Controllable Design of Metal-Organic Framework-Derived Vanadium Oxynitride for High-Capacity and Long-Cycle Aqueous Zn-Ion Batteries.

Introducing N atoms in vanadium oxides (VOx) of aqueous Zn-ion batteries (ZIBs) can reduce their bandgap energy and enhance their electronic conductivity, thereby promoting the diffusion of Zn2+. The close-packed vanadium oxynitride (VON) generated often necessitates the intercalation of water molecules for restructuring, rendering it more conducive for zinc ion intercalation. However, its dense structure often causes structural strain and the formation of by-products during this process, resulting in decreased electrochemical performance. Herein, carbon-coated porous V2O3/VN nanosheets (p-VON@C) are constructed by annealing vanadium metal-organic framework in an ammonia-contained environment. The designed p-VON@C nanosheets are efficiently converted to low-crystalline hydrated N-doped VOx during subsequent activation while maintaining structural stability. This is because the V2O3/VN heterojunction and abundant oxygen vacancies in p-VON@C alleviate the structural strain during water molecule intercalation, and accelerate the intercalation rate. Carbon coating is beneficial to prevent p-VON@C from sliding or falling off during the activation and cycling process. Profiting from these advantages, the activated p-VON@C cathode delivers a high specific capacity of 518 mAh g-1 at 0.2 A g-1 and maintains a capacity retention rate of 80.9% after 2000 cycles at 10 A g-1. This work provides a pathway to designing high-quality aqueous ZIB cathodes.

Largely Enhanced Thermoelectric Performance of Flexible Ag2Se Film by Cationic Doping and Dual-Phase Engineering.

Recent studies have shown that silver selenide is a promising thermoelectric material at room temperature. Herein, flexible films with a nominal composition of (Ag1-xCux)2Se are prepared by a simple and efficient one-pot method combined with vacuum-assisted filtration and hot pressing. The thermoelectric properties of the films are regulated by both cationic doping and a dual-phase strategy via a wet chemical method. As the x increases, not only Cu is doped into the Ag2Se, but different new phases (CuAgSe and/or CuSe2) also appear. The (Ag1-xCux)2Se film with x = 0.02 composed of Cu-doped Ag2Se and CuAgSe shows a high PF of ∼2540 µW m-1 K-2 (ZT ∼ 0.90) and outstanding flexibility at room temperature. The high thermoelectric properties of the film are due to the effect of Cu doping and the CuAgSe phase, including the increase in electrical conductivity caused by doping, the enhanced phonon scattering at the Ag2Se/CuAgSe interface, and the interaction between the energy filtering effect and the doping effect. In addition to the high output performance (PDmax = 28.08 W m-2, ΔT = 32.2 K), the flexible device assembled with the (Ag0.98Cu0.02)2Se film also has potential applications as a temperature sensor.

Purine permease (PUP) family gene PUP11 positively regulates the rice seed setting rate by influencing seed development.

KEY MESSAGE: Purine permease PUP11 is essential for rice seed development, regulates the seed setting rate, and influences the cytokinin content, sugar transport, and starch biosynthesis during grain development. The distribution of cytokinins in plant tissues determines plant growth and development and is regulated by several cytokinin transporters, including purine permease (PUP). Thirteen PUP genes have been identified within the rice genome; however, the functions of most of these genes remain poorly understood. We found that pup11 mutants showed extremely low seed setting rates and a unique filled seed distribution. Moreover, seed formation arrest in these mutants was associated with the disappearance of accumulated starch 10 days after flowering. PUP11 has two major transcripts with different expression patterns and subcellular locations, and further studies revealed that they have redundant positive roles in regulating the seed setting rate. We also found that type-A Response Regulator (RR) genes were upregulated in the developing grains of the pup11 mutant compared with those in the wild type. The results also showed that PUP11 altered the expression of several sucrose transporters and significantly upregulated certain starch biosynthesis genes. In summary, our results indicate that PUP11 influences the rice seed setting rate by regulating sucrose transport and starch accumulation during grain filling. This research provides new insights into the relationship between cytokinins and seed development, which may help improve cereal yield.

RETRACTED: Liu et al. Prediction of Ovarian Cancer Response to Therapy Based on Deep Learning Analysis of Histopathology Images. Cancers 2023, 15, 4044.

