bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient LDPC Encoder Design for IoT-Type Devices
Authors: Hyla Jakub , Sułek Wojciech , Izydorczyk Weronika , Dziczkowski Leszek , Filipowski Wojciech
Published: March 2022

Low-density parity-check (LDPC) codes are known to be one of the best error-correction coding (ECC) schemes in terms of correction performance. They have been utilized in many advanced data communication standards for which the codecs are typically implemented in custom integrated circuits (ICs). In this paper, we present a research work that shows that the LDPC coding scheme can also be applied in a system characterized by highly limited computational resources. We present a microcontroller-based application of an efficient LDPC encoding algorithm with efficient usage of memory resources for the code-parity-check matrix and the storage of the results of auxiliary computations. The developed implementation is intended for an IoT-type system, in which a low-complexity network node device encodes messages transmitted to a gateway. We present how the classic Richardson–Urbanke algorithm can be decomposed for the QC-LDPC subclass into cyclic shifts and GF(2) additions, directly corresponding to the CPU instructions. The experimental results show a significant gain in terms of memory usage and decoding timing of the proposed method in comparison with encoding with the direct parity check matrix representation. We also provide experimental comparisons with other known block codes (RS and BCH) showing that the memory requirements are not greater than for standard block codes, while the encoding time is reduced, which enables the energy consumption reduction. At the same time, the error-correction performance gain of LDPC codes is greater than for the mentioned standard block codes.
Impact of Waste Tea Litter on NH3 and CO2 Emissions during Broiler Rearing
Authors: Jie Dengfei , Zhang Zhanxiang , He Jincheng , Zhou Yafang , Zhu Guangyou
Published: March 2022

Pollution generated by livestock and poultry rearing is an important environmental issue, and gas emissions during animal production are continuously increasing. A digital rearing chamber inspection system was designed in the present study in order to examine the waste tea litter’s impact on the growth performance and harmful gas emissions, such as ammonia (NH3) and carbon dioxide (CO2), during broiler rearing. Broilers were raised without litter and with waste tea litter. According to the results, broiler growth showed little difference between the two groups during the experimental period, and it was concluded that waste tea litter had no impact on broiler growth. Meanwhile, the gas emissions of the waste tea-litter group were lower than the non-bedding-materials group. In detail, the average concentrations of NH3 and CO2 of the non-bedding-materials group were 9.33 ± 3.65 ppm and 797 ± 107 ppm, respectively; while these concentrations in the waste-tea-litter group were 1.01 ± 0.35 ppm and 713 ± 69 ppm, respectively. According to the analysis of the litter properties, it was suggested that waste tea litter can reduce the moisture content in litter, and affect microbial and urease activity due to its low carbon nitrogen ratio (C/N), weak acid, and porous structure characteristics. In conclusion, this study showed the potential of waste tea litter in NH3 and CO2 emission reduction during broiler rearing.
A Survey on Dynamic Corrective Control of Asynchronous Sequential Machines
Authors: Yang Jung-Min , Kwak Seong-Woo
Published: March 2022

As a feedback control methodology exclusively targeting asynchronous sequential machines (ASMs), corrective control has been rapidly developing for the past two decades. This paper presents a comprehensive survey on the theory and application of dynamic corrective control in which the controller also has the form of an ASM. First, basic notions and principles of dynamic corrective control, including models of ASMs and configurations of closed-loop systems, are reviewed. Next, assorted dynamic corrective control schemes are presented aiming at solving specific control problems of ASMs, such as model matching and fault-tolerant control. Variations of control aspects are classified according to modeling formalisms of controlled ASMs—input/state, input/output, and composite ASMs—and involved fault characteristics, such as transient, permanent, and intermittent faults and intelligent attacks. Representative results on the application of fault-tolerant corrective control to real-world engineering systems are also provided with an emphasis on space-borne digital systems. Finally, some challenging topics for future studies on corrective control are discussed.
Polycyclic Aromatic Hydrocarbons and Polychlorinated Biphenyls in Seawater, Sediment and Biota of Neritic Ecosystems: Occurrence and Partition Study in Southern Ligurian Sea
Authors: Rivoira Luca , Castiglioni Michele , Nurra Nicola , Battuello Marco , Sartor Rocco Mussat , Favaro Livio , Bruzzoniti Maria Concetta
Published: March 2022

