper aims to analyze the distribution efficiency of DC power distribution power system in commercial building based on measured data from a typical office building in Hong Kong. In this research, a real-scene comparative testbed was built in a Hong Kong office to compare the energy efficiencies of AC and DC power distribution system. Similar load characteristics and use schedules are set and used in the experiment. The distribution efficiency has been found to be affected by load type, voltage level and the loading conditions. The efficiency of this DC power system is derived, considering the PFC model was working in a good condition. For LED loads, the average distribution efficiencies after converter are 77.7% and 51.8 % under the condition of full lightning and normal lightning mode. The main loss in this system is transmission loss and switching loss. The average AC/DC converter efficiencies of LEDs are 92.21% and 88.85% respectively with the load working under full power and normal power, while the average AC power factors of LEDs are 85.31% and 56.22% respectively with the load working under the same as above. The average AC/DC converter efficiencies of the fan coil are 97.41%, 96.03%, 92.74%, 89.10%, 85.71%, 78.72%, 67.61%, 63.57% respectively with the load working under level 8 to level 1 while the average AC power factors of the fan coil are 98.0%, 99.0% and 99.4% respectively with the load working under low middle and high condition. As the PFC circuit does not have ideal power factor correction when the load is small, it is not recommended to add PFC circuit when the load power is low. Using uncontrollable rectifier circuit is going to lead to a better performance.

Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered ‘undruggable’ owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRASG12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

Over the past four decades, advancements in adjuvant treatments of bone sarcomas have catalyzed development of novel surgical technologies that continue to improve limb salvage surgeries. To date, these technologies have made limb salvage surgery the mainstay of treatment, while limb amputations became negligible. These advancements include pre-and intra-operative imaging technologies enabling accurate 3D-preoperative planning, and intraoperative patient-specific instruments allowing accurate execution of surgical plans. The introduction of customized 3D-printed porous titanium implants gave surgeons more freedom to retain surrounding healthy tissue and optimize reconstruction fit, thereby improving quality of life and reducing comorbidities post-operatively. Creating these custom implants has brought forth novel processes, materials and technologies and given rise to a new era in orthopedic oncology.

Nanophotonics based on localized surface plasmon resonance (LSPR) has emerged as a vibrant arena for research into enhanced light–matter interactions with potential applications in imaging, sensing, and computing. However, the low quality (Q) factor of LSPR is a significant barrier to comprehensive device applications. Here, we demonstrate that coupling the LSPR of a gold nanowire array with the optical bound states in the continuum (BIC) of a dielectric double-layer grating can significantly increase the Q factor of LSPR. We realize two hybrid modes with Q factors of up to 111 at 558 nm and 83 at 582 nm, which are about 14 and 10 times larger than those of an uncoupled gold nanowire array. Based on temporal coupled-mode theory, we further show that the resonance frequencies and Q factors of the hybrid modes can be modulated and optimized by varying relevant structural parameters. This coupled system provides a new platform for improving the figures of merit (FoMs) of LSPR-based refractive index sensors, and the concept of LSPR–BIC coupling can be extended to other similar nanosystems.

We investigate the scattering properties of coupled parity-time (PT) symmetric chiral nanospheres with scattering matrix formalism. The exceptional points, i.e., spectral singularities at which the eigenvalues and eigenvectors simultaneously coalesce in the parameter space, of scattering matrix can be tailored by the chirality of the nanospheres. We also calculate the scattering, absorption and extinction cross sections of the PT-symmetric chiral scatter under illumination by monochromatic left- and right-circularly polarized plane waves. We find that the scattering cross section of the nanostructures exhibits an asymmetry when the plane waves are incident from the loss and gain regions, respectively, especially in the broken phase, and the optical cross section exhibits circular dichroism, i.e., differential extinction when the PT-symmetric scatter is endowed with chirality. In particular, under illumination by linearly polarized monochromatic plane waves without intrinsic chirality, the ellipticity of scattered fields in the forward direction, denoting the chirality of light, becomes larger when the scatter is in the PT-symmetry-broken phase. Our findings demonstrate that the gain and loss can control the optical chirality and enhance the chiroptical interactions and pave the way for studying the resonant chiral light–matter interactions in non-Hermitian photonics.

ObjectiveOesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.DesignWe combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.ResultsWe identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.ConclusionThese results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

Inhibition of bacterial cell division is a novel mechanistic action in the development of new antimicrobial agents. The FtsZ protein is an important antimicrobial drug target because of its essential role in bacterial cell division. In the present study, potential inhibitors of FtsZ were identified by virtual screening followed by in vivoand in vitrobioassays. One of the candidates, Dacomitinib (S2727), shows for the first time its potent inhibitory activity against the MRSA strains. The binding mode of Dacomitinib in FtsZ was analyzed by docking, and Asp199and Thr265are thought to be essential residues involved in the interactions.

