bluuebunny/crossref_metadata_2025 huggingface dataset:
Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3
Authors: Gebauer Lukas , Rafehi Muhammad , Brockmöller Jürgen
Published: October 2022

Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported (S)-norepinephrine, SERT preferred the (R)-enantiomer. In contrast, NET and DAT showed higher transport for (R)-epinephrine and SERT for (S)-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most (R)-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their (R)-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters.
Loss of Chemerin in Rhabdomyosarcoma Cells Polarizes Adjacent Monocytes to an Immunosuppressive Phenotype
Authors: Sun Rui , Lin Jia Le , Cheng Man Si , Lee Kang Yi , Spruss Thilo , Buechler Christa , Schwarz Herbert
Published: October 2022

Chemerin is a multifunctional adipokine that regulates adipogenesis, insulin signaling and blood pressure and has thus a central function in metabolism. Mounting evidence confirmed a function of chemerin in various cancers. In this study, we investigated the role of chemerin in rhabdomyosarcoma (RMS), an aggressive soft tissue cancer that affects mainly children and young adults. We found chemerin expression in 93.8% (90 of 96) of RMS cases, with a range of 86.7–96.7% for the four RMS subgroups. While chemerin is uniformly expressed in normal skeletal muscle, its expression in RMS is patchy with interspersed areas that are devoid of chemerin. This variable chemerin expression is reflected by RMS cell lines as two of them (Rh41 and Rd18) were found to secrete chemerin while the two other ones (JR1 and RD) were negative. Deletion of chemerin in Rh41 and Rd18 cells did not alter their growth rate or morphology. We investigated the potential influence of chemerin on immune surveillance by coculturing parental and chemerin-deficient RMS cells with resting- or lipopolysaccharide (LPS)-activated human peripheral monocytes. The absence of chemerin in the RMS cells led to increased expression levels of the coinhibitory molecules PD-L1 and PD-L2 while levels of the costimulatory molecule CD86 were not changed. Further, the absence of chemerin enhanced the secretion of cytokines (IL-1β, IL-6, IL-10 and TNF) that have been shown to support RMS pathogenesis. These data indicate that the loss of chemerin expression by RMS cells repolarizes monocytes in the tumor microenvironment to supporting tumor progression.
Identification of COPD Inflammatory Endotypes Using Repeated Sputum Eosinophil Counts
Authors: Beech Augusta , Jackson Natalie , Singh Dave
Published: October 2022

Higher blood and sputum eosinophil counts are associated with a greater response to corticosteroids in COPD. Low blood eosinophil counts exhibit greater stability over time whereas higher counts demonstrate more variability. Stability of airway eosinophil levels is less well understood. We have studied the stability of sputum eosinophil counts. Differential cell count data for COPD patients (n = 100) were analysed. Subjects with two sputum eosinophil counts, 6 months apart, were included in the analysis. Patients were stratified based on baseline sputum eosinophil count into ‘low’, ‘intermediate’ and ‘high’ groups: eosinophilLOW (<1%), eosinophilINT (1–3%) and eosinophilHIGH (≥3%). Sputum eosinophil counts showed good stability (rho = 0.61, p < 0.0001, ICC of 0.77), with 67.4% of eosinophilLOW patients remaining in the same category on repeat sampling. Bland–Altman analysis of the whole cohort (median difference between measurements = 0.00%, 90th percentile = −1.4 and 4.7%) showed greater variation at higher counts. This was confirmed by the wider 90th centiles in the eosinophilINT (−1.50 to 5.65) and eosinophilHIGH groups (−5.33 to 9.80) compared to the eosinophilLOW group (−0.40 to 1.40). The repeatability of sputum eosinophil counts was related to the baseline eosinophil count; sputum eosinophilLOW COPD patients were relatively stable over time, while the eosinophilHIGH group showed greater variability. These results can facilitate the identification of COPD endotypes with differential responses to treatment.
A Touchscreen Device for Behavioral Testing in Pigs
Authors: Ao Will , Grace Megan , Floyd Candace L. , Vonder Haar Cole
Published: October 2022

Pigs are becoming more common research models due to their utility in studying neurological conditions such as traumatic brain injury, Alzheimer’s disease, and Huntington’s Disease. However, behavioral tasks often require a large apparatus and are not automated, which may disinterest researchers in using important functional measures. To address this, we developed a touchscreen that pigs could be trained on for behavioral testing. A rack-mounted touchscreen monitor was placed in an enclosed, weighted audio rack. A pellet dispenser was operated by a radio frequency transceiver to deliver fruit-flavored sugar pellets from across the testing room. Programs were custom written in Python and executed on a microcomputer. A behavioral shaping program was designed to train pigs to interact with the screen and setup responses for future tasks. Pigs rapidly learned to interact with the screen. To demonstrate efficacy in more complex behavior, two pigs were trained on a delay discounting tasks and two pigs on a color discrimination task. The device held up to repeated testing of large pigs and could be adjusted to the height of minipigs. The device can be easily recreated and constructed at a relatively low cost. Research topics ranging from brain injury to pharmacology to vision could benefit from behavioral tasks designed to specifically interrogate relevant function. More work will be needed to develop tests which are of specific relevance to these disciplines.
Bronchial Asthma as a Cardiovascular Risk Factor: A Prospective Observational Study
Authors: Kreslová Marcela , Kirchnerová Olga , Rajdl Daniel , Sudová Vendula , Blažek Jiří , Sýkorová Aneta , Jehlička Petr , Trefil Ladislav , Schwarz Jan , Pomahačová Renata , Sýkora Josef
Published: October 2022