The Mediterranean Sea is subjected to a high anthropic pressure, which determines direct or indirect discharges of persistent organic pollutants deriving from intensive industrial activities. These compounds could easily enter and contaminate the whole marine compartment, with possible transfers (and contamination) among water, sediment and biota. Based on the above-mentioned assumptions, in this work we studied the presence of 16 polycyclic aromatic hydrocarbons (PAHs) and 14 dioxin and non-dioxin-like polychlorinated biphenyls (PCBs) in the neritic protected marine area of the Southern Ligurian Sea, affected by the impact of human activities. The study was focused on the possible partition of micropollutants within seawater, sediment and zooplankton. Results showed that both seasonal and anthropic causes strongly affect contaminant transfer behaviors, with summertime periods more impacted by PAH and PCB contamination. Regarding the PAH contamination, low molecular weight congeners were mainly detected in the target matrices, revealing concentrations up to 1 µg/L in seawater (anthracene), 250 µg/Kg in sediments (benzo[b]fluoranthene) and 2.3 mg/Kg in carnivorous copepods. Concerning PCBs, only few congeners were detected in the matrices studied. To better understand the occurrence of preferential bioaccumulation pathways in zooplankton, partition studies were also performed in several taxa (hyperbenthic Isopoda, holoplanktonic crustacean copepods and ichthyoplankton) through the calculation of BAF values, observing that both living and feeding habits could influence the bioaccumulation process.
Scale-Up of Dark Fermentative Biohydrogen Production by Artificial Microbial Co-Cultures
Authors: Ergal İpek , Zech Elisa , Hanišáková Nikola , Kushkevych Ivan , Fuchs Werner , Vítěz Tomáš , Vítězová Monika , Bochmann Günther , Rittmann Simon K.-M. R.
Published: March 2022

As a renewable energy carrier, dark fermentative biohydrogen (H2) represents a promising future alternative to fossil fuels. Recently, the limited H2 yield of 4 moles of H2 per mole glucose, the so-called “Thauer limit”, was surpassed by a defined artificial consortium. In this article, we demonstrate the upscaling of this drawing board design, from serum bottles to laboratory scale bioreactors. Our results illustrate that this designed microbial co-culture can be successfully implemented in batch mode, with maximum H2 yields of 6.18 and 4.45 mol mol−1 substrate. Furthermore, we report volumetric H2 productivities of 105.6 and 80.8 mmol H2 L−1 h−1. These rates are higher than for any other dark fermentative H2 production system using a synthetic microbial co-culture applied in batch mode on a defined medium. Our study is an important step forward for the application of artificial microbial consortia in future biotechnology and energy production systems.
Spatiotemporal Changes of sc-PDSI and Its Dynamic Drivers in Yellow River Basin
Authors: Liu Wen , Zhang Yuqing
Published: March 2022

Droughts in the Yellow River Basin (YRB), a typical large river in arid to semiarid regions, have been studied extensively. However, the details of the dynamic drivers of meteorological droughts, such as precipitation (P), reference evapotranspiration (ET0), and actual evapotranspiration (AET), are unclear in the YRB, as is whether or not the main dynamic driver of meteorological drought in each subzone is consistent. In order to solve this issue, we analyzed (1) the seasonal distribution of drought in the YRB and (2) sc-PDSI and dynamic driver’s trends by using linear trends, Sen’s slope, and Z statistics in the YRB from 1951 to 2017; (3) the probability distribution of sc-PDSI, P, ET0, and AET; (4) the correlation of the sc-PDSI with some factors that drive drought; and (5) conducted a Pearson correlation analysis between sc-PDSI and the dynamic drivers at the 0.5° pixel scale. The results show that (1) the northwest region in the YRB was drier than the southeast region, and the drought in spring and winter was more severe than in other seasons. (2) The sc-PDSI showed a downwards trend (−0.47/decade), P and AET also showed a downwards trend (−3.408 mm/decade, −0.27 mm/decade), while ET0 showed a significant upwards trend (12.013 mm/decade) in the YRB. (3) The midstream of the YRB had the highest risk of drought. (4) The P, ET0, and AET were highly correlated with the sc-PDSI on a 12-month timescale. (5) The main dynamic driver of the upstream and downstream drought is P, and the main dynamic driver of the midstream drought was ET0.
Emission from Internal Combustion Engines and Battery Electric Vehicles: Case Study for Poland
Authors: Zimakowska-Laskowska Magdalena , Laskowski Piotr
Published: March 2022

The paper compares the emissions from vehicles including ICEVs (internal combustion engine vehicles) with equivalent emissions from BEVs (battery electric vehicles). Additionally, it analyzes the available source research and the specific energy mix for Poland based on carbon. Mathematical calculations estimate air pollutant emissions. To carry out the analysis and calculations, data were provided by the manufacturers of electricity consumption in the case of vehicles equipped with electric motors and the COPERT model for internal combustion engines. Air pollutants are considered: CO2, NOx, SOx, CO, and Total Suspended Particles (TSP). In addition to exhaust emissions, all solids emissions from road abrasion and tire and brake wear are also considered. The emission of pollutants is estimated based on the emission factors using the average mileage in Polish conditions. The paper compares emissions for three scenarios considering electric vehicles, combustion engine cars, and hybrid cars. Analyses show that introducing cars with electric engines into traffic at the expense of withdrawing vehicles with internal combustion engines is not favorable in Polish conditions. The analysis indicates that CO, CO2, and TSP emissions have decreased, while NOx and SOx emissions have increased.
Auroral Ionosphere Model with PC Index as an Input
Authors: Nikolaeva Vera , Gordeev Evgeny , Nikolaev Alexander , Rogov Denis , Troshichev Oleg
Published: March 2022