We report the guest-anion-induced photoluminescence enhancement of metal–organic frameworks (UiO-66-NH2), first based upon diffraction and computational evidence. We found that only limited anions, namely, carbonate and fluoride, can lead to a significant enhancement in photoluminescence, whereas their related anions, such as acetate and chloride, cannot. The optimized crystal structures reveal that the guest carbonate and fluoride ions interact with four framework amino functional groups through hydrogen bonding (ca. 1.6–1.7 Å) that ultimately forms a quaternary (−N(H))4···X–molecular bridge around the nodal center. Hence, the hydrogen-bonded molecular bridge not only restricts the intermolecular C–C rotation of the linker molecules but also greatly perturbs the electronic densities between the guest anions and the framework amino groups.

In selected extremity bone sarcomas, joint-preserving surgery retains the natural joints and nearby ligaments with a better function than in traditional joint-sacrificing surgery. Geometric multiplanar osteotomies around bone sarcomas were reported with the advantage of preserving more host bone. However, the complex surgical planning translation to the operating room is challenging.

Treatment of childhood cancer can cause acute life-threatening complications and chronic debilitating conditions, and radiologists should recognize the spectrum of imaging features of these complications and develop a systematic approach for diagnosis.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1–7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

Lung adenocarcinomas harboring EGFRmutations do not respond to immune checkpoint blockade therapy and their EGFRwildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood.

In this study, Tang et al. investigated how metastasis is regulated by a common hot spot mutation, p53R175H, in esophageal squamous cell carcinoma (ESCC). Using a carcinogen-induced approach in Trp53R172H/−mice to model ESCC, they demonstrate that expression of Survivin, an antiapoptotic protein encoded by BIRC5 increases in the presence of Trp53R172Hand depletion of Survivin specifically decreases Trp53R172H-driven lung metastasis.

BackgroundSurvivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide.MethodsThe PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence.Results427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN—comparable to the risk among members of the general population with at least two first-degree relatives affected.ConclusionsColonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken.

Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2largely maintains actions observed in normal tissue, Sox2overexpression with p53and p16inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2functions in ESCC, defining targetable vulnerabilities.

Lung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer with limited treatment options. Previous studies have elucidated the complex genetic landscape of LUSC and revealed multiple altered genes and pathways. However, in stark contrast to lung adenocarcinoma, few targetable driver mutations have been established so far and targeted therapies for LUSC remain unsuccessful. Immunotherapy has revolutionized LUSC treatment and is currently approved as the new standard of care. To gain a better understanding of the LUSC biology, improved modeling systems are urgently needed. Preclinical models, particularly those mimicking human disease with an intact tumor immune microenvironment, are an invaluable tool to study cancer development and evaluate new therapeutic targets. Here, we discuss recent advances in LUSC preclinical models, with a focus on genetically engineered mouse models (GEMMs) and organoids, in the context of evolving precision medicine and immunotherapy.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent ‘back-signaling’ in CD4+T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet−IFN-γ−phenotype in CD8+T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+T cells restrained effector T cells via the canonical PD-L1–PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+T cells engaged PD-1+macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+T cells have diverse tolerogenic effects on tumor immunity.

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting.

Tachyplesin I (TPI) is a cationic β-hairpin antimicrobial peptide with broad-spectrum, potent antimicrobial activity. In this study, the all d-amino acid analogue of TPI (TPAD) was synthesized, and its structure and activity were determined. TPAD has comparable antibacterial activity to TPI on 14 bacterial strains, including four drug-resistant bacteria. Importantly, TPAD has significantly improved stability against enzymatic degradation and decreased hemolytic activity compared to TPI, indicating that it has better therapeutic potential. The induction of bacterial resistance using low concentrations of TPAD resulted in the activation of the QseC/B two-component system. Deletion of this system resulted in at least five-fold improvement of TPAD activity, and the combined use of TPAD with LED209, a QseC/B inhibitor, significantly enhanced the bactericidal effect against three classes of multidrug-resistant bacteria.