Introduction: Asthma as a chronic inflammatory disorder has been suggested as a risk factor for endothelial dysfunction (ED), but studies on the association between asthma and cardiovascular disease (CVD) risk are limited. Background: We assessed associations of ED with the severity of asthma, eosinophilic inflammation, lung function, and asthma control. Methods: 52 young asthmatics (median age of 25.22 years) and 45 healthy individuals were included. Demographic, clinical, and laboratory findings were recorded. We evaluated microvascular responsiveness by recording the reactive hyperemia index (RHI) indicating post-occlusive peripheral endothelium-dependent changes in vascular tone using the Itamar Medical EndoPAT2000. VCAM-1, ADMA, high-sensitive CRP (hsCRP), and E-selectin were measured. Results: Asthmatics had considerably lower RHI values (p < 0.001) with a dynamic decreasing trend by asthma severity and higher hsCRP levels (p < 0.001). A substantial increase in hsCRP and E-selectin with asthma severity (p < 0.05) was also observed. We confirmed a higher body mass index (BMI) in asthmatics (p < 0.001), especially in women and in severe asthma. Conclusions: We demonstrated the progression of CVD in asthmatics and the association of the ongoing deterioration of ED with the inflammatory severity, suggesting that the increased risk of CVD in young asthmatics is dependent on disease severity. The underlying mechanisms of risk factors for CVD and disease control require further study.
Endothelial Progenitor Cells in Neurovascular Disorders—A Comprehensive Overview of the Current State of Knowledge
Authors: Rudnicka-Drożak Ewa , Drożak Paulina , Mizerski Grzegorz , Drożak Martyna
Published: October 2022

Endothelial progenitor cells (EPCs) are a population of cells that circulate in the blood looking for areas of endothelial or vascular injury in order to repair them. Endothelial dysfunction is an important component of disorders with neurovascular involvement. Thus, the subject of involvement of EPCs in such conditions has been gaining increasing scientific interest in recent years. Overall, decreased levels of EPCs are associated with worse disease outcome. Moreover, their functionalities appear to decline with severity of disease. These findings inspired the application of EPCs as therapeutic targets and agents. So far, EPCs appear safe and promising based on the results of pre-clinical studies conducted on their use in the treatment of Alzheimer’s disease and ischemic stroke. In the case of the latter, human clinical trials have recently started to be performed in this subject and provided optimistic results thus far. Whereas in the case of migraine, existing findings pave the way for testing EPCs in in vitro studies. This review aims to thoroughly summarize current knowledge on the role EPCs in four disorders with neurovascular involvement, which are Alzheimer’s disease, cerebral small vessel disease, ischemic stroke and migraine, with a particular focus on the potential practical use of these cells as a treatment remedy.
Treatment Assessment of pNET and NELM after Everolimus by Quantitative MRI Parameters
Authors: Ingenerf Maria , Kiesl Sophia , Winkelmann Michael , Auernhammer Christoph J. , Rübenthaler Johannes , Grawe Freba , Fabritius Matthias P. , Ricke Jens , Schmid-Tannwald Christine
Published: October 2022

Assessment of treatment response to targeted therapies such as everolimus is difficult, especially in slow-growing tumors such as NETs. In this retrospective study, 17 patients with pancreatic neuroendocrine tumors (pNETs) and hepatic metastases (NELMs) (42 target lesions) who received everolimus were analyzed. Intralesional signal intensities (SI) of non-contrast T1w, T2w and DCE imaging, and apparent diffusion coefficients (ADCmean and ADCmin) of DWI, were measured on baseline and first follow-up MRI after everolimus initiation. Response assessment was categorized according to progression-free survival (PFS), with responders (R) showing a PFS of ≥11 months. ADCmin of NELMs decreased in Rs whereas it increased in non-responders (NR). Percentual changes of ADCmin and ADCmean differed significantly between response groups (p < 0.03). By contrast, ADC of the pNETs tended to increase in Rs, while there was no change in NRs. Tumor-to-liver (T/L) ratio of T1 SI of NELMs increased in Rs and decreased in NRs, and percentual changes differed significantly between response groups (p < 0.02). T1 SI of the pNETs tended to decrease in Rs and increase in Ns. The quotient of pretherapeutic and posttherapeutic ADCmin values (DADCmin) and length of everolimus treatment showed significant association with PFS in univariable Cox analysis. In conclusion, quantitative MRI, especially DWI, seems to allow treatment assessment of pNETs with NELMs under everolimus. Interestingly, the responding NELMs showed decreasing ADC values, and there might be an opposite effect on ADC and T1 SI between NELMs and pNETs.
Non Coding RNAs as Regulators of Wnt/β-Catenin and Hippo Pathways in Arrhythmogenic Cardiomyopathy
Authors: Piquer-Gil Marina , Domenech-Dauder Sofía , Sepúlveda-Gómez Marta , Machí-Camacho Carla , Braza-Boïls Aitana , Zorio Esther
Published: October 2022

