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Incarcerated gravid uterus is a rare obstetric condition that contributes to pregnancy-related adverse outcomes, especially if the uterus remains incarcerated and the condition goes undiagnosed until delivery. An effective diagnosis of this condition is benefited from pelvic examination combined with imaging methods and based on suspected symptoms. We present a case of ultrasound-assisted instrument reposition of an incarcerated gravid uterus at mid-gestation and discuss its clinical characteristics, diagnosis, imaging features, and treatment. We believe that once manual reduction fails, the use of instruments will undoubtedly be a better choice.

BACKGROUND: The unilateral biportal endoscopic (UBE) technique has been widely used in spine surgery. At present, a traditional rigid working channel is available for the UBE system. A metal semicircular canal is located in the working channel. However, due to the metal material of the working channel, arthroscopy and instruments are constrained from moving in UBE surgery. Additionally, an assistant is needed during the procedure to hold the traditional working channel. OBJECTIVE: For simplicity of operation and convenient movement of the arthroscopy and instrument, we describe a new method for establishing operative channels in UBE surgery. METHODS: We retrospectively reviewed 50 patients who underwent unilateral biportal endoscopic discectomy (UBED) from February 2020 to August 2020 via our new method. The Oswestry Disability Index (ODI) and visual analogue scale (VAS) score were measured preoperatively and 1 month, 3 months, 6 months and 12 months postoperatively. Statistical comparisons were made using analysis of covariance and paired t tests. RESULTS: The VAS scores for back pain at the five time points were 5.20 ± 2.57, 1.96 ± 0.95, 1.50 ± 0.84, 1.64 ± 1.08 and 1.18 ± 0.39. The leg pain VAS scores were 7.02 ± 2.25, 2.02 ± 1.27, 1.48 ± 0.89, 1.32 ± 0.79 and 0.88 ± 0.52. The ODI values were 51.08 ± 19.97, 19.62 ± 15.51, 8.26 ± 7.40, and 7.54 ± 6.42 to 3.24 ± 1.10. The postoperative ODIs and VAS scores of low back pain and leg pain were significantly lower than those before surgery, and differences were statistically significant (all p< 0.05). The pressure of the closed outflow was significantly higher than that of the open outflow (37.35 ± 13.11 mm Hg vs. 24.55 ± 12.64 mm Hg p= 0.003). After we tightened the infusion strap to open the outflow, the pressure decreased significantly (26.4 ± 14.08 mm Hg vs. 37.35 ± 13.11 mm Hg p= 0.015). There were 2 cases of complications, including 1 case of postoperative recurrence and 1 case of dural tears. CONCLUSION: This study demonstrates the technical feasibility, safety, and efficacy of modified channel establishment in UBE surgery.

Multi-band photometric monitoring of comet 29P/Schwassmann–Wachmann 1 was conducted with the standard Johnson–Cousins filter set. Observations extended from 2018 July to 2021 December. The comet was detected to show at least 12 relatively large outbursts, during which its brightness increased by 1.5 to 5 mag as measured through a 5″ aperture. The outbursts resulted in a clear variation of the cometary brightness profile. The derived slopes of the surface brightness profiles showed a significant variation with time from a shallower slope to a steeper one at the beginning of each outburst and then slowly returning to pre-outburst values. There did not seem to be any obvious change in the color indices as the outbursts occurred. However, for the quadruple outbursts in late September of 2021, we could confidently spot a change in the color of the comet, indicating that the color indices seem to be less than the mean values, especially in the B − V term. Dust production derived by using the dust production rate parameter, Afρ, from the R-band photometry measurements shows the outburst to be accompanied by a large increasing trend. Using a simple model and the derived outflow velocity of 0.11 km s−1 from the expanding shell features, an estimated lower limit of 1.0 × 108 kg up to 2.7 × 109 kg of dust was released during the quadruple outbursts by using a specific dust size of 1 μm.

