bluuebunny/crossref_metadata_2025 huggingface dataset:
Peace-Making, Adat and Tama Bulan Wang
Authors: Mashman Valerie
Published: July 2020

Resident Charles Hose was credited with “the true civilization of the Baram people.” However, a careful examination of the role of Penghulu Tama Bulan Wang demonstrates that pacification of the Baram was achieved less by the mediation of Charles Hose and more by the role of local chiefs such as Penghulu Tama Bulan Wang. His source of power was the existing customary institution of chieftainship and the adat or system of customary law, which provided safeguards for preventing conflict, for making peace and creating alliances. The role of this local cultural component in establishment of the state of Sarawak has been underplayed in colonial accounts of peace-making and the contemporary written history of the state.
Revisiting early Political History of Modern Sarawak through the making of Stephen Kalong Ningkan as Sarawak’s first Chief Minister
Authors: Kadam-Kiai Stanley Bye , Dugun Dick Lembang
Published: July 2020

This paper narrates a political story of modern Sarawak from 1961 to 1974. The modern political history of Sarawak began with the conceptualisation and the formulation of the Federation Malaysia. The significant events that shaped and influenced the political history of modern Sarawak include: the British-Malayan Government meetings in November 1961 and July 1962; the setting up of the Cobbold Commission of Enquiry; the formulation of the Malaysia Solidarity and Consultative Committee (MSCC); the formation of the Inter-Governmental Committee (IGC); the signing the Malaysia Agreement of 1963; the controversies surrounding the making of the first Chief Minister and of the making of the first local State Governor; the cabinet crises of 1965 and 1966; the proclamation of the state of emergency in Sarawak in 1966 by the Federal Parliament which led to the removal of its first Chief Minister; and the establishment of the Sarawak Alliance and the Native Alliance. This historical account of the early history of modern Sarawak is not complete without the description of the ideas and the political struggles of Stephen Kalong Ningkan, the State’s first Chief Minister, and the issues affecting his political leadership
RETRACTED: ZFP36 Binds With PRC1 to Inhibit Tumor Growth and Increase 5-Fu Chemosensitivity of Hepatocellular Carcinoma
Authors: Chen Weiqian , Chen Minjiang , Zhao Zhongwei , Weng Qiaoyou , Song Jingjing , Fang Shiji , Wu Xulu , Wang Hailin , Zhang Dengke , Yang Weibin , Wang Zufei , Xu Min , Ji Jiansong
Published: July 2020

Hepatocellular carcinoma (HCC) is the fifth common cause of tumor-related death worldwide. ZFP36, a RNA-binding protein, decreases in many cancers and its role in HCC remains unclear. This study aimed to investigate the underlying mechanisms by which ZFP36 inhibited HCC progression and increased fluorouracil (5-Fu) sensitivity. We found that ZFP36 was downregulated and PRC1 was upregulated in HCC tissues compared with adjacent non-tumor tissues. In vitro investigation presented that ZFP36 acted as a tumor suppressor, while overexpression of PRC1 increased cell proliferation, colony formation and invasion. Further investigations demonstrated that overexpression of ZFP36 inhibited tumor growth and promoted 5-Fu sensitivity in xenograft tumor mice model, which could be reversed when PRC1 overexpressed simultaneously. Luciferase reporter assays and Ribonucleoprotein immunoprecipitation analysis indicated that ZFP36 could bind to adenylate uridylate-rich elements located in PRC1 mRNA 3′UTR to downregulate PRC1 expression. Taken together, our findings identified that ZFP36 regulated PRC1 to exert anti-tumor effect, which suggested a potential therapeutic strategy for treating HCC by exploiting ZFP36/PRC1 axis.
Trade-Offs between Sustainability Indicators in Response to the Production Choices of Different Farm Household Types in Drylands
Authors: El Ansari Loubna , Chenoune Roza , A. Yigezu Yigezu , Gary Christian , Belhouchette Hatem
Published: July 2020

