bluuebunny/crossref_metadata_2025 huggingface dataset:
Challenges involved in cell therapy for Parkinson’s disease using human pluripotent stem cells
Authors: Moon Heechang , Kim Bokwang , Kwon Inbeom , Oh Yohan
Published: October 2023

Neurons derived from human pluripotent stem cells (hPSCs) provide a valuable tool for studying human neural development and neurodegenerative diseases. The investigation of hPSC-based cell therapy, involving the differentiation of hPSCs into target cells and their transplantation into affected regions, is of particular interest. One neurodegenerative disease that is being extensively studied for hPSC-based cell therapy is Parkinson’s disease (PD), the second most common among humans. Various research groups are focused on differentiating hPSCs into ventral midbrain dopaminergic (vmDA) progenitors, which have the potential to further differentiate into neurons closely resembling DA neurons found in the substantia nigra pars compacta (SNpc) after transplantation, providing a promising treatment option for PD. In vivo experiments, where hPSC-derived vmDA progenitor cells were transplanted into the striatum or SNpc of animal PD models, the transplanted cells demonstrated stable engraftment and resulted in behavioral recovery in the transplanted animals. Several differentiation protocols have been developed for this specific cell therapy. However, the lack of a reliable live-cell lineage identification method presents a significant obstacle in confirming the precise lineage of the differentiated cells intended for transplantation, as well as identifying potential contamination by non-vmDA progenitors. This deficiency increases the risk of adverse effects such as dyskinesias and tumorigenicity, highlighting the importance of addressing this issue before proceeding with transplantation. Ensuring the differentiation of hPSCs into the target cell lineage is a crucial step to guarantee precise therapeutic effects in cell therapy. To underscore the significance of lineage identification, this review focuses on the differentiation protocols of hPSC-derived vmDA progenitors developed by various research groups for PD treatment. Moreover, in vivo experimental results following transplantation were carefully analyzed. The encouraging outcomes from these experiments demonstrate the potential efficacy and safety of hPSC-derived vmDA progenitors for PD cell therapy. Additionally, the results of clinical trials involving the use of hPSC-derived vmDA progenitors for PD treatment were briefly reviewed, shedding light on the progress and challenges faced in translating this promising therapy into clinical practice.
Physical properties of pyroclastic density currents: relevance, challenges and future directions
Authors: Jones Thomas J. , Beckett Frances , Bernard Benjamin , Breard Eric C. P. , Dioguardi Fabio , Dufek Josef , Engwell Samantha , Eychenne Julia
Published: October 2023

Pyroclastic density currents (PDCs) are hazardous and destructive phenomena that pose a significant threat to communities living in the proximity of active volcanoes. PDCs are ground-hugging density currents comprised of high temperature mixtures of pyroclasts, lithics, and gas that can propagate kilometres away from their source. The physical properties of the solid particles, such as their grain size distribution, morphology, density, and componentry play a crucial role in determining the dynamics and impact of these flows. The modification of these properties during transport also records the causative physical processes such as deposition and particle fragmentation. Understanding these processes from the study of deposits from PDCs and related co-PDC plumes is essential for developing effective hazard assessment and risk management strategies. In this article, we describe the importance and relevance of the physical properties of PDC deposits and provide a perspective on the challenges associated with their measurement and characterization. We also discuss emerging topics and future research directions such as electrical charging, granular rheology, ultra-fine ash and thermal and surface properties that are underpinned by the characterization of pyroclasts and their interactions at the micro-scale. We highlight the need to systematically integrate experiments, field observations, and laboratory measurements into numerical modelling approaches for improving our understanding of PDCs. Additionally, we outline a need for the development of standardised protocols and methodologies for the measurement and reporting of physical properties of PDC deposits. This will ensure comparability, reproducibility of results from field studies and also ensure the data are sufficient to benchmark future numerical models of PDCs. This will support more accurate simulations that guide hazard and risk assessments.
The patient’s sex determines the hemodynamic profile in patients with Cushing disease
Authors: Jurek Agnieszka , Krzesiński Paweł , Uziębło-Życzkowska Beata , Witek Przemysław , Zieliński Grzegorz , Kazimierczak Anna , Wierzbowski Robert , Banak Małgorzata , Gielerak Grzegorz
Published: October 2023

Background

Cushing disease (CD) may lead to accelerated cardiovascular remodeling and increased mortality. There are suspected differences in the mechanism of cardiovascular dysfunction between males and females with CD. The purpose of this study was to assess the effect of patient sex on the hemodynamic profile assessed via impedance cardiography and echocardiography in patients newly diagnosed with CD.

Material and methods

The 54 patients newly diagnosed with CD (mean age 41 years; 77.8% of females) who were included in this prospective clinical study underwent impedance cardiography to assess specific parameters (including systemic vascular resistance index [SVRI], total arterial compliance index [TACI], Heather index [HI], stroke index [SI], cardiac index [CI], velocity index [VI], and acceleration index [ACI]) and transthoracic echocardiography to assess heart chamber diameters and left ventricular systolic and diastolic function.

