Longitudinal ultrasound-based AI model predicts axillary lymph node response to neoadjuvant chemotherapy in breast cancer: a multicenter study.

OBJECTIVES: Developing a deep learning radiomics model from longitudinal breast ultrasound and sonographer's axillary ultrasound diagnosis for predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) in breast cancer. METHODS: Breast cancer patients undergoing NAC followed by surgery were recruited from three centers between November 2016 and December 2022. We collected ultrasound images for extracting tumor-derived radiomics and deep learning features, selecting quantitative features through various methods. Two machine learning models based on random forest were developed using pre-NAC and post-NAC features. A support vector machine integrated these data into a fusion model, evaluated via the area under the curve (AUC), decision curve analysis, and calibration curves. We compared the fusion model's performance against sonographer's diagnosis from pre-NAC and post-NAC axillary ultrasonography, referencing histological outcomes from sentinel lymph node biopsy or axillary lymph node dissection. RESULTS: In the validation cohort, the fusion model outperformed both pre-NAC (AUC: 0.899 vs. 0.786, p < 0.001) and post-NAC models (AUC: 0.899 vs. 0.853, p = 0.014), as well as the sonographer's diagnosis of ALN status on pre-NAC and post-NAC axillary ultrasonography (AUC: 0.899 vs. 0.719, p < 0.001). Decision curve analysis revealed patient benefits from the fusion model across threshold probabilities from 0.02 to 0.98. The model also enhanced sonographer's diagnostic ability, increasing accuracy from 71.9% to 79.2%. CONCLUSION: The deep learning radiomics model accurately predicted the ALN response to NAC in breast cancer. Furthermore, the model will assist sonographers to improve their diagnostic ability on ALN status before surgery. CLINICAL RELEVANCE STATEMENT: Our AI model based on pre- and post-neoadjuvant chemotherapy ultrasound can accurately predict axillary lymph node metastasis and assist sonographer's axillary diagnosis. KEY POINTS: Axillary lymph node metastasis status affects the choice of surgical treatment, and currently relies on subjective ultrasound. Our AI model outperformed sonographer's visual diagnosis on axillary ultrasound. Our deep learning radiomics model can improve sonographers' diagnosis and might assist in surgical decision-making.

FLOURY ENDOSPERM24, a heat shock protein 101 (HSP101), is required for starch biosynthesis and endosperm development in rice.

Endosperm is the main storage organ in cereal grain and determines grain yield and quality. The molecular mechanisms of heat shock proteins in regulating starch biosynthesis and endosperm development remain obscure. Here, we report a rice floury endosperm mutant flo24 that develops abnormal starch grains in the central starchy endosperm cells. Map-based cloning and complementation test showed that FLO24 encodes a heat shock protein HSP101, which is localized in plastids. The mutated protein FLO24T296I dramatically lost its ability to hydrolyze ATP and to rescue the thermotolerance defects of the yeast hsp104 mutant. The flo24 mutant develops more severe floury endosperm when grown under high-temperature conditions than normal conditions. And the FLO24 protein was dramatically induced at high temperature. FLO24 physically interacts with several key enzymes required for starch biosynthesis, including AGPL1, AGPL3 and PHO1. Combined biochemical and genetic evidence suggests that FLO24 acts cooperatively with HSP70cp-2 to regulate starch biosynthesis and endosperm development in rice. Our results reveal that FLO24 acts as an important regulator of endosperm development, which might function in maintaining the activities of enzymes involved in starch biosynthesis in rice.

Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification.

BACKGROUND: Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown. METHODS: A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis. RESULTS: We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively. CONCLUSION: We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Integrated network pharmacology and cellular assay reveal the biological mechanisms of Limonium sinense (Girard) Kuntze against Breast cancer.

