Reinforcement of Different Sands by Low-pH Bio-Mineralization.

Different sands have significant influences on MICP reinforcement effects. Using calcium carbonate production and bioflocculation lag period as evaluation criteria, this study investigates the optimal theoretical pH values of bacterial solutions with different concentrations. We reinforced four different sands using MICP at the optimal theoretical pH, and based on permeability, moisture retention, raindrop erosion, wind erosion, penetration, and SEM tests, the influence of sand properties on low-pH MICP reinforcement was analyzed and the low-pH MICP mechanism was revealed. The results indicate the following: (1) The optimal theoretical pH values for bacterial solutions with concentrations of 0.67 × 108 cells/mL, 3 × 108 cells/mL, and 10 × 108 cells/mL are 4.5, 3, and 4, respectively. (2) With 0.67 × 108, 3 × 108, and 10 × 108 cells/mL bacterial solutions, the strength of tailings sand containing calcium salt was 21.15%, 44.42%, and 13.61% higher than that of quartz sand, respectively. The effective reinforcement depth of alkaline reclaimed sand was 10, 8, and 6 mm lower than that of neutral calcareous sand, respectively. The strength of fine tailings sand was 70.41%, 58.04%, and 22.6% higher than that of coarse reclaimed sand. The effective reinforcement depth of fine quartz sand was 6, 4, and 4 mm lower than that of coarse calcareous sand. (3) Low pH temporarily suppresses urease activity, delaying calcium carbonate flocculation and enhancing reinforcement uniformity. To achieve optimal reinforcement effects, adjusting the actual optimal pH values of bacterial solution based on sand properties is essential in engineering applications.

Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones.

Ferroptosis, a cell death process driven by iron-dependent phospholipid peroxidation, has been implicated in various diseases. There are two major surveillance mechanisms to suppress ferroptosis: one mediated by glutathione peroxidase 4 (GPX4) that catalyzes the reduction of phospholipid peroxides and the other mediated by enzymes, such as FSP1, that produce metabolites with free radical-trapping antioxidant activity. In this study, through a whole-genome CRISPR activation screen, followed by mechanistic investigation, we identified phospholipid-modifying enzymes MBOAT1 and MBOAT2 as ferroptosis suppressors. MBOAT1/2 inhibit ferroptosis by remodeling the cellular phospholipid profile, and strikingly, their ferroptosis surveillance function is independent of GPX4 or FSP1. MBOAT1 and MBOAT2 are transcriptionally upregulated by sex hormone receptors, i.e., estrogen receptor (ER) and androgen receptor (AR), respectively. A combination of ER or AR antagonist with ferroptosis induction significantly inhibited the growth of ER+ breast cancer and AR+ prostate cancer, even when tumors were resistant to single-agent hormonal therapies.

[Tracking analysis of viral nucleic acid Ct value in patients with re-positive SARS-CoV-2 infection].

OBJECTIVE: To track analysis of viral nucleic acid test results in patients with re-positive SARS-CoV-2 infection, and provide clinical reference for nucleic acid test of re-positive cases. METHODS: A retrospective study was conducted. The multiple nucleic acid results of 96 cases with SARS-CoV-2 infection tested by medical laboratory of Shenzhen Luohu Hospital Group from January to September in 2022 were analyzed. The test dates and cycle threshold (Ct) values of detectable positive virus nucleic acid in the 96 cases were summarized and analyzed. RESULTS: A total of 96 patients with SARS-CoV-2 infection were retested re-sampled for nucleic acid testing at least 12 days after the initial positive screening. Among them, 54 cases (56.25%) had Ct value of < 35 for nucleocapsid protein gene (N) and/or open reading frame 1ab gene (ORF 1ab), 42 cases (43.75%) had Ct value ≥ 35. In the re-sampling of infected patients, N gene titers were 25.08 to 39.98 Ct cycles, and ORF 1ab gene titers were 23.16 to 39.56 Ct cycles. Compared with the positive results of the initial screening, the Ct values of N gene and/or ORF 1ab gene positive were increased in 90 cases (93.75%). Among them, the patients with the longest duration of nucleic acid positive could still be positive for double targets (the Ct value of N gene was 38.60, and the Ct value of ORF 1ab gene was 38.11) at an interval of 178 days after the initial positive screening. CONCLUSIONS: Patients infected with SARS-CoV-2 can be sustained or repeatedly tested positive for nucleic acid for a long period of time, and most of them had Ct values < 35. But whether it is infectious needs to be comprehensively evaluated by combining epidemiology, variant type, samples with the alive virus, and clinical symptoms and signs.

