Human-induced agricultural and developmental activities cause substantial alteration to the natural geography of a landscape; thereby accelerates the geologic soil erosion process. This necessitates ...quantification of catchment-scale soil erosion under both retrospective and future scenarios for efficient conservation of soil resources. Here, we present a revised universal soil loss equation (RUSLE) based soil erosion estimation framework at an unprecedentedly high spatial resolution (30 × 30 m) to quantify the average annual soil loss and sediment yield from an agriculture-dominated river basin. The input parameters were derived by using the observed rainfall data, soil characteristics (soil texture, hydraulic conductivity, organic matter content), and topographic characteristics (slope length and percent slope) derived from digital elevation model (DEM) and satellite imageries. The developed approach was evaluated in the Brahmani River basin (BRB) of eastern India, wherein the different RUSLE inputs, viz., rainfall erosivity (
R
factor), soil erodibility (
K
factor), topographic (
LS
factor), crop cover (
C
factor), and management practice (
P
factor) factors have the magnitude of 1937 to 4867 MJ mm ha
−1
h
−1
year
−1
, 0.023 to 0.039 t h ha MJ
−1
ha
−1
mm
−1
, 0.03 to 74, 0.16 to 1, and 0 to 1, respectively. The estimated average annual soil loss over the BRB ranged from 0 to 319.55 t ha
−1
year
−1
, and subsequent erosion categorization revealed that 54.2% of basin area comes under extreme soil erosion zones in the baseline period. Similarly, the sediment yield estimates varied in the range of 0.96 to 133.31 t ha
−1
year
−1
, and 35.81% area were identified as high soil erosion potential zones. The extent of erosion under climate change scenario was assessed using the outputs of HadGEM2-ES climate model for the future time scales of 2030, 2050, 2070, and 2080 under the four representative concentration pathways (RCPs) 2.6, 4.5, 6.0, and 8.5. The severity of soil erosion under climate change is expected to have a mixed impact in the range of −25 to 25% than the baseline scenario. The outcomes of this study will serve as a valuable tool for decision-makers while implementing management policies over the BRB, and can be well extended to any global catchment-scale applications.
Ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxyribonucleoside diphosphates (dNDPs) to provide dNTP precursors for DNA synthesis. Here, we report that acetylation and ...deacetylation of the RRM2 subunit of RNR acts as a molecular switch that impacts RNR activity, dNTP synthesis, and DNA replication fork progression. Acetylation of RRM2 at K95 abrogates RNR activity by disrupting its homodimer assembly. RRM2 is directly acetylated by KAT7, and deacetylated by Sirt2, respectively. Sirt2, which level peak in S phase, sustains RNR activity at or above a threshold level required for dNTPs synthesis. We also find that radiation or camptothecin-induced DNA damage promotes RRM2 deacetylation by enhancing Sirt2-RRM2 interaction. Acetylation of RRM2 at K95 results in the reduction of the dNTP pool, DNA replication fork stalling, and the suppression of tumor cell growth in vitro and in vivo. This study therefore identifies acetylation as a regulatory mechanism governing RNR activity.
Background
The eighth edition of AJCC cancer staging manual incorporated biomarker status into the prognostic staging group (PSG). We used data from National Cancer Database (NCDB) to validate and ...improve the PSG.
Methods
All patients had surgery and at least some systemic treatment (endocrine therapy, chemotherapy or HER2 targeted therapy). Information from 420,520 patients was assessed for potential predictors of overall survival (OS), including age at diagnosis (age), tumor grade (G), hormonal receptor and HER2 status, and presence of lymph vascular invasion (LVI), stratified by stage or sub-stages. Based on the multivariate Cox analyses, we built different point systems to predict OS and evaluated the different point systems by Akaike’s information criterion (AIC), Harrell’s concordance index (C-index), and Uno’s concordance index.