Auroral Ionosphere Model (AIM-E) is designed to calculate chemical content in the high-latitude E region ionosphere and takes into account both the solar EUV radiation and the electron precipitation of magnetospheric origin. The latter is extremely important for auroral ionosphere chemistry especially in disturbed conditions. In order to maximize the AIM-E timing accuracy when simulating highly variable periods in the course of geomagnetic storms and substorms, we suggest to parameterize the OVATION-Prime empirical precipitation model with the ground-based Polar Cap (PC) index. This gives an advantage to: (1) perform ionospheric simulation with actual input, since PC index reflects the geoeffective solar wind conditions; (2) promptly assess the current geomagnetic situation, since PC index is available in real-time with 1 min resolution. The simulation results of AIM-E with OVATION-Prime (PC) demonstrate a good agreement with the ground-based incoherent scatter radar data (EISCAT UHF, Tromso) and with the vertical sounding data in the Arctic zone during events of intense particle precipitation. The model reproduces well the electron content calculated in vertical column (90–140 km) and critical frequency of sporadic E layer (fOEs) formed by precipitating electrons. The AIM-E (PC) model can be applied to monitor the sporadic E layer in real-time and in the entire high-latitude ionosphere, including the auroral and subauroral zones, which is important for predicting the conditions of radio wave propagation.
Evaluation of Wave Contributions in Hurricane Irma Storm Surge Hindcast
Authors: Musinguzi Abram , Reddy Lokesh , Akbar Muhammad K.
Published: March 2022

This paper evaluates the contribution of waves to the total predicted storm surges in a Hurricane Irma hindcast, using ADCIRC+SWAN and ADCIRC models. The contribution of waves is quantified by subtracting the water levels hindcasted by ADCIRC from those hindcasted by ADCIRC+SWAN, using OWI meteorological forcing in both models. Databases of water level time series, wave characteristic time series, and high-water marks are used to validate the model performance. Based on the application of our methodology to the coastline around Florida, a peninsula with unique geomorphic characteristics, we find that wave runup has the largest contribution to the total water levels on the south and northeast coasts. Waves increase the surge on the south and northeast coasts, due to large fetch and wave runups. On the west coast, the wave effect is not significant, due to limited fetch. However, significant wave heights become greater as the waves propagate into the deep inner gulf. The continental shelf on Florida’s west coast plays a critical role in decreasing the significant wave height and sheltering the coastal areas from large wave effects. Both models underpredict the high-water marks, but ADCIRC+SWAN reduces the underprediction and improves the parity with the observed data, although the scatter is slightly higher than that of ADCIRC.
Implementation of a Practical Teaching Course on Protein Engineering
Authors: Gomes Luciana , Ferreira Carla , Mergulhão Filipe
Published: March 2022

Protein Engineering is a highly evolved field of engineering aimed at developing proteins for specific industrial, medical, and research applications. Here, we present a practical teaching course to demonstrate fundamental techniques used to express, purify and analyze a recombinant protein produced in Escherichia coli—the enhanced green fluorescent protein (eGFP). The methodologies used for eGFP production were introduced sequentially over six laboratory sessions and included (i) bacterial growth, (ii) sonication (for cell lysis), (iii) affinity chromatography and dialysis (for eGFP purification), (iv) bicinchoninic acid (BCA) and fluorometry assays for total protein and eGFP quantification, respectively, and (v) sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) for qualitative analysis. All groups were able to isolate the eGFP from the cell lysate with purity levels up to 72%. Additionally, a mass balance analysis performed by the students showed that eGFP yields up to 46% were achieved at the end of the purification process following the adopted procedures. A sensitivity analysis was performed to pinpoint the most critical steps of the downstream processing.
IMGT®Homo sapiens IG and TR Loci, Gene Order, CNV and Haplotypes: New Concepts as a Paradigm for Jawed Vertebrates Genome Assemblies
Authors: Lefranc Marie-Paule , Lefranc Gérard
Published: March 2022

IMGT®, the international ImMunoGeneTics information system®, created in 1989, by Marie-Paule Lefranc (Université de Montpellier and CNRS), marked the advent of immunoinformatics, a new science which emerged at the interface between immunogenetics and bioinformatics for the study of the adaptive immune responses. IMGT® is based on a standardized nomenclature of the immunoglobulin (IG) and T cell receptor (TR) genes and alleles from fish to humans and on the IMGT unique numbering for the variable (V) and constant (C) domains of the immunoglobulin superfamily (IgSF) of vertebrates and invertebrates, and for the groove (G) domain of the major histocompatibility (MH) and MH superfamily (MhSF) proteins. IMGT® comprises 7 databases, 17 tools and more than 25,000 pages of web resources for sequences, genes and structures, based on the IMGT Scientific chart rules generated from the IMGT-ONTOLOGY axioms and concepts. IMGT® reference directories are used for the analysis of the NGS high-throughput expressed IG and TR repertoires (natural, synthetic and/or bioengineered) and for bridging sequences, two-dimensional (2D) and three-dimensional (3D) structures. This manuscript focuses on the IMGT®Homo sapiens IG and TR loci, gene order, copy number variation (CNV) and haplotypes new concepts, as a paradigm for jawed vertebrates genome assemblies.
Project Extension for Community Health Outcomes (ECHO) Autism: A Successful Model to Increase Capacity in Community-Based Care
Authors: Sohl Kristin , Rynkiewicz Agnieszka , Nanclares-Nogués Valeria , Brewer Curran Alicia , Scorah Julie , Steiman Mandy , Lord Catherine , Vasa Roma A. , Słopień Agnieszka , Janas-Kozik Małgorzata , Łucka Izabela , Mazur Artur
Published: March 2022