A lot of national and international effort has been made to promote sustainable agricultural production systems in drylands. However, success has been seriously limited due to lack of thorough characterization of the impact of the diversity of farm household types on productivity, resource-use efficiency and economic and nutritional status. This study applied hierarchical ascendant classification to a random sample of 286 cereal-producing farm households in Morocco and identified distinct household typologies. It also carried out an analysis of trade-offs between economic, nutritional and environmental factors induced by the production decisions of the different farm household typologies. Our analysis identified three dominant farm household typologies in the production system, namely: (i) intensive predominantly-vegetable farming households with high input intensities, (ii) semi-intensive cereal mono-crop farming households with moderate input intensities and (iii) extensive mixed cereal-legume farming households with low input intensities. Extensive mixed cereal-legume farming households exhibited the highest resource-use efficiency and high biodiversity. These benefits, however, came at the expense of a much lower farm income and limited food supplies relative to the other two systems. These results show that, as is the case for many dryland regions, all three farm types showed precarious conditions for one or more of the sustainability-related indicators.
In-Vitro Plant Growth Promotion of Rhizobium Strains Isolated from Lentil Root Nodules under Abiotic Stresses
Authors: Sijilmassi Badreddine , Filali-Maltouf Abdelkarim , Fahde Sara , Ennahli Youness , Boughribil Said , Kumar Shiv , Amri Ahmed
Published: July 2020

Plant growth-promoting rhizobia are known to improve crop performance by multiple mechanisms. However, the interaction between host plants and Rhizobium strains is highly influenced by growing conditions, e.g., heat, cold, drought, soil salinity, nutrient scarcity, etc. The present study was undertaken to assess the use of Rhizobium as plant growth promoters under abiotic stress conditions. Fifteen Rhizobium strains isolated from lentil root nodules were tested for phosphate solubilization activity (PSA) and phytohormones production under salt and drought conditions. The results showed that 15 Rhizobium strains were significant phosphate solubilizers, and indole acedic acid (IAA) and gibberellic acid (GA3) producers based on least significant difference (LSD) analysis (p ≤ 0.05). The highest rate of PSA was attributed to three strains namely, 1145N5, 1159N11, and 1159N32 with a range of 144.6 to 205.6 P2O5 (µg/mL). The highest IAA production was recorded in the strain 686N5 with 57.68 ± 4.25 µg/mL as compared to 50.8667 ± 1.41 µg/mL and 37.32 ± 12.59 µg/mL for Rhizobium tropici CIAT 899 and Azospirillum brasilense DSM-1690, respectively. Strain 318N2111 produced 329.24 ± 7.84 µg/mL of GA3 as against 259.84 ± 25.55 µg/mL for A. brasilense DSM-1690. R. tropici CIAT 899 showed tolerance to salt (5% NaCl) and drought (ψ = −2.6 MPa) stress, whereas strain 686N5 showed an extremely high level of salt-tolerance (5% NaCl) and moderate level of drought tolerance (ψ = −0.75 MPa). These results indicate different pathways for drought and salt tolerance mechanisms. The assessment of plant growth promoting (PGP) activities of Rhizobium showed differences between bacterial viability and bacterial PGP activity in terms of abiotic stress tolerance where bacterial PGP activity is interrupted before reaching the bacterial tolerance threshold. These results integrate a new concept of PGPR screening based on PGP activity under abiotic stress.
Wild Micromammals as Bioindicators of Antibiotic Resistance in Ecopathology in Northern Italy
Authors: Zanardi Giovanna , Iemmi Tiziano , Spadini Costanza , Taddei Simone , Cavirani Sandro , Cabassi Clotilde Silvia
Published: July 2020

Antimicrobial resistance (AMR) is an increasing threat to human health and an important issue also in the natural environment. For this study, an ecopathological approach was applied to the monitoring of the antimicrobial resistance in the province of Parma, Northern Italy. Fourteen monitoring sites and seventy-four faecal samples from four species of wild micromammals (Apodemus sylvaticus, Microtus savii, Mus domesticus and Suncus etruscus) were collected. Samples were subjected to bacteriological examination and antimicrobial susceptibility testing. Antibiotics belonging to 13 different antibiotic classes were tested. Collected data showed a prevalence of multi-drug resistant (MDR) strains of 55.13% and significant differences in the prevalence of MDR strains among the different micromammal species, while sex, age and anthropization level did not significantly affected MDR strains prevalence. Moreover, a high prevalence of bacterial strains resistant to colistin (95%), gentamicin (87%) and amikacin (83%) was observed. To our knowledge, this is the first report on antibiotic resistance in wild micromammals in the province of Parma.
Differential Transcription of Selected Cytokine and Neuroactive Ligand-receptor Genes in Peripheral Leukocytes from Calves in Response to Cautery Disbudding
Authors: Kongara Kavitha , Dukkipati Venkata Sayoji Rao , Tai Hui Min , Heiser Axel , Murray Alan , Webster James , Johnson Craig Brian
Published: July 2020