Complex nanostructures with distinct spatial architectures and more active sites hold broad prospects in new energy conversion fields. Herein, a facile strategy was carried out to construct triple-shelled Co-VSexnanocages, starting with an ion-exchange process between Co-based zeolitic imidazolate framework-67 (ZIF-67) nanopolyhedrons and VO3–followed by the formation of triple-shelled Co-VSexhollow nanocages during the process of increasing the solvothermal temperature under the assistance of SeO32–. Meanwhile, triple-shelled Co-VSxand yolk–double shell Co-VOxnanocages were fabricated as references by a similar process. Benefiting from the larger surface areas and more electrolyte adsorption sites, the triple-shelled Co-VSexnanocages exhibited excellent electrocatalytic performances when applied as the electrochemical catalysts for dye-sensitized solar cells (DSSC) and hydrogen evolution reactions (HER). More concretely, the DSSC based on the Co-VSexcounter electrode showed outstanding power conversion efficiency of 9.68% when its Pt counterpart was 8.46%. Moreover, the Co-VSexelectrocatalyst exhibited prominent HER performance with a low onset overpotential of 40 mV and a small Tafel slope of 39.1 mV dec–1in an acidic solution.

The CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, has a central role in gene control by facilitating or constraining interactions between genes and their regulatory elements1,2. In cancer cells, the disruption of CTCF binding at specific loci by somatic mutation3,4or DNA hypermethylation5results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ-cell-specific paralogue of CTCF, BORIS(brother of the regulator of imprinted sites, also known as CTCFL)6, is overexpressed in several cancers7–9, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORISpromotes chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma10cells that develop resistance to ALK inhibition. These cells are reprogrammed to a distinct phenotypic state during the acquisition of resistance, a process defined by the initial loss of MYCNexpression followed by subsequent overexpression of BORISand a concomitant switch in cellular dependence from MYCN to BORIS. The resultant BORIS-regulated alterations in chromatin looping lead to the formation of super-enhancers that drive the ectopic expression of a subset of proneural transcription factors that ultimately define the resistance phenotype. These results identify a previously unrecognized role of BORIS—to promote regulatory chromatin interactions that support specific cancer phenotypes. The CTCF paralogue BORIS is upregulated in transcriptionally reprogrammed neuroblastoma cells rendered resistant to targeted therapy, in which it promotes regulatory chromatin interactions that maintain the resistance phenotype.

Denosumab is gradually applied to refractory or unresectable giant cell tumour of the bone. Whether denosumab can effectively reduce the blood supply of tumour and bring benefit is worthy of study. The aim of the study is to evaluate the related changes after treatment: blood supply, surgical plan downstaging, surgical difficulty and oncological prognosis.

Two-dimensional (2D) metal-organic frameworks (MOFs) and covalent-organic frameworks (COFs) have recently emerged as a new class of crystalline materials with ultrahigh porosity and enormous surface area. These materials have attracted vast research interest due to their unique properties originating from ultrathin thickness, highly accessible active sites, and versatile structures. With many common features, MOFs and COFs also have distinct differences, both in synthetic and application aspects, as their building components are different. This review mainly focuses on the recent advances in the synthetic approaches of 2D MOFs and COFs and their applications in energy conversion reactions and storage devices. First, we discuss various strategies recently developed for the preparation of 2D MOFs and COFs by using self-assembly, template-directed method, surfactant-directed method, solid-supported growth, and decomposition, and the different considerations needed for desired 2D MOFs and COFs are compared. Secondly, energy-related applications of 2D MOFs and COFs are summarized with discussion on the structure-reactivity relationships. Finally, we give the insights into the challenges and outlook on the future research direction for 2D MOFs and COFs.

IMPORTANCE: Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential, but epidemiologic data are poor. Changes to the National Cancer Registration and Analysis Service (NCRAS) in England have allowed more accurate data analysis of primary and metastatic cSCC since 2013. OBJECTIVE: To assess the national incidence of cSCC and metastatic cSCC (mcSCC) in England from 2013 through 2015. DESIGN, SETTING, AND PARTICIPANTS: This national population-based study identified a cohort of patients with cSCC and mcSCC in England from January 1, 2013, through December 31, 2015. Patients were identified using diagnostic codes derived from pathology reports in the NCRAS. Data were analyzed from March 1, 2017, through March 1, 2018. MAIN OUTCOMES AND MEASURES: Incidence rates across sex and risk factors for cSCC were derived from the NCRAS data. Risk of occurrence of mcSCC among the population with cSCC was assessed with Cox proportional hazards regression analysis to determine indicators of mcSCC. RESULTS: Among the 76 977 patients with first primary cSCC in 2013 through 2015 (62.7% male; median age, 80 years [interquartile range, 72-86 years]), the age-standardized rates for the first registered cSCC in England from 2013 through 2015 were 77.3 per 100 000 person-years (PY) (95% CI, 76.6-78.0) in male patients and 34.1 per 100 000 PY (95% CI, 33.7-34.5) in female patients. Increased primary cSCC tumor count was observed in older, white male patients in lower deprivation quintiles. After a maximum follow-up of 36 months, cumulative incidence of mcSCC developed in 1.1% of women and 2.4% of men with a primary cSCC. Significant increases in the risk of metastasis with adjusted hazard rates of approximately 2.00 were observed in patients who were aged 80 to 89 years (hazard ratio [HR], 1.23; 95% CI, 1.07-1.43), 90 years or older (HR, 1.35; 95% CI, 1.09-1.66), male (HR, 1.79; 95% CI, 1.52-2.10), immunosuppressed (HR, 1.99; 95% CI, 1.64-2.42), and in higher deprivation quintiles (HR for highest quintile, 1.64; 95% CI, 1.35-2.00). Primary cSCC located on the ear (HR, 1.70; 95% CI, 1.42-2.03) and lip (HR, 1.85; 95% CI, 1.29-2.63) were at highest risk of metastasis. CONCLUSIONS AND RELEVANCE: This study presents the first national study of the incidence of mcSCC. With limited health care resources and an aging population, accurate epidemiologic data are essential for informing future health care planning, identifying high-risk patients, and evaluating skin cancer prevention policies.