The journal and authors wish to retract the article entitled 'Prediction of Ovarian Cancer Response to Therapy Based on Deep Learning Analysis of Histopathology Images' cited above [...].

Is there any difference in urinary continence between bilateral and unilateral nerve sparing during radical prostatectomy? A systematic review and meta-analysis.

CONTEXT: In men with prostate cancer, urinary incontinence is one of the most common long-term side effects of radical prostatectomy (RP). The recovery of urinary continence in patients is positively influenced by preserving the integrity of the neurovascular bundles (NVBs). However, it is still unclear if bilateral nerve sparing (BNS) is superior to unilateral nerve sparing (UNS) in terms of post-RP urinary continence. The aim of this study is to systematically compare the differences in post-RP urinary continence outcomes between BNS and UNS. METHODS: The electronic databases of PubMed and Web of Science were comprehensively searched. The search period was up to May 31, 2023. English language articles comparing urinary continence outcomes of patients undergoing BNS and UNS radical prostatectomy were included. Meta-analyses were performed to calculate pooled relative risk (RR) estimates with 95% confidence intervals for urinary continence in BNS and UNS groups at selected follow-up intervals using a random-effects model. Sensitivity analyses were performed in prospective studies and robotic-assisted RP studies. RESULTS: A meta-analysis was conducted using data from 26,961 participants in fifty-seven studies. A meta-analysis demonstrated that BNS improved the urinary continence rate compared to UNS at all selected follow-up points. RRs were 1.36 (1.14-1.63; p = 0.0007) at ≤ 1.5 months (mo), 1.28 (1.08-1.51; p = 0.005) at 3-4 mo, 1.12 (1.03-1.22; p = 0.01) at 6 mo, 1.08 (1.05-1.12; p < 0.00001) at 12 mo, and 1.07 (1.00-1.13; p = 0.03) at ≥ 24 mo, respectively. With the extension of the follow-up time, RRs decreased from 1.36 to 1.07, showing a gradual downward trend. Pooled estimates were largely heterogeneous. Similar findings were obtained through sensitivity analyses of prospective studies and robotic-assisted RP studies. CONCLUSION: The findings of this meta-analysis demonstrate that BNS yields superior outcomes in terms of urinary continence compared to UNS, with these advantages being sustained for a minimum duration of 24 months. It may be due to the real effect of saving the nerves involved. Future high-quality studies are needed to confirm these findings.

Syntheses of Substituted α,ß-Unsaturated δ-Lactams from N-Boc-2,4-dioxopiperidine.

A method for the syntheses of substituted α,ß-unsaturated δ-lactams (2) from the commercially available compound N-Boc-2,4-dioxopiperidine (1) has been developed. The α-substituents were introduced by a reductive Knoevenagel condensation reaction, and the ß-substituents were installed by palladium-catalyzed cross coupling reactions. More than 20 diverse examples were prepared in 2-3 steps. The synthesis was operationally simple, user-friendly, and easy to scale up.

SOCS1 acts as a ferroptosis driver to inhibit the progression and chemotherapy resistance of triple-negative breast cancer.

OBJECTIVES: Ferroptosis is involved in many types of cancers, including triple-negative breast cancer (TNBC). Suppressor of cytokine signaling 1 (SOCS1) has recently been implicated as a regulator of ferroptosis. We aim to explore whether targeting SOCS1 is a potential therapeutic strategy for TNBC therapy. METHODS: Stable cell lines were constructed using lentivirus transfection. Cell viability was determined using CCK-8 and cell colony formation assays, respectively. Assays including lactate dehydrogenase release, lipid peroxidation and malondialdehyde assays were conducted to evaluate ferroptosis. Real-time quantitative polymerase chain reaction and western blotting were performed to evaluate mRNA and protein expression, respectively. A xenograft animal model was established by subcutaneous injection of cells into the flank. RESULTS: Our results showed that SOCS1 overexpression inhibited cell proliferation and induced ferroptosis in TNBC cells, while SOCS1 knockdown promoted cell proliferation and reduced ferroptosis. We also found that SOCS1 regulated ferroptosis by modulating GPX4 expression. Furthermore, SOCS1 regulated cisplatin resistance in TNBC cells by promoting ferroptosis. Our in vivo data suggested that SOCS1 regulated tumor growth and cisplatin resistance in vivo. CONCLUSIONS: SOCS1 inhibits the progression and chemotherapy resistance of TNBC by regulating GPX4 expression.