Calf disbudding is a painful husbandry practice on dairy and beef cattle farms. An objective measurement of pain is useful to reliably evaluate the pain intensity and anti-nociceptive (analgesic) efficacy of therapeutic agents. The aim of this study was to investigate the changes in peripheral leucocyte inflammatory cytokine gene expression in calves after disbudding, and to assess whether the changes in cytokine gene expression could be an indicator of the efficacy of analgesic drugs. In a randomised controlled study, 16 calves (aged 31 to 41 days and weighing 58 to 73 kg), undergoing routine disbudding, were randomly allocated into two groups (n = 8 in each group). Calves in the control group received no analgesic, while those in the treatment group received 0.5 mg kg−1 meloxicam subcutaneously prior to disbudding. Disbudding was performed using an electric debudder. Blood (10 mL) was sampled from the jugular vein just before and 4 and 24 h post-disbudding, RNA was extracted from leukocytes, and the transcription of 12 genes of interest was assessed using nCounter gene expression assay. The results showed significantly higher transcription (compared to baseline values) of the studied genes (except CRH, IFNγ, and IL10) in the control group calves at either 4 or 24 h post-disbudding. The administration of meloxicam one hour before disbudding significantly attenuated the upregulation of IL6, PGHS2, TAC1, NOS1, and CRH gene transcription post-disbudding, while it did not suppress the elevated transcription of acute and pro-inflammatory cytokines such as IL1β, IFNγ, IL8, and TNFα genes. In conclusion, nCounter gene expression assay seems to be a promising tool to study the expression of cytokine genes and thus could be used for the pre-clinical evaluation of novel analgesics.
Mapping Shade Availability and Use in Zoo Environments: A Tool for Evaluating Thermal Comfort
Authors: Wark Jason D. , Wierzal Natasha K. , Cronin Katherine A.
Published: July 2020

For many species in zoos, particularly megafauna vulnerable to heat stress, shade is a key environmental resource. However, shade availability has received comparatively less attention than other aspects of the zoo environment. In this study, we share a simple low-cost approach that we applied to document shade availability across 33 zoo enclosures. We then combined these assessments with behavioral observations of enclosure use and shade-seeking behavior during summer months in a case study focused on Sichuan takin (Budorcas taxicolor tibetana) (n = 3), a large cold-adapted bovid. Behavioral observations were conducted before and after installation of a shade sail for the takin. Results indicated that shade availability varied widely across zoo enclosures, with the percent of shaded space ranging from 85 % to 22 % across enclosures during summer months. Shade was a dynamic resource and increased throughout the year and fluctuated across the day, with the least shade available midday. Takin showed general preferences for shaded areas near the walls of their enclosure but were observed using newly available shade from the shade sail after its installation. These accessible methods can be easily applied to assess shade within existing enclosures, evaluate enclosure modifications, and provide guidance for the design of new enclosures.
Diet Composition Affects Liver and Mammary Tissue Transcriptome in Primiparous Holstein Dairy Cows
Authors: Gao Shengtao , Zhou Zheng , Wang Jiaqi , Loor Juan , Bionaz Massimo , Ma Lu , Bu Dengpan
Published: July 2020

The objective of the present study was to evaluate the overall adaptations of liver and mammary tissue to a corn stover (CS) compared to a mixed forage (MF) diet in mid-lactation primiparous dairy cows. Twenty-four primiparous lactating Holstein cows were randomly allocated to 2 groups receiving either an alfalfa forage diet (MF, F:C = 60:40) with Chinese wildrye, alfalfa hay and corn silage as forage source or a corn stover forage diet (CS, F:C = 40:60). A subgroup of cows (n = 5/diet) was used for analysis of liver and mammary transcriptome using a 4 × 44K Bovine Agilent microarray chip. The results of functional annotation analysis showed that in liver CS vs. MF inhibited pathways related to lipid metabolism while induced the activity of the potassium channel. In mammary tissue, fatty acid metabolism was activated in CS vs. MF. In conclusion, the analysis of genes affected by CS vs. MF indicated mammary gland responding to lower level of linoleate from the diet (lower in CS vs. MF) by activating the associated biosynthesis metabolic pathway while the liver adaptively activated potassium transport to compensate for a lower K ingestion.
Sleeping without Prescription: Management of Sleep Disorders in Children with Autism with Non-Pharmacological Interventions and Over-the-Counter Treatments
Authors: Esposito Dario , Belli Arianna , Ferri Raffaele , Bruni Oliviero
Published: July 2020

