bluuebunny/crossref_metadata_2025 huggingface dataset:
Heatwaves in the Future Warmer Climate of South Africa
Authors: Mbokodo Innocent , Bopape Mary-Jane , Chikoore Hector , Engelbrecht Francois , Nethengwe Nthaduleni
Published: July 2020

Weather and climate extremes, such as heat waves (HWs), have become more frequent due to climate change, resulting in negative environmental and socioeconomic impacts in many regions of the world. The high vulnerability of South African society to the impacts of warm extreme temperatures makes the study of the effect of climate change on future HWs necessary across the country. We investigated the projected effect of climate change on future of South Africa with a focus on HWs using an ensemble of regional climate model downscalings obtained from the Conformal Cubic Atmospheric Model (CCAM) for the periods 2010–2039, 2040–2069, and 2070–2099, with 1983–2012 as the historical baseline. Simulations were performed under the Representative Concentration Pathway (RCP) 4.5 (moderate greenhouse gas (GHG) concentration) and 8.5 (high GHG concentration) greenhouse gas emission scenarios. We found that the 30-year period average maximum temperatures may rise by up to 6 °C across much of the interior of South Africa by 2070–2099 with respect to 1983–2012, under a high GHG concentration. Simulated HW thresholds for all ensemble members were similar and spatially consistent with observed HW thresholds. Under a high GHG concentration, short lasting HWs (average of 3–4 days) along the coastal areas are expected to increase in frequency in the future climate, however the coasts will continue to experience HWs of relatively shorter duration compared to the interior regions. HWs lasting for shorter duration are expected to be more frequent when compared to HWs of longer durations (over two weeks). The north-western part of South Africa is expected to have the most drastic increase in HWs occurrences across the country. Whilst the central interior is not projected to experience pronounced increases in HW frequency, HWs across this region are expected to last longer under future climate change. Consistent patterns of change are projected for HWs under moderate GHG concentrations, but the changes are smaller in amplitude. Increases in HW frequency and duration across South Africa may have significant impacts on human health, economic activities, and livelihoods in vulnerable communities.
Summer Monsoon Season Streamflow Variations in the Middle Yellow River since 1570 CE Inferred from Tree Rings of Pinus tabulaeformis
Authors: Chen Feng , Opała-Owczarek Magdalena , Owczarek Piotr , Chen Youping
Published: July 2020

This study investigates the potential reconstruction of summer monsoon season streamflow variations in the middle reaches of the Yellow River from tree rings in the Qinling Mountains. The regional chronology is significantly positively correlated with the July–October streamflow of the middle Yellow River from 1919 to 1949, and the derived reconstruction explains 36.4% of the actual streamflow variance during this period. High streamflows occurred during 1644–1757, 1795–1806, 1818–1833, 1882–1900, 1909–1920 and 1933–1963. Low streamflows occurred during 1570–1643, 1758–1794, 1807–1817, 1834–1868, 1921–1932 and 1964–2012. High and low streamflow intervals also correspond well to the East Asian summer monsoon (EASM) intensity. Some negative correlations of our streamflow reconstruction with Indo-Pacific sea surface temperature (SST) also suggest the linkage of regional streamflow changes to the Asian summer monsoon circulation. Although climate change has some important effects on the variation in streamflow, anthropogenic activities are the primary factors mediating the flow cessation of the Yellow River, based on streamflow reconstruction.
A Collaborative Training Program to Assess Mercury Pollution from Gold Shops in Guyana’s Artisanal and Small-Scale Gold Mining Sector
Authors: Brown Samantha T. , Bandoo Lloyd L. , Agard Shenelle S. , Thom Shemeiza T. , Gilhuys Tamara E. , Mudireddy Gautham K. , Eechampati Arnith V. , Hasan Kazi M. , Loving Danielle C. , Seney Caryn S. , Kiefer Adam M.
Published: July 2020

A three-phase, 11-day training program designed to monitor elemental mercury (Hg0) emissions originating from gold shops was conducted in Georgetown and Bartica, Guyana, during May of 2019. The first phase consisted of interactive lectures and discussions on mercury use in artisanal and small-scale gold mining throughout Guyana, the region, and the world. In addition, specific training in the theory and use of analytical instrumentation to quantify Hg0 pollution associated with the processing of amalgams and sponge gold occurred. Trainees participated in the mapping of smelting facilities in Georgetown where, outside of one gold shop, Hg0 concentrations exceeded 100,000 ng/m3. During the second phase of training, a subset of trainees traveled to Bartica, where they mapped the town center to identify point sources of Hg0 pollution, all of which corresponded to the location of shops where amalgams and sponge gold were heated and purchased. Once mapped, Hg0 concentrations were measured during the smelting of gold inside the Guyana Gold Board (GGB) facility and two privately-owned gold shops. Maximum Hg0 concentrations at the GGB facility did not exceed 98,700 ng/m3 during the measurement period, while maximum concentrations at the two privately owned shops were measured as 527,500 ng/m3 and 302,200 ng/m3. With guidance from the training team, trainees were responsible for the collection and interpretation of all data. The third phase of the training involved the collaborative production of a report summarizing the findings from the training. This work represents the first formal training opportunity for the assessment of Hg0 concentrations in and around gold shops in Guyana, and provides baseline data to assist the government of Guyana to generate air quality standards for Hg0 emissions.
Culture Time Needed to Scale up Infrapatellar Fat Pad Derived Stem Cells for Cartilage Regeneration: A Systematic Review
Authors: Francis Sam L. , Yao Angela , Choong Peter F. M.
Published: July 2020