Individuals with autism spectrum disorder (ASD) struggle to access high-quality health care due to the shortage of trained providers. ECHO (Extension for Community Healthcare Outcomes) Autism is a unique educational program that allows ASD experts to provide knowledge and skills to professionals in local communities to deliver evidence-based care to children with ASD and their families. The model teaches clinicians how to screen and diagnose ASD, as well as manage common co-occurring medical and mental health issues. ECHO Autism is particularly useful for addressing the complex needs of children with ASD and reducing disparities often present in rural and underserved communities. The model can be disseminated globally due to its flexibility in accommodating local and regional differences in social norms and constructs. This article provides an overview of the format of the ECHO Autism model, data supporting the model’s efficacy, and discusses future research directions.
A Breakdown of Immune Tolerance in the Cerebellum
Authors: Hampe Christiane S. , Mitoma Hiroshi
Published: March 2022

Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood–brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum—or any structure in the CNS—is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood–brain barrier, blood–CSF barrier, and blood–leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often—particularly in infectious diseases—the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum.
Thalamic and Cerebellar Regional Involvement across the ALS–FTD Spectrum and the Effect of C9orf72
Authors: Bocchetta Martina , Todd Emily G. , Tse Nga Yan , Devenney Emma M. , Tu Sicong , Caga Jashelle , Hodges John R. , Halliday Glenda M. , Irish Muireann , Piguet Olivier , Kiernan Matthew C. , Rohrer Jonathan D. , Ahmed Rebekah M.
Published: March 2022

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic–cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS–FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS–FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS–FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions. Thalamic involvement was evident across all ALS–FTD clinical phenotypes, with the laterodorsal nucleus commonly affected across all groups (values below the 2.5th control percentile). The mediodorsal nucleus was disproportionately affected in bvFTD and ALS–FTD but not in ALS. Cerebellar changes were only observed in bvFTD and ALS–FTD predominantly in the superior–posterior region. Comparison of genetic versus sporadic cases revealed significantly lower volumes exclusively in the pulvinar in C9orf72 expansion carriers compared to non-carriers, irrespective of clinical syndrome. Overall, bvFTD showed significant correlations between thalamic subregions, level of cognitive dysfunction and severity of behavioural symptoms. Notably, strong associations were evident between mediodorsal nucleus atrophy and severity of behavioural changes in C9orf72-bvFTD (r = −0.9, p < 0.0005). Our findings reveal distinct thalamic and cerebellar atrophy profiles across the ALS–FTD spectrum, with differential impacts on behaviour and cognition, and point to a unique contribution of C9orf72 expansions in the clinical profiles of these patients.
Stress and Its Correlates in Migraine-Headache Patients with a Family History of Migraine
Authors: Al-Quliti Khalid
Published: March 2022

Purpose: Stress and migraine are often comorbid. However, no studies have examined stress severity in a sample of migraine patients. That is why this study investigated the determinants of stress level in a sample of migraine patients with a family history of migraine (MWFH) in Saudi Arabia. Material and Methods: A quantitative observational study with a cross-sectional data collection and convenient sampling of (MWFH) was performed in Madinah, Saudi Arabia. Participants completed the Perceived Stress Scale-4 (PSS-4) and a list of items to register clinical history and demographics information. Results: Out of eight independent variables that were explored, only two variables —both sleep related, i.e., insufficient sleep (β = 0.22, p = 0.04) and non-refreshing sleep (β = 0.22, p = 0.04), F(8, 127) = 5.13, p < 0.001, R2 = 0.244—were associated with stress severity. The majority of (MWFH) were female (73.7%), recorded a lack of habitual physical activity (56.2%), received treatment for co-morbidities (56.9%), reported sleep insufficiency (54%), non-refreshing sleep (52.6%) and traumatic incidents (50.4%). Discussion: Stress severity increased with sleep complaints, indicating a comorbidity of stress–sleep problems among migraine patients with a family history of migraine.
Architecture, City, People, and Structure
Authors: Gronostajska Barbara Ewa , Tarczewski Romuald , Jablonska Joanna
Published: March 2022

Architecture and structure are the basis for working, living, and resting for almost every human being [...]
Innovation Pattern Heterogeneity: Data-Driven Retrieval of Firms’ Approaches to Innovation
Authors: Capasso Marco , Rybalka Marina
Published: March 2022