Autism Spectrum Disorders (ASD) are lifelong neurodevelopmental conditions characterized by abnormal social interaction, communication, and behavior. Sleep disturbances represent a common comorbidity in children and adolescents with ASD, with prevalence ranging from 50 to 80%. It has been proved that sleep disruption worsens the symptoms of autism and results in challenging behaviors. Improving sleep should therefore be a primary therapeutic goal. Treatment options range from lifestyle modifications to pharmacological therapy. Several reviews have been written on pharmacological treatments, but very few on the beneficial effects of non-pharmacological interventions, over-the-counter drugs, and nutritional supplements. This study consists of a narrative review of the literature, presenting the available evidence on the following treatments: sleep education, behavioral interventions, complementary and alternative medicine (special mattresses and blankets, massage, aromatherapy, yoga, physical activity), and commonly used over-the-counter medications and supplements (antihistamines, melatonin, tryptophan, carnosine, iron, vitamins, and herbal remedies). For some treatments—such as melatonin and behavioral interventions—effectiveness in ASD is well established in the literature, while other interventions appear of benefit in clinical practice, even if specific studies in children and adolescents with ASD are lacking. Conversely, other treatments only seem to show anecdotal evidence supporting their use.
The Combined Effect of Exercise and Behavioral Therapy for Depression and Anxiety: Systematic Review and Meta-Analysis
Authors: Bourbeau Kelsey , Moriarty Terence , Ayanniyi Akeisha , Zuhl Micah
Published: July 2020

Behavioral therapy (BT) and exercise are efficacious treatments for depression and anxiety when employed separately. The combination of BT and exercise (BT+Ex) may augment improvements but the combined effect of these therapies is not fully elucidated. The purpose of this meta-analysis was to determine if BT+Ex yielded a significant reduction in depression and anxiety symptoms compared to BT alone (BT). Randomized controlled studies published prior to September 2019 were searched among several databases (PUBMED, MEDLINE, PsychArticle, and Cochrane Central Register of Clinical Trials). Studies that measured depression and anxiety symptoms following BT+Ex vs. BT were extracted and analyzed. The effect of these therapies on depression and anxiety were analyzed. Subgroup analyses were performed to evaluate the effect of exercise intensity (moderate and high), exercise type (aerobic and combined exercise), and baseline levels of depression. The moderating effects of gender, age, and treatment duration were performed. Data were extracted from 18 studies (1686 participants, mean age = 47 years, 65% female). There was a significant effect of BT+Ex on symptoms of depression. The effect of BT+Ex was significant for moderate intensity exercise and elevated baseline levels of depression. Age moderated the effect for depression. There was a significant effect of BT+Ex on depressive symptoms in humans. Exercise intensity and elevated depressive symptoms may play a role in the effect of exercise.
Influence of Foundation Quality on the Stress in the Elements of Steel Façade Scaffolding
Authors: Błazik-Borowa Ewa , Jamińska-Gadomska Paulina , Pieńko Michał
Published: July 2020

The purpose of this paper is to show the influence of incorrect scaffolding foundations on the stress in their elements. Static stress analysis was performed for exemplary steel façade scaffolding. The scaffolding was formed using the Plettac 70 system and was composed of 16 modules and 13 working levels. The total dimensions of the scaffolding were 45.0 × 26.36 × 0.74 m. The scaffolding was set up partly on concrete and partly on a created ground classified as coarse sand with discontinuous graining. The boundary conditions modelling the foundation considered the heterogeneity of the ground both along the scaffolding and in the direction perpendicular to the façade. The effect of uneven subsidence on the scaffolding frames was checked, adopting a constant stiffness of 3500 kN/m in half of the supports, while in the rest of them the stiffness varied from 35 to 3500 kN/m. Due to additional bending moments, normal stresses in stands and transoms of the frames increased. Incorrect scaffolding foundation has the greatest negative effect on normal forces in anchors and bracings. Because these elements are responsible for the stability of the scaffolding, their damage may result in scaffolding failure and would certainly lead to a reduction of the values of free vibration frequencies, thus resulting in the discomfort of the workers on the scaffolding and a lack of safety.
Muscle Characteristics Obtained Using Computed Tomography as Prognosticators in Patients with Castration-Resistant Prostate Cancer
Authors: Lee Jongsoo , Park Jee Soo , Heo Ji Eun , Ahn Hyun Kyu , Jang Won Sik , Ham Won Sik , Rha Koon Ho , Choi Young Deuk
Published: July 2020