Results

Males with CD exhibited higher afterload, with higher SVRI (3,169.3 ± 731.8 vs. 2,339.3 ± 640.8 dyn*s*cm-5*m² in males and females, respectively; p=0.002), lower TACI (0.80 ± 0.30 vs. 1.09 ± 0.30 mL/mmHg*m2; p=0.008), and lower hemodynamic parameters of left ventricular function, with lower HI (9.46 ± 2.86 vs. 14.1 ± 5.06 Ohm/s2; p=0.0007), lower VI (35.1 ± 11.9 vs. 44.9 ± 13.1 1*1000-1*s-1; p=0.009), lower SI (36.5 ± 11.7 vs. 43.6 ± 9.57 mL/m2; p=0.04), lower CI (2.36 ± 0.46 vs. 3.17 ± 0.76 mL*m-2*min-1; p=0.0009), and lower ACI (50.4 ± 19.8 vs. 73.6 ± 25.0 1/100/s2; p=0.006). There were no significant differences between the sexes in left ventricular systolic or diastolic function assessed by echocardiography.

Conclusion

In comparison with females with CD, males with CD have a less favorable hemodynamic profile, with higher afterload and worse left ventricular function. Sex differences in cardiovascular system function should be taken into consideration in designing personalized diagnostic and therapeutic management of patients with CD.
Marine oligotrophication due to fine sediments and nutrient starvation caused by anthropogenic sediment and water retention in large rivers: the Nile damming case
Authors: Herut Barak , Guy-Haim Tamar , Almogi-Labin Ahuva , Fischer Helmut W. , Ransby Daniela , Sandler Amir , Katz Timor , Avnaim-Katav Simona
Published: October 2023

In the last two centuries, human activities have radically reduced the transport of suspended sediment and water to marine systems, mainly in the northern hemisphere, while complete sediment retention has been reported for the Nile River after the construction of the Aswan High Dam (AHD). Here, we focused on changes in the inner-shelf sediments most exposed to the pre-AHD flood plume in the distal part of its littoral cell as a predictor of the ecological response to large river fragmentation. Substantial reductions in fine (15-40%) and increases in coarse (~8 fold) sediment accumulation rates, increases in CaCO3 (~50%), decreases in autochthonous and total organic carbon (OC), and changes in the benthic foraminiferal assemblage toward more OC-sensitive species suggest an enhanced oligotrophication trend. The reduced nutrient fluxes and OC accumulation, and the coarsening of the shelf sediments inhibit the retention of “blue” carbon. Combined with fast climate warming and salinization, river fragmentation may have essential implications for the Eastern Mediterranean ecosystem via benthic oligotrophication processes.
Gait pattern after electromechanically-assisted gait training with the Hybrid Assistive Limb and conventional gait training in sub-acute stroke rehabilitation—A subsample from a randomized controlled trial
Authors: Wall Anneli , Palmcrantz Susanne , Borg Jörgen , Gutierrez-Farewik Elena M.
Published: October 2023

Introduction

Electromechanically-assisted gait training has been introduced in stroke rehabilitation as a means to enable gait training with a large number of reproducible and symmetrical task repetitions, i.e. steps. However, few studies have evaluated its impact on gait pattern functions. This study includes persons with no independent ambulation function at the start of a 4-week neurorehabilitation period in the sub-acute phase after stroke. The primary aim of the study was to evaluate whether the addition of electromechanically-assisted gait training to conventional training resulted in better gait pattern function than conventional training alone. The secondary aim was to identify correlations between overall gait quality and standardized clinical assessments.

Participants and methods

Seventeen patients with no independent ambulation function who participated in a Prospective Randomized Open Blinded End-point study in the sub-acute phase after stroke were randomized into two groups; one group (n = 7) to undergo conventional training only (CONV group) and the other group (n = 10) to undergo conventional training with additional electromechanically-assisted gait training (HAL group). All patients were assessed with 3D gait analysis and clinical assessments after the 4-week intervention period. Overall gait quality as per the Gait Profile Score (GPS), as well as kinematic, and kinetic and other spatiotemporal metrics were collected and compared between intervention groups. Correlations between biomechanical and clinical outcomes were evaluated.

Results

Both the CONV and HAL groups exhibited similar gait patterns with no significant differences between groups in any kinematic, kinetic parameters or other spatiotemporal metrics. The GPS for the paretic limb had a median (IQR) of 12.9° (7.8°) and 13.4° (4.3°) for the CONV and HAL groups, respectively (p = 0.887). Overall gait quality was correlated with independence in walking, walking speed, movement function and balance. We found no added benefit in gait pattern function from the electromechanically-assisted gait training compared to the conventional training alone.

Discussion

This finding raises new questions about how to best design effective and optimal post-stroke rehabilitation programs in patients with moderate to severe gait impairments to achieve both independent walking and optimal gait pattern function, and about which patients should be in focus in further studies on the efficacy of electromechanically-assisted gait training.

Clinical trial registration

The study was retrospectively registered at ClinicalTrials.gov, identifier (NCT02410915) on April 2015.
Risk factors for lower extremity deep vein thrombosis in acute stroke patients following endovascular thrombectomy: a retrospective cohort study
Authors: Han Li , Yang Jian-Miao , Qian Wei-Yang , Xu Xiao-Ping , Tung Tao-Hsin , Liu Yang , Wang Feng
Published: October 2023

Background

Deep vein thrombosis (DVT) in lower extremities as a common complication of acute ischemic stroke (AIS) has long been studied. However, as the therapeutic options for AIS continue to advance, the pathogenic mechanisms behind DVT may change. Endovascular thrombectomy (EVT) has replaced intravenous thrombolysis and become the preferred treatment for AIS patients with large vessel occlusions. Therefore, it is important to update our understanding of DVT and its management. This study aimed to determine the prevalence and risk factors of DVT in AIS patients following EVT.