Adipose tissue is a rich source of stem cells, which are reported to represent 2% of the stromal vascular fraction (SVF). The infrapatellar fat pad (IFP) is a unique source of tissue, from which human adipose-derived stem cells (hADSCs) have been shown to harbour high chondrogenic potential. This review aims to calculate, based on the literature, the culture time needed before an average knee articular cartilage defect can be treated using stem cells obtained from arthroscopically or openly harvested IFP. Firstly, a systematic literature review was performed to search for studies that included the number of stem cells isolated from the IFP. Subsequent analysis was conducted to identify the amount of IFP tissue harvestable, stem cell count and the overall yield based on the harvesting method. We then determined the minimum time required before treating an average-sized knee articular cartilage defect with IFP-derived hADSCs by using our newly devised equation. The amount of fat tissue, the SVF cell count and the stem cell yield are all lower in arthroscopically harvested IFP tissue compared to that collected using arthrotomy. As an extrapolation, we show that an average knee defect can be treated in 20 or 17 days using arthroscopically or openly harvested IFP-derived hADSCs, respectively. In summary, the systematic review conducted in this study reveals that there is a higher amount of fat tissue, SVF cell count and overall yield (cells/volume or cells/gram) associated with open (arthrotomy) compared to arthroscopic IFP harvest. In addition to these review findings, we demonstrate that our novel framework can give an indication about the culture time needed to scale up IFP-derived stem cells for the treatment of articular cartilage defects based on harvesting method.
Techno-Economic Assessment of Bio-Syngas Production for Methanol Synthesis: A Focus on the Water–Gas Shift and Carbon Capture Sections
Authors: Giuliano Aristide , Freda Cesare , Catizzone Enrico
Published: July 2020

The biomass-to-methanol process may play an important role in introducing renewables in the industry chain for chemical and fuel production. Gasification is a thermochemical process to produce syngas from biomass, but additional steps are requested to obtain a syngas composition suitable for methanol synthesis. The aim of this work is to perform a computer-aided process simulation to produce methanol starting from a syngas produced by oxygen–steam biomass gasification, whose details are reported in the literature. Syngas from biomass gasification was compressed to 80 bar, which may be considered an optimal pressure for methanol synthesis. The simulation was mainly focused on the water–gas shift/carbon capture sections requested to obtain a syngas with a (H2 – CO2)/(CO + CO2) molar ratio of about 2, which is optimal for methanol synthesis. Both capital and operating costs were calculated as a function of the CO conversion in the water–gas shift (WGS) step and CO2 absorption level in the carbon capture (CC) unit (by Selexol® process). The obtained results show the optimal CO conversion is 40% with CO2 capture from the syngas equal to 95%. The effect of the WGS conversion level on methanol production cost was also assessed. For the optimal case, a methanol production cost equal to 0.540 €/kg was calculated.
Neck Pain- and Unsteadiness-Inducing Activities and their Relationship to the Presence, Intensity, Frequency, and Disability of Headaches
Authors: Rodríguez-Almagro Daniel , Achalandabaso-Ochoa Alexander , Molina-Ortega Francisco , Obrero-Gaitán Esteban , Ibáñez-Vera Alfonso , Lomas-Vega Rafael
Published: July 2020

(1) Background: Headache is a significant public health problem. Despite the association between headache and neck pain, little is known about the relationships among specific activities that generate neck pain and headache. The aim of this study was to identify the specific activities that result in neck pain and unsteadiness, and determine how they are linked to headache in university students. (2) Methods: One hundred and six patients with physician-diagnosed headache and 92 healthy university students completed surveys assessing demographics; the presence, frequency, intensity, and disability of headaches; and activities generating neck pain and unsteadiness. (3) Results: The presence of headache was related to female gender (p = 0.001), neck pain when reading or watching television (p = 0.024), and unsteadiness when moving the head (p = 0.005). Headache-related disability was associated with intensity of neck pain (p < 0.001), neck pain when reading or watching television (p = 0.033), and stumbling (p < 0.001). Headache frequency was related to smoking (p = 0.004), the duration of neck pain-associated symptoms (p = 0.047), and neck pain when driving (p = 0.039). Intensity of headache was associated with female gender (p = 0.002), smoking (p = 0.013), and neck pain-related sleep alterations (p = 0.024). (4) Conclusions: Female gender, smoking, neck pain, and unsteadiness when moving the head are factors related to headache in university students.
Celiac Disease Diagnosed in an Older Adult Patient with a Complex Neuropsychiatric Involvement: A Case Report and Review of the Literature
Authors: Falato Emma , Capone Fioravante , Ranieri Federico , Florio Lucia , Corbetto Marzia , Taffon Chiara , Niolu Cinzia , Di Lorenzo Giorgio , Di Lazzaro Vincenzo
Published: July 2020