Some active asteroids have been proposed to be the result of impact events. Because active asteroids are generally discovered serendipitously only after their tail formation, the process of the impact ejecta evolving into a tail has never been directly observed. NASA's Double Asteroid Redirection Test (DART) mission, apart from having successfully changed the orbital period of Dimorphos, demonstrated the activation process of an asteroid from an impact under precisely known impact conditions. Here we report the observations of the DART impact ejecta with the Hubble Space Telescope (HST) from impact time T+15 minutes to T+18.5 days at spatial resolutions of ~2.1 km per pixel. Our observations reveal a complex evolution of ejecta, which is first dominated by the gravitational interaction between the Didymos binary system and the ejected dust and later by solar radiation pressure. The lowest-speed ejecta dispersed via a sustained tail that displayed a consistent morphology with previously observed asteroid tails thought to be produced by impact. The ejecta evolution following DART's controlled impact experiment thus provides a framework for understanding the fundamental mechanisms acting on asteroids disrupted by natural impact., accepted by Nature

Recent experiment reported the self-passivated electride Hf2S with excellent stability and continuous electrocatalytic ability [S. H. Kang et al., Sci. Adv. 6, eaba7416 (2020)]. Starting from its 2H-type layered structure, we have studied the electronic, magnetic, and transport properties of the electride Hf2S in the monolayer and multilayer forms by combining first-principles electronic structure calculations and Kubo formula approach. Our calculations indicate that these thin films of Hf2S electride are both dynamically and thermodynamically stable. Astonishingly, the calculations further show that the outmost Hf atoms and the surface electron gas of the Hf2S multilayers are spin polarized, while the inner Hf atoms and the electron gas in the interlayer regions remain nonmagnetic. Due to the magnetic surface, the multilayer Hf2S exhibits many unusual transport properties such as the surface anomalous Hall effect and the electric-field-induced layer Hall effect. Our theoretical predictions on Hf2S call for future experimental verification., Comment: 5 pages, 5 figures, 34 references

As an important environmental amenity, sunlight brings us a large number of benefits and improves the quality of our daily lives, and its welfare measurement depends on concrete living conditions. The purpose of this article is to empirically document the non-marketed value of sunlight in light of the view orientation of an apartment in the context of the housing market. Using a hedonic pricing model estimated with the real estate transaction data over 40,000 housing units in 2019–2021 in Shanghai, it is found that: (1) homeowners, on average, are willing to pay an extra 7.2% to choose the apartments with a high level of sunshine (facing south), relative to those with no direct access to sunlight (facing north); (2) the value of sunlight shrinks with pollution and becomes larger if living in a higher apartment; (3) residents living in higher units have a larger willingness to pay for the sunlight and environmental quality improvement. These empirical findings shed light on the welfare measurement of sunlight and have profound implications for the capitalization of environmental amenities reflected in housing prices.

Background Retrospective or single-center prospective studies with relatively small samples have shown that contrast-enhanced US (CEUS) can improve the diagnostic accuracy of percutaneous biopsy, but larger prospective studies are lacking. Purpose To assess the diagnostic performance of CEUS-guided biopsy (CEUS-GB) of focal liver lesions (FLLs) compared with US-guided biopsy (US-GB) in a prospective multicenter study. Materials and Methods In this randomized controlled study conducted in nine hospitals in China between March 2016 and August 2019, adult participants with FLLs detected with US, CT, or MRI and planned for percutaneous biopsy were randomly assigned to undergo either US-GB or CEUS-GB. Lesions diagnosed as malignant at histopathologic analysis were considered true-positive findings. Benign or indeterminate lesions required further confirmation with either repeat biopsy or clinical follow-up at 6 months or later. The primary endpoint was the diagnostic accuracy rate, and comparison between groups was made using the χ