Methods

In this retrospective study, 245 AIS patients who had received EVT were recruited between January 2020 and December 2021. Within 10 days (median 4 days) of thrombectomy, DVT was diagnosed by ultrasonography. Demographic characteristics, clinical findings, and therapeutic procedures were compared between patients with and without DVT using univariate analysis. Cutoff points were defined for EVT time and plasma D-dimer concentration. Multivariable logistic regression was then used to determine the independent risk factors for DVT and evaluate their predictive power.

Results

The prevalence of DVT in AIS patients after EVT was 27.3%. Multifactorial logistic regression analysis showed that age (OR 1.036, 95% CI 1.001–1.073; P = 0.045), female sex (OR 3.015, 95% CI 1.446–6.289; P = 0.003), lower limb muscle strength less than grade three (OR 7.015, 95% CI 1.887–26.080; P = 0.004), longer EVT time (OR 1.012, 95% CI 1.004–1.020; P = 0.003), and higher D-dimer levels (OR 1.350, 95% CI 1.150–1.585; P < 0.001) were independently associated with higher DVT risk in AIS patients following EVT. The cutoff points for operative time of EVT and plasma D-dimer were 65.5 min and 1.62 mg/L, respectively, above which the risk for DVT was dramatically increased with OR > 4 in AIS patients.

Conclusion

AIS patients are at increased risk of developing DVT following EVT particularly if they have undergone prolonged thrombectomy procedures and exhibit high plasma levels of D-dimers. However, the results of our study need to be validated by a multicenter prospective study with a larger population of stroke patients.
The effects of olive oil consumption on cognitive performance: a systematic review
Authors: Fazlollahi Asra , Motlagh Asghari Kimia , Aslan Cynthia , Noori Maryam , Nejadghaderi Seyed Aria , Araj-Khodaei Mostafa , Sullman Mark J. M. , Karamzad Nahid , Kolahi Ali-Asghar , Safiri Saeid
Published: October 2023

Introduction

The Mediterranean diet is marked by the regular intake of olive oil, which may play a role in preventing and protecting against cognitive deterioration and dementia. The strength of these effects have been examined by several recent randomized controlled trials (RCTs), but their findings have not been consistent. In light of this inconsistency, the present study performed a systematic review to examine the relationship between the consumption of olive oil and cognition.

Methods

The Web of Science, Scopus, PubMed, and Google Scholar were systematically searched up to August 11, 2023. The review included RCTs, cross-sectional studies, cohort studies and case–control studies that explored the impact of olive oil consumption on cognitive performance among those older than 55 years old. Studies were excluded if they employed a design other than those mentioned above, involved participants under 55 years old, or did not specifically examine the cognitive effects of olive oil consumption. The quality of the included studies were measured using the Cochrane risk-of-bias tool and the Newcastle Ottawa Scale checklists.

Results

Eleven studies were identified, which were comprised of four cross-sectional studies, four prospective cohort studies and three RCTs. The cohort studies and RCTs consistently found that olive oil consumption had a favorable effect on cognitive performance across a number of cognitive domains over time. Similarly, all of the cross-sectional studies reported that the consumption of olive oil was positively associated with cognitive health.

Conclusion

The consumption of olive oil was found to enhance cognitive functioning and to reduce cognitive decline. Further large-scale investigations are required to strengthen this conclusion.
Research progress of Claudin-low breast cancer
Authors: Pan Chenglong , Xu Anqi , Ma Xiaoling , Yao Yanfei , Zhao Youmei , Wang Chunyan , Chen Ceshi
Published: October 2023

Claudin-low breast cancer (CLBC) is a subgroup of breast cancer discovered at the molecular level in 2007. Claudin is one of the primary proteins that make up tight junctions, and it plays crucial roles in anti-inflammatory and antitumor responses as well as the maintenance of water and electrolyte balance. Decreased expression of claudin results in the disruption of tight junction structures and the activation of downstream signaling pathways, which can lead to tumor formation. The origin of Claudin-low breast cancer is still in dispute. Claudin-low breast cancer is characterized by low expression of Claudin3, 4, 7, E-cadherin, and HER2 and high expression of Vimentin, Snai 1/2, Twist 1/2, Zeb 1/2, and ALDH1, as well as stem cell characteristics. The clinical onset of claudin-low breast cancer is at menopause age, and its histological grade is higher. This subtype of breast cancer is more likely to spread to lymph nodes than other subtypes. Claudin-low breast cancer is frequently accompanied by increased invasiveness and a poor prognosis. According to a clinical retrospective analysis, claudin-low breast cancer can achieve low pathological complete remission. At present, although several therapeutic targets of claudin-low breast cancer have been identified, the effective treatment remains in basic research stages, and no animal studies or clinical trials have been designed. The origin, molecular biological characteristics, pathological characteristics, treatment, and prognosis of CLBC are extensively discussed in this article. This will contribute to a comprehensive understanding of CLBC and serve as the foundation for the individualization of breast cancer treatment.
Analysis of insecticides in long-lasting insecticidal nets using X-ray fluorescence spectroscopy and correlation with bioefficacy
Authors: Koinari Melanie , Bubun Nakei , Wilson David , Anetul Evodia , Timinao Lincoln , Johnson Petrina , Daly Norelle L. , Laman Moses , Freeman Tim , Karl Stephan
Published: October 2023

Background

Long-lasting insecticidal nets (LLINs) are a key vector control tool used for the prevention of malaria. Active ingredient (AI) measurements in LLINs are essential for evaluating their quality and efficacy. The main aim of the present study was to determine the utility of X-ray fluorescence (XRF) spectroscopy as a suitable field-deployable tool for total AI quantification in LLINs.