According to a strong and diversified theoretical framework, innovation is one of the usual suspects in defining differences in firm performance. Understanding the diversity that exists within the population of innovative firms is essential for developing appropriate innovation policies. Our study explored the diversity of innovation patterns among Norwegian firms included in the 2018 Community Innovation Survey (CIS2018). By applying factor analysis to a wide array of survey variables and a large sample of firms, we identified eleven typical approaches to innovation, which connect innovation inputs and outputs at the firm level. A main outcome of our study is a novel fine-grained view of innovation as a multifaceted concept. Our research path helps us to find commonalities in innovation behavior across industries and, as a consequence, to better isolate those innovation patterns that differentiate industries from one another. We also show the relation between firm size, on one hand, and each of the firm scores associated to the eleven typical approaches to innovation, on the other hand, thus uncovering ways in which small firms may survive in sectors dominated by large firms.
Post-Neoadjuvant Treatment Strategies in Breast Cancer
Authors: Matuschek Christiane , Jazmati Danny , Bölke Edwin , Tamaskovics Bálint , Corradini Stefanie , Budach Wilfried , Krug David , Mohrmann Svjetlana , Ruckhäberle Eugen , Fehm Tanja , Nestle Krämling Carolin , Dommach Markus , Haussmann Jan
Published: March 2022

Neoadjuvant chemotherapy enables close monitoring of tumor response in patients with breast cancer. Being able to assess tumor response during treatment provides an opportunity to evaluate new therapeutic strategies. Thus, for triple-negative breast tumors, it was demonstrated that additional immunotherapy could improve prognosis compared with chemotherapy alone. Furthermore, adjuvant therapy can be escalated or de-escalated correspondingly. The CREATE-X trial randomly assigned HER2-negative patients with residual tumor after neoadjuvant therapy to either observation or capecitabine. In HER2-negative patients with positive BRCA testing, the OlympiA study randomly assigned patients to either observation or olaparib. HER2-positive patients without pathologic remission were randomly assigned to trastuzumab or trastuzumab–emtansine within the KATHERINE study. These studies were all able to show an improvement in oncologic outcome associated with the escalation of therapy in patients presenting with residual tumor after neoadjuvant treatment. On the other hand, this individualization of therapy may also offer the possibility to de-escalate treatment, and thereby reduce morbidity. Among WSG-ADAPT HER2+/HR-, HER2-positive patients achieved comparable results without chemotherapy after complete remission following neoadjuvant treatment. In summary, the concept of post-neoadjuvant therapy constitutes a great opportunity for individualized cancer treatment, potentially improving outcome. In this review, the most important trials of post-neoadjuvant therapy are compiled and discussed.
Immune-Related Thyroid Adverse Events Predict Response to PD-1 Blockade in Patients with Melanoma
Authors: Dawidowska Anna , Jagodzinska-Mucha Paulina , Koseła-Paterczyk Hanna , Jaczewska Sylwia , Sobczuk Paweł , Chelstowska Monika , Kowalska Maria , Badziak-Sterczewska Honorata , Poleszczuk Jan , Rutkowski Piotr , Lugowska Iwona
Published: March 2022

Antibodies against programmed cell death protein-1 or its ligand (PD-(L)1) are a standard of care in melanoma; however, this treatment may cause immune-related adverse events. The aim of this study was to evaluate the immune-related thyroid adverse events (irTAEs) during anti-PD-1 therapy and analyze their influence on the overall survival rates in melanoma. We included 249 patients with metastatic melanoma treated in our institution between 2014 and 2021; the median age was 62 years (range: 17–90); 58% were males, and 37% of patients had the BRAF mutation. We included patients with a normal TSH at baseline and followed up with measurement of TSH levels during immunotherapy. In our group, 95 patients had a TSH outside the normal range: 63 not clinically significant and 32 with clinical symptoms of hypothyroidism. The 3-year overall survival rate was related to the irTAEs of clinical hypothyroidism, abnormal clinically not significant TSH, and euthyreosis at 56%, 43%, and 32%, respectively (p = 0.002). After adjusting the Cox model for potential confounding variables, clinically significant hypothyroidism was an independent prognostic factor with HR 0.51 (95% CI 0.29–0.87). In conclusion, the patients who developed clinically significant hypothyroidism requiring replacement therapy with L-thyroxin were the group who benefitted most from anti-PD-1 treatment.
Evolving Paradigms in the Systemic Treatment of Advanced Gallbladder Cancer: Updates in Year 2022
Authors: Hu Zishuo Ian , Lim Kian-Huat
Published: March 2022

Gallbladder cancer (GBC) is a biological, anatomical, and clinically distinct subset of biliary tract cancers (BTC), which also include extra- and intra-hepatic cholangiocarcinoma. The advent of next-generation sequencing (NGS) clearly shows that GBC is genetically different from cholangiocarcinoma. Although GBC is a relatively rare cancer, it is highly aggressive and carries a grave prognosis. To date, complete surgical resection remains the only path for cure but is limited to patients with early-stage disease. The majority of the patients are diagnosed at an advanced, inoperable stage when systemic treatment is administered as an attempt to enable surgery or for palliation. Gemcitabine and platinum-based chemotherapies have been the main treatment modality for unresectable, locally advanced, and metastatic gallbladder cancer. However, over the past decade, the treatment paradigm has evolved. These include the introduction of newer chemotherapeutic strategies after progression on frontline chemotherapy, incorporation of targeted therapeutics towards driver mutations of genes including HER2, FGFR, BRAF, as well as approaches to unleash host anti-tumor immunity using immune checkpoint inhibitors. Notably, due to the rarity of BTC in general, most clinical trials included both GBC and cholangiocarcinomas. Here, we provide a review on the pathogenesis of GBC, past and current systemic treatment options focusing specifically on GBC, clinical trials tailored towards its genetic mutations, and emerging treatment strategies based on promising recent clinical studies.
Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies
Authors: Lee Lingaku , Ramos-Alvarez Irene , Jensen Robert T.
Published: March 2022

Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
Targeting Ribosome Biogenesis to Combat Tamoxifen Resistance in ER+ve Breast Cancer
Authors: Tsoi Ho , You Chan-Ping , Leung Man-Hong , Man Ellen P. S. , Khoo Ui-Soon
Published: March 2022

Breast cancer is a heterogeneous disease. Around 70% of breast cancers are estrogen receptor-positive (ER+ve), with tamoxifen being most commonly used as an adjuvant treatment to prevent recurrence and metastasis. However, half of the patients will eventually develop tamoxifen resistance. The overexpression of c-MYC can drive the development of ER+ve breast cancer and confer tamoxifen resistance through multiple pathways. One key mechanism is to enhance ribosome biogenesis, synthesising mature ribosomes. The over-production of ribosomes sustains the demand for proteins necessary to maintain a high cell proliferation rate and combat apoptosis induced by therapeutic agents. c-MYC overexpression can induce the expression of eIF4E that favours the translation of structured mRNA to produce oncogenic factors that promote cell proliferation and confer tamoxifen resistance. Either non-phosphorylated or phosphorylated eIF4E can mediate such an effect. Since ribosomes play an essential role in c-MYC-mediated cancer development, suppressing ribosome biogenesis may help reduce aggressiveness and reverse tamoxifen resistance in breast cancer. CX-5461, CX-3543 and haemanthamine have been shown to repress ribosome biogenesis. Using these chemicals might help reverse tamoxifen resistance in ER+ve breast cancer, provided that c-MYC-mediated ribosome biogenesis is the crucial factor for tamoxifen resistance. To employ these ribosome biogenesis inhibitors to combat tamoxifen resistance in the future, identification of predictive markers will be necessary.
Triple Negative Breast Cancer: Updates on Classification and Treatment in 2021
Authors: Bou Zerdan Maroun , Ghorayeb Tala , Saliba Fares , Allam Sabine , Bou Zerdan Morgan , Yaghi Marita , Bilani Nadeem , Jaafar Rola , Nahleh Zeina
Published: March 2022

Breast cancer (BC) is the most common malignancy affecting women. It is a highly heterogeneous disease broadly defined by the differential expression of cell surface receptors. In the United States, triple negative breast cancer (TNBC) represents 15 to 20% of all BC. When compared with other subtypes of BC, TNBC tends to present in younger women, and has a higher mortality rate of 40% in advanced stages within the first 5 years after diagnosis. TNBC has historically had limited treatment options when compared to other types of BC. The mainstay of treatment for TNBC remains cytotoxic chemotherapy despite the emergence of new biologic and targeted agents. Defining the specific tumor molecular profile including PDL-1 and androgen receptor testing is expanding treatment options in the clinical setting. Identifying more targetable, novel biomarkers that may better define therapeutic targets or prognostic markers is currently underway. TNBC nomenclature is expected to be updated in favor of other nomenclature which would help direct therapy, and further redefine TNBC’s heterogeneity. Given the continuous advances in the field of TNBC, this review assesses the latest developments in basic characterization, subtyping, and treatment of TNBC, including novel drug developments with antibody-drug conjugates, immune checkpoint inhibitors, PARP inhibitors and androgen receptor targeted agents. Future trials are necessary in the face of these innovations to further support the use of new therapies in TNBC and the detection of the appropriate biomarkers.
Surgical Treatment of Metastatic Bone Disease in the Appendicular Skeleton: A Population-Based Study
Authors: Ladegaard Thea Hovgaard , Sørensen Celine Lykke , Nielsen Rasmus , Troelsen Anders , Al-Mousawi Dhergam Ahmed Ali , Bielefeldt Rikke , Petersen Michael Mørk , Sørensen Michala Skovlund
Published: March 2022

Background: Population-based studies of patients with bone metastases in the appendicular skeleton (aBM) requiring surgery for complete or impending fracture are rare. In this epidemiologically-based observational study we created a large population-based cohort of patients treated for aBM, aiming to: (1) monitor possible time-related changes of the incidence of surgical treatment of aBM-lesions, (2) examine differences in the population and care of patients treated at different treatment centers and (3) examine if findings from a previous pilot study regarding absence of a suitable biopsy of the lesions representing debut of cancer or a relapse has improved the awareness of aBM and hereby increased the focus on regular tumor biopsies and follow-up imaging of cancer patients. Methods: We examined a population-based cohort consisting of all patients treated for aBM 2014–2019. Procedures were performed at five secondary surgical centers (SSC) or one tertiary referral Musculoskeletal Tumor Center (MTC). Patients were followed until end of study (30 September 2021) or death. No patients were lost to follow-up. Results: Four-hundred-fifty-seven patients (493 primary aBM-lesions, 482 procedures) were included. Annual incidence of aBM-surgery was 46 aBM-lesions/million. MTC-patients had a significant better preoperative status than SSC-patients considering factors known for survival. Patients with complete fracture experienced longer surgical delay when treated at MTC compared to SSC: 4 (1–9) and 1 (1–3) days (p < 0.001), respectively. Overall survival for the entire cohort was 37% and 11% at 1 and 5 years (MTC and SSC 1 and 5 year respectively: 44% and 15% vs. 29% and 5%, p < 0.001). In patients with debut or relapse of cancer, 8% and 9% had insufficient biopsies, and 21% and 12% had no biopsy, respectively. Comparison showed no change over time. Conclusions: The current study highlights the low awareness on treating aBM at SSC and emphasizes the importance of caution in interpretation of studies not representing an entire population, thus introducing selection bias.
The Effect of Hypoxia on Relative Biological Effectiveness and Oxygen Enhancement Ratio for Cells Irradiated with Grenz Rays
Authors: Chan Chun-Chieh , Chen Fang-Hsin , Hsueh Kuang-Lung , Hsiao Ya-Yun
Published: March 2022