BACKGROUND: Limonium Sinense (Girard) Kuntze (L. sinense) has been widely used for the treatment of anaemia, bleeding, cancer, and other disorders in Chinese folk medicine. The aim of this study is to predict the therapeutic effects of L. sinense and investigate the potential mechanisms using integrated network pharmacology methods and in vitro cellular experiments. METHODS: The active ingredients of L. sinense were collected from published literature, and the potential targets related to L. sinense were obtained from public databases. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and DisGeNET enrichment analyses were performed to explore the underlying mechanisms. Molecular docking, cellular experiments, RNA-sequencing (RNA-seq) and Gene Expression Omnibus (GEO) datasets were employed to further evaluate the findings. RESULTS: A total of 15 active ingredients of L. sinense and their corresponding 389 targets were obtained. KEGG enrichment analysis revealed that the biological effects of L. sinense were primarily associated with "Pathways in cancer". DisGeNET enrichment analysis highlighted the potential role of L. sinense in the treatment of breast cancer. Apigenin within L. sinense showed promising potential against cancer. Cellular experiments demonstrated that the L. sinense ethanol extract (LSE) exhibited a significant growth inhibitory effect on multiple breast cancer cell lines in both 2D and 3D cultures. RNA-seq analysis revealed a potential impact of LSE on breast cancer. Additionally, analysis of GEO datasets verified the significant enrichment of breast cancer and several cancer-related pathways upon treatment with Apigenin in human breast cancer cells. CONCLUSION: This study predicts the biological activities of L. sinense and demonstrates the inhibitory effect of LSE on breast cancer cells, highlighting the potential application of L. sinense in cancer treatment.

Long noncoding RNA X-inactive specific transcript (lncRNA XIST) inhibits hepatic insulin resistance by competitively binding microRNA-182-5p.

BACKGROUND: What is highlighted in this study refers to the role and molecular mechanism of long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) in cells with insulin resistance (IR). METHODS: In this study, LX-2 cells were applied to establish IR model in vitro. The expressions of lncRNA XIST, phosphoenolpyruvate carboxykinase (PEPCK,) and glucose-6-phosphatase (G6Pase) were quantified by quantitative reverse transcription polymerase chain reaction. The 2-deoxy-d-glucose-6-phosphate (2-DG6P) level was detected utilizing 2-deoxy-d-glucose (2-DG) uptake measurement kit. Western blot was adopted to measure the protein expressions of insulin-like growth factor-1 receptor (IGF-1R), G6Pase, PEPCK, and phosphatidylinositol 3-kinase (PI3K)/Akt pathway-related genes. StarBase was used to predict the targeting relationship between lncRNA XIST or IGF-1R with miR-182-5p, the results of which were verified by dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation assays. Rescue experiments were conducted to investigate the effect of miR-182-5p on IR cells. Next, low-expressed lncRNA XIST and high-expressed miR-182-5p were observed in IR cells. RESULTS: Upregulation of lncRNA XIST increased IGF-1R and 2-DG6P levels, decreased G6Pase and PEPCK expressions, and promoted PI3K/Akt pathway activation in IR cells. LncRNA XIST sponged miR-182-5p which targeted IGF-1R. MiR-182-5p mimic reversed the above effects of lncRNA XIST overexpression on IR cells. CONCLUSIONS: In conclusion, lncRNA XIST/miR-182-5p axis alleviates hepatic IR in vitro via IGF-1R/PI3K/Akt signaling pathway, which could be the promising therapeutic target.

Differential vascular endothelial cell toxicity of established and novel BCR-ABL tyrosine kinase inhibitors.

BCR-ABL tyrosine kinase inhibitors (TKIs) have dramatically improved survival in Philadelphia chromosome-positive leukemias. Newer BCR-ABL TKIs provide superior cancer outcomes but with increased risk of acute arterial thrombosis, which further increases in patients with cardiovascular comorbidities and mitigates survival benefits compared to imatinib. Recent studies implicate endothelial cell (EC) damage in this toxicity by unknown mechanisms with few side-by-side comparisons of multiple TKIs and with no available data on endothelial impact of recently approved TKIs or novels TKIs being tested in clinical trials. To characterize BCR-ABL TKI induced EC dysfunction we exposed primary human umbilical vein ECs in 2D and 3D culture to clinically relevant concentrations of seven BCR-ABL TKIs and quantified their impact on EC scratch-wound healing, viability, inflammation, and permeability mechanisms. Dasatinib, ponatinib, and nilotinib, the TKIs associated with thrombosis in patients, all significantly impaired EC wound healing, survival, and proliferation compared to imatinib, but only dasatinib and ponatinib impaired cell migration and only nilotinib enhanced EC necrosis. Dasatinib and ponatinib increased leukocyte adhesion to ECs with upregulation of adhesion molecule expression in ECs (ICAM1, VCAM1, and P-selectin) and leukocytes (PSGL1). Dasatinib increased permeability and impaired cell junctional integrity in human engineered microvessels, consistent with its unique association with pleural effusions. Of the new agents, bafetinib decreased EC viability and increased microvessel permeability while asciminib and radotinib did not impact any EC function tested. In summary, the vasculotoxic TKIs (dasatinib, ponatinib, nilotinib) cause EC toxicity but with mechanistic differences, supporting the potential need for drug-specific vasculoprotective strategies. Asciminib and radotinib do not induce EC toxicity at clinically relevant concentrations suggesting a better safety profile.