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy histologically characterized by the replacement of myocardium by fibrofatty infiltration, cardiomyocyte loss, and inflammation. ACM has been defined as a desmosomal disease because most of the mutations causing the disease are located in genes encoding desmosomal proteins. Interestingly, the instable structures of these intercellular junctions in this disease are closely related to a perturbed Wnt/β-catenin pathway. Imbalance in the Wnt/β-catenin signaling and also in the crosslinked Hippo pathway leads to the transcription of proadipogenic and profibrotic genes. Aiming to shed light on the mechanisms by which Wnt/β-catenin and Hippo pathways modulate the progression of the pathological ACM phenotype, the study of non-coding RNAs (ncRNAs) has emerged as a potential source of actionable targets. ncRNAs comprise a wide range of RNA species (short, large, linear, circular) which are able to finely tune gene expression and determine the final phenotype. Some share recognition sites, thus referred to as competing endogenous RNAs (ceRNAs), and ensure a coordinating action. Recent cancer research studies regarding the key role of ceRNAs in Wnt/β-catenin and Hippo pathways modulation pave the way to better understanding the molecular mechanisms underlying ACM.
SARS-CoV-2-on-Chip for Long COVID Management
Authors: Cherusseri Jayesh , Savio Claire Mary , Khalid Mohammad , Chaudhary Vishal , Numan Arshid , Varma Sreekanth J. , Menon Amrutha , Kaushik Ajeet
Published: October 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a “wicked evil” in this century due to its extended progression and huge human mortalities. Although the diagnosis of SARS-CoV-2 viral infection is made simple and practical by employing reverse transcription polymerase chain reaction (RT-PCR) investigation, the process is costly, complex, time-consuming, and requires experts for testing and the constraints of a laboratory. Therefore, these challenges have raised the paradigm of on-site portable biosensors on a single chip, which reduces human resources and enables remote access to minimize the overwhelming burden on the existing global healthcare sector. This article reviews the recent advancements in biosensors for long coronavirus disease (COVID) management using a multitude of devices, such as point-of-care biosensors and lab-on-chip biosensors. Furthermore, it details the shift in the paradigm of SARS-CoV-2-on-chip biosensors from the laboratory to on-site detection with intelligent and economical operation, representing near-future diagnostic technologies for public health emergency management.
Universal Lifespan Trajectories of Source-Space Information Flow Extracted from Resting-State MEG Data
Authors: Dimitriadis Stavros I.
Published: October 2022

Source activity was extracted from resting-state magnetoencephalography data of 103 subjects aged 18–60 years. The directionality of information flow was computed from the regional time courses using delay symbolic transfer entropy and phase entropy. The analysis yielded a dynamic source connectivity profile, disentangling the direction, strength, and time delay of the underlying causal interactions, producing independent time delays for cross-frequency amplitude-to-amplitude and phase-to-phase coupling. The computation of the dominant intrinsic coupling mode (DoCM) allowed me to estimate the probability distribution of the DoCM independently of phase and amplitude. The results support earlier observations of a posterior-to-anterior information flow for phase dynamics in {α1, α2, β, γ} and an opposite flow (anterior to posterior) in θ. Amplitude dynamics reveal posterior-to-anterior information flow in {α1, α2, γ}, a sensory-motor β-oriented pattern, and an anterior-to-posterior pattern in {δ, θ}. The DoCM between intra- and cross-frequency couplings (CFC) are reported here for the first time and independently for amplitude and phase; in both domains {δ, θ, α1}, frequencies are the main contributors to DoCM. Finally, a novel brain age index (BAI) is introduced, defined as the ratio of the probability distribution of inter- over intra-frequency couplings. This ratio shows a universal age trajectory: a rapid rise from the end of adolescence, reaching a peak in adulthood, and declining slowly thereafter. The universal pattern is seen in the BAI of each frequency studied and for both amplitude and phase domains. No such universal age dependence was previously reported.
Full-Scale Testing on Seismic Performance of Surge Arrester with Retrofitted Composite Insulators
Authors: Li Sheng , Cheng Yongfeng , Lu Zhicheng , Lam Nelson , Xue Yaodong , Wang Haibo
Published: October 2022

In electrical substations, glass-fibre reinforced polymer (GFRP) insulators provide an alternative to porcelain insulators for better seismic performance. The bonded connection between the composite tube and the metal end fitting is a weak link under earthquake actions, and the failure risk of ultra-high voltage (UHV) substation equipment with GFRP composite insulators can be considerable in places with high seismicity. This study solved the problem by retrofitting and experimentally qualifying the seismic performance of surge arresters made of composite insulators. To ensure safety under a bending moment corresponding to the seismic demand, the bonded sleeve joint between the tube and end fitting was retrofitted by shear stiffeners and higher strength end fitting. A full-scale shaking table test was carried out to verify the performance of the retrofitted surge arrester, and the seismic responses to increasing earthquake actions were analyzed. The specimens in this study were full-scale, had the largest dimensions among substation equipment of the same type, and were subjected to an extremely high earthquake action of 0.5 g; therefore, the seismic testing results produced in this study can serve as an important reference for the industry.
Numerical Investigation on Fire Performance of LSF and Steel Modular Floor Panels
Authors: Perera Dilini , Upasiri Irindu R , Poologanathan Keerthan , O’Grady Kate , Nagaratnam Brabha , Kanthasamy Elilarasi , Rajanayagam Heshachanaa
Published: October 2022