Beating the break-even point with a discrete-variable-encoded logical qubit.

Quantum error correction (QEC) aims to protect logical qubits from noises by using the redundancy of a large Hilbert space, which allows errors to be detected and corrected in real time1. In most QEC codes2-8, a logical qubit is encoded in some discrete variables, for example photon numbers, so that the encoded quantum information can be unambiguously extracted after processing. Over the past decade, repetitive QEC has been demonstrated with various discrete-variable-encoded scenarios9-17. However, extending the lifetimes of thus-encoded logical qubits beyond the best available physical qubit still remains elusive, which represents a break-even point for judging the practical usefulness of QEC. Here we demonstrate a QEC procedure in a circuit quantum electrodynamics architecture18, where the logical qubit is binomially encoded in photon-number states of a microwave cavity8, dispersively coupled to an auxiliary superconducting qubit. By applying a pulse featuring a tailored frequency comb to the auxiliary qubit, we can repetitively extract the error syndrome with high fidelity and perform error correction with feedback control accordingly, thereby exceeding the break-even point by about 16% lifetime enhancement. Our work illustrates the potential of hardware-efficient discrete-variable encodings for fault-tolerant quantum computation19.

Treatment of engineering waste slurries by microbially induced struvite precipitation mechanisms.

With societal development, the growing scale of engineering construction, and the increase in environmental protection requirements, the necessity of engineering waste mud disposal is becoming increasingly prominent. In this study, microbially induced struvite precipitation (MISP) was introduced to treat engineering waste mud. The study mainly focused on: i) the optimal mineralization scheme for microbially induced struvite precipitation, ii) the feasibility of the process and the effect of reaction parameters on treating engineering waste mud with microbially induced struvite precipitation, and iii) the mechanism of microbially induced struvite precipitation in treating engineering waste mud. The results showed that the waste mud could be well treated with 8.36 × 10 6   c e l l ⋅ m L - 1 bacteria, 10 mM urea, 20 mM phosphate buffer, and 25 mM M g C l 2 at pH 7. The kaolin suspension could be effectively flocculated. The flocculation rate reached approximately 87.2% under the optimum mineralization conditions. The flocculation effect was mainly affected by the concentrations of reactants and heavy metals and the suspension pH. The X-ray diffraction (XRD) patterns showed a strong struvite (MAP) diffraction peak. Scanning electron microscopy (SEM) images indicated that under the optimal mineralization conditions, the crystals were large and showed prismatic shapes tilted at both ends with adhered kaolin particles. In summary, this manuscript provides an effective way to treat engineering waste mud, and the findings should have a positive effect on enhancing soil fertility and preventing secondary pollution.

Identification of miRNA profile in the peripheral blood and clinical significance of miR-355 and miR-2911 expression in children with Kawasaki disease.

OBJECTIVE: To identify the abnormal expression profile of miRNA in peripheral blood of children with Kawasaki disease (KD) and explore its diagnostic value for Kawasaki disease. METHODS: From January 2020 to June 2021, 62 children with KD (KD group) and 158 children with febrile disease (Con group) were selected as subjects. Peripheral blood was collected before treatment, and differentially expressed miRNAs in peripheral blood were identified by next generation sequencing, and the identified targets were verified by RT-PCR. The diagnostic value of miRNAs in KD was analyzed by ROC curves and linear SVM model. RESULTS: Compared to Con group, a total of 163 differentially expressed miRNAs were detected in peripheral blood of children in the KD group, including 126 up-regulated miRNAs and 37 down-regulated miRNAs. Hierarchical clustering showed that miRNA profiles of children in the KD group and Con group were significantly different, among which 3 miRNAs wereup-regulated and 3 miRNAs were down-regulated (P<0.05). The results of miRanda and TargetScanS software showed that a total of 17159 target genes were predicted. GO function and KEGG signal pathway enrichment analysis showed that target genes were involved in a wide range of biological functions; ROC curve results showed that the sensitivity of miR-355 and miR-2911 in diagnosing KD were 73.8% and 71.2%, the specificity was 72.4% and 73.9%, and the AUC was 0.793 and 0.757, respectively. The AUC for combined detection of miR-355 and miR-2911 was increased to 0.806. A linear SVM model further verified the diagnostic value of joint detection of miR-355 and miR-2911. CONCLUSION: Expression levels of miR-355 and miR-2911 were significantly up-regulated in peripheral blood of children with Kawasaki disease. miR-355 and miR-2911 could serve as biomarkers for diagnosis of Kawasaki disease.