We present a case of celiac disease (CD) diagnosis in a 75-year-old woman with a long-term history of chronic delusional jealousy and a complex neurological involvement. The case describes a very unusual clinical picture, provides some clinical clues, and highlights the importance of being aware of CD extraintestinal manifestations in order to get a timely diagnosis.
Where Sounds Occur Matters: Context Effects Influence Processing of Salient Vocalisations
Authors: Azhari Atiqah , Rigo Paola , Bornstein Marc H. , Esposito Gianluca
Published: July 2020

The social context in which a salient human vocalisation is heard shapes the affective information it conveys. However, few studies have investigated how visual contextual cues lead to differential processing of such vocalisations. The prefrontal cortex (PFC) is implicated in processing of contextual information and evaluation of saliency of vocalisations. Using functional Near-Infrared Spectroscopy (fNIRS), we investigated PFC responses of young adults (N = 18) to emotive infant and adult vocalisations while they passively viewed the scenes of two categories of environmental contexts: a domestic environment (DE) and an outdoors environment (OE). Compared to a home setting (DE) which is associated with a fixed mental representation (e.g., expect seeing a living room in a typical house), the outdoor setting (OE) is more variable and less predictable, thus might demand greater processing effort. From our previous study in Azhari et al. (2018) that employed the same experimental paradigm, the OE context was found to elicit greater physiological arousal compared to the DE context. Similarly, we hypothesised that greater PFC activation will be observed when salient vocalisations are paired with the OE compared to the DE condition. Our finding supported this hypothesis: the left rostrolateral PFC, an area of the brain that facilitates relational integration, exhibited greater activation in the OE than DE condition which suggests that greater cognitive resources are required to process outdoor situational information together with salient vocalisations. The result from this study bears relevance in deepening our understanding of how contextual information differentially modulates the processing of salient vocalisations.
The Endless Grief in Waiting: A Qualitative Study of the Relationship between Ambiguous Loss and Anticipatory Mourning amongst the Relatives of Missing Persons in Italy
Authors: Testoni Ines , Franco Chiara , Palazzo Lorenza , Iacona Erika , Zamperini Adriano , Wieser Michael Alexander
Published: July 2020

This article presents the results of a qualitative study aiming to consider the relationship between ambiguous loss and anticipatory mourning amongst relatives of missing people in Italy. Eight people participated in the research, narrating their experiences of losing a beloved person (one found alive, three found dead, and four still missing). Findings suggest the presence of a particular form of ambiguous loss, characterised by traits typical of both prolonged and traumatic grief. These findings describe how families are faced with an emotional vortex related to a never-ending wait, and how the mourning is solved only when the missing person is found dead or alive. The discovery of a corpse is traumatic but it allows mourners to fully recognise their grief. When a person is found, it changes the relationship in a positive way. When neither of these events happen, mourners have two different kinds of reactions: they experience either a prolonged grief or a drive to solve their suffering by helping other people (post-traumatic growth). In this study, it is highlighted how a community can be useful or detrimental in this process, and the importance of psychological and social support to prevent significant clinical outcomes is stressed.
Preclinical and Clinical Immunotherapeutic Strategies in Epithelial Ovarian Cancer
Authors: Martinez Alejandra , Delord Jean-Pierre , Ayyoub Maha , Devaud Christel
Published: July 2020

In the past 20 years, the immune system has increasingly been recognized as a major player in tumor cell control, leading to considerable advances in cancer treatment. While promising with regards to melanoma, renal cancer and non-small cell lung cancer, immunotherapy provides, for the time being, limited success in other cancers, including ovarian cancer, potentially due to insufficient immunogenicity or to a particularly immunosuppressive microenvironment. In this review, we provide a global description of the immune context of ovarian cancer, in particular epithelial ovarian cancer (EOC). We describe the adaptive and innate components involved in the EOC immune response, including infiltrating tumor-specific T lymphocytes, B lymphocytes, and natural killer and myeloid cells. In addition, we highlight the rationale behind the use of EOC preclinical mouse models to assess resistance to immunotherapy, and we summarize the main preclinical studies that yielded anti-EOC immunotherapeutic strategies. Finally, we focus on major published or ongoing immunotherapy clinical trials concerning EOC.
Cancer Immune Therapy for Philadelphia Chromosome-Negative Chronic Myeloproliferative Neoplasms
Authors: Holmström Morten Orebo , Hasselbalch Hans Carl , Andersen Mads Hald
Published: July 2020