The steel Modular Building Systems (MBSs) that have been influenced by the Light-gauge Steel Frame (LSF) techniques have become a prominent culture in the industry. However, the detrimental behaviour of steel structural components at high temperatures has elevated the risk of fatal accidents in the event of a fire. Although several research investigations have addressed the fire performance of steel modular wall systems, the behaviour of modular floor systems has not been adequately addressed in the state of the art. Hence, to promote the fire safety and optimum design techniques in the modular construction industry by addressing the aforementioned research gap, this study investigated 48 conventional LSF and MBS floors for their structural and insulation Fire Resistance Levels using Finite Element Modelling (FEM) and Heat Transfer Analyses (HTA) techniques. Initially, full-scale experimental fire tests were modelled using FEM methods, and the validity of the techniques was verified prior to the analyses of parametric floor systems. Furthermore, the structural behaviour of the channel section joists in the elevated temperatures was studied, and hence a correlation was established to determine the critical steel temperature at the structural fire failure with respect to the applied Load Ratio (LR). An additional 12.5 mm thick plasterboard sheathing on single plasterboard sheathed floors resulted a 30 min improvement in structural and insulation FRLs. In addition, the modular floor systems demonstrated enhanced structural and insulation Fire Resistance Levels (FRLs) against the corresponding conventional LSF floor designs due to double LSF skin build-up. The incorporation of rockwool insulation and the increase in the insulation volume implied increased structural and fire performances. However, insulation material in the modular designs was more effective. The fire-rated conventional and modular LSF floor systems are expected to be practised in the construction industry to achieve required fire resistances with optimum material usage.
Rural Space Aesthetics and Rural Construction Paths from the Perspective of the Montage: The Cases of Seven Villages in Guangdong, China
Authors: Wang Zhongwei , Zhuang Qianda , Ma Yue , Li Pengnan
Published: October 2022

In the rural areas of China, construction is growing vigorously, and the question of how to realize the creative inheritance and development of these areas in the regional context, as well as the exploration of new construction methods and paths, are important problems. Nowadays, there are two developing trends in terms of research methods. Firstly, the boundaries between various disciplines are becoming increasingly blurred, and interdisciplinary theoretical reference has become an effective means of realizing innovation in this field. The other trend relates to the great development of digital technology, such as parameterization and spatial information technology. This technological innovation sheds new light on rural image construction. This study aims to draw on the montage art concept and organization techniques and to integrate the new technical language into the construction of new aesthetic orientations and context-related inheritance paths of rural historical places in China. Based on the aesthetic relevance of montage aesthetics to rural regional characteristics, the aesthetic cognition of the rural area in Guangdong is analyzed and demonstrated. Then, the strategies and methods used for the construction of rural area are established based on four layers, i.e., the narrative clues, base site pattern, spatial interfaces and monomer construction. The present research expands on the perspectives and methods of rural reconstruction, provides new ideas for the current rural practice, and is conducive to promoting the systematic study of rural construction theory.
Progressive Collapse Resistance of RC Beam–Slab Substructures Made with Rubberized Concrete
Authors: Alshaikh Ibrahim M. H. , Abadel Aref A. , Sennah Khaled , Nehdi Moncef L. , Tuladhar Rabin , Alamri Mohammed
Published: October 2022

Abnormal loads can produce localized damage that can eventually cause progressive collapse of the whole reinforced concrete (RC) structure. This might have devastating financial repercussions and cause numerous severe casualties. Numerical simulation, using the finite element method (FEM), of the consequences of abnormal loads on buildings is thus required to avoid the significant expenses associated with testing full-scale buildings and to save time. In this paper, FEM simulations, using ABAQUS software, were employed to investigate the progressive collapse resistance of the full-scale three-dimensional (3D) beam–slab substructures, considering two concrete mixes, namely: normal concrete (NC) and rubberized concrete (RuC) which was made by incorporating crumb rubber at 20% by volume replacement for sand. The FEM accuracy and dependability were validated using available experimental test results. Concrete and steel material non-linearity were considered in the FE modelling. The numerical study is extended to include eight new models with various specifics (a set of parameters) for further understanding of progressive collapse. Results showed that slabs contribute more than a third of the load resistance, which also significantly improves the building’s progressive collapse resistance. Moreover, the performance of the RuC specimens was excellent in the catenary stage, which develops additional resilience to significant deformation to prevent or even mitigate progressive collapse.
Research on the Shear Behaviour of Composite Shear Connectors
Authors: Xue Chengfeng , Fan Zhou , Wu Fangwen , Liu Laijun , He Lanqing , Cui Xuan
Published: October 2022