This paper develops a simulated dynamics model focused on the vibration coupling between a heavy-duty vehicle and the protective structure of the payload and verifies it through field experiments, which monitor the dynamic response under complex driving conditions such as uneven surfaces, turning, deceleration, and excessive gradients in real time. Compared with the results of the experiments and the simulations (with numerical methods), it can be found that the model can accurately estimate dynamic response of protective structures. The maximum acceleration at the bottom of the protective structure becomes larger as the amplitude of the road surface roughness increases. Furthermore, when the vehicle turns, the vibration of the protective structure increases sharply with braking, and when the vehicle begins decelerating, the lateral acceleration of the freight increases significantly in the first few seconds. In addition, the maximum acceleration at the bottom of the protective structure increases with the increase in speed when the heavy-duty vehicle is driving on a gradient, but that increase is small when the speed exceeds 80 km/h.

We systematically analyze the geochemical characteristics of source rocks of the Yan Chang Formation in the Ordos Basin to reveal the influence mechanisms of the volcano on lacustrine organic matter enrichment. Organic matter enrichment is not synchronous with the volcanic eruption in time, but it has a “hysteresis” effect. The evidence of volcanic activity mainly includes two aspects: one is a large amount of volcanic ash in black shale, and the other is a negative shift of organic carbon isotopes of source rocks and finding that black shale was affected by climate events caused by the volcano. The climate event caused by the volcano has three effects on organic matter enrichment in black shale: (1) it brought nutrients for the growth of organisms and released a large amount of greenhouse gases, such as CO2, to accelerate photosynthesis and promote the growth of organisms; (2) a large amount of toxic gases, such as SO2 and H2S, were released and O2 was consumed and diluted in the air, forming a severe anoxic environment and accelerating the preservation of organic matter; and (3) it caused extremely hot weather, resulting in long-time surface runoff and other climate events, increasing input of terrestrial organic matter, and forming light components of hydrocarbons.

Electrical Impedance Tomography (EIT) can perform non-invasive, low-cost, safe, fast, and simple system structure and functional imaging to map the distribution and changes of root zone. Multi frequency EIT solves the problem that single-frequency EIT can only carry more impedance information than a given single excitation frequency. It still remains challenges to simultaneously obtain multi-frequency electrical impedance tomography. To address the problem, a mixed signal superimposed by multiple frequencies is injected to the object. Essentially, separating the measured mixed voltage signals, which can be used to obtain electrical impedance information at different frequencies at the same time quickly. Since the measurement signal is a multi-frequency signal, the effect of decomposing the multi-frequency signal directly affects the accuracy of imaging. In order to obtain more accurate data, this article used the variational mode decomposition (VMD) method to decompose the measured multi-frequency signal. Accurate amplitude and phase information could be obtained simultaneously at the same time in multi-frequency excitation, and these data could be used to reconstruct electrical impedance distribution The results showed that the proposed method can achieve the expected imaging effect. It was concluded that using the variational modal decomposition method to process the data of multi-frequency signals is more accurate and the imaging effect is better, and it can be applied to multi-frequency electrical impedance imaging in practice.

The presence of a central baryonic potential can have a significant impact on the gravothermal evolution of self-interacting dark matter (SIDM) haloes. We extend a semi-analytical fluid model to incorporate the influence of a static baryonic potential and calibrate it using controlled N-body simulations. We construct benchmark scenarios with varying baryon concentrations and different SIDM models, including constant and velocity-dependent self-interacting cross sections. The presence of the baryonic potential induces changes in SIDM halo properties, including central density, core size, and velocity dispersion, and it accelerates the halo's evolution in both expansion and collapse phases. Furthermore, we observe a quasi-universality in the gravothermal evolution of SIDM haloes with the baryonic potential, resembling a previously known feature in the absence of the baryons. By appropriately rescaling the physical quantities that characterize the SIDM haloes, the evolution of all our benchmark cases exhibits remarkable similarity. Our findings offer a framework for testing SIDM predictions using observations of galactic systems where baryons play a significant dynamical role., 9 pages + references + appendices, 10 figures, 3 tables; v2: add references, fix typos