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A deeper understanding of the anti-cancer immune response and of the different immune regulatory mechanisms in patients with MPN has paved the way for an increased perception of the potential of cancer immunotherapy in MPN. Therapeutic vaccination targeting the driver mutations in MPN is one recently described potential new treatment modality. Furthermore, T cells can directly react against regulatory immune cells because they recognize proteins like arginase and programmed death ligand 1 (PD-L1). Therapeutic vaccination with arginase or PD-L1 therefore offers a novel way to directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens like mutant CALR and mutant JAK2. Other therapeutic options that could be used in concert with therapeutic cancer vaccines are immune checkpoint–blocking antibodies and interferon-α. For more advanced MPN, adoptive cellular therapy is a potential option that needs more preclinical investigation. In this review, we summarize current knowledge about the immune system in MPN and discuss the many opportunities for anti-cancer immunotherapy in patients with MPN.
The CCL5/CCR5 Axis in Cancer Progression
Authors: Aldinucci Donatella , Borghese Cinzia , Casagrande Naike
Published: July 2020

Tumor cells can “hijack” chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in hematological malignancies and solid tumors. Numerous preclinical in vitro and in vivo studies have shown a key role of the CCL5/CCR5 axis in cancer, and thus provided the rationale for clinical trials using the repurposed drug maraviroc, a CCR5 antagonist used to treat HIV/AIDS. This review summarizes current knowledge on the role of the CCL5/CCR5 axis in cancer. First, it describes the involvement of the CCL5/CCR5 axis in cancer progression, including autocrine and paracrine tumor growth, ECM (extracellular matrix) remodeling and migration, cancer stem cell expansion, DNA damage repair, metabolic reprogramming, and angiogenesis. Then, it focuses on individual hematological and solid tumors in which CCL5 and CCR5 have been studied preclinically. Finally, it discusses clinical trials of strategies to counteract the CCL5/CCR5 axis in different cancers using maraviroc or therapeutic monoclonal antibodies.
Endocrine Risk Factors of Endometrial Cancer: Polycystic Ovary Syndrome, Oral Contraceptives, Infertility, Tamoxifen
Authors: Ignatov Atanas , Ortmann Olaf
Published: July 2020

Endometrial cancer is the most common gynecologic cancer and is predominantly endocrine-related. The role of unopposed estrogen in the development of endometrial cancer has been investigated in numerous studies. Different reproductive factors such as younger age at menarche, late age at menopause, infertility, nulliparity, age of birth of the first child, and long-term use of unopposed estrogens during hormone replacement therapy have been associated with an increased risk of endometrial cancer. In contrast, there is a growing body of evidence for a protective role of oral contraceptives. Most of the published data on the association between infertility and polycystic ovary syndrome are inconclusive, whereas the effect of tamoxifen on the risk of endometrial cancer has been well established. With this review, we aim to summarize the evidence on the association between infertility, polycystic ovary syndrome, oral contraceptives, and tamoxifen and the development of endometrial cancer.
Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status
Authors: Varanda Ana Beatriz , Martins-Logrado Ana , Godinho Ferreira Miguel , Fior Rita
Published: July 2020

Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may show resistance to this drug and BRCA1/2 wild-type tumors can show a striking sensitivity, making BRCA status a poor biomarker for treatment choice. Aiming to investigate if the zebrafish model can discriminate sensitivities to olaparib, we developed zebrafish xenografts with different BRCA status and measured tumor response to treatment, as well as its impact on angiogenesis and metastasis. When challenged with olaparib, xenografts revealed sensitivity phenotypes independent of BRCA. Moreover, its combination with ionizing radiation increased the cytotoxic effects, showing potential as a combinatorial regimen. In conclusion, we show that the zebrafish xenograft model may be used as a sensitivity profiling platform for olaparib in monotherapy or in combinatorial regimens. Hence, this model presents as a promising option for the future establishment of patient-derived xenografts for personalized medicine approaches beyond BRCA status.
Merkel Cell Polyomavirus and Merkel Cell Carcinoma
Authors: Pietropaolo Valeria , Prezioso Carla , Moens Ugo
Published: July 2020

Viruses are the cause of approximately 15% of all human cancers. Both RNA and DNA human tumor viruses have been identified, with Merkel cell polyomavirus being the most recent one to be linked to cancer. This virus is associated with about 80% of Merkel cell carcinomas, a rare, but aggressive cutaneous malignancy. Despite its name, the cells of origin of this tumor may not be Merkel cells. This review provides an update on the structure and life cycle, cell tropism and epidemiology of the virus and its oncogenic properties. Putative strategies to prevent viral infection or treat virus-positive Merkel cell carcinoma patients are discussed.
Potential Added Value of PET/CT Radiomics for Survival Prognostication beyond AJCC 8th Edition Staging in Oropharyngeal Squamous Cell Carcinoma
Authors: Haider Stefan P. , Zeevi Tal , Baumeister Philipp , Reichel Christoph , Sharaf Kariem , Forghani Reza , Kann Benjamin H. , Judson Benjamin L. , Prasad Manju L. , Burtness Barbara , Mahajan Amit , Payabvash Seyedmehdi
Published: July 2020