Grenz-ray therapy (GT) is commonly used for dermatological radiotherapy and has a higher linear energy transfer, relative biological effectiveness (RBE) and oxygen enhancement ratio (OER). GT is a treatment option for lentigo maligna and lentigo maligna melanoma. This study aims to calculate the RBE for DNA double-strand break (DSB) induction and cell survival under hypoxic conditions for GT. The yield of DSBs induced by GT is calculated at the aerobic and hypoxic conditions, using a Monte Carlo damage simulation (MCDS) software. The RBE value for cell survival is calculated using the repair–misrepair–fixation (RMF) model. The RBE values for cell survival for cells irradiated by 15 kV, 10 kV and 10 kVp and titanium K-shell X-rays (4.55 kV) relative to 60Co γ-rays are 1.0–1.6 at the aerobic conditions and moderate hypoxia (2% O2), respectively, but increase to 1.2, 1.4 and 1.9 and 2.1 in conditions of severe hypoxia (0.1% O2). The OER values for DSB induction relative to 60Co γ-rays are about constant and ~2.4 for GT, but the OER for cell survival is 2.8–2.0 as photon energy decreases from 15 kV to 4.55 kV. The results indicate that GT results in more DSB induction and allows effective tumor control for superficial and hypoxic tumors.
Understanding Retinoblastoma Post-Translational Regulation for the Design of Targeted Cancer Therapies
Authors: Janostiak Radoslav , Torres-Sanchez Ariadna , Posas Francesc , de Nadal Eulàlia
Published: March 2022

The retinoblastoma protein (Rb1) is a prototypical tumor suppressor protein whose role was described more than 40 years ago. Together with p107 (also known as RBL1) and p130 (also known as RBL2), the Rb1 belongs to a family of structurally and functionally similar proteins that inhibits cell cycle progression. Given the central role of Rb1 in regulating proliferation, its expression or function is altered in most types of cancer. One of the mechanisms underlying Rb-mediated cell cycle inhibition is the binding and repression of E2F transcription factors, and these processes are dependent on Rb1 phosphorylation status. However, recent work shows that Rb1 is a convergent point of many pathways and thus the regulation of its function through post-translational modifications is more complex than initially expected. Moreover, depending on the context, downstream signaling can be both E2F-dependent and -independent. This review seeks to summarize the most recent research on Rb1 function and regulation and discuss potential avenues for the design of novel cancer therapies.
Targeting IGF2BP2 Promotes Differentiation of Radioiodine Refractory Papillary Thyroid Cancer via Destabilizing RUNX2 mRNA
Authors: Sa Ri , Liang Rui , Qiu Xian , He Ziyan , Liu Zhiyan , Chen Libo
Published: March 2022

N6-methyladenosine (m6A) regulators play an important role in multiple biological and pathological processes of radioiodine refractory papillary thyroid cancer (RR-PTC). However, the function of m6A regulators in differentiation of RR-PTC remains unclear. In this study, online data, clinical samples, and RR-PTC cell lines (K1 and TPC1) were used to identify the m6A regulators that contributed to the differentiation of RR-PTC. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was found to be associated with thyroid-specific genes in online data analyses, and metastatic PTCs with high expression of IGF2BP2 were prone to be 131I-nonavid in clinical analyses. Furthermore, targeting IGF2BP2 increased 125I uptake in RR-PTC cell lines and enhanced the sodium/iodide symporter (NIS) expression. Mechanistically, IGF2BP2 bound to the m6A modification site of runt-related transcription factor 2 (RUNX2) 3′-UTR and enhanced the RUNX2 mRNA stability. Moreover, RUNX2 could bind to the promoter region of NIS to block the differentiation of RR-PTC. Together, these results demonstrated that IGF2BP2 represents a diagnostic marker for RR-PTC, suggesting a novel differentiation therapeutic strategy of targeting IGF2BP2.
In Silico Designed Gain-of-Function Variants of Complement C2 Support Cytocidal Activity of Anticancer Monoclonal Antibodies
Authors: Urban Aleksandra , Majeranowski Alan , Stasiłojć Grzegorz , Koszałka Patrycja , Felberg Anna , Taszner Michał , Zaucha Jan M. , Okrój Marcin
Published: March 2022

