Salivary Protein Sfapyrase of Spodoptera frugiperda Stimulates Plant Defence Response.

Plants have developed various resistance mechanisms against herbivorous insects through prolonged coevolution. Plant defence responses can be triggered by specific compounds present in insect saliva. Apyrase, a known enzyme that catalyzes the hydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine monophosphate (AMP) and inorganic phosphorus, has recently been identified in some herbivorous insects. However, whether insect salivary apyrase induces or inhibits plant responses remains poorly understood. In this study, we identified an apyrase-like protein in the salivary proteome of the fall armyworm, Spodoptera frugiperda, named Sfapyrase. Sfapyrase was primarily expressed in the salivary gland and secreted into plants during insect feeding. Transient expression of Sfapyrase in tobacco and maize enhanced plant resistance and resulted in decreased insect feeding. Knockdown of Sfapyrase through RNA interference led to increased growth and feeding of S. frugiperda. Furthermore, we showed that Sfapyrase activates the jasmonic acid signalling pathway and promotes the synthesis of secondary metabolites, especially benzoxazinoids, thereby enhancing resistance to S. frugiperda. In summary, our findings demonstrated that Sfapyrase acts as a salivary elicitor, inducing maize jasmonic acid defence responses and the production of insect-resistant benzoxazinoids. This study provides valuable insights into plant-insect interactions and offers potential targets for developing innovative insect pest management strategies.

Comparable efficacy and safety for bicuspid aortic valve stenosis patients undergoing transcatheter aortic valve replacement with balloon-expandable or self-expanding valves using Wei's sizing method.

BACKGROUND: The present study aimed to investigate whether proper sizing can improve the procedural and clinical outcomes of transcatheter aortic valve replacement (TAVR) with new-generation self-expanding valves (SEVs) and balloon-expandable valves (BEVs) for treating bicuspid aortic stenosis (BAS). METHODS: We retrospectively evaluated consecutive patients who underwent TAVR with Sapien 3 valves (Edwards Lifesciences, Irvine, CA) or Evolut R/PRO valves (Medtronic, Minneapolis, MN) for severe BAS from 2017 to 2022. The primary endpoints were device success rate and major adverse cardiac and cerebral events (MACCEs), including mortality, non-fatal myocardial infarction or disabling stroke, transcatheter heart valve failure, or clinically relevant valve thrombosis during follow-up. Our team employed a complementary approach of supra-annular sizing in addition to the conventional annular sizing method (Wei's method) to guide the TAVR procedures. RESULTS: We recruited a total of 75 consecutive patients, of whom 43 (57%) were treated with BEVs from October 2017 to June 2021, and 32 (43%) were treated with SEVs from July 2021 to December 2022. Device success was similar between the BEV and SEV groups (93% vs. 94%; p > 0.99), and no cases of annular rupture occurred in either group. Similar rates of moderate-to-severe paravalvular leak were observed in the BEV and SEV groups (5% vs. 6%, p > 0.99). At a median follow-up of 464 days, the MACCE rates were comparable between the two groups. In multivariate analysis, the presence of previous percutaneous coronary interventions (hazard ratio: 5.43; p = 0.039) and New York Heart Association functional class III/IV heart failure at 30 days of follow-up after TAVR (hazard ratio: 9.90; p = 0.037) were independently associated with long-term MACCEs. CONCLUSION: Our results demonstrated comparable efficacy and safety for BAS patients undergoing TAVR using either BEVs or SEVs when using Wei's sizing method.

Principles and Methods for Improving the Thermoelectric Performance of SiC: A Potential High-Temperature Thermoelectric Material.

Thermoelectric materials that can convert thermal energy to electrical energy are stable and long-lasting and do not emit greenhouse gases; these properties render them useful in novel power generation devices that can conserve and utilize lost heat. SiC exhibits good mechanical properties, excellent corrosion resistance, high-temperature stability, non-toxicity, and environmental friendliness. It can withstand elevated temperatures and thermal shock and is well suited for thermoelectric conversions in high-temperature and harsh environments, such as supersonic vehicles and rockets. This paper reviews the potential of SiC as a high-temperature thermoelectric and third-generation wide-bandgap semiconductor material. Recent research on SiC thermoelectric materials is reviewed, and the principles and methods for optimizing the thermoelectric properties of SiC are discussed. Thus, this paper may contribute to increasing the application potential of SiC for thermoelectric energy conversion at high temperatures.