Amide proton transfer-weighted magnetic resonance imaging for the differentiation of parotid gland tumors.

Purpose: To assess the usefulness of amide proton transfer-weighted (APTw) imaging in the differentiation of parotid gland tumors. Materials and methods: Patients with parotid gland tumors who underwent APTw imaging were retrospectively enrolled and divided into groups according to pathology. Two radiologists evaluated the APTw image quality independently, and APTw images with quality score ≥3 were enrolled. The maximum and average values of APTw imaging for tumor lesions (APTmax and APTmean) were measured. The differences in APTmax and APTmean were compared between malignant tumors (MTs) and benign tumors (BTs), as well as between MTs and pleomorphic adenomas (PAs) and between MTs and Warthin tumors (WTs). Independent-samples t-test, Kruskal-Wallis H test, and receiver operating characteristic (ROC) curve analyses were used for statistical analysis. Results: Seventy-three patients were included for image quality evaluation. In this study, 32/73 and 29/73 parotid tumors were scored as 4 and 3, respectively. After excluding lesions with quality score ≤2 (12/73), the APTmean and APTmax of MTs were 4.15% ± 1.33% and 7.43% ± 1.61%, higher than those of BTs 2.74% ± 1.04% and 5.25% ± 1.54%, respectively (p < 0.05). The areas under the ROC curve (AUCs) of the APTmean and APTmax for differentiation between MTs and BTs were 0.819 and 0.821, respectively. MTs indicated significantly higher APTmean and APTmax values than those of PAs (p < 0.05) and WTs (p < 0.05). The AUCs of the APTmean and APTmax for differentiation between MTs and PAs were 0.830 and 0.815 and between MTs and WTs were 0.847 and 0.920, respectively. Conclusion: Most APTw images for parotid tumors had acceptable image quality for APTw value evaluation. Both APTmax and APTmean can be used to differentiate MTs from BTs and to differentiate MTs from subtype parotid gland tumors.

It is the Frequency that Matters: Effects of Electromagnetic Fields on the Release and Content of Extracellular Vesicles.

Extracellular vesicles (EVs) are small membrane-bound structures that originate from various cell types and carry molecular cargo to influence the behavior of recipient cells. The use of EVs as biomarkers and delivery vehicles for diagnosis and treatment in a wide range of human disease is a rapidly growing field of research and clinical practice. Four years ago, we postulated the hypothesis that electromagnetic fields (EMF) will influence the release and content of EVs (1). Since then, we have optimized several technical aspects of our experimental setup. We used a bioreactor system that allows cells to grow in a three-dimensional environment mimicking in-vivo conditions. We designed a custom-made EMF stimulation device that encompasses the bioreactor and delivers uniform EMFs. We established a three-step EV purification protocol that enables high-density production of EVs. We then performed mass spectrometry-based proteomics analysis on EV-related proteins and used high-resolution nanoparticle flowcytometry for single-vesicle analysis. We demonstrate that electrical stimulations of current amplitudes at physiological level that are currently applied in therapeutic deep brain stimulation can modulate EV content in a frequency-dependent manner, which may have important implications for basic biology and medical applications. First, it raises intriguing questions about how the endogenous electrical activity of neuronal and other cellular assemblies influence the production and composition of EVs. Second, it reveals an additional underlying mechanism of how therapeutic electrical stimulations can modulate EVs and treat human brain disorders. Third, it provides a novel approach of utilizing electrical stimulations in generating specific EV cargos.

Safety and effectiveness of dulaglutide in Chinese adults with type 2 diabetes mellitus in a real-world setting: A prospective, observational post-marketing study.