Limited studies have investigated the correlation between body composition and prostate cancer outcomes. We analyzed the effect of muscle mass and quality on castration-resistant prostate cancer (CRPC) outcomes. Skeletal muscle index (SMI) and skeletal muscle attenuation (SMA) were measured for 411 patients at the L3 vertebral level using computed tomography at CRPC diagnosis and were dived to low and high groups at the value of median. Analysis of the skeletal phenotypes and age (<70 and >70 years) was performed to evaluate the effect of SMI and SMA. The median survival rates for patients with low and high SMI were 19 and 24 months (p = 0.015), and those with low and high SMAs were 15 and 26 months (p < 0.001), respectively. In the subgroup analysis by age, SMA was a significant prognosticator in both groups, while SMI was a significant prognosticator only in patients aged >70 years. Patients with low SMA + low SMI had the worst prognosis. Muscle characteristics seems to be a prognosticator in survival of CRPC patients and may be considered in treatment planning.
Targeting SRC Family Kinases in Mesothelioma: Time to Upgrade
Authors: Indovina Paola , Forte Iris Maria , Pentimalli Francesca , Giordano Antonio
Published: July 2020

Malignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC and other SRC family kinase (SFK) members are frequently hyperactivated in many cancer types, including MM. Several works have indeed suggested that SFKs underlie MM cell proliferation, survival, motility, and invasion, overall affecting multiple oncogenic pathways. Consistently, SFK inhibitors effectively counteracted MM cancerous features at the preclinical level. Dasatinib, a multi-kinase inhibitor targeting SFKs, was also assessed in clinical trials either as second-line treatment for patients with unresectable MM or, more recently, as a neoadjuvant agent in patients with resectable MM. Here, we provide an overview of the molecular mechanisms implicating SFKs in MM progression and discuss possible strategies for a more successful clinical application of SFK inhibitors. Our aim is to stimulate discussion and further consideration of these agents in better designed preclinical and clinical studies to make the most of another class of powerful antitumoral drugs, which too often are lost in translation when applied to MM.
Cost-Effectiveness of Early Detection and Prevention Strategies for Endometrial Cancer—A Systematic Review
Authors: Sroczynski Gaby , Gogollari Artemisa , Conrads-Frank Annette , Hallsson Lára R. , Pashayan Nora , Widschwendter Martin , Siebert Uwe
Published: July 2020

Endometrial cancer is the most common female genital tract cancer in developed countries. We systematically reviewed the current health-economic evidence on early detection and prevention strategies for endometrial cancer based on a search in relevant databases (Medline/Embase/Cochrane Library/CRD/EconLit). Study characteristics and results including life-years gained (LYG), quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratios (ICERs) were summarized in standardized evidence tables. Economic results were transformed into 2019 euros using standard conversion methods (GDP-PPP, CPI). Seven studies were included, evaluating (1) screening for endometrial cancer in women with different risk profiles, (2) risk-reducing interventions for women at increased or high risk for endometrial cancer, and (3) genetic testing for germline mutations followed by risk-reducing interventions for diagnosed mutation carriers. Compared to no screening, screening with transvaginal sonography (TVS), biomarker CA-125, and endometrial biopsy yielded an ICER of 43,600 EUR/LYG (95,800 EUR/QALY) in women with Lynch syndrome at high endometrial cancer risk. For women considering prophylactic surgery, surgery was more effective and less costly than screening. In obese women, prevention using Levonorgestrel as of age 30 for five years had an ICER of 72,000 EUR/LYG; the ICER for using oral contraceptives for five years as of age 50 was 450,000 EUR/LYG. Genetic testing for mutations in women at increased risk for carrying a mutation followed by risk-reducing surgery yielded ICERs below 40,000 EUR/QALY. Based on study results, preventive surgery in mutation carriers and genetic testing in women at increased risk for mutations are cost-effective. Except for high-risk women, screening using TVS and endometrial biopsy is not cost-effective and may lead to overtreatment. Model-based analyses indicate that future biomarker screening in women at increased risk for cancer may be cost-effective, dependent on high test accuracy and moderate test costs. Future research should reveal risk-adapted early detection and prevention strategies for endometrial cancer.
The Biological Function of Sigma-2 Receptor/TMEM97 and Its Utility in PET Imaging Studies in Cancer
Authors: Zeng Chenbo , Riad Aladdin , Mach Robert H.
Published: July 2020