Silver Nanocomposites with Enhanced Shelf-Life for Fruit and Vegetable Preservation: Mechanisms, Advances, and Prospects.

Reducing fruit and vegetable waste and maintaining quality has become challenging for everyone. Nanotechnology is a new and intriguing technology that is currently being implemented in fruit and vegetable preservation. Silver nanomaterials provide superior antibacterial qualities, biodegradability, and biocompatibility, which expands their potential applications in fruit and vegetable preservation. Silver nanomaterials include silver nanocomposites and Ag-MOF, of which silver nanocomposites are mainly composed of silver nanoparticles. Notably, not all kinds of silver nanoparticles utilized in the preservation of fruits and vegetables are thoroughly described. Therefore, the synthesis, mechanism of action, and advancements in research on silver nanocomposites for fruit and vegetable preservation were discussed in this study.

Impact of pulmonary rehabilitation on exercise capacity, health-related quality of life, and cardiopulmonary function in lung surgery patients: a retrospective propensity score-matched analysis.

Background: Pulmonary rehabilitation is considered beneficial for patients undergoing lung surgery, yet its specific impacts on exercise capacity, health-related quality of life (HRQL), and cardiopulmonary function require further elucidation. This study aimed to evaluate the effect of PR on these outcomes in patients undergoing lung surgery using a retrospective propensity score-matched analysis. Methods: We retrospectively analyzed 420 patients with non-small cell lung cancer (NSCLC) who underwent lung surgery from January 2022 to May 2024. Among these, 84 patients received PR while 336 did not (control group). Propensity score matching (PSM) at a 1:1 ratio yielded 46 patients in each group. Baseline characteristics, spirometry, cardiopulmonary exercise testing, respiratory muscle strength, HRQL, and muscle measurements were assessed pre-and post-surgery. Results: Before PSM, significant differences existed between groups, with the PR group being older and having different pulmonary function baselines. After PSM, groups were well-balanced. Postoperatively, the PR group showed significant improvements in FEV1/FVC (64.17% vs. 50.87%, p < 0.001), FEV1 (2.31 L/min vs. 1.75 L/min, p < 0.001), and predicted FVC percentage (88.75% vs. 68.30%, p < 0.001). Cardiovascular responses showed a lower CI during exercise in the PR group post-PSM (6.24 L/min/m2 vs. 7.87 L/min/m2, p < 0.001). In terms of exercise capacity, the PR group had higher maximal WR percentage (104.76% vs. 90.00%, p = 0.017) and peak VO2 (1150.70 mL/min vs. 1004.74 mL/min, p = 0.009). PR also resulted in less leg soreness and lower total CAT scores postoperatively. Muscle measurements indicated significantly smaller reductions in ΔHUESMCSA and percentage change in the PR group. Conclusion: Pulmonary rehabilitation significantly enhances exercise capacity, HRQL, and cardiopulmonary function in patients undergoing lung surgery. It also mitigates postoperative muscle loss, underscoring its importance in the postoperative management of lung surgery patients.

Indole-3-Lactic Acid Derived from Lacticaseibacillus paracasei Inhibits Helicobacter pylori Infection via Destruction of Bacteria Cells, Protection of Gastric Mucosa Epithelial Cells, and Alleviation of Inflammation.