In order to make full use of the advantages of welded stud and perfobond rib shear connectors, a new type of composite shear connector is proposed. Studs are welded to the perforated steel plate of the PBL connectors. Six specimens were designed and tested to investigate the shear behaviour of the composite connectors. The effects of the hole number, welded stud number, and end-bearing modes on the shear behaviour of the composite connectors were discussed. In addition, the composite connectors were compared with the conventional welded stud and perfobond rib connectors to analyse the difference in shear performance. The composite connectors’ shear behaviours are significantly better than those of welded stud connectors and PBL connectors. The experimental results show that increasing the number of welded studs and perforated holes and end-bearing concrete can significantly improve the shear performance of composite connectors. Secondly, a finite element model was established considering the nonlinearity of the structure and was validated based on the experimental results. Finally, the effects of reinforcement diameter, welded stud diameter, and concrete strength on the shear performance of composite connectors were analysed. The shear resistance increases as the penetrating rebar diameter, welded stud diameter, and concrete strength increase. Moreover, the overall damage level of the concrete can be significantly affected.
Stochastic Semi-Physical Model for Nonstationary Spatially Variable Ground Motions in an Engineering Site
Authors: Miao Huiquan , Ding Yanqiong , Shen Jiaxu
Published: October 2022

Spatially variable ground motions are crucial for the seismic analysis and design of extended and multi-support structures. In this study, a new random nonstationary spatially variable ground motion model based on the propagation process of seismic waves is proposed. In particular, the amplitude and phase transfer functions of seismic waves at the local site are studied herein. The probability density function of the corresponding parameters is given. Two simple examples are used to show the generation of random ground motions. Compared with traditional methods, our proposed model not only has a clear physical background but also shows good practicability. The model should be for those researchers who want to use nonstationary spatially variable ground motions to study the seismic response of lifeline systems or building portfolios.
Comment on Kesić et al. Early Diagnostics of Vulvar Intraepithelial Neoplasia. Cancers 2022, 14, 1822
Authors: De Giorgi Vincenzo , Magnaterra Elisabetta , Magliulo Manfredi , Silvestri Flavia , Venturi Federico , Zuccaro Biancamaria , Colombo Jacopo , Trane Luciana
Published: October 2022

We have read with great interest the paper by Kesić, V. et al. entitled “Early Diagnostics of Vulvar Intraepithelial Neoplasia” [...]
Reply to De Giorgi et al. Comment on “Kesić et al. Early Diagnostics of Vulvar Intraepithelial Neoplasia. Cancers 2022, 14, 1822”
Authors: Kesić Vesna , Vieira-Baptista Pedro , Stockdale Colleen K.
Published: October 2022

We thank you and your co-authors for the comment [...]
Challenges and Learning Curves in Adopting TaTME and Robotic Surgery for Rectal Cancer: A Cusum Analysis
Authors: Planellas Pere , Cornejo Lídia , Pigem Anna , Gómez-Romeu Núria , Julià-Bergkvist David , Ortega Nuria , Rodríguez-Hermosa José Ignacio , Farrés Ramon
Published: October 2022

New techniques are being developed to improve the results of laparoscopic surgery for rectal cancer. This paper analyzes the learning curves for transanal total mesorectal excision (taTME) and robot-assisted surgery in our colorectal surgery department. We analyzed retrospectively data from patients undergoing curative and elective surgery for rectal cancer ≤12 cm from the anal verge. We excluded extended surgeries. We used cumulative sum (CUSUM) curve analysis to identify inflection points. Between 2015 and 2021, 588 patients underwent surgery for rectal cancer at our center: 67 taTME and 79 robot-assisted surgeries. To overcome the operative time learning curve, 14 cases were needed for taTME and 53 for robot-assisted surgery. The morbidity rate started to decrease after the 17th case in taTME and after the 49th case in robot-assisted surgery, but it is much less abrupt in robot-assisted group. During the initial learning phase, the rate of anastomotic leakage was higher in taTME (35.7% vs. 5.7%). Two Urological lesions occurred in taTME but not in robot-assisted surgery. The conversion rate was higher in robot-assisted surgery (1.5% vs. 10.1%). Incorporating new techniques is complex and entails a transition period. In our experience, taTME involved a higher rate of serious complications than robot-assisted surgery during initial learning period but required a shorter learning curve.
miR-214-Enriched Extracellular Vesicles Released by Acid-Adapted Melanoma Cells Promote Inflammatory Macrophage-Dependent Tumor Trans-Endothelial Migration
Authors: Andreucci Elena , Ruzzolini Jessica , Bianchini Francesca , Versienti Giampaolo , Biagioni Alessio , Lulli Matteo , Guasti Daniele , Nardini Patrizia , Serratì Simona , Margheri Francesca , Laurenzana Anna , Nediani Chiara , Peppicelli Silvia , Calorini Lido
Published: October 2022

The understanding of the molecular mechanisms leading to melanoma dissemination is urgently needed in view of the identification of new targets and the development of innovative strategies to improve patients’ outcomes. Within the complexity of tumor intercellular communications leading to metastatic dissemination, extracellular vesicles (EV) released by tumor cells are central players. Indeed, the ability to travel through the circulatory system conveying oncogenic bioactive molecules even at distant sites makes EV capable of modulating recipient cells to facilitate metastatic dissemination. The dynamic remodeling of the tumor microenvironment might influence, along with a number of other events, tumoral EV release. We observed that, in melanoma, extracellular acidosis increases the release of EV enriched in miR-214, an onco-miRNA involved in melanoma metastasis. Then, miR-214-enriched EV were found to induce a state of macrophage activation, leading to an overproduction of proinflammatory cytokines and nitric oxide. Such an inflammatory microenvironment was able to alter the endothelial cell permeability, thereby facilitating the trans-endothelial migration of melanoma cells, a crucial step in the metastatic cascade. The use of synthetic miR-214 inhibitors and miR-214 overexpression allowed us to demonstrate the key role of miR-214 in the EV-dependent induction of macrophage activation. Overall, our in vitro study reveals that the release of tumor miR-214-enriched EV, potentiated by adapting tumor cells to extracellular acidosis, drives a macrophage-dependent trans-endothelial migration of melanoma cells. This finding points to miR-214 as a potential new therapeutic target to prevent melanoma intravasation.
Nanomedicine-Based Gene Delivery for a Truncated Tumor Suppressor RB94 Promotes Lung Cancer Immunity
Authors: Kim Sang-Soo , Doherty Caroline , Moghe Manish , Rait Antonina , Pirollo Kathleen F. , Harford Joe B. , Chang Esther H.
Published: October 2022