Methods

New and unused LLIN samples containing deltamethrin (PermaNet® 2.0, n = 35) and alpha-cypermethrin (SafeNet®, n = 43) were obtained from batches delivered to Papua New Guinea (PNG) for mass distribution. Insecticides were extracted from the LLINs using a simple extraction technique and quantified using liquid chromatography mass spectrometry (LC-MS). The LC-MS results were correlated with XRF spectroscopy measurements on the same nets. Operators were blinded regarding the type of net. Bioefficacy of the LLIN samples was tested using WHO cone bioassays and test results were correlated with total AI content.

Results

The results indicate correlation between quantitative XRF and LC-MS. Interestingly, the total AI content was negatively correlated with bioefficacy in PermaNet® 2.0 (especially in recently manufactured nets). In contrast, AI content was positively correlated with bioefficacy in SafeNet®. These results indicate that the chemical content analysis in predelivery inspections does not always predict bioefficacy.

Conclusion

XRF is a promising field-deployable tool for quantification of both deltamethrin- and alpha-cypermethrin-coated LLINs. Because total AI content is not always a predictor of the efficacy of LLINs to kill mosquitoes, bioefficacy measurements should be included in predelivery inspections.
Prenatal cannabinoid exposure: why expecting individuals should take a pregnancy pause from using cannabinoid products
Authors: Lin Alexis , Dent Gelonia L. , Davies Suzy , Dominguez Zarena M. , Cioffredi Leigh-Anne , McLemore Gabrielle L. , Maxwell Jessie R.
Published: October 2023

Cannabinoid use in all populations is increasing as legalization across the United States continues. Concerningly, there is a lack of caution provided by medical providers to pregnant individuals as to the impact the use of cannabinoids could have on the developing fetus. Research continues in both the preclinical and clinical areas, and is severely needed, as the potency of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, has increased dramatically since the initial studies were completed. Thus far, clinical studies raise compelling evidence for short term memory deficits, impulse control issues, and attention deficiencies following prenatal cannabinoid exposure (PCE). These changes may be mediated through epigenetic modifications that not only impact the current offspring but could carry forward to future generations. While additional studies are needed, a pregnancy pause from cannabinoid products should be strongly recommended by providers to ensure the optimal health and well-being of our future generations.
Hypoxia releases S-nitrosocysteine from carotid body glomus cells—relevance to expression of the hypoxic ventilatory response
Authors: Seckler James M. , Getsy Paulina M. , May Walter J. , Gaston Benjamin , Baby Santhosh M. , Lewis Tristan H. J. , Bates James N. , Lewis Stephen J.
Published: October 2023

We have provided indirect pharmacological evidence that hypoxia may trigger release of the S-nitrosothiol, S-nitroso-L-cysteine (L-CSNO), from primary carotid body glomus cells (PGCs) of rats that then activates chemosensory afferents of the carotid sinus nerve to elicit the hypoxic ventilatory response (HVR). The objective of this study was to provide direct evidence, using our capacitive S-nitrosothiol sensor, that L-CSNO is stored and released from PGCs extracted from male Sprague Dawley rat carotid bodies, and thus further pharmacological evidence for the role of S-nitrosothiols in mediating the HVR. Key findings of this study were that 1) lysates of PGCs contained an S-nitrosothiol with physico-chemical properties similar to L-CSNO rather than S-nitroso-L-glutathione (L-GSNO), 2) exposure of PGCs to a hypoxic challenge caused a significant increase in S-nitrosothiol concentrations in the perfusate to levels approaching 100 fM via mechanisms that required extracellular Ca2+, 3) the dose-dependent increases in minute ventilation elicited by arterial injections of L-CSNO and L-GSNO were likely due to activation of small diameter unmyelinated C-fiber carotid body chemoafferents, 4) L-CSNO, but not L-GSNO, responses were markedly reduced in rats receiving continuous infusion (10 μmol/kg/min, IV) of both S-methyl-L-cysteine (L-SMC) and S-ethyl-L-cysteine (L-SEC), 5) ventilatory responses to hypoxic gas challenge (10% O2, 90% N2) were also due to the activation of small diameter unmyelinated C-fiber carotid body chemoafferents, and 6) the HVR was markedly diminished in rats receiving L-SMC plus L-SEC. This data provides evidence that rat PGCs synthesize an S-nitrosothiol with similar properties to L-CSNO that is released in an extracellular Ca2+-dependent manner by hypoxia.
Differences in ventricular wall composition may explain inter-patient variability in the ECG response to variations in serum potassium and calcium
Authors: Bukhari Hassaan A. , Sánchez Carlos , Laguna Pablo , Potse Mark , Pueyo Esther
Published: October 2023

Objective: Chronic kidney disease patients have a decreased ability to maintain normal electrolyte concentrations in their blood, which increases the risk for ventricular arrhythmias and sudden cardiac death. Non-invasive monitoring of serum potassium and calcium concentration, [K+] and [Ca2+], can help to prevent arrhythmias in these patients. Electrocardiogram (ECG) markers that significantly correlate with [K+] and [Ca2+] have been proposed, but these relations are highly variable between patients. We hypothesized that inter-individual differences in cell type distribution across the ventricular wall can help to explain this variability.