Indole-3-lactic acid (ILA) has exhibited antimicrobial properties. However, its role in inhibiting Helicobacter pylori infection remains elusive. This study investigated the inhibitory effect of ILA produced by Lacticaseibacillus paracasei on H. pylori, which was further confirmed by cell and animal experiments. 5 mg/mL ILA was sufficient to directly inhibit the growth of H. pylori in vitro, with a urease inhibitory activity reaching 60.94 ± 1.03%, and the cell morphology and structure were destroyed. ILA inhibited 56.5% adhesion of H. pylori to GES-1 and significantly reduced the number of apoptotic cells. Furthermore, ILA suppresses H. pylori colonization by approximately 38% to 63%, reduced inflammation and oxidative stress in H. pylori-infected mice, and enhanced the enrichment and variety of gut microbiota, notably fostering the growth of beneficial bacteria such as Lactobacillus and Bifidobacterium strains. The results support that ILA derived from Lactobacillus can be applicated as a novel prebiotic in anti-H. pylori functional foods.

PFOS impairs cardiac function and energy metabolism under high-fat diet: Insights into role of circulating macrophage emphasized by exposure distribution.

Per- and polyfluoroalkyl substances (PFAS), widely utilized in consumer products, have been linked to an increased risk of cardiovascular disease (CVD). With the increasing prevalence of high-fat diet, a common risk factor for CVD, the PFAS exposed populations who consume a high-fat diet will inevitably grow and may have a higher CVD risk. However, the potential toxic effect and mode of action remain elusive. We constructed a mouse model orally exposed to perfluorooctane sulfonate (PFOS), a prototypical PFAS, and fed a high-fat diet. PFOS exposure induced cardiomyopathy and structural abnormalities in the mice heart. Moreover, a characteristic of energy metabolism remodeling from aerobic to anaerobic process was observed. Interestingly, PFOS was rarely detected in heart but showed high level in serum, suggesting an indirect route of action for PFOS-caused cardiac toxicity. We further demonstrated that PFOS-caused circulating inflammation promoted metabolic remodeling and contractile dysfunction in cardiomyocytes. Wherein, PFOS stimulated the release of IL-1ß from circulating proinflammatory macrophages mediated by NF-κB and caspase-1. This study provides valuable data on PFAS-induced cardiac risks associated with exposed populations with increasing high-fat diet consumption, highlighting the significance of indirect pathways in PFOS's impact on the heart, based on the distribution of internal exposure.

RNA modification gene WDR4 facilitates tumor progression and immunotherapy resistance in breast cancer.

INTRODUCTION: Growing interest toward RNA modification in cancer has inspired the exploration of gene sets related to multiple RNA modifications. However, a comprehensive elucidation of the clinical value of various RNA modifications in breast cancer is still lacking. OBJECTIVES: This study aimed to provide a strategy based on RNA modification-related genes for predicting therapy response and survival outcomes in breast cancer patients. METHODS: Genes related to thirteen RNA modification patterns were integrated for establishing a nine-gene-containing signature-RMscore. Alterations of tumor immune microenvironment and therapy response featured by different RMscore levels were assessed by bulk transcriptome, single-cell transcriptome and genomics analyses. The biological function of key RMscore-related molecules was investigated by cellular experiments in vitro and in vivo, using flow cytometry, immunohistochemistry and immunofluorescence staining. RESULTS: This study has raised an effective therapy strategy for breast cancer patients after a well-rounded investigation of RNA modification-related genes. With a great performance of predicting patient prognosis, high levels of the RMscore proposed in this study represented suppressive immune microenvironment and therapy resistance, including adjuvant chemotherapy and PD-L1 blockade treatment. As the key contributor of the RMscore, inhibition of WDR4 impaired breast cancer progression significantly in vitro and in vivo, as well as participated in regulating cell cycle and mTORC1 signaling pathway via m7G modification. CONCLUSION: Briefly, this study has developed promising and effective tactics to achieve the prediction of survival probabilities and treatment response in breast cancer patients.

BBX9 forms feedback loops with PIFs and BBX21 to promote photomorphogenic development.