Racial/ethnic disparities in the cause of death among patients with prostate cancer in the United States from 1995 to 2019: a population-based retrospective cohort study.

Background: Racial/ethnic disparities in prostate cancer are reported in the United States (US). However, long-term trends and contributors of racial/ethnic disparities in all-cause and cause-specific death among patients with prostate cancer remain unclear. We analysed the trends and contributors of racial/ethnic disparities in prostate cancer survivors according to the cause of death in the US over 25 years. Methods: In this retrospective, population-based longitudinal cohort study, we identified patients diagnosed with first primary prostate cancer between 1995 and 2019, with follow-up until Dec 31, 2019, using population-based cancer registries' data from the Surveillance, Epidemiology, and End Results (SEER) Program. We calculated the cumulative incidence of death for each racial/ethnic group (Black, white, Hispanic, Asian or Pacific Islander [API], and American Indian or Alaska Native [AI/AN] people), by diagnostic period and cause of death. We quantified absolute disparities using rate changes for the 5-year cumulative incidence of death between racial/ethnic groups and diagnostic periods. We estimated relative (Hazard ratios [HR]) racial/ethnic disparities and the percentage of potential factors contributed to racial/ethnic disparities using Cox regression models. Findings: Despite a decreasing trend in the cumulative risk of death across five racial/ethnic groups, AI/AN and Black patients consistently had the highest rate of death between 1995 and 2019 with an adjusted HR of 1.48 (1.40-1.58) and 1.40 (1.38-1.42) respectively. The disparities in all-cause mortality between AI/AN and white patients increased over time, with adjusted HR 1.32 (1.17-1.49) in 1995-1999 and 1.95 (1.53-2.49) in 2015-2019. Adjustment of stage at diagnosis, initial treatment, tumor grade, and household income explained 33% and 24% of the AI/AN-white and Black-white disparities in all-cause death among patients with prostate cancer. Interpretation: The enduring racial/ethnic disparities in patients with prostate cancer, call for new interventions to eliminate health disparities. Our study provides important evidence and ways to address racial/ethnic inequality. Funding: National Key R&D Program of China, National Natural Science Foundation of China, Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, the Open Research Fund from Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Key Projects of Philosophy and Social Sciences Research, Ministry of Education of China.

Prediction of Ovarian Cancer Response to Therapy Based on Deep Learning Analysis of Histopathology Images.

BACKGROUND: Ovarian cancer remains the leading gynecological cause of cancer mortality. Predicting the sensitivity of ovarian cancer to chemotherapy at the time of pathological diagnosis is a goal of precision medicine research that we have addressed in this study using a novel deep-learning neural network framework to analyze the histopathological images. METHODS: We have developed a method based on the Inception V3 deep learning algorithm that complements other methods for predicting response to standard platinum-based therapy of the disease. For the study, we used histopathological H&E images (pre-treatment) of high-grade serous carcinoma from The Cancer Genome Atlas (TCGA) Genomic Data Commons portal to train the Inception V3 convolutional neural network system to predict whether cancers had independently been labeled as sensitive or resistant to subsequent platinum-based chemotherapy. The trained model was then tested using data from patients left out of the training process. We used receiver operating characteristic (ROC) and confusion matrix analyses to evaluate model performance and Kaplan-Meier survival analysis to correlate the predicted probability of resistance with patient outcome. Finally, occlusion sensitivity analysis was piloted as a start toward correlating histopathological features with a response. RESULTS: The study dataset consisted of 248 patients with stage 2 to 4 serous ovarian cancer. For a held-out test set of forty patients, the trained deep learning network model distinguished sensitive from resistant cancers with an area under the curve (AUC) of 0.846 ± 0.009 (SE). The probability of resistance calculated from the deep-learning network was also significantly correlated with patient survival and progression-free survival. In confusion matrix analysis, the network classifier achieved an overall predictive accuracy of 85% with a sensitivity of 73% and specificity of 90% for this cohort based on the Youden-J cut-off. Stage, grade, and patient age were not statistically significant for this cohort size. Occlusion sensitivity analysis suggested histopathological features learned by the network that may be associated with sensitivity or resistance to the chemotherapy, but multiple marker studies will be necessary to follow up on those preliminary results. CONCLUSIONS: This type of analysis has the potential, if further developed, to improve the prediction of response to therapy of high-grade serous ovarian cancer and perhaps be useful as a factor in deciding between platinum-based and other therapies. More broadly, it may increase our understanding of the histopathological variables that predict response and may be adaptable to other cancer types and imaging modalities.