AIM: To our knowledge, this is the first real-world study to investigate the safety and effectiveness of a glucagon-like peptide-1 receptor agonist in Chinese patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This prospective, observational, post-marketing study conducted at 46 hospitals in China included adults with T2DM prescribed dulaglutide in routine clinical practice. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and serious AEs in patients who received ≥1 dose of dulaglutide, for up to 24 weeks. Exploratory endpoints included changes in patient-reported glycated haemoglobin (HbA1c) and body weight. Post hoc analyses and multivariate regression were also performed. RESULTS: From 20 January 2020 to 24 November 2021, 3291 patients received dulaglutide and entered the safety analysis. TEAEs were reported in 1333 (40.5%) patients; the most commonly reported were nausea (n = 193, 5.9%), diarrhoea (n = 183, 5.6%) and decreased appetite (n = 179, 5.4%). serious AEs were reported in 160 (4.9%) patients. TEAEs led to treatment discontinuation in 212 (6.4%) patients. The mean absolute change in HbA1c from baseline to week 24 was -1.65% (p < .001). Greater reductions in HbA1c at week 24 were observed in patients with T2DM duration ≤5 years (p = .002), baseline HbA1c ≥8.5% (p < .001), and without atherosclerotic cardiovascular disease (p = .002). The mean absolute change in body weight from baseline at week 24 was -2.62 kg (p < .001). CONCLUSION: Dulaglutide showed a safety profile consistent with previous reports and significantly reduced HbA1c in a real-world setting. These findings support the clinical use of dulaglutide and inform the individualized treatment of patients with T2DM in China.

Synthetic lethal approaches to target cancers with loss of PTEN function.

Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene and has a role in inhibiting the oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumour phenotype and tumorigenesis. Identifying targeted therapies for inactive tumour suppressor genes such as PTEN has been challenging as it is difficult to restore the tumour suppressor functions. Therefore, focusing on the downstream signalling pathways to discover a targeted therapy for inactive tumour suppressor genes has highlighted the importance of synthetic lethality studies. This review focuses on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.

KRASG12C mutation-induced TOPK overexpression contributes to tumour progression in non-small cell lung cancer.

KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRASG12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRASG12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRASG12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRASG12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics.

Directed Nickel-Catalyzed Selective Arylhydroxylation of Unactivated Alkenes under Air.

An expeditious and novel nickel-catalyzed selective arylhydroxylation of unactivated alkenes with arylboronic acids was developed. This protocol is compatible with ß,γ- and γ,δ-alkene amides, including traditionally challenging internal alkenes, to provide important ß-arylethylalcohol scaffolds. The free hydroxyl group in the final product could be smoothly further transformed into other functional groups. Control experiments indicated that the oxygen atom of the hydroxyl group in the product is derived from the oxygen in the air.

Efficacy of Alveolar Type II Epithelial Cell Transplantation for Pulmonary Fibrosis: A Meta-Analysis.

Background: Cell transplantation is a promising therapeutic strategy for pulmonary fibrosis. In order to clarify the alveolar type II epithelial cell potential utility in the treatment of lung disease, we conducted a meta-analysis, to evaluate alveolar type II epithelial cells in animal models of lung injury and pulmonary fibrosis. Methods: This review followed the recommendations from the PRISMA statements, Comprehensive retrieval method was used to search Embase, PubMed, Cochrane, Chinese Knowledge Infrastructure, VIP and Wanfang databases. A total of 7 studies and 286 model rats were included. Two researchers independently screened the identified studies, based on inclusion and exclusion criteria. All analyses were conducted using Review Manager V.5.3 software. The combined standard mean difference (SMD) and 95% confidence interval (CI) of data from the included studies were calculated using fixed or random-effects models. Results: The analysis of three outcome indexes showed that the heterogeneity of the oxygen saturation group was high (I2=85%), the lung weight group (I2=64%) was close to moderate heterogeneity, and the lung hydroxyproline content group (I2=0) was not heterogeneous. Conclusion: Meta-analysis showed that transplantation of alveolar type II epithelial cells has beneficial effects, and no obvious adverse reactions. Alveolar type II epithelial cell transplantation can significantly reduce the intervention group and lung hydroxyproline content weight, improve the blood oxygen saturation, lung histo-pathology showed significant improvement in pulmonary fibrosis.

The impact of postmastectomy radiotherapy on cT1-2N1 breast cancer patients with ypN0 after neoadjuvant chemotherapy: a retrospective study based on real-world data.