Accurate risk-stratification can facilitate precision therapy in oropharyngeal squamous cell carcinoma (OPSCC). We explored the potential added value of baseline positron emission tomography (PET)/computed tomography (CT) radiomic features for prognostication and risk stratification of OPSCC beyond the American Joint Committee on Cancer (AJCC) 8th edition staging scheme. Using institutional and publicly available datasets, we included OPSCC patients with known human papillomavirus (HPV) status, without baseline distant metastasis and treated with curative intent. We extracted 1037 PET and 1037 CT radiomic features quantifying lesion shape, imaging intensity, and texture patterns from primary tumors and metastatic cervical lymph nodes. Utilizing random forest algorithms, we devised novel machine-learning models for OPSCC progression-free survival (PFS) and overall survival (OS) using “radiomics” features, “AJCC” variables, and the “combined” set as input. We designed both single- (PET or CT) and combined-modality (PET/CT) models. Harrell’s C-index quantified survival model performance; risk stratification was evaluated in Kaplan–Meier analysis. A total of 311 patients were included. In HPV-associated OPSCC, the best “radiomics” model achieved an average C-index ± standard deviation of 0.62 ± 0.05 (p = 0.02) for PFS prediction, compared to 0.54 ± 0.06 (p = 0.32) utilizing “AJCC” variables. Radiomics-based risk-stratification of HPV-associated OPSCC was significant for PFS and OS. Similar trends were observed in HPV-negative OPSCC. In conclusion, radiomics imaging features extracted from pre-treatment PET/CT may provide complimentary information to the current AJCC staging scheme for survival prognostication and risk-stratification of HPV-associated OPSCC.
Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases: Multidisciplinary Consensus Document from the COLLISION Trial Group
Authors: Nieuwenhuizen Sanne , Puijk Robbert S. , van den Bemd Bente , Aldrighetti Luca , Arntz Mark , van den Boezem Peter B. , Bruynzeel Anna M. E. , Burgmans Mark C. , de Cobelli Francesco , Coolsen Marielle M. E. , Dejong Cornelis H. C. , Derks Sarah , Diederik Arjen , van Duijvendijk Peter , Eker Hasan H. , Engelsman Anton F. , Erdmann Joris I. , Fütterer Jurgen J. , Geboers Bart , Groot Gerie , Haasbeek Cornelis J. A. , Janssen Jan-Jaap , de Jong Koert P. , Kater G. Matthijs , Kazemier Geert , Kruimer Johan W. H. , Leclercq Wouter K. G. , van der Leij Christiaan , Manusama Eric R. , Meier Mark A. J. , van der Meijs Bram B. , Melenhorst Marleen C. A. M. , Nielsen Karin , Nijkamp Maarten W. , Potters Fons H. , Prevoo Warner , Rietema Floris J. , Ruarus Alette H. , Ruiter Simeon J. S. , Schouten Evelien A. C. , Serafino Gian Piero , Sietses Colin , Swijnenburg Rutger-Jan , Timmer Florentine E. F. , Versteeg Kathelijn S. , Vink Ted , de Vries Jan J. J. , de Wilt Johannes H. W. , Zonderhuis Barbara M. , Scheffer Hester J. , van den Tol Petrousjka M. P. , Meijerink Martijn R.
Published: July 2020

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a ‘toolbox’ of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.
Loss of HMGCS2 Enhances Lipogenesis and Attenuates the Protective Effect of the Ketogenic Diet in Liver Cancer
Authors: Wang Yuan-Hsi , Suk Fat-Moon , Liao Yi-Jen
Published: July 2020

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor with limited treatment. The ketogenic diet (KD) emerged as a metabolic therapy for cancer; however, the antitumor effect on HCC remains controversial. We previously reported that the ketogenesis rate-limiting enzyme, 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), was downregulated in most patients with HCC. The knockdown of HMGCS2 enhanced the proliferation and metastasis ability of HCC cells. However, the role of HMGCS2 in affecting KD-mediated metabolic effects remains unclear. Here, we report that KD feeding upregulates HMGCS2 expression and inhibits HCC tumor growth, while a reverse correlation between tumor size and HMGCS2 expression was observed. We found that HCC cells with HMGCS2 downregulation possess altered lipid metabolism that increases fatty acid, triglyceride, and cholesterol synthesis. Under KD feeding, a higher tumor growth rate was observed in HMGCS2 knockdown tumors, which had increased lipid synthesis-related marker expression and a positive correlation between lipid quantity and tumor weight. In conclusion, these results demonstrate that the downregulation of HMGCS2 attenuates the protective effect of the KD by shifting ketone production to enhance de novo lipogenesis in HCC. Our study elucidates a new molecular mechanism underlying the crosstalk between HMGCS2 expression and the KD in cancer treatment, which provides more information for precision medicine in developing personalized treatment strategies.
The Premature Senescence in Breast Cancer Treatment Strategy
Authors: Milczarek Małgorzata
Published: July 2020