Adjacent Fu's subcutaneous needling as an adjunctive healing strategy for diabetic foot ulcers: Two case reports.

RATIONALE: Diabetic foot ulcers (DFUs) present with different grades of ischemia and infection and are associated with high mortality and disability rates with little effective treatment. We used Fu Subcutaneous Needling (FSN) to treat 2 cases with DFUs and achieved satisfactory results. PATIENT CONCERNS: Two cases of DFUs showed poor recovery after conventional wound care treatment, and case 2 was confronted with the risk of amputation. DIAGNOSIS: Two patients with history of diabetes were diagnosed with DFUs, presenting with lower leg and foot ulcers. INTERVENTIONS: Case 1 received 6 sessions of FSN treatment in 8 days, and case 2 received 10 sessions of FSN treatment in 14 days. OUTCOMES: Case 1 completely healed from a 1 × 0.5-cm blister and a 0.5 × 0.5-cm ulcer of the right lower leg 14 days after the first FSN treatment. The ulcer area of the left foot in case 2 decreased from 6 × 7 cm to 4 × 3.5 × 0.2 cm. Three months of follow-up revealed full wound closure. LESSONS: FSN is effective for healing with DFUs, and it may be used as an adjunctive healing strategy for DFUs patients when conventional treatments such as infection, glycemic control, and local ulcer care are not available.

ERα-LBD, an isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance.

Estrogen receptor alpha (ERα) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of an ERα isoform, ERα-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ERα-LBD is found to promote breast cancer growth and resistance to the ERα antagonist fulvestrant. ERα-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ERα-LBD expression and function does not appear to be restricted to cancers that express full length ERα but also promotes growth of triple-negative breast cancers and ERα-LBD transcript (ESR1-LBD) is also present in BC samples from both ERα(+) and ERα(-) human tumors. These findings point to ERα-LBD as a potential mediator of breast cancer progression and therapy resistance.

Impact of socio-economic environment and its interaction on the initial spread of COVID-19 in mainland China.

Coronavirus disease 2019 (COVID-19) has strongly impacted society since it was first reported in mainland China in December 2020. Understanding its spread and consequence is crucial to pandemic control, yet difficult to achieve because we deal with a complex context of social environment and variable human behaviour. However, few efforts have been made to comprehensively analyse the socio-economic influences on viral spread and how it promotes the infection numbers in a region. Here we investigated the effect of socio-economic factors and found a strong linear relationship between the gross domestic product (GDP) and the cumulative number of confirmed COVID-19 cases with a high value of R2 (between 0.57 and 0.88). Structural equation models were constructed to further analyse the social-economic interaction mechanism of the spread of COVID-19. The results show that the total effect of GDP (0.87) on viral spread exceeds that of population influx (0.58) in the central cities of mainland China and that the spread mainly occurred through its interplay with other factors, such as socio-economic development. This evidence can be generalized as socio-economic factors can accelerate the spread of any infectious disease in a megacity environment. Thus, the world is in urgent need of a new plan to prepare for current and future pandemics.

Causation inference in complicated atmospheric environment.

Reliable attribution is crucial for understanding various climate change issues. However, complicated inner-interactions between various factors make causation inference in atmospheric environment highly challenging. Taking PM2.5-Meteorology causation, which involves a large number of non-Linear and uncertain interactions between many meteorological factors and PM2.5, as a case, we examined the performance of a series of mainstream statistical models, including Correlation Analysis (CA), Partial Correlation Analysis (PCA), Structural Equation Model (SEM), Convergent Cross Mapping (CCM), Partial Cross Mapping (PCM) and Geographical Detector (GD). From a coarse perspective, the Top 3 major meteorological factors for PM2.5 in 190 cities across China extracted using different models were generally consistent. From a strict perspective, the extracted dominant meteorological factor for PM2.5 demonstrated large model variations and shared a limited consistence. Such models as SEM and PCM, which are capable of further separating direct and indirect causation in simple systems, performed poorly to identify the direct and indirect PM2.5-Meteorology causation. The notable inconsistence denied the feasibility of employing multiple models for better causation inference in atmospheric environment. Instead, the sole use of CCM, which is advantageous in dealing with non-linear causation and removing disturbing factors, is a preferable strategy for causation inference in complicated ecosystems. Meanwhile, given the multi-direction, uncertain interactions between many variables, we should be more cautious and less ambitious on the separation of direct and indirect causation. For better causation inference in the complicated atmospheric environment, the combination of statistical models and atmospheric models, and the further exploration of Deep Neural Network can be promising strategies.