The sigma-2 receptor was originally defined pharmacologically and recently identified as TMEM97. TMEM97 has been validated as a biomarker of proliferative status and the radioligand of TMEM97, [18F]ISO-1, has been developed and validated as a PET imaging biomarker of proliferative status of tumors and as a predictor of the cancer therapy response. [18F]ISO-1 PET imaging should be useful to guide treatment for cancer patients. TMEM97 is a membrane-bound protein and localizes in multiple subcellular organelles including endoplasmic reticulum and lysosomes. TMEM97 plays distinct roles in cancer. It is reported that TMEM97 is upregulated in some tumors but downregulated in other tumors and it is required for cell proliferation in certain tumor cells. TMEM97 plays important roles in cholesterol homeostasis. TMEM97 expression is regulated by cholesterol-regulating signals such as sterol depletion and SREBP expression levels. TMEM97 regulates cholesterol trafficking processes such as low density lipoprotein (LDL) uptake by forming complexes with PGRMC1 and low density lipoprotein receptor (LDLR), as well as cholesterol transport out of lysosome by interacting with and regulating NPC1 protein. Understanding molecular functions of TMEM97 in proliferation and cholesterol metabolism will be important to develop strategies to diagnose and treat cancer and cholesterol disorders using a rich collection of TMEM97 radiotracers and ligands.
Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib
Authors: Znati Sami , Carter Rebecca , Vasquez Marcos , Westhorpe Adam , Shahbakhti Hassan , Prince Jessica , Vlckova Petra , De Vellis Chiara , Bascal Zainab , Loizidou Marilena , Sharma Ricky A.
Published: July 2020

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.
Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Gauert Anton , Olk Nadine , Pimentel-Gutiérrez Helia , Astrahantseff Kathy , Jensen Lasse , Cao Yihai , Eggert Angelika , Eckert Cornelia , Hagemann Anja
Published: July 2020

Only half of patients with relapsed B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) currently survive with standard treatment protocols. Predicting individual patient responses to defined drugs prior to application would help therapy stratification and could improve survival. With the purpose to aid personalized targeted treatment approaches, we developed a human–zebrafish xenograft (ALL-ZeFiX) assay to predict drug response in a patient in 5 days. Leukemia blast cells were pericardially engrafted into transiently immunosuppressed Danio rerio embryos, and engrafted embryos treated for the test case, venetoclax, before single-cell dissolution for quantitative whole blast cell analysis. Bone marrow blasts from patients with newly diagnosed or relapsed BCP-ALL were successfully expanded in 60% of transplants in immunosuppressed zebrafish embryos. The response of BCP-ALL cell lines to venetoclax in ALL-ZeFiX assays mirrored responses in 2D cultures. Venetoclax produced varied responses in patient-derived BCP-ALL grafts, including two results mirroring treatment responses in two refractory BCP-ALL patients treated with venetoclax. Here we demonstrate proof-of-concept for our 5-day ALL-ZeFiX assay with primary patient blasts and the test case, venetoclax, which after expanded testing for further targeted drugs could support personalized treatment decisions within the clinical time window for decision-making.
Correction: Ordoñez, et al.; DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters? Cancers 2019, 11, 1424
Authors: Ordoñez Raquel , Martínez-Calle Nicolás , Agirre Xabier , Prosper Felipe
Published: July 2020

The authors would like to make a correction to their published paper [...]
The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis
Authors: Bonollo Francesco , Thalmann George N. , Kruithof-de Julio Marianna , Karkampouna Sofia
Published: July 2020

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.
Towards Clinical Implementation of Adeno-Associated Virus (AAV) Vectors for Cancer Gene Therapy: Current Status and Future Perspectives
Authors: Hacker Ulrich T. , Bentler Martin , Kaniowska Dorota , Morgan Michael , Büning Hildegard
Published: July 2020

Adeno-associated virus (AAV) vectors have gained tremendous attention as in vivo delivery systems in gene therapy for inherited monogenetic diseases. First market approvals, excellent safety data, availability of large-scale production protocols, and the possibility to tailor the vector towards optimized and cell-type specific gene transfer offers to move from (ultra) rare to common diseases. Cancer, a major health burden for which novel therapeutic options are urgently needed, represents such a target. We here provide an up-to-date overview of the strategies which are currently developed for the use of AAV vectors in cancer gene therapy and discuss the perspectives for the future translation of these pre-clinical approaches into the clinic.
Clinical, Hematologic, Biologic and Molecular Characteristics of Patients with Myeloproliferative Neoplasms and a Chronic Myelomonocytic Leukemia-Like Phenotype
Authors: Heibl Sonja , Gisslinger Bettina , Jäger Eva , Barna Agnes , Gurbisz Michael , Stegemann Maike , Bettelheim Peter , Machherndl-Spandl Sigrid , Pfeilstöcker Michael , Nösslinger Thomas , Uyanik Gökhan , Hoermann Gregor , Stauder Reinhard , Thaler Josef , Kusec Rajko , Valent Peter , Gisslinger Heinz , Geissler Klaus
Published: July 2020

Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from JAK2-mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the JAK2 V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (JAK2-mutated, 28 months; JAK2-nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management.
Pre-Treatment T2-WI Based Radiomics Features for Prediction of Locally Advanced Rectal Cancer Non-Response to Neoadjuvant Chemoradiotherapy: A Preliminary Study
Authors: Petresc Bianca , Lebovici Andrei , Caraiani Cosmin , Feier Diana Sorina , Graur Florin , Buruian Mircea Marian
Published: July 2020