Due to the wide energy gap as well as short life of TiO2 and its photocatalytic active only under ultraviolet light, its application is greatly limited. TiO2 can form a heterojunction with other semiconductors to enhance its photocatalytic ability under visible light. In this study, a TiO2/Bi2SiO5 photocatalyst with n-n heterojunction is successfully synthesized by sol-gel method and hydrothermal method. Eggshell waste has long been used as fertilizer for planting plants or food additives for livestock, or as an adsorbent in metal ions and organic dyes. Using eggshell as a carrier of photocatalyst reduces its cracking of the substrate. The photocatalyst is deposited on eggshell powder by solid state dispersion (SSD). It is analyzed for the adsorption and degradation of methylene blue by various compositions of the photocatalysts and eggshell powder under visible light. The results show that the ratio of TiO2/Bi2SiO5: eggshell powder at 1:1 has the best removal ability. To facilitate the recovery of the photocatalyst from the aqueous solution, we use electrostatic spraying and electrospinning techniques to prepare nylon 6,6 nanofiber membranes with various composite photocatalyst (TiO2/Bi2SiO5/Eggshell/Nylon 6,6 NFM), the nanofiber membrane degraded 98% of methylene blue after 30 minutes of dark adsorption and 1 hour of visible light irradiation.

While Current TTS systems perform well in synthesizing high-quality speech, producing highly expressive speech remains a challenge. Emphasis, as a critical factor in determining the expressiveness of speech, has attracted more attention nowadays. Previous works usually enhance the emphasis by adding intermediate features, but they can not guarantee the overall expressiveness of the speech. To resolve this matter, we propose Emphatic Expressive TTS (EE-TTS), which leverages multi-level linguistic information from syntax and semantics. EE-TTS contains an emphasis predictor that can identify appropriate emphasis positions from text and a conditioned acoustic model to synthesize expressive speech with emphasis and linguistic information. Experimental results indicate that EE-TTS outperforms baseline with MOS improvements of 0.49 and 0.67 in expressiveness and naturalness. EE-TTS also shows strong generalization across different datasets according to AB test results., Accepted by INTERSPEECH2023

Background Previous studies have shown that secondary metabolites of Bacillus subtilis strain Z15 (BS-Z15) are effective in treating fungal infections in mice. To evaluate whether it also modulates immune function in mice to exert antifungal effects, we investigated the effect of BS-Z15 secondary metabolites on both the innate and adaptive immune functions of mice, and explored its molecular mechanism through blood transcriptome analysis. Results The study showed that BS-Z15 secondary metabolites increased the number of monocytes and platelets in the blood, improved natural killer (NK) cell activity and phagocytosis of monocytes-macrophages, increased the conversion rate of lymphocytes in the spleen, the number of T lymphocytes and the antibody production capacity of mice, and increased the levels of Interferon gamma (IFN-γ), Interleukin-6 (IL-6), Immunoglobulin G (IgG) and Immunoglobulin M (IgM) in plasma. The blood transcriptome analysis revealed 608 differentially expressed genes following treatment with BS-Z15 secondary metabolites, all of which were significantly enriched in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms for immune-related entries and pathways such as Tumor Necrosis Factor (TNF) and Toll-like receptor (TLR) signaling pathways, and upregulated expression levels of immune-related genes such as Complement 1q B chain (C1qb), Complement 4B (C4b), Tetracyclin Resistant (TCR) and Regulatory Factor X, 5 (RFX5). Conclusions BS-Z15 secondary metabolites were shown to enhance innate and adaptive immune function in mice, laying a theoretical foundation for its development and application in the field of immunity.