Cellular senescence is a permanent blockade of cell proliferation. In response to therapy-induced stress, cancer cells undergo apoptosis or premature senescence. In apoptosis-resistant cancer cells or at lower doses of anticancer drugs, therapy-induced stress leads to premature senescence. The role of this senescence in cancer treatment is discussable. First of all, the senescent cells lose the ability to proliferate, migrate, and invade. In addition, the senescent cells secrete a set of proteins (inflammatory cytokines, chemokines, growth factors) known as the senescence-associated secretory phenotype (SASP), which influences non-senescent normal cells and non-senescent cancer cells in the tumor microenvironment and triggers tumor promotion and recurrence. Recently, many studies have examined senescence induction through breast cancer therapy and potentially using this phenomenon to treat this cancer. This review summarizes the recent in vitro, in vivo, and clinical studies investigating senescence in breast cancer treatments. Senescence inductors, senolytics, as well as their action mechanism are discussed herein. Potential SASP-modulating treatment strategies are also described.
Beyond IDH-Mutation: Emerging Molecular Diagnostic and Prognostic Features in Adult Diffuse Gliomas
Authors: Mirchia Kanish , Richardson Timothy E.
Published: July 2020

Diffuse gliomas are among the most common adult central nervous system tumors with an annual incidence of more than 16,000 cases in the United States. Until very recently, the diagnosis of these tumors was based solely on morphologic features, however, with the publication of the WHO Classification of Tumours of the Central Nervous System, revised 4th edition in 2016, certain molecular features are now included in the official diagnostic and grading system. One of the most significant of these changes has been the division of adult astrocytomas into IDH-wildtype and IDH-mutant categories in addition to histologic grade as part of the main-line diagnosis, although a great deal of heterogeneity in the clinical outcome still remains to be explained within these categories. Since then, numerous groups have been working to identify additional biomarkers and prognostic factors in diffuse gliomas to help further stratify these tumors in hopes of producing a more complete grading system, as well as understanding the underlying biology that results in differing outcomes. The field of neuro-oncology is currently in the midst of a “molecular revolution” in which increasing emphasis is being placed on genetic and epigenetic features driving current diagnostic, prognostic, and predictive considerations. In this review, we focus on recent advances in adult diffuse glioma biomarkers and prognostic factors and summarize the state of the field.
Biomass Pyrolysis Technology by Catalytic Fast Pyrolysis, Catalytic Co-Pyrolysis and Microwave-Assisted Pyrolysis: A Review
Authors: Liu Junjian , Hou Qidong , Ju Meiting , Ji Peng , Sun Qingmei , Li Weizun
Published: July 2020

With the aggravation of the energy crisis and environmental problems, biomass resource, as a renewable carbon resource, has received great attention. Catalytic fast pyrolysis (CFP) is a promising technology, which can convert solid biomass into high value liquid fuel, bio-char and syngas. Catalyst plays a vital role in the rapid pyrolysis, which can increase the yield and selectivity of aromatics and other products in bio-oil. In this paper, the traditional zeolite catalysts and metal modified zeolite catalysts used in CFP are summarized. The influence of the catalysts on the yield and selectivity of the product obtained from pyrolysis was discussed. The deactivation and regeneration of the catalyst were discussed. Catalytic co-pyrolysis (CCP) and microwave-assisted pyrolysis (MAP) are new technologies developed in traditional pyrolysis technology. CCP improves the problem of hydrogen deficiency in the biomass pyrolysis process and raises the yield and character of pyrolysis products, through the co-feeding of biomass and hydrogen-rich substances. The pyrolysis reactions of biomass and polymers (plastics and waste tires) in CCP were reviewed to obtain the influence of co-pyrolysis on composition and selectivity of pyrolysis products. The catalytic mechanism of the catalyst in CCP and the reaction path of the product are described, which is very important to improve the understanding of co-pyrolysis technology. In addition, the effects of biomass pretreatment, microwave adsorbent, catalyst and other reaction conditions on the pyrolysis products of MAP were reviewed, and the application of MAP in the preparation of high value-added biofuels, activated carbon and syngas was introduced.
Expression of miR-135b in Psoriatic Skin and Its Association with Disease Improvement
Authors: Chicharro Pablo , Rodríguez-Jiménez Pedro , Llamas-Velasco Mar , Montes Nuria , Sanz-García Ancor , Cibrian Danay , Vara Alicia , Gómez Manuel J , Jiménez-Fernández María , Martínez-Fleta Pedro , Sánchez-García Inés , Lozano-Prieto Marta , Triviño Juan C , Miñambres Rebeca , Sánchez-Madrid Francisco , de la Fuente Hortensia , Dauden Esteban
Published: July 2020