Most tumours have an aberrantly activated lipid metabolism1,2that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation3. This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

Chordoma is a primary bone cancer with no approved therapy1. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T(brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors4,5. In chordoma, we find that Tis associated with a 1.5-Mb region containing ‘super-enhancers’ and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of Tgene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.

In this study from Oser et al., the authors investigated how RB1 loss causes a neuroendocrine phenotype in different tumor types. They show that histone demethylase KDM5A (also known as RBP2 or JARID1A) promotes small cell lung cancer (SCLC) proliferation and SCLCs neuroendocrine differentiation phenotype through sustained expression of the neuroendocrine transcription factor ASCL1 by repressing NOTCH2 and NOTCH target genes, thereby establishing a role for KDM5A in SCLC tumorigenesis.

Background and purposeCerebral microbleeds (CMBs), which predict future intracerebral haemorrhage (ICH), may guide anticoagulant decisions for atrial fibrillation (AF). We aimed to evaluate the risk of warfarin-associated ICH in Chinese patients with AF with CMBs.MethodsIn this prospective, observational, multicentre study, we recruited Chinese patients with AF who were on or intended to start anticoagulation with warfarin from six hospitals in Hong Kong. CMBs were evaluated with 3T MRI brain at baseline. Primary outcome was clinical ICH at 2-year follow-up. Secondary outcomes were ischaemic stroke, systemic embolism, mortality of all causes and modified Rankin Scale ≥3. Outcome events were compared between patients with and without CMBs.ResultsA total of 290 patients were recruited; 53 patients were excluded by predefined criteria. Among the 237 patients included in the final analysis, CMBs were observed in 84 (35.4%) patients, and 11 had ≥5 CMBs. The mean follow-up period was 22.4±10.3 months. Compared with patients without CMBs, patients with CMBs had numerically higher rate of ICH (3.6% vs 0.7%, p=0.129). The rate of ICH was lower than ischaemic stroke for patients with 0 to 4 CMBs, but higher for those with ≥5 CMBs. CMB count (C-index 0.82) was more sensitive than HAS-BLED (C-index 0.55) and CHA2DS2-VASc (C-index 0.63) scores in predicting ICH.ConclusionsIn Chinese patients with AF on warfarin, presence of multiple CMBs may be associated with higher rate of ICH than ischaemic stroke. Larger studies through international collaboration are needed to determine the risk:benefit ratio of oral anticoagulants in patients with AF of different ethnic origins.

Two-dimensional (2D) layered nanomaterials have trigged intensive interest in the photocatalytic field due to their intriguing physicochemical properties, which offer the possibility to develop highly-efficient visible-light-driven photocatalysts. In this review, we first discuss the historical developments of 2D nanomaterials, and outline their advantages as the building blocks to construct photocatalysts. Then, we summarize the typical synthesis methods, electronic and optical properties, and the corresponding influences on photocatalytic activity. Then, we in detail discuss some strategies for improving their photocatalytic activity by the modification or surface functionalization of 2D layered nanomaterial photocatalysts. Further, we highlight the applications of some typical 2D layered nanomaterials, including the graphene family, graphitic carbon nitride, transition metal dichalcogenides, and oxides for water splitting under the visible light illumination. Finally, we provide some personal perspectives on future challenges and opportunities in utilizing 2D layered nanomaterials for large-scale photocatalysis applications.