Objective: To compare therapeutic efficacy between systemic chemotherapy (SC) alone and preoperative SC followed by radiofrequency ablation (SC+RFA) in patients with colorectal cancer liver metastases (CRLM). Methods: This study identified a cohort of patients with CRLM after treatment between 2010 and 2016. Patients who received SC+RFA were compared with SC patients by propensity score matching. Overall survival (OS) and intrahepatic progression-free survival (PFS) were compared using stratified log-rank test. The outcomes after SC and SC+RFA were also assessed in patient subgroups. Results: This study identified 338 patients with CRLM who had underwent SC and had different response to chemotherapy, including non-progressive disease (non-PD) or progressive disease (PD). Of this cohort, 64 patients in SC+RFA group were matched by propensity score to 64 patients who received SC alone. Compared with SC cohort, the SC+RFA cohort yielded better OS (HR, 0.403; 95% CI, 0.271–0.601) and PFS (HR, 0.190; 95% CI, 0.113–0.320). The estimated OS rates at 1, 3 and 5 years were 93.8%, 51.6% and 15.6% for SC+RFA group and 81.3%, 26.6% and 10.9% for SC group (p＜0.001). The cumulative PFS rates at 1, 3, and 5 years were 43.8 %, 14.1% and 3.1% for the SC+RFA group and 1.6%, 0 and 0% for SC group (p＜0.0001). In subgroup analysis, compared with patients with PD response, patients with non-PD response could gain better PFS (HR, 0.207; 95% CI, 0.121–0.354) and OS (HR, 0.390; 95% CI, 0.246–0.617). Conclusions: RFA was associated with improved OS and intrahepatic PFS in CRLM patients with preoperative SC,especially in non-PD response subgroup after SC. Advances in knowledge: The addition of RFA was advocated for CRLM patients with preoperative SC. This study will provide important reference and evidence to better perform the management of unresectable CRLM.

The performances of RIETE, VTE-BLEED, SWITCO65 + , and Hokusai-VTE scores for predicting major bleeding events in hospitalized elderly cancer patients with venous thromboembolism (VTE) have not been evaluated. This study validated the performances of these scoring systems in a cohort of elderly cancer patients with VTE. Between June 2015 and March 2021, a total of 408 cancer patients (aged ≥ 65 years) with acute VTE were consecutively enrolled. The overall rates of in-hospital major bleeding and clinically relevant bleeding (CRB) were 8.3% (34/408) and 11.8% (48/408), respectively. RIETE score could categorize patients with increasing rate of major bleeding and CRB into low-/intermediate- and high-risk categories (7.1 vs. 14.1%, p = 0.05 and 10.1 vs. 19.7%, p = 0.02, respectively). The discriminative power of the four scores for predicting major bleeding was poor to moderate, indicated by areas under the receiver operating characteristic curves (0.45 [95% confidence interval, CI: 0.35–0.55] for Hokusai-VTE, 0.54 [95% CI: 0.43–0.64] for SWITCO65 + , 0.58 [95% CI: 0.49–0.68] for VTE-BLEED, and 0.61 [95% CI: 0.51–0.71] for RIETE). RIETE score might be used to predict major bleeding in hospitalized elderly cancer patients with acute VTE.

Current gene delivery methods for maize are limited to specific genotypes and depend on time-consuming and labor-intensive tissue culture techniques. Here, we report a new method to transfect maize that is culture-free and genotype independent. To enhance efficiency of DNA entry and maintain high pollen viability of 32%-55%, transfection was performed at cool temperature using pollen pretreated to open the germination aperture (40%-55%). Magnetic nanoparticles (MNPs) coated with DNA encoding either red fluorescent protein (RFP), β-glucuronidase gene (GUS), enhanced green fluorescent protein (EGFP) or bialaphos resistance (bar) was delivered into pollen grains, and female florets of maize inbred lines were pollinated. Red fluorescence was detected in 22% transfected pollen grains, and GUS stained 55% embryos at 18 d after pollination. Green fluorescence was detected in both silk filaments and immature kernels. The T1 generation of six inbred lines showed considerable EGFP or GUS transcripts (29%-74%) quantitated by polymerase chain reaction, and 5%-16% of the T1 seedlings showed immunologically active EGFP or GUS protein. Moreover, 1.41% of the bar transfected T1 plants were glufosinate resistant, and heritable bar gene was integrated into the maize genome effectively as verified by DNA hybridization. These results demonstrate that exogenous DNA could be delivered efficiently into elite maize inbred lines recalcitrant to tissue culture-mediated transformation and expressed normally through our genotype-independent pollen transfection system.