miRNAs have been associated with psoriasis since just over a decade. However, we are far from a complete understanding of their role during the development of this disease. Our objective was to characterize the cutaneous expression of miRNAs not previously described in psoriasis, the changes induced following the treatment with biologicals and their association with disease improvement. Next generation sequencing was performed from five skin samples from psoriasis patients (lesional and non-lesional skin) and five controls, and from this cohort, 12 microRNAs were selected to be analyzed in skin samples from 44 patients with plaque psoriasis. In 15 patients, an additional sample was obtained after three months of biological treatment. MiR-9-5p, miR-133a-3p and miR-375 were downregulated in the lesional skin of psoriasis patients. After treatment, expression of miR-133a-3p, miR-375, miR-378a and miR-135b in residual lesions returned towards the levels observed in non-lesional skin. The decrease in miR-135b levels after treatment with biologics was associated with both the improvement of patients evaluated through Psoriasis Area and Severity Index score and the decrease in local inflammatory response. Moreover, basal expression of miR-135b along with age was associated with the improvement of psoriasis, suggesting its possible usefulness as a prognostic biomarker.
The Diversity of Intermediate Filaments in Astrocytes
Authors: Potokar Maja , Morita Mitsuhiro , Wiche Gerhard , Jorgačevski Jernej
Published: July 2020

Despite the remarkable complexity of the individual neuron and of neuronal circuits, it has been clear for quite a while that, in order to understand the functioning of the brain, the contribution of other cell types in the brain have to be accounted for. Among glial cells, astrocytes have multiple roles in orchestrating neuronal functions. Their communication with neurons by exchanging signaling molecules and removing molecules from extracellular space takes place at several levels and is governed by different cellular processes, supported by multiple cellular structures, including the cytoskeleton. Intermediate filaments in astrocytes are emerging as important integrators of cellular processes. Astrocytes express five types of intermediate filaments: glial fibrillary acidic protein (GFAP); vimentin; nestin; synemin; lamins. Variability, interactions with different cellular structures and the particular roles of individual intermediate filaments in astrocytes have been studied extensively in the case of GFAP and vimentin, but far less attention has been given to nestin, synemin and lamins. Similarly, the interplay between different types of cytoskeleton and the interaction between the cytoskeleton and membranous structures, which is mediated by cytolinker proteins, are understudied in astrocytes. The present review summarizes the basic properties of astrocytic intermediate filaments and of other cytoskeletal macromolecules, such as cytolinker proteins, and describes the current knowledge of their roles in normal physiological and pathological conditions.
The Role of Hyaluronic Acid in Cartilage Boundary Lubrication
Authors: Lin Weifeng , Liu Zhang , Kampf Nir , Klein Jacob
Published: July 2020

Hydration lubrication has emerged as a new paradigm for lubrication in aqueous and biological media, accounting especially for the extremely low friction (friction coefficients down to 0.001) of articular cartilage lubrication in joints. Among the ensemble of molecules acting in the joint, phosphatidylcholine (PC) lipids have been proposed as the key molecules forming, in a complex with other molecules including hyaluronic acid (HA), a robust layer on the outer surface of the cartilage. HA, ubiquitous in synovial joints, is not in itself a good boundary lubricant, but binds the PC lipids at the cartilage surface; these, in turn, massively reduce the friction via hydration lubrication at their exposed, highly hydrated phosphocholine headgroups. An important unresolved issue in this scenario is why the free HA molecules in the synovial fluid do not suppress the lubricity by adsorbing simultaneously to the opposing lipid layers, i.e., forming an adhesive, dissipative bridge between them, as they slide past each other during joint articulation. To address this question, we directly examined the friction between two hydrogenated soy PC (HSPC) lipid layers (in the form of liposomes) immersed in HA solution or two palmitoyl–oleoyl PC (POPC) lipid layers across HA–POPC solution using a surface force balance (SFB). The results show, clearly and surprisingly, that HA addition does not affect the outstanding lubrication provided by the PC lipid layers. A possible mechanism indicated by our data that may account for this is that multiple lipid layers form on each cartilage surface, so that the slip plane may move from the midplane between the opposing surfaces, which is bridged by the HA, to an HA-free interface within a multilayer, where hydration lubrication is freely active. Another possibility suggested by our model experiments is that lipids in synovial fluid may complex with HA, thereby inhibiting the HA molecules from adhering to the lipids on the cartilage surfaces.
Show Me Your Friends and I Tell You Who You Are: The Many Facets of Prion Protein in Stroke
Authors: Puig Berta , Yang Denise , Brenna Santra , Altmeppen Hermann Clemens , Magnus Tim
Published: July 2020