Results
Age, G, hormonal receptor and HER2 status, LVI and being TNBC were significantly associated with OS (all
P
< 0.0001). Three staging systems were correlated with OS: system 1 was the conventional anatomic TNM staging; system 2 included TNM, age, G, hormonal receptor, HER2, and LVI; system 3 included TNM, age, G, TNBC versus non-TNBC, and LVI. System 3 (C-index; 0.7316; AIC: 488138.91) achieved the best balance between predictive performance and goodness-of-fit to the NCDB data as compared to system 2 (C-index: 0.7325; AIC: 498087.73) and system 1 (C-index: 0.716; AIC: 688536.49).
Conclusions
The new PSG is a better staging system than the conventional anatomic TNM system. Grouping breast cancer into TNBC versus non-TNBC may be simpler while retaining similar accuracy as using ER/PR/HER2 status to predict OS.
Background
High‐grade neuroendocrine carcinomas are rare in the gastrointestinal tract. However, treatment patterns and outcomes have not been well described.
Subjects, Materials, and Methods
The ...National Cancer Database was analyzed. The primary objective was to describe the clinical outcomes and identify prognostic factors. Univariate and multivariate analyses were done to identify factors associated with patient outcome.
Results
A total of 1,861 patients were identified between 2004 and 2013. The mean age was 63 years (standard deviation ±13). The majority of the patients (78.1%) were non‐Hispanic whites. The most common primary sites were pancreas (pancreatic neuroendocrine tumor PNET = 19.4%), large intestine (18.1%), esophagus (17.8%), and rectum (15.5%). Stage at presentation was I (6.6%), II (10.5%), III (18%) and IV (64.6%). Only 1.6% of the patients had brain metastases. Surgical resection was the primary therapy in 27.9%, and their median overall survival (OS) was 13.3 months. Patients treated with palliative chemotherapy had a median OS of 11.2 months, compared with 1.7 months for untreated patients. The median OS for high‐grade PNET was 6 months, compared with 9.9 months for other high‐grade gastrointestinal neuroendocrine carcinomas (HG GI NEC). On univariable analysis, age < 65 years (hazard ratio HR 0.72; 0.66–0.8; p < .001) and treatment at an academic center (HR 0.88; 0.79–0.99; p < .034) were associated with improved survival. Multivariable analysis confirmed prognostic advantage of treatment at an academic center.
Conclusion
This is the largest series of HG GI NEC. Most patients present with metastatic disease, and overall survival remains poor. Treatment at an academic center, younger age, and use of chemotherapy were associated with improved survival. Multiagent chemotherapy was found to be associated with superior survival compared with single‐agent chemotherapy, which was superior to no chemotherapy. Temporal sequences of chemotherapy, surgery, and radiation administration were not found to be associated with survival differences on multivariable analysis.
Implications for Practice
Management of patients with high‐grade gastrointestinal neuroendocrine carcinomas (HG GI NEC) is based on experience with small‐cell lung cancer. In this retrospective review, most patients had advanced disease and pancreatic primary had worse outcomes. Treatment at an academic center, younger age, and use of chemotherapy are associated with improved survival. Patients with early‐stage disease treated with resection alone had inferior outcomes compared with patients who received neoadjuvant or adjuvant therapy, suggesting that micrometastases contribute to poor surgical outcomes. The relatively high proportion of positive surgical margin favors downstaging with neoadjuvant therapy to improve resection and lower the risk of systemic recurrence.