Methods: A population of human heart-torso models were built with different proportions of endocardial, midmyocardial and epicardial cells. Propagation of ventricular electrical activity was described by a reaction-diffusion model, with modified Ten Tusscher-Panfilov dynamics. [K+] and [Ca2+] were varied individually and in combination. Twelve-lead ECGs were simulated and the width, amplitude and morphological variability of T waves and QRS complexes were quantified. Results were compared to measurements from 29 end-stage renal disease (ESRD) patients undergoing hemodialysis (HD).

Results: Both simulations and patients data showed that most of the analyzed T wave and QRS complex markers correlated strongly with [K+] (absolute median Pearson correlation coefficients, r, ranging from 0.68 to 0.98) and [Ca2+] (ranging from 0.70 to 0.98). The same sign and similar magnitude of median r was observed in the simulations and the patients. Different cell type distributions in the ventricular wall led to variability in ECG markers that was accentuated at high [K+] and low [Ca2+], in agreement with the larger variability between patients measured at the onset of HD. The simulated ECG variability explained part of the measured inter-patient variability.

Conclusion: Changes in ECG markers were similarly related to [K+] and [Ca2+] variations in our models and in the ESRD patients. The high inter-patient ECG variability may be explained by variations in cell type distribution across the ventricular wall, with high sensitivity to variations in the proportion of epicardial cells.

Significance: Differences in ventricular wall composition help to explain inter-patient variability in ECG response to [K+] and [Ca2+]. This finding can be used to improve serum electrolyte monitoring in ESRD patients.
Effect of mechanical stimulation on tissue heterotopic ossification: an in vivo experimental study
Authors: Zhu Zhengya , He Zhongyuan , Tang Tao , Wang Fuan , Chen Hongkun , Zhou Jiaxiang , Lin Chengkai , Chen Guoliang , Wang Jianmin , Li Jianfeng , Liu Xizhe , Zhou Zhiyu , Liu Shaoyu
Published: October 2023

Background: Heterotopic ossification of tendons and ligaments (HOTL) is a common clinical condition characterized by the absence of discernible features and a lack of effective treatment. In vitro experiments have demonstrated that mechanical stimulation can induce cell differentiation toward osteogenesis, thereby promoting heterotopic ossification. Currently, there are few experimental designs aimed at inducing ligament stretching in mice, and the mechanism of heterotopic ossification may not entirely mirror that observed in clinical cases. Therefore, there is an urgent imperative to develop a novel and feasible animal model.

Methods: In this study, all the Enpp1 gene deficiency mice (a mouse model with heterotopic ossification of multiple ligaments) were divided into three groups: the control group, the spinal brake group, and the hyperactive group (treadmill training group). An external spinal fixation device was designed to restrict mice’s spinal flexion and extension at 6 weeks of age. The brace was adjusted weekly according to the changes in the size of the mice. Additionally, treadmill training was used to increase activity in the spinal ligaments and Achilles tendons of the mice. Micro-CT scanning and HE staining were performed at 12, 20, and 28 W to evaluate the degree of ossification in the spinal ligament and Achilles tendon. What’s more, As one of the mechanical stimulation transduction signals, YAP plays a crucial role in promoting osteogenic differentiation of cells. Immunofluorescence was utilized to assess YAP expression levels for the purpose of determining the extent of mechanical stimulation in tissues.

Results: Our findings showed that a few ossification lesions were detected behind the vertebral space of mice at 8 weeks of age. Spinal immobilization effectively restricts the flexion and extension of cervical and thoracic vertebrae in mice, delaying spinal ligament ossification and reducing chronic secondary spinal cord injury. Running exercises not only enhance the ossification area of the posterior longitudinal ligament (PLL) and Achilles tendons but also exacerbate secondary spinal cord injury. Further immunofluorescence results revealed a notable increase in YAP expression levels in tissues with severe ossification, suggesting that these tissues may be subjected to higher mechanical stimulation.