Locally advanced rectal cancer (LARC) response to neoadjuvant chemoradiotherapy (nCRT) is very heterogeneous and up to 30% of patients are considered non-responders, presenting no tumor regression after nCRT. This study aimed to determine the ability of pre-treatment T2-weighted based radiomics features to predict LARC non-responders. A total of 67 LARC patients who underwent a pre-treatment MRI followed by nCRT and total mesorectal excision were assigned into training (n = 44) and validation (n = 23) groups. In both datasets, the patients were categorized according to the Ryan tumor regression grade (TRG) system into non-responders (TRG = 3) and responders (TRG 1 and 2). We extracted 960 radiomic features/patient from pre-treatment T2-weighted images. After a three-step feature selection process, including LASSO regression analysis, we built a radiomics score with seven radiomics features. This score was significantly higher among non-responders in both training and validation sets (p < 0.001 and p = 0.03) and it showed good predictive performance for LARC non-response, achieving an area under the curve (AUC) = 0.94 (95% CI: 0.82–0.99) in the training set and AUC = 0.80 (95% CI: 0.58–0.94) in the validation group. The multivariate analysis identified the radiomics score as an independent predictor for the tumor non-response (OR = 6.52, 95% CI: 1.87–22.72). Our results indicate that MRI radiomics features could be considered as potential imaging biomarkers for early prediction of LARC non-response to neoadjuvant treatment.
Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma
Authors: Rodríguez-Nogales Carlos , Moreno Haritz , Zandueta Carolina , Desmaële Didier , Lecanda Fernando , Couvreur Patrick , Blanco-Prieto María J.
Published: July 2020

Due to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl–gemcitabine (SQ–Gem) to form nanoassemblies (NAs) of 50 nm. SQ–Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ–Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ–Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy.
Radiotherapy-Induced High Neutrophil-to-Lymphocyte Ratio is a Negative Prognostic Factor in Patients with Breast Cancer
Authors: Yoon Chang Ik , Kim Dooreh , Ahn Sung Gwe , Bae Soong June , Cha Chihwan , Park Soeun , Park Seho , Kim Seung Il , Lee Hye Sun , Park Ju Young , Jeong Joon
Published: July 2020

Radiotherapy (RT) is the standard of care following breast-conserving operation in breast cancer patients. The neutrophil-to-lymphocyte ratio (NLR) reflects the systemic change caused as a result of the radiotherapy. We aimed to evaluate the association between RT and the change in NLR following the receipt of RT, and to investigate the prognostic impact. We retrospectively reviewed NLR values of breast cancer patients taken before the administration of the first and the last session of RT. The cut-off point for the NLR was determined using the Youden index and receiver operating characteristic (ROC) curve within the training set. Recurrence-free survival (RFS), distant metastasis free survival, and overall survival were the main outcomes. Patients with an NLR higher than 3.49 after RT were classified to an RT-induced high NLR group and showed a significantly higher recurrence rate compared to those with low NLR (p < 0.001). In a multivariate Cox proportional hazards model, RT-induced high NLR remained a significant prognostic factor (HR 2.194, 95% CI 1.230–3.912, p = 0.008 for tumor recurrence. We demonstrated that an increase in NLR over the course of RT has a negative impact on survival, putting these patients with RT-susceptible host immunity at a higher risk of tumor recurrence.
Rapid and Sensitive Quantification of Osimertinib in Human Plasma Using a Fully Validated MALDI–IM–MS/MS Assay
Authors: Fresnais Margaux , Roth André , Foerster Kathrin I. , Jäger Dirk , Pfister Stefan M. , Haefeli Walter E. , Burhenne Jürgen , Longuespée Rémi
Published: July 2020