Emergence of consciousness from anesthesia through ubiquitin degradation of KCC2 in the ventral posteromedial nucleus of the thalamus.

The emergence of consciousness from anesthesia, once assumed to be a passive process, is now considered as an active and controllable process. In the present study, we show in mice that, when the brain is forced into a minimum responsive state by diverse anesthetics, a rapid downregulation of K+/Cl- cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) serves as a common mechanism by which the brain regains consciousness. Ubiquitin-proteasomal degradation is responsible for KCC2 downregulation, which is driven by ubiquitin ligase Fbxl4. Phosphorylation of KCC2 at Thr1007 promotes interaction between KCC2 and Fbxl4. KCC2 downregulation leads to γ-aminobutyric acid type A receptor-mediated disinhibition, enabling accelerated recovery of VPM neuron excitability and emergence of consciousness from anesthetic inhibition. This pathway to recovery is an active process and occurs independent of anesthetic choice. The present study demonstrates that ubiquitin degradation of KCC2 in the VPM is an important intermediate step en route to emergence of consciousness from anesthesia.

Clinical implications of tumor-based next-generation sequencing in high-grade epithelial ovarian cancer.

BACKGROUND: Tumor-based next-generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in patients with ovarian cancer. METHODS: This retrospective study included patients with high-grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression-free survival (PFS) and overall survival were calculated and compared using log-rank tests. Multivariate Cox regression and clustering analyses were used to identify patterns of genetic alterations associated with survival. RESULTS: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results. Nearly all (96.1% [393/409]) had one or more genetic alterations. In 25.9% (106/409) of patients, an alteration that aligned with a targeted treatment was identified, and in an additional 48.7% (199/409), tbNGS results suggested eligibility for an investigational agent or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations, and CCNE1 amplification. Together, BRCA1 and BRCA2 mutations were associated with longer PFS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.42-0.92; p = .02), whereas AKT2 amplification was associated with shorter PFS (HR, 3.86; 95% CI, 1.002-14.88; p < .05). Multivariate Cox regression and clustering analyses identified several combinations of genetic alterations that corresponded to outcomes in patients with high-grade serous carcinoma. CONCLUSIONS: tbNGS often yields clinically relevant information. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools. PLAIN LANGUAGE SUMMARY: Although more and more patients with ovarian cancer are undergoing tumor-based next-generation sequencing to identify genetic mutations in their tumors, the benefits of such testing are not well established. In a group of over 400 patients with ovarian cancer who underwent tumor-based next-generation sequencing in the course of their treatment, nearly all patients had one or more genetic alterations detected, and one out of four patients had a mutation that qualified them for a personalized treatment option.

Recent strategies for electrochemical sensing detection of miRNAs in lung cancer.

MicroRNAs (miRNAs) associated with lung cancer are diversifying. MiR-21, Let-7, and miR-141 are common diagnostic targets. Some new lung cancer miRNAs, such as miR-25, miR-145, and miR-126, have received increasing attention. Although various techniques are available for the analysis of lung cancer miRNAs, electrochemistry has been recognized for its high sensitivity, low cost, and rapid response. However, how to realize the signal amplification is one of the most important contents in the design of electrochemical biosensors. Herein, we mainly introduce the amplification strategy based on enzyme-free amplification and signal conversion, including non-linear HCR, catalytic hairpin assembly (CHA), electrochemiluminescence (ECL), and Faraday cage. Furthermore, new progress has emerged in the fields of nanomaterials, low oxidation potential, and simultaneous detection of multiple targets. Finally, we summarize some new challenges that electrochemical techniques may encounter in the future, such as improving single-base discrimination ability, shortening electrochemical detection time, and providing real body fluid samples assay.

Relationship between Cardiorespiratory Fitness and Executive Function in Young Adults: Mediating Effects of Gray Matter Volume.