Because lung cancer remains the most common and lethal of cancers, novel therapeutic approaches are urgently needed. RB94 is a truncated form of retinoblastoma tumor suppressor protein with elevated anti-tumor efficacy. Our investigational nanomedicine (termed scL-RB94) is a tumor-targeted liposomal formulation of a plasmid containing the gene encoding RB94. In this research, we studied anti-tumor and immune modulation activities of scL-RB94 nanocomplex in preclinical models of human non-small cell lung cancer (NSCLC). Systemic treatment with scL-RB94 of mice bearing human NSCLC tumors significantly inhibited tumor growth by lowering proliferation and increasing apoptosis of tumor cells in vivo. scL-RB94 treatment also boosted anti-tumor immune responses by upregulating immune recognition molecules and recruiting innate immune cells such as natural killer (NK) cells. Antibody-mediated depletion of NK cells blunted the anti-tumor activity of scL-RB94, suggesting that NK cells were crucial for the observed anti-tumor activity in these xenograft models. Treatment with scL-RB94 also altered the polarization of tumor-associated macrophages by reducing immune-suppressive M2 macrophages to lower immune suppression in the tumor microenvironment. Collectively, our data suggest that the efficacy of scL-RB94 against NSCLC is due to an induction of tumor cell death as well as enhancement of innate anti-tumor immunity.
Evolution of Head and Neck Cutaneous Squamous Cell Carcinoma Nodal Staging—An Australian Perspective
Authors: Hurrell Michael J. L. , Low Tsu-Hui (Hubert) , Ebrahimi Ardalan , Veness Michael , Ashford Bruce , Porceddu Sandro , Clark Jonathan R.
Published: October 2022

Cutaneous squamous cell carcinoma of the head and neck (HNcSCC) is one of the commonest malignancies. When patients present with regional metastatic disease, treatment escalation results in considerable morbidity and survival is markedly reduced. Owing to the high incidence, Australian institutions have been at the forefront of advocating for reliable, accurate, and clinically useful staging systems that recognise the distinct biological characteristics of HNcSCC. As a result, an extensive body of literature has been produced over the past two decades, which has defined critical prognostic factors, critiqued existing staging systems, and proposed alternative staging models. Notwithstanding, a suitable staging system has proved elusive. The goal of cancer staging is to group patients according to cancer characteristics for which survival differs between groups (distinctiveness), consistently decreases with increasing stage (monotonicity), and is similar within a group (homogeneity). Despite implementing major changes based on published data, the latest edition of the American Joint Committee on Cancer (AJCC) staging manual fails to satisfy these fundamental requirements. This review chronologically explores and summarises the Australian contribution to prognostication and nodal staging of HNcSCC and highlights the ongoing challenges.
Mayo Clinic Clival Chordoma Case Series: Impact of Endoscopic Training on Clinical Care
Authors: Hong Sukwoo , Laack Nadia , Mahajan Anita , O’Brien Erin K. , Stokken Janalee K. , Janus Jeffrey R. , Choby Garret , Van Gompel Jamie J.
Published: October 2022

The management of clival chordoma in our group shifted around 2013 to mostly endoscopic, and proton beam was introduced for our multidisciplinary team. Consecutive patients who had surgical resection from 1987 to 2021 were reviewed. A total of 58 patients (39 patients after 2013) were analyzed. The mean tumor size was 3.7 cm, and the most common location was the upper clivus (43%). Compared to before 2013, after 2013, the endoscopic endonasal approach was more common (90%, p < 0.001), and more gross or near total resections (64%, p = 0.002) were attained. Ten cases (17%) were revision surgeries referred from elsewhere, and three cases (5%) underwent additional surgery elsewhere before adjuvant radiation. The postoperative cerebrospinal fluid leak occurred in 7%. Post-operative new cranial nerve deficits occurred in 32% before 2013, compared to 2.6% after 2013 (p = 0.004). For cases before 2013, 10 patients (53%) recurred during the median follow-up of 144 months (mean, 142 months), whereas for cases after 2013, seven patients (18%) recurred with a median follow-up of 35 months (mean, 42 months). 5-year progression-free survival was 58%, and 5-year overall survival was 87%. A specialized multidisciplinary team improved the resection rate compared to a historical cohort with an excellent morbidity profile.
Exploration of a Novel Circadian miRNA Pair Signature for Predicting Prognosis of Lung Adenocarcinoma
Authors: Yin Zhengrong , Deng Jingjing , Zhou Mei , Li Minglei , Zhou E , Liu Jiatong , Jia Zhe , Yang Guanghai , Jin Yang
Published: October 2022