BACKGROUND: The role of postmastectomy radiation therapy (PMRT) in clinical T1-2N1 breast cancer patients who achieve axillary pathological complete response (ypN0) after neoadjuvant chemotherapy (NAC) is controversial. METHODS: Data from cT1-2N1 breast cancer patients who converted to ypN0 after NAC and subsequent surgery were retrospectively analyzed. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan‒Meier method. Univariate and multivariate Cox regression models were applied to investigate the correlations between clinical or pathological parameters and survival. RESULTS: From 2012-2019, we identified 116 cases for analysis, including 31 (26.7%) who received PMRT and 85 (73.3%) who did not. At a median follow-up time of 56.4 months, the 5-year DFS and OS rates were 90.2% and 96.7% with PMRT and 93.7% and 97.3% without PMRT, respectively. PMRT did not affect either DFS (p = 0.234) or OS (p = 0.878). On multivariate analyses, no differences in DFS or OS between the two groups were detected, taking into consideration the following factors: age, molecular subtype, Ki67 index, cT stage, and in-breast pathologic complete response (DFS: HR 2.260; 95% CI 0.465-10.982; p = 0.312. OS: HR 1.400; 95% CI 0.138-14.202; p = 0.776). This nonsignificant difference was also consistent in subgroup analyses (all p > 0.05). CONCLUSIONS: PMRT has limited ability to confer DFS or OS benefits for cT1-2N1 breast cancer patients who achieved axillary pathological complete response after NAC and total mastectomy. It is imperative to conduct prospective studies to investigate the safety and feasibility of omitting PMRT. TRIAL REGISTRATION: This research was approved by the Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (ID: No. 2021-442).

Who Are the Local Policy Innovators? Cluster Analysis of Municipal Tobacco Control Policies in Massachusetts.

CONTEXT: Tobacco use is a leading cause of preventable death, yet it is challenging to establish public policy to reduce tobacco use. Massachusetts has been a national leader in tobacco control, and its policy-making patterns can be informative to the country. OBJECTIVE: To identify factors associated with the adoption of tobacco policy within 351 Massachusetts municipalities. DESIGN: We obtained the 2019 Massachusetts municipality-level tobacco control policy information from Massachusetts' Tobacco Automated Fact Sheet Information system and compiled it with data from American Community Survey, Massachusetts Municipal Association, and Massachusetts state government's Web sites. We used k -means clustering method to identify statistical clustering patterns and hotspot analysis (Getis-Ord Gi*) and Local Indicators of Spatial Association to identify geographic clustering patterns. We then performed multinomial logistic regression to identify factors associated with policy clusters. SETTING: Massachusetts. PARTICIPANTS: Three hundred fifty-one municipalities in Massachusetts. MAIN OUTCOME MEASURE: Policy clusters-groups of municipalities with similar tobacco control policy behaviors. RESULTS: Based on the k -means analyses, we identified 3 clusters in Massachusetts municipal tobacco control policy behaviors: 54% (N = 191) of municipalities were "Policy Leaders" with a high adoption rate of the 6 tobacco control policies; 18% (N = 63) were "Peer-Influenced Actors" focused on tobacco purchase restrictions for individuals younger than 21 years; and 28% (N = 97) were "Policy Non-Actors," with no tobacco control policies in place. Policy Leaders were geographically clustered in larger cities and the MetroWest region. Policy Non-Actors were clustered in rural areas of Western and Central Massachusetts. Larger municipal population size, higher municipal tax income, and higher percentages of residents voting Democratic were associated with higher policy adoption activities. CONCLUSIONS: Local variation in the adoption of tobacco policies may exacerbate inequities in tobacco use and population health. Opportunities remain to implement additional tobacco control regulations at the local level to promote public health.

A deleterious Sar1c variant in rice inhibits export of seed storage proteins from the endoplasmic reticulum.

KEY MESSAGE: We identified a dosage-dependent dominant negative form of Sar1c, which confirms the essential role of COPII system in mediating ER export of storage proteins in rice endosperm. Higher plants accumlate large amounts of seed storage proteins (SSPs). However, mechanisms underlying SSP trafficking are largely unknown, especially the ER-Golgi anterograde process. Here, we showed that a rice glutelin precursor accumulation13 (gpa13) mutant exhibited floury endosperm and overaccumulated glutelin precursors, which phenocopied the reported RNAi-Sar1abc line. Molecular cloning revealed that the gpa13 allele encodes a mutated Sar1c (mSar1c) with a deletion of two conserved amino acids Pro134 and Try135. Knockdown or knockout of Sar1c alone caused no obvious phenotype, while overexpression of mSar1c resulted in seedling lethality similar to the gpa13 mutant. Transient expression experiment in tobacco combined with subcellular fractionation experiment in gpa13 demonstrated that the expression of mSar1c affects the subcellular distribution of all Sar1 isoforms and Sec23c. In addition, mSar1c failed to interact with COPII component Sec23. Conversely, mSar1c competed with Sar1a/b/d to interact with guanine nucleotide exchange factor Sec12. Together, we identified a dosage-dependent dominant negative form of Sar1c, which confirms the essential role of COPII system in mediating ER export of storage proteins in rice endosperm.