To analyze the survival outcomes and prognostic factors of radiofrequency ablation (RFA) for pancreatic adenocarcinoma liver metastasis (PALM).Between January 2010 and July 2021, 20 patients (13 males) with an average age of 58.9 ± 11.7 years who underwent RFA for PALM were included. The mean maximum diameter of PALMs was 2.6 ± 1.1 cm (1.0-6.0 cm). Survival curves were built using the Kaplan-Meier method and compared by the log-rank test. Multivariable analyses were performed by using the Cox proportional hazards model.Twenty patients with 29 PALMs underwent 23 RFA sessions. Technical efficacy was achieved in 28 PALMs (28/29, 96.6%). The mean overall survival (OS) after RFA was 14.6 months and the 1-, 2-year survival rates were 39.5%, 18.1%, respectively. With multivariate analysis, abnormal serum levels of CA199 (RFA is a safe and effective treatment for patients with PALM, especially in patients with normal serum level of CA199 or the patients without extrahepatic metastases before RFA.

AIM: To demonstrate an improved surgical technique of whole piece consecutive internal limiting membrane (ILM) peeling without preservation of the epi-fovea to treat high myopic foveoschisis (MF). METHODS: A 23-gauge 3-port pars plana vitrectomy was performed on 16 patients with high MF. A parallel arc line along the vascular arcades was scraped out with a curved membrane scraper DSP. Next, an ILM forceps was used to catch hold of the incisal edge of the ILM flap, and the action of releasing and separating was subsequently taken toward the direction of the macular fovea. Next, the ILM forceps was used to grasp the released area, and the whole area coherent ILM peeling covering the macular fovea was implemented thereafter. Finally, the ILM was folded backwards and peeled off in the arc direction. RESULTS: At the final visit, the average central macular thickness decreased remarkably from 423.76±177.67 to 178.24±66.21 µm. The mean logarithm of the minimum angle of resolution best-corrected visual acuity of 1.37±0.59 was significantly alleviated to 0.74±0.59. CONCLUSION: The wide range of whole piece consecutive ILM peeling without preservation of the epi-fovea is proven to be effective and significantly reduced the occurrence of retinal tear and macular hole.

Background Living with a partner and separation is becoming more common among older people. Mortality disparities associated with marital status are significant in increasingly diverse aging populations. The link between marital status and all-cause mortality risk in older adults remains uncertain. Methods This prospective cohort study included data from the US National Health and Nutrition Examination Survey (NHANES). We included NHANES participants ≥ 60 years of age (data from 1999 to 2014). Data for mortality follow-up beginning from the commencement date of survey participation to the last day of December 2015. Univariate- and multivariate-adjusted Cox proportional hazard models for marital status were estimated, and the findings were presented as regression coefficients and 95% confidence intervals (CI). Kaplan–Meier curves were reported. Results Compared to never married individuals, the risk of all-cause mortality was 0.77 (0.50–1.18), 0.72 (0.56–0.93), 0.56 (0.36–0.88), and 0.84 (0.67–1.07) in those people living with a partner, married, separated, and divorced, respectively, after adjusting for demographics, socioeconomics, behavior, anthropometric variables, and medical history. The risk of all-cause mortality was 1.24 (0.97–1.59) in widowed participants. Conclusion This population-based cohort study included a large sample size followed by long-term follow-up. The association between marriage, health, and reduced mortality in older individuals has been illustrated in this study. Being married or separated was associated with a lower risk of mortality.