Lung adenocarcinoma (LUAD) is the primary histological subtype of lung cancer with a markedly heterogeneous prognosis. Therefore, there is an urgent need to identify optimal prognostic biomarkers. We aimed to explore the value of the circadian miRNA (cmiRNA) pair in predicting prognosis and guiding the treatment of LUAD. We first retrieved circadian genes (Cgenes) from the CGDB database, based on which cmiRNAs were predicted using the miRDB and mirDIP databases. The sequencing data of Cgenes and cmiRNAs were retrieved from TCGA and GEO databases. Two random cmiRNAs were matched to a single cmiRNA pair. Finally, univariate Cox proportional hazard analysis, LASSO regression, and multivariate Cox proportional hazard analysis were performed to develop a prognostic signature consisting of seven cmiRNA pairs. The signature exhibited good performance in predicting the overall and progression-free survival. Patients in the high-risk group also showed lower IC50 values for several common chemotherapy and targeted medicines. In addition, we constructed a cmiRNA–Cgenes network and performed a corresponding Gene Ontology and Gene Set enrichment analysis. In conclusion, the novel circadian-related miRNA pair signature could provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for LUAD.
Advances and Hurdles in CAR T Cell Immune Therapy for Solid Tumors
Authors: Boccalatte Francesco , Mina Roberto , Aroldi Andrea , Leone Sarah , Suryadevara Carter M. , Placantonakis Dimitris G. , Bruno Benedetto
Published: October 2022

Chimeric antigen receptor (CAR) T cells in solid tumors have so far yielded limited results, in terms of therapeutic effects, as compared to the dramatic results observed for hematological malignancies. Many factors involve both the tumor cells and the microenvironment. The lack of specific target antigens and severe, potentially fatal, toxicities caused by on-target off-tumor toxicities constitute major hurdles. Furthermore, the tumor microenvironment is usually characterized by chronic inflammation, the presence of immunosuppressive molecules, and immune cells that can reduce CAR T cell efficacy and facilitate antigen escape. Nonetheless, solid tumors are under investigation as possible targets despite their complexity, which represents a significant challenge. In preclinical mouse models, CAR T cells are able to efficiently recognize and kill several tumor xenografts. Overall, in the next few years, there will be intensive research into optimizing novel cell therapies to improve their effector functions and keep untoward effects in check. In this review, we provide an update on the state-of-the-art CAR T cell therapies in solid tumors, focusing on the preclinical studies and preliminary clinical findings aimed at developing optimal strategies to reduce toxicity and improve efficacy.
Exponential Slope from Absolute Lymphocyte Counts during Radio-Chemotherapy Can Predict an Aggressive Course of Cervical Cancer
Authors: Cho Oyeon , Chun Mison , Chang Suk-Joon
Published: October 2022

This study aimed to investigate whether the exponential slope α from absolute lymphocyte counts during concurrent radio–chemotherapy (CRT) is associated with aggressive and non-aggressive courses of cervical cancer. We analyzed 362 patients with stage IB–IVB cervical cancer treated with CRT in two groups: 323 patients without mRNA data (cohort 1) and 39 with mRNA data (cohort 2) from plasma exosomes. We calculated the α of each patient; 69 patients who died of cancer in cohort 1 were divided into 44 who died within 30 months (aggressive group), and 25 who died after more than 30 months (non-aggressive group). The median follow-up periods of cohorts 1 and 2 were 63 and 28 months, respectively. The log2 fold change (log2FC) between read counts of mRNAs before treatment and after the second week of CRT was calculated. Multivariate analyses from cohort 1 showed that neutrophil-to-lymphocyte ratio (NLR) ≥ 2.43 and α < 0.08 were statistically significant predictors of disease-specific survival (DSS) in the aggressive group (DSS-A), whereas α ≥ 0.08 was the only significant predictor of DSS in the non-aggressive group (DSS-NA). The 2.5-year DSS-A and 8-year DSS-NA rates of patients with α ≥ 0.08 and α < 0.08 were 86.7% and 73%, and 78.5% and 94.8% in the high-NLR group, respectively. In cohort 2, patients with both NLR < 2.7 and α ≥ 0.07 had a higher 2.5-year DSS rate than did those with either NLR ≥ 2.72 or α < 0.07. E2F8 and STX6 significantly correlated with ɑ and survival. The 2.5-year DSS rates in patients with E2F8 + STX6 (log2FC) < 0.2429 and ≥0.2429 were 100% and 77.2%, respectively. The exponential slope α can potentially distinguish between aggressive and non-aggressive courses in cervical cancer patients.
Highly Efficient Synthesis of Cinnamamides from Methyl Cinnamates and Phenylethylamines Catalyzed by Lipozyme® TL IM under Continuous-Flow Microreactors
Authors: Du Lihua , Zheng Lingyan , Pan Yue , Sheng Zhikai , Zhang Shiyi , Lin Hang , Zhang Aoying , Xie Hanjia , Luo Xiping
Published: October 2022