Conclusion: Mechanical stimulation plays a pivotal role in the process of heterotopic ossification in tissues. Our study provided valid animal models to further explore the pathological mechanism of mechanical stimulation in HOTL development.
The Role of Reirradiation in Childhood Progressive Diffuse Intrinsic Pontine Glioma (DIPG): An Ongoing Challenge beyond Radiobiology
Authors: Lo Greco Maria Chiara , Milazzotto Roberto , Liardo Rocco Luca Emanuele , Foti Pietro Valerio , Palmucci Stefano , Basile Antonio , Pergolizzi Stefano , Spatola Corrado
Published: October 2023

To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a retrospective case series on three children treated at our institution from 2018 to 2022. All children were candidates to receive systemic therapy with vinorelbine and nimotuzumab. Radiotherapy was administered to a total dose of 54 Gy. At any disease progression, our local tumor board evaluated the possibility of offering a new course of radiotherapy. To determine feasibility and assess toxicity rates, all children underwent clinical and hematological evaluation both during and after the treatment. To assess efficacy, all children performed contrast-enhanced MRI almost quarterly after the end of the treatment. In all children, following any treatment course, neurological improvement (>80%) was associated with a radiological response (41.7–46%). The longest overall survival (24 months) was observed in the child who underwent three courses of radiotherapy, without experiencing significant side effects. Even though it goes beyond the understanding of conventional radiobiology, first and second reirradiation in pediatric patients with progressive DIPG may represent a feasible and safe approach, capable of increasing overall survival and disease-free survival in selected patients and improving their quality of life.
A Method for Extracting Contours of Building Facade Hollowing Defects Using Polarization Thermal Images Based on Improved Canny Algorithm
Authors: Zhu Darong , Li Jianguo , Wang Fangbin , Gong Xue , Cong Wanlin , Wang Ping , Liu Yanli
Published: October 2023

During the service process of high-rise buildings, hollowing defects may be produced in the decorative layer, which not only affect the appearance, but also create a safety hazard of wall covering and shattered plaster peeling. Numerous studies have shown that hollowing can be detected using infrared thermal imagery under normal conditions. However, it is difficult to detect the edge and calculate the area of the hollowing on an exterior facade accurately because of the low contrast and fuzzy boundaries of the obtained infrared thermal images. To address these problems, a method for extracting the contours of building facade hollowing defects using polarization thermal images based on an improved Canny algorithm has been proposed in this paper. Firstly, the principle of thermal polarization imaging was introduced for hollowing detection. Secondly, considering the shortcomings of the Canny edge detection algorithm and the features of polarization thermal images, an improved Canny edge detection algorithm is proposed, including adaptive bilateral filtering to improve noise reduction ability while ensuring defect edges are not virtualized, Laplacian sharpening and histogram equalization to achieve contour sharpening and contrast enhancement, and eight-direction gradient templates for calculating image gradients, which make interpolation with non-maximum suppression more accurate, and the Tsallis entropy threshold segmentation algorithm based on the OTSU algorithm verification makes the image contour information more complete and accurate. Finally, a long-wave infrared polarization thermal imaging experimental platform was established and validation experiments were conducted. The experimental results demonstrate that the distinct, smooth, and precise location edges of the hollowing polarization infrared thermal images can be obtained, and the average error of the detected hollowing area is about 10% using the algorithm proposed in this paper.
A Critical Perspective on Current Research Trends in Building Operation: Pressing Challenges and Promising Opportunities
Authors: Saloux Etienne , Zhang Kun , Candanedo José A.
Published: October 2023

Despite the development of increasingly efficient technologies and the ever-growing amount of available data from Building Automation Systems (BAS) and connected devices, buildings are still far from reaching their performance potential due to inadequate controls and suboptimal operation sequences. Advanced control methods such as model-based controls or model-based predictive controls (MPC) are widely acknowledged as effective solutions for improving building operation. Although they have been well-investigated in the past, their widespread adoption has yet to be reached. Based on our experience in this field, this paper aims to provide a broader perspective on research trends on advanced controls in the built environment to researchers and practitioners, as well as to newcomers in the field. Pressing challenges are explored, such as inefficient local controls (which must be addressed in priority) and data availability and quality (not as good as expected, despite the advent of the digital era). Other major hurdles that slow down the large-scale adoption of advanced controls include communication issues with BAS and lack of guidelines and standards tailored for controls. To encourage their uptake, cost-effective solutions and successful case studies are required, which need to be further supported by better training and engagement between the industry and research communities. This paper also discusses promising opportunities: while building modelling is already playing a critical role, data-driven methods and data analytics are becoming a popular option to improve buildings controls. High-performance local and supervisory controls have emerged as promising solutions. Energy flexibility appears instrumental in achieving decarbonization targets in the built environment.
Clinical Effectiveness of Fluorescence Lymph Node Mapping Using ICG for Laparoscopic Right Hemicolectomy: A Prospective Case–Control Study
Authors: Son Gyung Mo , Yun Mi Sook , Lee In Young , Im Sun Bin , Kim Kyung Hee , Park Su Bum , Kim Tae Un , Shin Dong-Hoon , Nazir Armaan M. , Ha Gi Won
Published: October 2023