Gastrointestinal (GI) cancer is one of the most common malignancies, and a leading cause of cancer-related death worldwide. However, molecular targeted therapies are still lacking, leading to poor treatment efficacies. As an important layer of epigenetic regulation, RNA N6-Methyladenosine (m6A) modification is recently linked to various biological hallmarks of cancer by orchestrating RNA metabolism, including RNA splicing, export, translation, and decay, which is partially involved in a novel biological process termed phase separation. Through these regulatory mechanisms, m6A dictates gene expression in a dynamic and reversible manner and may play oncogenic, tumor suppressive or context-dependent roles in GI tumorigenesis. Therefore, regulators and effectors of m6A, as well as their modified substrates, represent a novel class of molecular targets for cancer treatments. In this review, we comprehensively summarize recent advances in this field and highlight research findings that documented key roles of RNA m6A modification in governing hallmarks of GI cancers. From a historical perspective, milestone findings in m6A machinery are integrated with a timeline of developing m6A targeting compounds. These available chemical compounds, as well as other approaches that target core components of the RNA m6A pathway hold promises for clinical translational to treat human GI cancers. Further investigation on several outstanding issues, e.g. how oncogenic insults may disrupt m6A homeostasis, and how m6A modification impacts on the tumor microenvironment, may dissect novel mechanisms underlying human tumorigenesis and identifies next-generation anti-cancer therapeutics.

Olaparib-derived dual effects sensitize LKB1-deficient tumors to anti-PD-1 immunotherapy in preclinical models. (a) Mice-bearing orthotopic lung tumors were treated with different therapies. Bioluminescent images were shown. (b) Immunofluorescence staining of PD-L1 and CD8+T cells in resected lung tumors of mice bearing orthotopic tumors (n= 6 fields from independent tumors). Scale bar, 100 μm. (c). Quantification of tumor-infiltrating CD8+ T cells in immunofluorescence staining. (d, e) IHC statistical analysis of PAR and PD-L1 expression in resected lung tumors of mice bearing orthotopic tumors (n=5 fields from independent tumors). (f) Quantification of tumor-infiltrating CD8+ T cells in IHC staining in resected lung tumors of mice bearing orthotopic tumors (n= 5 fields from independent tumors). Data are represented as mean ± SD; Student's t-tests; * P < 0.05; ** P < 0.01; ***P

Supplementary figure legends

Olaparib promoted STING activation in LKB1-mutant/loss NSCLC cells and LLC-derived tumors. (a) Cells were pre-treated with olaparib (5 μM) for 6 hours and then stimulated with IFNγ for 24 hours. The cell lysates were then subjected to western blot analysis for key proteins in the STING signaling pathway. (b) Representative IHC staining of STING and pSTING in LLC-LV-Lkb1 tumors and LLC-LV-Ctrl tumors following different treatments. Scale bar: 200 μm. (c) IHC statistical analysis of STING and pSTING expression in LLC-LV-Ctrl/Lkb1 tumors following indicated treatment. n=5 fields from independent tumors. Data are represented as mean ± SD; Student's t-tests; ***P

LKB1-interacting proteins identified by LC-MS/MS analysis.

Relationship between HRD mutation and TMB in (A) MSK NSCLC ICI cohort and (B) Dana-Farber ICI cohort. For each cohort, a plot is shown containing the HRD mutation status versus the tumor mutation burden. The P value is shown.

Relationship between CNA level and TMB in (A) MSK pan-cancer non-ICI treated cohort and (B) other three ICI-treated cohorts (MSK NSCLC, SKCM, and Dana-Farber ICI cohort). For each cancer type and each cohort, a plot is shown containing the CNA level versus tumor mutation burden. The spearman correlation coefficient and P value are shown.

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non–small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti–PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012–24. ©2016 AACR.

Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)–mutant non–small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation–mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.Significance:Targeting PARP exerts dual effects to overcome LKB1 loss–driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.

Analysis of GC>TA transversion in four groups compared common mutations (TP53/KRAS/EGFR/STK11) with corresponding wild type.

Demographic and clinicopathologic characteristics of three cohorts treated with immune checkpoint inhibitors.

Sequences for qPCR primers.