While a few derivatives of cinnamamides exhibited anti-inflammatory and/ or analgesic activity, in this study, we developed a highly efficient method for the synthesis of cinnamamides from methyl cinnamates and phenylethylamines catalyzed by Lipozyme® TL IM in continuous-flow microreactors. The reaction parameters and broad substrate range of the new method was studied. Maximum conversion (91.3%) was obtained under the optimal condition of substrate molar ratio of 1:2 (methyl 4-chlorocinnamate: phenylethylamine) at 45 °C for about 40 min. The remarkable features of this work include short residence time, mild reaction conditions, easy control of the reaction process, and that the catalyst can be recycled or reused, which provide a rapid and economical strategy for the synthesis and design of cinnamamide derivatives for further research on drug activity.
Surface Modification of GdMn2O5 for Catalytic Oxidation of Benzene via a Mild A-Site Sacrificial Strategy
Authors: Gao Ju , Dong Xu , Li Zhenguo , Shao Yuankai , Ren Xiaoning , Li Kaixiang , Lu Yiren
Published: October 2022

Thermal catalytic oxidation technology is an effective way to eliminate refractory volatile organic pollutants, such as Benzene. Nevertheless, a high reaction temperature is usually an obstacle to practical application. Here, GdMn2O5 mullite (GMO-H) catalyst with disordered surface Gd-deficient and oxygen-vacancy-rich concentrations was synthesized via a controllable low-temperature acid-etching route. Results show that the preferentially broken Gd-O bond is conducive to exposing more Mn-Mn active sites, which Gd species covered. The affluent surface oxygen vacancies supply sufficient adsorption sites for oxygen molecules, facilitating the oxygen cycles during Benzene catalytic oxidation. Furthermore, surface exposed Mn3+ species were oxidized to Mn4+, which is beneficial to increase catalytic activity at a lower temperature. Compared with the conventional GdMn2O5, the reaction temperature for removing 90% Benzene over GMO-H was dropped from 405 to 310 °C with WHSV of 30,000 mL g−1 h−1. Significantly, during a 72 h catalytic test, the catalytic activity remains constant at 90% of the Benzene removal at 300 °C, indicating excellent activity stability. This work reported an efficient approach to preparing manganese-base mullite thermal catalyst, providing insight into the catalytic oxidation of Benzene.
Solar Light-Induced Photocatalytic Degradation of Ciprofloxacin Antibiotic Using Biochar Supported Nano Bismuth Ferrite Composite
Authors: Mohd Azan Nur Azra Aqilah , Sagadevan Suresh , Mohamed Abdul Rahman , Nor Azazi Amirul Hazwan , Suah Faiz Bukhari Mohd , Kobayashi Takaomi , Adnan Rohana , Mohd Kaus Noor Haida
Published: October 2022

Research on advanced materials for environmental remediation and pollutant degradation is rapidly progressing because of their numerous applications. Biochar is an excellent material support for the catalytic activity of bismuth ferrite (BiFeO3), which is one of the best perovskite-based photocatalysts in this work for diverse pollutant degradation when exposed to direct sunlight. Biochar was produced by pyrolyzing oil palm empty fruit bunches (OPEFBs) and then integrate with BiFeO3 in the presence of cross-linked chitosan to create a BFO/biochar coupled magnetic photocatalyst (CBB). This research was conducted to examine the performance of the photocatalytic activity of CBB towards the degradation of ciprofloxacin antibiotics. To determine the optimal condition, two operational parameters that are photocatalyst dosage and initial pollutant concentrations, were evaluated. The results of the powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscope-energy dispersive X-ray (SEM-EDX) analyses confirmed the high purity of the rhombohedral BiFeO3 with a high surface area, as well as the successful coupling of BiFeO3 and biochar at a ratio of 1:1. The most effective conditions for the various variables are 1.5 g/L CBB dosage at 10 ppm with 77.08% photodegradation under direct sunlight for 2 h. Further, a pseudo-first-order kinetic reaction was followed and observed with decreasing k values as the initial concentration increased. This shows that the system performs best at low concentrations. This finding confirms that the catalytic parameters improved the efficiency of photocatalysts with biochar assistance in removing antibiotic pollutants.
Enhancing NO Uptake in Metal-Organic Frameworks via Linker Functionalization. A Multi-Scale Theoretical Study
Authors: Livas Charalampos G. , Tylianakis Emmanuel , Froudakis George E.
Published: October 2022

In the present work, ab initio calculations and Monte Carlo simulations were combined to investigate the effect of linker functionalization on nitric oxide (NO)’s storage ability of metal–organic frameworks (MOFs). The binding energy (BE) of nitric oxide with a set of forty-two strategically selected, functionalized benzenes was investigated using Density Functional Theory calculations at the RI-DSD-BLYP/def2-TZVPP level of theory. It was found that most of the functional groups (FGs) increased the interaction strength compared to benzene. Phenyl hydrogen sulfate (–OSO3H) was the most promising among the set of ligands, with an enhancement of 150%. The organic linker of IRMOF-8 was modified with the three top-performing functional groups (–OSO3H, –OPO3H2, –SO3H). Their ability for NO adsorption was investigated using Grand Canonical Monte Carlo (GCMC) simulations at an ambient temperature and a wide pressure range. The results showed great enhancement in NO uptake constituting the above-mentioned FGs, suggesting them to be promising modification candidates in a plethora of porous materials.