We evaluated the association between cardiorespiratory fitness (CRF) and executive function (EF) in young adults and the mediating effects of GMV on this relationship. This study involved 217 college students. An incremental load exercise program was used to evaluate VO2max. EF was estimated by the Flanker task, the 2-back task, and the more-odd shifting task, while structural magnetic resonance and region-based morphometry (RBM) were used to analyze GMV. The high CRF group had a shorter updating reaction time (RT) (p ≤ 0.05). CRF was positively correlated with the right orbital part of the middle frontal gyrus (ORBmid.R) GMV (p ≤ 0.05). ORBmid.R GMV was negatively correlated with updating RT (p ≤ 0.05). Model 4 in SPSS was used to assess the mediating effects of ORBmid.R GMV between CRF and updating RT. ORBmid.R GMV was established to have a partially mediating role between CRF and updating RT, which accounted for 19.6% of the total effect value. These findings indicate that the negative correlation between CRF and EF was significant, and ORBmid.R GMV played a mediating role in the relationship between CRF and EF, providing new evidence toward comprehensively revealing that CRF promotes EF performance.

Construction of hierarchical polypyrrole coated copper-catecholate grown on poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) fibers for high-performance supercapacitors.

Fiber-shaped supercapacitors (FSCs) are considered as the optimal candidate for wearable energy devices, due to their high safety, excellent electrochemical stability, workability and body adaptability. However, the specific capacitances of today's FSCs such as carbon nanotube fibers and graphene fibers, are still not high enough for practical applications due to the limitation of their energy storage mode. So, we design a ternary composite fiber-shaped electrode: First, a kind of metal organic framework (MOF), copper-catecholate (Cu-CAT) nanorods, are in-situ grown on a wet-spun poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS) fiber at the ambient temperature. Second, polypyrrole (PPy) is electrodeposited on the surface of the Cu-CAT/PEDOT:PSS fiber to obtain PPy@Cu-CAT@PEDOT:PSS fiber (PPy@Cu-CAT@PF). The growing Cu-CAT with high porosity anchored on the fiber surface provides electrochemical activate sites and the encapsulation of PPy effectively provides a continuous charge transfer path and improve its cycling stability. Notably, the PPy@Cu-CAT@PF electrode exhibits a satisfactory areal capacitance of 669.93 mF cm-2 at 2 mA cm-2, which remains 61.66% even at a high current density of 20 mA cm-2. Furthermore, the assembled symmetric FSC displays excellent electrochemical properties and outstanding mechanical flexibility, demonstrating its feasibility as a wearable supercapacitor.

LIMD2 promotes tumor proliferation, invasion, and epithelial-mesenchymal transition in clear cell renal cell carcinoma.

LIMD2 was found upregulated in various tumors and metastatic samples and associated with a poor prognosis. But the role of LIMD2 in clear cell renal cell carcinoma (ccRCC) remains elusive. The expression of LIMD2 in ccRCC was analyzed using cohort data downloaded from TCGA and ICGC databases. In vitro and in vivo experiments were then conducted to study the biological role of LIMD2 in ccRCC and explore the possible mechanism. The results indicated that LIMD2 was overexpressed and correlated with a poor outcome in ccRCC. LIMD2 promoted the malignancy of ccRCC both in vitro and in vivo. LIMD2 induced epithelial-mesenchymal transition (EMT) via activating the ILK/Akt pathway in ccRCC. In conclusion, LIMD2 is overexpressed and promotes proliferation, invasion, and EMT in ccRCC, which may serve as a potential novel therapeutic target for ccRCC.

Cytokinin oxidase/dehydrogenase family genes exhibit functional divergence and overlap in rice growth and development, especially in control of tillering.

Cytokinins play key roles in plant growth and development, and hence their biosynthesis and degradation have been extensively studied. Cytokinin oxidase/dehydrogenases (CKXs) are a group of enzymes that regulate oxidative cleavage to maintain cytokinin homeostasis. In rice, 11 CKX genes have been identified to date; however, most of their functions remain unknown. In this study, we comprehensively examined the expression patterns and functions of the CKXs in rice by using CRISPR/Cas9 technology to construct mutants of all 11 genes. The results revealed that the ckx single-mutants and higher-order ckx4 ckx9 mutant lines showed functional overlaps and sub-functionalization. Notably, the ckx1 ckx2 and ckx4 ckx9 double-mutants displayed contrasting phenotypic changes in tiller number and panicle size compared to the wild-type. In addition, we identified several genes with significantly altered expression in both the ckx4 and ckx9 single-mutant and double-mutant plants. Many of the differentially expressed genes were found to be associated with auxin and cytokinin pathways, and cytokinins in the ckx4 ckx9 double-mutant were increased compared to the wild-type. Taken together, our findings provide new insights into the functions of CKX genes in rice growth and may provide the foundations for future studies aimed at improving rice yield.