Background: The distinction between D3 lymph nodes and actual lymphatic pathways in primary tumors can be difficult during surgery, making it challenging to confirm the completeness of D3 lymph node dissection. Fluorescence lymph node mapping (FLNM) is a promising method for lymph node visualization. Purpose: This study aimed to assess whether FLNM enhances the effectiveness of D3 lymph node dissection in patients with right-sided colon cancer. Methods: Endoscopic submucosal indocyanine green injection were performed on the distal margin of the colon cancer. In an FLNM group, the lymphatic drainage pathway and distribution of D3 lymph nodes were explored. Pathological evaluations were conducted for the fluorescent D3 and non-fluorescent D3 lymph nodes. Results: The FLNM group showed a significantly higher number of harvested lymph nodes in the D3 area. In stage III patients, the proportion of D3 lymph node metastasis was significantly higher in the FLNM group. The harvested D3 lymph node count showed a proportional correlation with a metastatic lymph node count of up to 15. Conclusion: FLNM could be considered a promising new strategy to potentially increase harvested D3 lymph node counts in colon cancer surgery.
Patients with Advanced Pancreatic Cancer Treated with Mistletoe and Hyperthermia in Addition to Palliative Chemotherapy: A Retrospective Single-Center Analysis
Authors: Hohneck Anna Lena , Sadikaj Largsi , Heinemann Lara , Schroeder Maik , Riess Hartmut , Gerhards Annette , Burkholder Iris , Heckel-Reusser Stefan , Gottfried Julia , Hofheinz Ralf-Dieter
Published: October 2023

This retrospective analysis investigated the influence of integrative therapies in addition to palliative chemotherapy in patients with advanced pancreatic cancer, treated at a single institution specialized in integrative oncology between January 2015 and December 2019. In total, 206 consecutive patients were included in the study, whereof 142 patients (68.9%) received palliative chemotherapy (gemcitabine/nab-paclitaxel 33.8%; FOLFIRINOX 35.9%; gemcitabine 30.3%) while the remainder were treated with best supportive and integrative care. Integrative therapies were used in 117 of 142 patients (82.4%) in addition to conventional chemotherapy, whereby mistletoe was used in 117 patients (82.4%) and hyperthermia in 74 patients (52.1%). A total of 107/142 patients (86.3%) died during the observation period, whereby survival times differed significantly depending on the additional use of integrative mistletoe or hyperthermia: chemotherapy alone 8.6 months (95% CI 4.7–15.4), chemotherapy and only mistletoe therapy 11.2 months (95% CI 7.1–14.2), or a combination of chemotherapy with mistletoe and hyperthermia 18.9 months (95% CI 15.2–24.5). While the survival times observed for patients with advanced pancreatic cancer receiving chemotherapy alone are consistent with pivotal phase-III studies and German registry data, we found significantly improved survival using additional mistletoe and/or hyperthermia.
Immunotherapy Enhancement by Targeting Extracellular Tumor pH in Triple-Negative Breast Cancer Mouse Model
Authors: Rahman Azizur , Janic Branislava , Rahman Tasnim , Singh Harshit , Ali Haythem , Rattan Ramandeep , Kazi Mohsin , Ali Meser M.
Published: October 2023

Triple-negative breast cancer (TNBC), as one of the most aggressive forms of breast cancer, is characterized by a poor prognosis and a very low rate of disease-free and overall survival. In recent years, immunotherapeutic approaches targeting T cell checkpoint molecules, such as cytotoxic lymphocyte antigen-4 (CTLA-4), programmed death1 (PD-1) or its ligand, programmed death ligand 1 (PD-L1), have shown great potential and have been used to treat various cancers as single therapies or in combination with other modalities. However, despite this remarkable progress, patients with TNBC have shown a low response rate to this approach, commonly developing resistance to immune checkpoint blockade, leading to treatment failure. Extracellular acidosis within the tumor microenvironment (also known as the Warburg effect) is one of the factors preventing immune cells from mounting effective responses and contributing to immunotherapy treatment failure. Therefore, reducing tumor acidity is important for increasing cancer immunotherapy effectiveness and this has yet to be realized in the TNBC environment. In this study, the oral administration of sodium bicarbonate (NaHCO3) enhanced the antitumor effect of anti-PD-L1 antibody treatment, as demonstrated by generated antitumor immunity, tumor growth inhibition and enhanced survival in 4T1-Luc breast cancer model. Here, we show that NaHCO3 increased extracellular pH (pHe) in tumor tissues in vivo, an effect that was accompanied by an increase in T cell infiltration, T cell activation and IFN-γ, IL2 and IL12p40 mRNA expression in tumor tissues, as well as an increase in T cell activation in tumor-draining lymph nodes. Interestingly, these changes were further enhanced in response to combined NaHCO3 + anti-PD-L1 therapy. In addition, the acidic extracellular conditions caused a significant increase in PD-L1 expression in vitro. Taken together, these results indicate that alkalizing therapy holds potential as a new tumor microenvironment immunomodulator and we hypothesize that NaHCO3 can enhance the antitumor effects of anti-PD-L1 breast cancer therapy. The combination of these treatments may have an exceptional impact on future TNBC immunotherapeutic approaches by providing a powerful personalized medicine paradigm. Therefore, our findings have a great translational potential for improving outcomes in TNBC patients.
Respiratory Tract Oncobiome in Lung Carcinogenesis: Where Are We Now?
Authors: Czarnecka-Chrebelska Karolina H. , Kordiak Jacek , Brzeziańska-Lasota Ewa , Pastuszak-Lewandoska Dorota
Published: October 2023