Light is one of the most essential environmental factors that tightly and precisely control various physiological and developmental processes in plants. B-box CONTAINING PROTEINs (BBXs) play central roles in the regulation of light-dependent development. In this study, we report that BBX9 is a positive regulator of light signaling. BBX9 interacts with the red light photoreceptor PHYTOCHROME B (phyB) and transcription factors PHYTOCHROME-INTERACTING FACTORs (PIFs). phyB promotes the stabilization of BBX9 in light, while BBX9 inhibits the transcriptional activation activity of PIFs. In turn, PIFs directly bind to the promoter of BBX9 to repress its transcription. On the other hand, BBX9 associates with the positive regulator of light signaling, BBX21, and enhances its biochemical activity. BBX21 associates with the promoter regions of BBX9 and transcriptionally up-regulates its expression. Collectively, this study unveiled that BBX9 forms a negative feedback loop with PIFs and a positive one with BBX21 to ensure that plants adapt to fluctuating light conditions.

circPTP4A2 knockdown suppresses NSCLC progression via regulating proliferation and activating anti-tumor immunity.

BACKGROUND: With a considerable variety of cancer subtypes, Non-small cell lung cancer (NSCLC) poses a substantial threat to public health, affecting a large number of individuals and resulting in a high mortality rate. Circular RNA (circRNA) has been applied in various diseases, including cancers. This study aims to investigate the clinial significance and functional role of circPTP4A2 in NSCLC. METHODS: The serum and tissue samples were collected for detecting circPTP4A2 expression in NSCLC using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Actinomycin D was used to treat NSCLC cells to detect circPTP4A2 stability. The CCK-8 and Transwell assays were utilized to assess the effects of circPTP4A2 in NSCLC cells. The ELISA assay and cytotoxicity analysis were used to detect the roles of circPTP4A2 in immune escape. RESULTS: The serum and tissue circPTP4A2 expression was upregulated in NSCLC. The high circPTP4A2 had a relatively high value in differentiating NSCLC patients from healthy individuals. The proliferation, invasion, and immune escape were repressed by circPTP4A2 knockdown. CONCLUSIONS: High circPTP4A2 has the potential to be a diagnostic biomarker in NSCLC. Silencing of circPTP4A2 receded the progression of NSCLC and enhanced antitumor immunity, which might provide potential targets and new ideas for improving the diagnosis and effect of immunotherapy in NSCLC patients.

Deep learning for colorectal cancer detection in contrast-enhanced CT without bowel preparation: a retrospective, multicentre study.

BACKGROUND: Contrast-enhanced CT scans provide a means to detect unsuspected colorectal cancer. However, colorectal cancers in contrast-enhanced CT without bowel preparation may elude detection by radiologists. We aimed to develop a deep learning (DL) model for accurate detection of colorectal cancer, and evaluate whether it could improve the detection performance of radiologists. METHODS: We developed a DL model using a manually annotated dataset (1196 cancer vs 1034 normal). The DL model was tested using an internal test set (98 vs 115), two external test sets (202 vs 265 in 1, and 252 vs 481 in 2), and a real-world test set (53 vs 1524). We compared the detection performance of the DL model with radiologists, and evaluated its capacity to enhance radiologists' detection performance. FINDINGS: In the four test sets, the DL model had the area under the receiver operating characteristic curves (AUCs) ranging between 0.957 and 0.994. In both the internal test set and external test set 1, the DL model yielded higher accuracy than that of radiologists (97.2% vs 86.0%, p < 0.0001; 94.9% vs 85.3%, p < 0.0001), and significantly improved the accuracy of radiologists (93.4% vs 86.0%, p < 0.0001; 93.6% vs 85.3%, p < 0.0001). In the real-world test set, the DL model delivered sensitivity comparable to that of radiologists who had been informed about clinical indications for most cancer cases (94.3% vs 96.2%, p > 0.99), and it detected 2 cases that had been missed by radiologists. INTERPRETATION: The developed DL model can accurately detect colorectal cancer and improve radiologists' detection performance, showing its potential as an effective computer-aided detection tool. FUNDING: This study was supported by National Science Fund for Distinguished Young Scholars of China (No. 81925023); Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (No. U22A20345); National Natural Science Foundation of China (No. 82072090 and No. 82371954); Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (No. 2022B1212010011); High-level Hospital Construction Project (No. DFJHBF202105).

A case of congenital bronchial atresia with tracheobronchial stenosis caused by emphysema: Successful management with thoracoscopic surgery.