Prophylactic cranial irradiation for limited-stage small-cell lung cancer in the magnetic resonance imaging era.

BACKGROUND: We investigated the role of prophylactic cranial irradiation (PCI) in limited-stage small-cell lung cancer (LS-SCLC) according to tumor response in the magnetic resonance imaging (MRI) era. METHODS: We retrospectively evaluated patients with LS-SCLC without brain metastases (BMs) on MRI who achieved either complete response (CR) or partial response (PR) after initial chemoradiotherapy at our center from 2006 to 2017. RESULTS: This study comprised 116 patients (median age, 58 years; men, 92; women, 24). After initial chemoradiotherapy, 53 patients achieved CR, while 63 patients achieved PR. Eighty-three patients received PCI. Patients who received PCI had better overall survival (OS, 5-year: 52.5% vs. 35.1%; p = 0.012) and progression-free survival (PFS, 5-year: 45.0% vs. 28.2%; p = 0.001) and a lower incidence of BMs (5-year: 18.3% vs. 39.4%; p = 0.010). In the subgroup analysis, PCI improved OS (5-year: 67.8% vs. 46.7%, p = 0.005) and PFS (5-year: 65.2% vs. 35.0%, p = 0.021) and decreased BM risk (5-year: 12.1% vs. 52.4%, p = 0.002) for patients with CR. However, PCI had no benefit (5-year OS: 40.5% vs. 35.6%, p = 0.763; 5-year BMs: 24.6% vs. 31.9%, p = 0.561) for patients with PR. CONCLUSIONS: Tumor response remained an important factor for selecting patients for PCI in the MRI era. PCI should be recommended for patients with LS-SCLC who achieve CR after initial thoracic chemoradiotherapy.

Bone Marrow Histology in Hemophagocytic Lymphohistiocytosis.

CONTEXT.­: Bone marrow (BM) samples are obtained through aspiration and trephine biopsy. Hemophagocytic lymphohistiocytosis (HLH) has been largely studied in BM aspirate smears. OBJECTIVE.­: To investigate the histologic features of HLH in trephine biopsy. DESIGN.­: Patients with hemophagocytosis in BM aspirate smears were assigned to HLH (n = 127) and non-HLH (n = 203) groups. We quantified hematoxylin-eosin and CD68 immunohistochemical staining of their trephine biopsies. RESULTS.­: No significant correlation was noted in the hemophagocytosis count between aspirate smears and trephine biopsies. Compared with the non-HLH group, the HLH group had a higher hemophagocytosis count (13 versus 9 per tissue section, P = .046), lower percentage of the adipocytic area (36.7% versus 50.3%, P < .001), and higher percentage of the foamy area (19.1% versus 14.5%, P < .001). The HLH group had more histiocyte infiltrates (total histiocyte density, 9.2% versus 7.3%; P < .001) and more fat-infiltrating histiocytes (histiocyte density of the fat-associated part [HD-FA], 7.6% versus 6.2%; P < .001). We identified the following poor prognostic factors in the HLH group: age 50 years or older (median overall survival [mOS], 95 versus 499 days; P = .04), Epstein-Barr virus-positive T-cell lymphoproliferative diseases (EBV+TLPDs) (mOS, 51 versus 425 days; P < .001), hemophagocytosis count of 6 or higher per tissue section (mOS, 66 versus 435 days; P = .02), and HD-FA of 9% or greater (mOS, 61 versus 359 days; P = .02). Multivariate analysis revealed that age 50 years or older (hazard ratio [HR], 2.38; P < .001), EBV+TLPDs (HR, 2.07; P < .001), and hemophagocytosis count of 6 or higher per tissue section (HR, 2.07; P = .002) were independent prognostic factors for HLH. CONCLUSIONS.­: The HLH group had higher hemophagocytic activity, higher cellularity, a more foamy appearance, more histiocyte infiltrates, and more fat-infiltrating histiocytes. High hemophagocytic activity and marked histiocyte infiltrates in the BM fat were associated with poorer prognosis.