The role of N-cadherin/c-Jun/NDRG1 axis in the progression of prostate cancer.

The dysregulation of androgen receptor (AR) signaling is a critical event in the progression of prostate cancer (PCa) and hormone therapy consisting of androgen deprivation (ADT) or AR inhibition is therefore used to treat advanced cases. It is known that N-cadherin becomes upregulated following ADT and can directly induce PCa transformation to the castration-resistant stage (CRPC). However, the relationship between AR and N-cadherin is unclear and may promote better understanding of CRPC pathogenesis and progression. Here, we demonstrate a new axis of N-cadherin/c-Jun/N-myc downstream regulated gene 1 (NDRG1) that N-cadherin promotes c-Jun expression and suppresses NDRG1 to promote invasion and migration of PCa cells through epithelial to mesenchymal transition (EMT). Targeting N-cadherin in combination with enzalutamide (ENZ) treatment synergistically suppressed PC3 cell proliferation in vivo and in vitro. Further studies showed that compared to lower Gleason score (GS) (GS < 7) cases, high GS (GS > 7) cases exhibited elevated N-cadherin expression and reduced NDRG1 expression, corroborating our in vitro observations. We further demonstrate that c-Jun, AR, and DNA methyltransferase-1 (DNMT1) form a complex in the 12-O-tetradecanoyl phorbol-13-acetate (TPA) response elements (TREs) region of the NDRG1 promoter, which suppresses NDRG1 transcription through DNA hypermethylation. In conclusion, we demonstrate an underlying mechanism for how N-cadherin collaborates with AR and NDRG1 to promote CRPC progression. Controlling N-cadherin/c-Jun/NDRG1 axis may help to overcome resistance to commonly used hormone therapy to improve long-term patient outcomes.

Pilose Antler Peptide-3.2KD Ameliorates Adriamycin-Induced Myocardial Injury Through TGF-ß/SMAD Signaling Pathway.

Adriamycin (ADR)-based combination chemotherapy is the standard treatment for some patients with tumors in clinical, however, long-term application can cause dose-dependent cardiotoxicity. Pilose Antler, as a traditional Chinese medicine, first appeared in the Han Dynasty and has been used to treat heart disease for nearly a thousand years. Previous data revealed pilose antler polypeptide (PAP, 3.2KD) was one of its main active components with multiple biological activities for cardiomyopathy. PAP-3.2KD exerts protective effects againt myocardial fibrosis. The present study demonstrated the protective mechanism of PAP-3.2KD against Adriamycin (ADR)-induced myocardial injury through using animal model with ADR-induced myocardial injury. PAP-3.2KD markedly improved the weight increase and decreased the HW/BW index, heart rate, and ST height in ADR-induced groups. Additionally, PAP-3.2KD reversed histopathological changes (such as disordered muscle bundles, myocardial fibrosis and diffuse myocardial cellular edema) and scores of the heart tissue, ameliorated the myocardial fibrosis and collagen volume fraction through pathological examination, significantly increased the protein level of Bcl-2, and decreased the expression levels of Bax and caspase-3 in myocardial tissue by ELISA, compared to those in ADR-induced group. Furthermore, ADR stimulation induced the increased protein levels of TGF-ß1 and SMAD2/3/4, the increased phosphorylation levels of SMAD2/3 and the reduced protein levels of SMAD7. The expression levels of protein above in ADR-induced group were remarkably reversed in PAP-3.2KD-treated groups. PAP-3.2KD ameliorated ADR-induced myocardial injury by regulating the TGF-ß/SMAD signaling pathway. Thus, these results provide a strong rationale for the protective effects of PAP against ADR-induced myocardial injury, when ADR is used to treat cancer.

Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.