Introduction: Congenital bronchial atresia (CBA), as a rare developmental abnormality of the lung, is usually asymptomatic and is accidently discovered in most cases. Currently, no standardized guidelines for the treatment or management of CBA have been established. Case presentation: A 22-year-old male soldier was referred to Shanghai Changhai Hospital, The First Affiliated Hospital of Naval Medical University due to chest tightness and shortness of breath after repeated strenuous activities. Contrast-enhanced computed tomography (CT) revealed an 18mm × 11mm solitary, well-circumscribed, and solid nodule with no enhancement in the right upper lobe (RUL), and emphysematous changes distributed throughout the RUL. A flexible bronchoscopic examination showed extrinsic compression stenosis in the bronchial opening of the right middle lobe (RML). After three-dimensional (3D) reconstruction CT and a multidisciplinary consultation, a diagnosis of CBA in the anterior segment (B3) of RUL was established. Subsequently, thoracoscopic right upper lobectomy was performed and resulted in an improved respiratory capacity 6 months after surgery. To date, the patient has good quality of life without any complication. Conclusion: This study underscores the role of bronchoscopy, 3D reconstruction CT, and a multidisciplinary consultation in the diagnosis of CBA, and highlights that a thoracoscopic intervention should be considered in such case.

Bacterial evolution in Biofiltration of drinking water treatment plant: Different response of phage and plasmid to varied water sources.

Biofiltration in drinking water treatment (BDWT) are popular as it holds promise as an alternative to chemical treatments, yet our understanding of the key drivers and trends underlying bacterial evolution within this process remains limited. While plasmids and phages are recognized as the main vectors of horizontal gene transfer (HGT), their roles in shaping bacterial evolution in BDWT remain largely unknown. Here we leverage global metagenomic data to unravel the primary forces driving bacterial evolution in BDWT. Our results revealed that the primary vector of HGT varies depending on the type of source water (groundwater and surface water). Both plasmids and phages accelerated bacterial evolution in BDWT by enhancing genetic diversity within species, but they drove contrasting evolutionary trends in functional redundancy in different source water types. Specifically, trends towards and away from functional redundancy (indicated as gene-protein ratio) were observed in surface-water and groundwater biofilters, respectively. Virulent phages drove bacterial evolution through synergistic interactions with bacterial species capable of natural transformation and with certain natural compounds that disrupt bacterial cytoplasmic membranes. Genes relating to water purification (such as Mn(II)-oxidizing genes), microbial risks (antibiotic resistance genes), and chemical risk (polycyclic aromatic hydrocarbons) were enriched via HGT in BDWT, highlighting the necessity for heighted focus on these useful and risky objects. Overall, these discoveries enhance our understanding of bacterial evolution in BDWT and have implications for the optimization of water treatment strategies.

The prognostic value of lymph node to primary tumor standardized uptake value ratio in cancer patients: a meta-analysis.

OBJECTIVE: The lymph node to primary tumor standardized uptake value ratio (NTR) is an innovative parameter derived from positron emission tomography/computed tomography (PET/CT) scans that captures the intricate relationship between primary tumors and associated lymph nodes. This meta-analysis aimed to investigate the prognostic value of NTR in cancer patients. METHODS: A systematic search of PubMed, Cochrane, and Embase databases was conducted to identify studies investigating the association between NTR and survival outcomes in cancer patients. The pooled adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Twelve studies comprising a total of 2037 patients were included in the meta-analysis. Elevated NTR was significantly associated with worse overall survival aHR (2.21, 95% CI 1.63 to 2.99), disease-free survival aHR (3.27, 95% CI 2.12 to 5.05), and distant metastasis-free survival aHR (2.07, 95% CI 1.55 to 2.78) in cancer patients. Subgroup analyses by cancer type showed consistent results across various malignancies, including head and neck squamous cell carcinoma, endometrial carcinoma, lung cancer, breast cancer, and nasopharyngeal carcinoma. CONCLUSIONS: This meta-analysis provides evidence for a significant association between elevated NTR and worse survival outcomes in cancer patients. Elevated NTR may serve as a useful prognostic biomarker for cancer patients and could potentially be used to guide treatment decisions and monitor disease progression. Future studies should aim to validate these findings in larger and more diverse patient populations and investigate the underlying mechanisms for the observed association between NTR and survival outcomes.