Reinforcement of Calcareous Sands by Stimulation of Native Microorganisms Induced Mineralization.

Calcareous sand is a special soil formed by the accumulation of carbonate fragments. Its compressibility is caused by a high void ratio and breakable particles. Because of its high carbonate content and weak cementation, its load-bearing capacity is limited. In this study, the optimal stimulation solution was obtained with response surface methodology. Then, the effect of reinforcing calcareous sand was analysed with unconfined compressive strength (UCS) tests, calcium carbonate content tests, microscopy and microbial community analyses. The components and concentrations of the optimal stimulation solution were as follows: sodium acetate (38.00 mM), ammonium chloride (124.24 mM), yeast extract (0.46 g/L), urea (333 mM), and nickel chloride (0.01 mM), and the pH was 8.75. After the calcareous sand was treated with the optimal stimulation scheme, the urease activity was 6.1891 mM urea/min, the calcium carbonate production was 8.40%, and the UCS was 770 kPa, which constituted increases of 71.41%, 35.40%, and 83.33%, respectively, compared with the initial scheme. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) analyses showed that calcium carbonate crystals were formed between the particles of the calcareous sand after the reaction, and the calcium carbonate crystals were mainly calcite. Urease-producing microorganisms became the dominant species in calcareous sand after treatment. This study showed that biostimulation-induced mineralization is feasible for reinforcing calcareous sand.

Global burden of acute viral hepatitis and its association with socioeconomic development status, 1990-2019.

BACKGROUND & AIMS: Acute viral hepatitis (AVH) represents an important global health problem; however, the progress in understanding AVH is limited because of the priority of combating persistent HBV and HCV infections. Therefore, an improved understanding of the burden of AVH is required to help design strategies for global intervention. METHODS: Data on 4 major AVH types, including acute hepatitis A, B, C, and E, excluding D, were collected by the Global Burden of Disease (GBD) 2019 database. Age-standardized incidence rates and disability-adjusted life year (DALY) rates for AVH were extracted from GBD 2019 and stratified by sex, level of socio-demographic index (SDI), country, and territory. The association between the burden of AVH and socioeconomic development status, as represented by the SDI, was described. RESULTS: In 2019, there was an age-standardized incidence rate of 3,615.9 (95% CI 3,360.5-3,888.3) and an age-standardized DALY rate of 58.0 (47.3-70.0) per 100,000 person-years for the 4 major types of AVH. Among the major AVH types, acute hepatitis A caused the heaviest burden. There was a significant downward trend in age-standardized DALY rates caused by major incidences of AVH between 1990 and 2019. In 2019, regions or countries located in West and East Africa exhibited the highest age-standardized incidence rates of the 4 major AVH types. These rates were stratified by SDI: high SDI and high-middle SDI locations recorded the lowest incidence and DALY rates of AVH, whereas the low-middle SDI and low SDI locations showed the highest burden of AVH. CONCLUSIONS: The socioeconomic development status and burden of AVH are associated. Therefore, the GBD 2019 data should be used by policymakers to guide cost-effective interventions for AVH. LAY SUMMARY: We identified a negative association between socioeconomic development status and the burden of acute viral hepatitis. The lowest burden of acute viral hepatitis was noted for rich countries, whereas the highest burden of acute viral hepatitis was noted for poor countries.

Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors.

PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER+) patients with breast cancer. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3Kα inhibition. Among the top candidates were TSC1, TSC2, TBC1D7, AKT1S1, STK11, MARK2, PDE7A, DEPDC5, NPRL2, NPRL3, C12orf66, SZT2, and ITFG2. Loss of these genes invariably results in sustained mTOR signaling under pharmacologic inhibition of the PI3K-AKT pathway. Moreover, resistance could be prevented or overcome by mTOR inhibition, confirming the causative role of sustained mTOR activity in limiting the sensitivity to PI3Kα inhibition. Cumulatively, genomic alterations affecting these genes are identified in about 15% of PIK3CA-mutated breast tumors and appear to be mutually exclusive. This study improves our understanding of the role of mTOR signaling restoration in leading to resistance to PI3Kα inhibition and proposes therapeutic strategies to prevent or revert this resistance. SIGNIFICANCE: These findings show that genetic lesions of multiple negative regulators of mTORC1 could limit the efficacy of PI3Kα inhibitors in breast cancer, which may guide patient selection strategies for future clinical trials.

Liver Chemistries in Patients With COVID-19 Who Were Discharged Alive or Died: A Meta-analysis.

Although abnormal liver chemistries are linked to a higher risk of coronavirus disease 2019 (COVID-19)-related death, liver manifestations may be diverse and even confusing. Thus, we performed a meta-analysis of published liver manifestations and described the liver damage in patients with COVID-19 who died or discharged alive. We searched PubMed, Google Scholar, medRxiv, bioRxiv, the Cochrane Library, Embase, and three Chinese electronic databases through April 22, 2020. We analyzed pooled data on liver chemistries stratified by the main clinical outcome of COVID-19, using a fixed or random-effects model. In our meta-analysis of 19 studies, which included a total of 4,103 patients, the pooled mean alanine aminotransferase and aspartate aminotransferase levels were, respectively, 31.7 IU/L and 51.0 IU/L in the patients with COVID-19 who died and 27.7 IU/L and 32.9 IU/L in those discharged alive (both P < 0.0001). Compared with the patients discharged alive, those who died tended to have lower albumin levels but longer prothrombin time and higher international normalized ratio. Conclusion: In this meta-analysis, according to the main clinical outcome of COVID-19, we comprehensively describe three patterns of liver impairment related to COVID-19: hepatocellular injury, cholestasis, and hepatocellular disfunction. The patients who died from COVID-19 tended to have different liver chemistries from those discharged alive. Special caution should be given to the patients with a relatively higher index of liver chemistries.

TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors.

On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKAG667 and TRKCG696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leveraging inhibitor class affinity switching to address recalcitrant resistant alterations. SIGNIFICANCE: In TRK fusion-positive cancers, TRK xDFG substitutions represent a shared liability for type I TRK inhibitors. In contrast, they represent a potential biomarker of type II TRK inhibitor activity. As all currently available type II agents are multikinase inhibitors, rational drug design should focus on selective type II inhibitor creation.This article is highlighted in the In This Issue feature, p. 1.

FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer.

Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER+) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third ß strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.

Phase and context shape the function of composite oncogenic mutations.

Cancers develop as a result of driver mutations1,2 that lead to clonal outgrowth and the evolution of disease3,4. The discovery and functional characterization of individual driver mutations are central aims of cancer research, and have elucidated myriad phenotypes5 and therapeutic vulnerabilities6. However, the serial genetic evolution of mutant cancer genes7,8 and the allelic context in which they arise is poorly understood in both common and rare cancer genes and tumour types. Here we find that nearly one in four human tumours contains a composite mutation of a cancer-associated gene, defined as two or more nonsynonymous somatic mutations in the same gene and tumour. Composite mutations are enriched in specific genes, have an elevated rate of use of less-common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. cis-acting composite mutations are hypermorphic in some genes in which dosage effects predominate (such as TERT), whereas they lead to selection of function in other genes (such as TP53). Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures that are dependent in part on gene and mutation function, and which lead to complex-often neomorphic-functions of biological and therapeutic importance.

HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers.

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627.

ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer.

Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER+) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER+ breast cancer. An epigenome CRISPR-CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A inactivation in cells and in patients leads to resistance to ER degraders by facilitating a switch from ER-dependent luminal cells to ER-independent basal-like cells. Cellular plasticity is mediated by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the luminal lineage-determining transcription factors including ER, forkhead box protein A1 (FOXA1) and GATA-binding factor 3 (GATA3). ARID1A also regulates genome-wide ER-FOXA1 chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in maintaining luminal cell identity and endocrine therapeutic response in ER+ breast cancer.

Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer.

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161.