Ischemic stroke belongs to the leading causes of mortality and disability worldwide. Although treatments for the acute phase of stroke are available, not all patients are eligible. There is a need to search for therapeutic options to promote neurological recovery after stroke. The cellular prion protein (PrPC) has been consistently linked to a neuroprotective role after ischemic damage: it is upregulated in the penumbra area following stroke in humans, and animal models of stroke have shown that lack of PrPC aggravates the ischemic damage and lessens the functional outcome. Mechanistically, these effects can be linked to numerous functions attributed to PrPC: (1) as a signaling partner of the PI3K/Akt and MAPK pathways, (2) as a regulator of glutamate receptors, and (3) promoting stem cell homing mechanisms, leading to angio- and neurogenesis. PrPC can be cleaved at different sites and the proteolytic fragments can account for the manifold functions. Moreover, PrPC is present on extracellular vesicles (EVs), released membrane particles originating from all types of cells that have drawn attention as potential therapeutic tools in stroke and many other diseases. Thus, identification of the many mechanisms underlying PrPC-induced neuroprotection will not only provide further understanding of the physiological functions of PrPC but also new ideas for possible treatment options after ischemic stroke.
Deep Characterization of Circular RNAs from Human Cardiovascular Cell Models and Cardiac Tissue
Authors: Jakobi Tobias , Siede Dominik , Eschenbach Jessica , Heumüller Andreas W. , Busch Martin , Nietsch Rouven , Meder Benjamin , Most Patrick , Dimmeler Stefanie , Backs Johannes , Katus Hugo A. , Dieterich Christoph
Published: July 2020

For decades, cardiovascular disease (CVD) has been the leading cause of death throughout most developed countries. Several studies relate RNA splicing, and more recently also circular RNAs (circRNAs), to CVD. CircRNAs originate from linear transcripts and have been shown to exhibit tissue-specific expression profiles. Here, we present an in-depth analysis of sequence, structure, modification, and cardiac circRNA interactions. We used human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), human healthy and diseased (ischemic cardiomyopathy, dilated cardiomyopathy) cardiac tissue, and human umbilical vein endothelial cells (HUVECs) to profile circRNAs. We identified shared circRNAs across all samples, as well as model-specific circRNA signatures. Based on these circRNAs, we identified 63 positionally conserved and expressed circRNAs in human, pig, and mouse hearts. Furthermore, we found that the sequence of circRNAs can deviate from the sequence derived from the genome sequence, an important factor in assessing potential functions. Integration of additional data yielded evidence for m6A-methylation of circRNAs, potentially linked to translation, as well as, circRNAs overlapping with potential Argonaute 2 binding sites, indicating potential association with the RISC complex. Moreover, we describe, for the first time in cardiac model systems, a sub class of circRNAs containing the start codon of their primary transcript (AUG circRNAs) and observe an enrichment for m6A-methylation for AUG circRNAs.
Astrocyte- and Neuron-Derived Extracellular Vesicles from Alzheimer’s Disease Patients Effect Complement-Mediated Neurotoxicity
Authors: Nogueras-Ortiz Carlos J. , Mahairaki Vasiliki , Delgado-Peraza Francheska , Das Debamitra , Avgerinos Konstantinos , Eren Erden , Hentschel Matthew , Goetzl Edward J. , Mattson Mark P. , Kapogiannis Dimitrios
Published: July 2020

We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV/NEV uptake, as effectors of neurodegeneration in AD.
Canonical and Noncanonical Autophagy as Potential Targets for COVID-19
Authors: Bello-Perez Melissa , Sola Isabel , Novoa Beatriz , Klionsky Daniel J. , Falco Alberto
Published: July 2020

The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. The precise manipulation of this pathway allows these viruses to exploit the autophagy molecular machinery while avoiding its protective apoptotic drift and cellular innate immune responses. In turn, the maneuverability margins of such hijacking appear to be so narrow that the modulation of the autophagy, regardless of whether using inducers or inhibitors (many of which are FDA-approved for the treatment of other diseases), is usually detrimental to viral replication, including SARS-CoV-2. Recent discoveries indicate that these interactions stretch into the still poorly explored noncanonical autophagy pathway, which might play a substantial role in coronavirus replication. Still, some potential therapeutic targets within this pathway, such as RAB9 and its interacting proteins, look promising considering current knowledge. Thus, the combinatory treatment of COVID-19 with drugs affecting both canonical and noncanonical autophagy pathways may be a turning point in the fight against this and other viral infections, which may also imply beneficial prospects of long-term protection.
Kinase-Independent Functions of MASTL in Cancer: A New Perspective on MASTL Targeting
Authors: Conway James Ronald William , Närvä Elisa , Taskinen Maria Emilia , Ivaska Johanna
Published: July 2020

Microtubule-associated serine/threonine kinase-like (MASTL; Greatwall) is a well-characterized kinase, whose catalytic role has been extensively studied in relation to cell-cycle acceleration. Importantly, MASTL has been implicated to play a substantial role in cancer progression and subsequent studies have shown that MASTL is a significant regulator of the cellular actomyosin cytoskeleton. Several kinases have non-catalytic properties, which are essential or even sufficient for their functions. Likewise, MASTL functions have been attributed both to kinase-dependent phosphorylation of downstream substrates, but also to kinase-independent regulation of the actomyosin contractile machinery. In this review, we aimed to highlight the catalytic and non-catalytic roles of MASTL in proliferation, migration, and invasion. Further, we discussed the implications of this dual role for therapeutic design.