Spatial distance between tumor and lymphocyte can predict the survival of patients with resectable lung adenocarcinoma.

Background and objective: Spatial interaction between tumor-infiltrating lymphocytes (TILs) and tumor cells is valuable in predicting the effectiveness of immune response and prognosis amongst patients with lung adenocarcinoma (LUAD). Recent evidence suggests that the spatial distance between tumor cells and lymphocytes also influences the immune responses, but the distance analysis based on Hematoxylin and Eosin (H&E) -stained whole-slide images (WSIs) remains insufficient. To address this issue, we aim to explore the relationship between distance and prognosis prediction of patients with LUAD in this study. Methods: We recruited patients with resectable LUAD from three independent cohorts in this multi-center study. We proposed a simple but effective deep learning-driven workflow to automatically segment different cell types in the tumor region using the HoVer-Net model, and quantified the spatial distance (DIST) between tumor cells and lymphocytes based on H&E-stained WSIs. The association of DIST with disease-free survival (DFS) was explored in the discovery set (D1, n = 276) and the two validation sets (V1, n = 139; V2, n = 115). Results: In multivariable analysis, the low DIST group was associated with significantly better DFS in the discovery set (D1, HR, 0.61; 95 % CI, 0.40-0.94; p = 0.027) and the two validation sets (V1, HR, 0.54; 95 % CI, 0.32-0.91; p = 0.022; V2, HR, 0.44; 95 % CI, 0.24-0.81; p = 0.009). By integrating the DIST with clinicopathological factors, the integrated model (full model) had better discrimination for DFS in the discovery set (C-index, D1, 0.745 vs. 0.723) and the two validation sets (V1, 0.621 vs. 0.596; V2, 0.671 vs. 0.650). Furthermore, the computerized DIST was associated with immune phenotypes such as immune-desert and inflamed phenotypes. Conclusions: The integration of DIST with clinicopathological factors could improve the stratification performance of patients with resectable LUAD, was beneficial for the prognosis prediction of LUAD patients, and was also expected to assist physicians in individualized treatment.

Development of a dual point humidity sensor using POF based on twisted fiber structure.

The humidity has often been measured through a single point sensor. Where, the humidity could be varied at different locations as well as depending on environmental conditions. The present paper developed the dual point humidity measuring sensor by using a polymer optical fiber (POF) based on a single illuminating fiber. The sensor's basic structure is to twist two fibers and bend them at a certain radius. However, the dual point sensor is developed through the cascading of twisted micro bend (TMB-1 and TMB-2). The twisting of fibers couples the light from one fiber to another fiber through the side coupling method. An increase in the humidity level leads to a change in the reflective index, which helps to get variation in coupled light intensity. To measure the humidity, the dual point sensors are placed into the control humidity chamber at two random positions. The power reading variation is significantly linear when the humidity level increases from 30 to 80%. The sensor has a fast response of about 1 s and a recovery time of about 4 s. Furthermore, the chemical coating is applied to improve the sensor's sensitivity. Between 30 and 80% range of humidity, the both sensors of dual point TMB-1 and TMB-2 have appropriate sensitivity and detection limits, which is about 680.8 nW/% and 763.9 nW/% and 1.37% and 1.98%, respectively. To measure the humidity at variable positions, the present dual points humidity sensor is well-stable, easy, and straightforward, which uses a less expensive method.

A Modified Tip-to-Base LAMPOON to Prevent Left Ventricular Outflow Tract Obstruction in Valve-in-Ring or Valve-in-Valve Transcatheter Mitral Valve Replacement.