The third-generation tyrosine kinase inhibitor (TKI), osimertinib, has revolutionized the treatment of patients with non-small cell lung carcinoma with epidermal growth factor receptor (EGFR)-activating mutation, and resistant to first- and second-generation TKIs. Osimertinib is now also proposed as a first-line therapy, thus extending the scope of applications in lung oncology. Personalized medicine approaches are still necessary to monitor if patients are exposed to adequate concentrations of osimertinib during their treatment. It would also help to understand the appearance of new resistances in patients after several months of dosing with osimertinib. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) is currently the gold standard for the quantification of drugs in plasma enabling pharmacokinetic analyses and patient monitoring. In the present study, we propose an alternative to LC–MS/MS methods for the rapid and sensitive quantification of osimertinib in plasma using matrix-assisted laser desorption/ionization (MALDI) –MS. The presented assay requires only 3 min per sample for their preparation, analysis, and data extraction, and less than 3 h for quantification. A lower limit of quantification (LLOQ) of 5 ng/mL in plasma was retrieved. The method was fully validated, following the guidelines of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for bioanalytical method validation. The present developments prove the importance to consider alternative MS assays for time-efficient quantification of small molecule inhibitors in plasma in the context of personalized medicine for targeted therapies.
Efficacy and Safety of the Combination of Pravastatin and Sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial)
Authors: Riaño Ioana , Martín Leticia , Varela Maria , Serrano Trinidad , Núñez Oscar , Mínguez Beatriz , Rodrigues Pedro M. , Perugorria Maria J. , Banales Jesus M. , Arenas Juan I.
Published: July 2020

Pravastatin has demonstrated anti-tumor activity in preclinical and clinical studies. This multicentric randomized double-blind placebo-controlled phase II study (NCT01418729) investigated the efficacy and safety of sorafenib + pravastatin combination on the overall survival (OS) and time to progression (TTP) of patients with advanced hepatocellular carcinoma (aHCC). A total of 31 patients were randomized. Median OS did not differ between both groups (12.4 months for the sorafenib + pravastatin group vs. 11.6 months for the control group). Of note, however, the radiological TTP was higher in patients treated with sorafenib + pravastatin than in the control group (9.9 months vs. 3.2 months; p = 0.008). Considering all the study population, the presence of portal vein thrombosis (PVT) was associated with worse OS, being lower in patients with PVT compared to patients without PVT (6.3 months vs. 14.8 months; p = 0.026). Data also showed a decrease in OS in patients with vascular invasion (VI) compared to patients who did not present it (6.3 months vs. 14.8 months; p = 0.041). The group of patients without dermatological events (DE) showed lower OS (6.9 months vs. 14.5 months; p = 0.049). In conclusion, combination of sorafenib + pravastatin was safe and well-tolerated, prolonging the TTP of patients with aHCC but not improving the OS compared to sorafenib + placebo. The absence of PVT and VI and the development of DE are positive prognostic factors of sorafenib response.
ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer
Authors: Griguolo Gaia , Brasó-Maristany Fara , González-Farré Blanca , Pascual Tomás , Chic Núria , Saurí Tamara , Kates Ronald , Gluz Oleg , Martínez Débora , Paré Laia , Tsvetkova Vassilena , Pesantez David , Vidal Maria , Adamo Barbara , Muñoz Montserrat , Galván Patricia , Barberá Laura , Cuatrecasas Miriam , Christgen Mathias , Kreipe Hans , Monge-Escartín Inés , Villagrasa Patricia , Soy Dolors , Giarratano Tommaso , Dieci Maria Vittoria , Conte Pierfranco , Harbeck Nadia , Guarneri Valentina , Prat Aleix
Published: July 2020

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20–8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.
Inconsistent Intersample ALK FISH Results in Patients with Lung Cancer: Analysis of Potential Causes
Authors: Tang Zhenya , Chen Hui , Hong Lingzhi , Tang Guilin , Toruner Gokce A. , Wang Wei , Roy Chowdhuri Sinchita , Yin Wei , Jung Hai Suk , Gu Jun , Routbort Mark J. , Zhang Jianjun , Khoury Joseph D. , Medeiros L. Jeffrey
Published: July 2020

ALK FISH analyses of multiple specimens occasionally yield inconsistent intersample results in lung cancer patients, posing clinical challenges requiring intensive analysis of all potential causative pre- and post- analytic factors. In this study, 19 patients (8M/11F) with inconsistent intersample ALK FISH results were analyzed, representing 4.9% of patients assessed ≥ twice in our institution. Fifteen patients received ALK tyrosine kinase inhibitor(s) (TKIs). Nine patients died, and ten were alive for 8 to 74-month follow-ups (median, 40 months). Through strict and stringent laboratory and case-review policies, all postanalytic factors were excluded. Correlating clinical information, ALK results obtained by RNA sequencing (RNA-seq) and other concurrent tests, several pre-analytic factors were determined. A suboptimal specimen was likely the cause in three patients, supported by the failure of one or more concurrent tests or discrepant results between FISH and RNA-seq. ALK inhibition by TKIs might have been responsible for the change of ALK status from positive to negative in eight patients. Other potential explanations include the existence of multiple primary lung cancer lesions, tumor heterogeneity, and the clonal evolution of tumor cells, related or not to ALK TKI therapy. This study is helpful for both pathologists and clinicians encountering inconsistent and/or discrepant intersample results.