摘要
背景。高级别神经内分泌肿瘤在胃肠道领域很罕见。然而，人们尚未很好地描述治疗模式及预后。
受试者、材料和方法。我们对国家癌症数据库进行分析。主要目标为描述临床预后并识别预后因素。为了识别与患者预后相关的因素，我们执行了单变量和多变量分析。
结果。在 2004 年至 2013 年期间，一共找到 1 861 名患者。平均年龄为 63 岁(标准差 ±13 岁)。大多数患者 (78.1%) 为非西班牙裔白人。最常见的好发部位为胰腺 胰腺神经内分泌肿瘤 (PNET)= 19.4%、大肠 (18.1%)、食道 (17.8%) 和直肠 (15.5%)。患者出现症状的分期为 I 期 (6.6%)、II 期 (10.5%)、III 期 (18%) 和 IV 期 (64.6%)。仅有 1.6% 的患者出现脑转移。手术切除为首选治疗措施，占 27.9%，患者的中位总生存期 (OS) 为 13.3 个月。接受姑息化疗的患者的中位 OS 为 11.2 个月，而未经治疗的患者的中位 OS 为 1.7 个月。高级别 PNET 的中位 OS 为 6 个月，而其他高级别胃肠道神经内分泌肿瘤 (HG GI NEC) 的中位 OS 为 9.9 个月。在单变量分析中，年龄 < 65 岁 风险比 (HR)0.72；0.66–0.8；p < 0.001和在学术中心接受治疗(HR 0.88；0.79–0.99；p < 0.034)与延长生存期相关。多变量分析确认了在学术中心接受治疗的预后优势。
结论。这是最大系列的HG GI NEC。大多数患者出现了转移性疾病，总生存期仍然很短。在学术中心接受治疗、年龄较小以及采用化疗均与延长生存期相关。我们发现，与优于不采用化疗的单药剂化疗相比，多药剂化疗与更长的生存期相关。我们未发现化疗、手术和放疗的时间顺序与多变量分析中的生存期差异相关。
实践意义:高级别胃肠道神经内分泌肿瘤 (HG GI NEC) 患者的治疗以小细胞肺癌方面的经验为依据。在本次回顾性调查中，大多数患者患有晚期疾病，原发性胰腺疾病患者的预后较差。在学术中心接受治疗、年龄较小以及采用化疗均与延长生存期相关。与接受新辅助治疗或辅助治疗的患者相比，仅接受切除术治疗的早期疾病患者具有较差的预后，这表明微小转移会导致手术效果不好。手术切缘阳性比例相对较高，这促进了采用新辅助治疗降期，从而改进切除术并降低全身复发的风险。
The analysis presented in this article provides a guide to health care providers for the management of gastrointestinal high‐grade neuroendocrine carcinoma, based on data available to date.
To analyze outcomes and predictors associated with proton radiation therapy for non-small cell lung cancer (NSCLC) in the National Cancer Database.
The National Cancer Database was queried to capture ...patients with stage I-IV NSCLC treated with thoracic radiation from 2004 to 2012. A logistic regression model was used to determine the predictors for utilization of proton radiation therapy. The univariate and multivariable association with overall survival were assessed by Cox proportional hazards models along with log–rank tests. A propensity score matching method was implemented to balance baseline covariates and eliminate selection bias.
A total of 243,822 patients (photon radiation therapy: 243,474; proton radiation therapy: 348) were included in the analysis. Patients in a ZIP code with a median income of <$46,000 per year were less likely to receive proton treatment, with the income cohort of $30,000 to $35,999 least likely to receive proton therapy (odds ratio 0.63 95% confidence interval (CI) 0.44-0.90; P=.011). On multivariate analysis of all patients, non-proton therapy was associated with significantly worse survival compared with proton therapy (hazard ratio 1.21 95% CI 1.06-1.39; P<.01). On propensity matched analysis, proton radiation therapy (n=309) was associated with better 5-year overall survival compared with non-proton radiation therapy (n=1549), 22% versus 16% (P=.025). For stage II and III patients, non-proton radiation therapy was associated with worse survival compared with proton radiation therapy (hazard ratio 1.35 95% CI 1.10-1.64, P<.01).
Thoracic radiation with protons is associated with better survival in this retrospective analysis; further validation in the randomized setting is needed to account for any imbalances in patient characteristics, including positron emission tomography–computed tomography staging.
Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic ...signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.
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