Background: The Laceration of the Anterior Mitral leaflet to Prevent Outflow ObtructioN (LAMPOON) procedure may be performed from the leaflet tip to base to prevent left ventricular outflow tract obstruction (LVOTO) in patients with high-risk anatomy undergoing valve-in-valve (VIV) or valve-in-(complete)-ring (VIR) transcatheter mitral valve replacement (TMVR). Methods and Results: Thirteen consecutive patients (6 females, average age 67.7 years) with a mean left ventricular ejection fraction of 60%, a median STS score of 3.2%, and degenerative surgical mitral bioprosthesis or ring were treated with a combined, single-stage procedure of preventive LAMPOON and trans-septal TMVR with SAPIEN 3 valves (Edwards Lifesciences, Irvine, CA). Under real-time 3-dimensional transesophageal echocardiography (RT 3D-TEE) guidance, we included the rendezvous technique in the LAMPOON procedure, and all 13 patients were successfully treated by tip-to-base LAMPOON and TMVR. The use of a modified LAMPOON procedure, aided by a rendezvous technique and guided by RT 3D-TEE imaging, offers precise guidance for positioning and aligning the guidewire. This approach not only reduces the need for fluoroscopy and shortens procedure times, but also significantly increases the likelihood of a successful outcome. Importantly, none of the patients in our study experienced unintentional aortic or aortic valve injuries, nor did they develop significant LVOTO following TMVR. In 11 of the 13 (85%) patients, we used a transcatheter SENTINELTM cerebral protection device (Boston Scientific, Marlborough, MA) for stroke prevention and capture of debris ≥ 2 mm were detected in 8/11 (73%) of the cases. Conclusions: Utilizing intra-operative RT 3D-TEE in conjunction with the rendezvous technique can make the tip-to-base LAMPOON procedure even safer and more effective for patients undergoing VIV or VIR TMVR. Our study also suggests that cerebral protection is indicated in patients undergoing TMVR.

Monoallelic KRAS (G13C) mutation triggers dysregulated expansion in induced pluripotent stem cell-derived hematopoietic progenitor cells.

BACKGROUND: Although oncogenic RAS mutants are thought to exert mutagenic effects upon blood cells, it remains uncertain how a single oncogenic RAS impacts non-transformed multipotent hematopoietic stem or progenitor cells (HPCs). Such potential pre-malignant status may characterize HPCs in patients with RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). This study sought to elucidate the biological and molecular alterations in human HPCs carrying monoallelic mutant KRAS (G13C) with no other oncogene mutations. METHODS: We utilized induced pluripotent stem cells (iPSCs) derived from two unrelated RALD patients. Isogenic HPC pairs harboring either wild-type KRAS or monoallelic KRAS (G13C) alone obtained following differentiation enabled reliable comparative analyses. The compound screening was conducted with an established platform using KRAS (G13C) iPSCs and differentiated HPCs. RESULTS: Cell culture assays revealed that monoallelic KRAS (G13C) impacted both myeloid differentiation and expansion characteristics of iPSC-derived HPCs. Comprehensive RNA-sequencing analysis depicted close clustering of HPC samples within the isogenic group, warranting that comparative studies should be performed within the same genetic background. When compared with no stimulation, iPSC-derived KRAS (G13C)-HPCs showed marked similarity with the wild-type isogenic control in transcriptomic profiles. After stimulation with cytokines, however, KRAS (G13C)-HPCs exhibited obvious aberrant cell-cycle and apoptosis responses, compatible with "dysregulated expansion," demonstrated by molecular and biological assessment. Increased BCL-xL expression was identified amongst other molecular changes unique to mutant HPCs. With screening platforms established for therapeutic intervention, we observed selective activity against KRAS (G13C)-HPC expansion in several candidate compounds, most notably in a MEK- and a BCL-2/BCL-xL-inhibitor. These two compounds demonstrated selective inhibitory effects on KRAS (G13C)-HPCs even with primary patient samples when combined. CONCLUSIONS: Our findings indicate that a monoallelic oncogenic KRAS can confer dysregulated expansion characteristics to non-transformed HPCs, which may constitute a pathological condition in RALD hematopoiesis. The use of iPSC-based screening platforms will lead to discovering treatments that enable selective inhibition of RAS-mutated HPC clones.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.