The molecular target for the classical complement pathway (CP) is defined by surface-bound immunoglobulins. Therefore, numerous anticancer monoclonal antibodies (mAbs) exploit the CP as their effector mechanism. Conversely, the alternative complement pathway (AP) is spontaneously induced on the host and microbial surfaces, but complement inhibitors on host cells prevent its downstream processing. Gain-of-function (GoF) mutations in the AP components that oppose physiological regulation directly predispose carriers to autoimmune/inflammatory diseases. Based on the homology between AP and CP components, we modified the CP component C2 so that it emulates the known pathogenic mutations in the AP component, factor B. By using tumor cell lines and patient-derived leukemic cells along with a set of clinically approved immunotherapeutics, we showed that the supplementation of serum with recombinant GoF C2 variants not only enhances the cytocidal effect of type I anti-CD20 mAbs rituximab and ofatumumab, but also lowers the threshold of mAbs necessary for the efficient lysis of tumor cells and efficiently exploits the leftovers of the drug accumulated in patients’ sera after the previous infusion. Moreover, we demonstrate that GoF C2 acts in concert with other therapeutic mAbs, such as type II anti-CD20, anti-CD22, and anti-CD38 specimens, for overcoming cancer cells resistance to complement attack.
Risk Factors for Occurrence and Relapse of Soft Tissue Sarcoma
Authors: Weskamp Pia , Ufton Dominic , Drysch Marius , Wagner Johannes Maximilian , Dadras Mehran , Lehnhardt Marcus , Behr Björn , Wallner Christoph
Published: March 2022

The diagnosis and prognostic outcome of STS pose a therapeutic challenge in an interdisciplinary setting. The treatment protocols are still discussed controversially. This systematic meta-analysis aimed to determine prognostic factors leading to the development and recurrence of STS. Eligible studies that investigated potential risk factors such as smoking, genetic dispositions, toxins, chronic inflammation as well as prognostic relapse factors including radiation, chemotherapy and margins of resection were identified. Data from 24 studies published between 1993 and 2019 that comprised 6452 patients were pooled. A statistically significant effect developing STS was found in overall studies stating a causality between risk factors and the development of STS (p < 0.01). Although subgroup analysis did not meet statistical significances, it revealed a greater magnitude with smoking (p = 0.23), genetic predisposition (p = 0.13) chronic inflammation, (p = 0.20), and toxins (p = 0.14). Secondly, pooled analyses demonstrated a higher risk of relapse for margin of resection (p = 0.78), chemotherapy (p = 0.20) and radiation (p = 0.16); after 3 years of follow-up. Therefore, we were able to identify risk and relapse prognostic factors for STS, helping to diagnose and treat this low incidental cancer properly.
A Systematic Comparative Assessment of the Response of Ovarian Cancer Cells to the Chemotherapeutic Cisplatin in 3D Models of Various Structural and Biochemical Configurations—Does One Model Type Fit All?
Authors: Gupta Priyanka , Miller Aline , Olayanju Adedamola , Madhuri Thumuluru Kavitha , Velliou Eirini
Published: March 2022

Epithelial Ovarian Cancer (EOC) is a silent, deadly and aggressive gynaecological disease with a relatively low survival rate. This has been attributed, to some extent, to EOC’s high recurrence rate and resistance to currently available platinum-based chemotherapeutic treatment methods. Multiple groups have studied and reported the effect of chemotherapeutic agents on various EOC 3D in vitro models. However, there are very few studies wherein a direct comparative study has been carried out between the different in vitro 3D models of EOC and the effect of chemotherapy within them. Herein, we report, for the first time, a direct comprehensive systematic comparative study of three different 3D in vitro platforms, namely (i) spheroids, (ii) synthetic PeptiGels/hydrogels of various chemical configurations and (iii) polymeric scaffolds with coatings of various extracellular matrices (ECMs) on the cell growth and response to the chemotherapeutic (Cisplatin) for ovary-derived (A2780) and metastatic (SK-OV-3) EOC cell lines. We report that all three 3D models are able to support the growth of EOC, but for different time periods (varying from 7 days to 4 weeks). We have also reported that chemoresistance to Cisplatin, in vitro, observed especially for metastatic EOC cells, is platform-dependent, in terms of both the structural and biochemical composition of the model/platform. Our study highlights the importance of selecting an appropriate 3D platform for in vitro tumour model development. We have demonstrated that the selection of the best platform for producing in vitro tumour models depends on the cancer/cell type, the experimental time period and the application for which the model is intended.
Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas
Authors: Minson Adrian , Tam Constantine , Dickinson Michael , Seymour John F.
Published: March 2022

Targeted therapies continue to change the landscape of lymphoma treatment, resulting in improved therapy options and patient outcomes. Numerous agents are now approved for use in the indolent lymphomas and many others under development demonstrate significant promise. In this article, we review the landscape of targeted agents that apply to the indolent lymphomas, predominantly follicular lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia and marginal zone lymphoma. The review covers small molecule inhibitors, immunomodulators and targeted immunotherapies, as well as presenting emerging and promising combination therapies.