The importance of microbiota in developing and treating diseases, including lung cancer (LC), is becoming increasingly recognized. Studies have shown differences in microorganism populations in the upper and lower respiratory tracts of patients with lung cancer compared to healthy individuals, indicating a link between dysbiosis and lung cancer. However, it is not only important to identify “which bacteria are present” but also to understand “how” they affect lung carcinogenesis. The interactions between the host and lung microbiota are complex, and our knowledge of this relationship is limited. This review presents research findings on the bacterial lung microbiota and discusses the mechanisms by which lung-dwelling microorganisms may directly or indirectly contribute to the development of lung cancer. These mechanisms include influences on the host immune system regulation and the local immune microenvironment, the regulation of oncogenic signaling pathways in epithelial cells (causing cell cycle disorders, mutagenesis, and DNA damage), and lastly, the MAMPs-mediated path involving the effects of bacteriocins, TLRs signaling induction, and TNF release. A better understanding of lung microbiota’s role in lung tumor pathology could lead to identifying new diagnostic and therapeutic biomarkers and developing personalized therapeutic management for lung cancer patients.
Breast Cancer Molecular Subtypes Differentially Express Gluconeogenic Rate-Limiting Enzymes—Obesity as a Crucial Player
Authors: Luís Carla , Schmitt Fernando , Fernandes Rute , Coimbra Nuno , Rigor Joana , Dias Paula , Leitão Dina , Fernandes Rúben , Soares Raquel
Published: October 2023

Breast cancer is a heterogeneous entity, where different molecular subtypes (MS) exhibit distinct prognostic and therapeutic responses. A series of 62 breast cancer samples stratified by MS was obtained from the tumor biobank of IPO-Porto. The expression of glycolysis and gluconeogenesis-regulating enzymes was investigated by immunohistochemistry. Data analysis included stratification according to MS, body mass index (BMI), and BMI with MS (mBMI). We observed significant differences in pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PCK), and fructose-1,6-bisphosphatase (FBP) tumor cell expression when stratified by MS and mBMI. The expression of these enzymes was also statistically dependent on hormonal receptors and HER2 status and correlated with pathological stage and histological grade. Obesity tended to attenuate these differences, particularly in PC expression, although these were not affected by adipocyte deposition or inflammatory infiltration at the tumor microenvironment. Nonetheless, PCK and FBP expression was also modified by the presence of obesity-associated disorders like diabetes, hypertension, and dyslipidemia. Taken together, these findings identify metabolic fingerprints for breast cancer as distinct histological types, which are affected by the presence of obesity and obesity-associated conditions. Despite the biological role of the differential expression of enzymes remaining unknown, the current study highlights the need to identify the expression of gluconeogenic-regulating enzymes as a tool for personalized medicine.
Introduction to the Beckwith–Wiedemann Syndrome and Cancer Special Issue
Authors: Mussa Alessandro , Kalish Jennifer M.
Published: October 2023

Beckwith–Wiedemann syndrome (BWS) is a genetic imprinting disorder that most commonly presents as overgrowth, macroglossia, abdominal wall defects, lateralized overgrowth, and embryonal tumors [...]
TIM-3 Expression and M2 Polarization of Macrophages in the TGFβ-Activated Tumor Microenvironment in Colorectal Cancer
Authors: Katagata Masanori , Okayama Hirokazu , Nakajima Shotaro , Saito Katsuharu , Sato Takahiro , Sakuma Mei , Fukai Satoshi , Endo Eisei , Sakamoto Wataru , Saito Motonobu , Saze Zenichiro , Momma Tomoyuki , Mimura Kosaku , Kono Koji
Published: October 2023

TGFβ signaling in the tumor microenvironment (TME) drives immune evasion and is a negative predictor of immune checkpoint inhibitor (ICI) efficacy in colorectal cancer (CRC). TIM-3, an inhibitory receptor implicated in anti-tumor immune responses and ICI resistance, has emerged as an immunotherapeutic target. This study investigated TIM-3, M2 macrophages and the TGFβ-activated TME, in association with microsatellite instability (MSI) status and consensus molecular subtypes (CMSs). Transcriptomic cohorts of CRC tissues, organoids and xenografts were examined (n = 2240). TIM-3 and a TGFβ-inducible stromal protein, VCAN, were evaluated in CRC specimens using immunohistochemistry (n = 45). TIM-3 expression on monocytes and generated M2 macrophages was examined by flow cytometry. We found that the expression of HAVCR2 (TIM-3) significantly correlated with the transcriptional signatures of TGFβ, TGFβ-dependent stromal activation and M2 macrophage, each of which were co-upregulated in CMS4, CMS1 and MSI CRCs across all datasets. Tumor-infiltrating TIM-3+ immune cells accumulated in TGFβ-responsive cancer stroma. TIM-3 was increased on M2-polarized macrophages, and on monocytes in response to TGFβ treatment. In conclusion, we identified a close association between TIM-3 and M2-like polarization of macrophages in the TGFβ-rich TME. Our findings provide new insights into personalized immunotherapeutic strategies based on the TME for CRCs.
De Novo Metastatic Prostate Cancer: Are We Moving toward a Personalized Treatment?
Authors: Piombino Claudia , Oltrecolli Marco , Tonni Elena , Pirola Marta , Matranga Rossana , Baldessari Cinza , Pipitone Stefania , Dominici Massimo , Sabbatini Roberto , Vitale Maria Giuseppa
Published: October 2023

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5–10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities for de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have modified the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as a predictive biomarker requires further validation, and it remains to be ascertained how the genomic variants detected in mHSPC, which are regarded as predictive in the castration-resistant disease, can be exploited in the mHSPC setting.