bluuebunny/crossref_metadata_2025 huggingface dataset:
Wild-Type α-Synuclein and Variants Occur in Different Disordered Dimers and Pre-Fibrillar Conformations in Early Stage of Aggregation
Authors: Guzzo Adrien , Delarue Patrice , Rojas Ana , Nicolaï Adrien , Maisuradze Gia G. , Senet Patrick
Published: June 2022

α-Synuclein is a 140 amino-acid intrinsically disordered protein mainly found in the brain. Toxic α-synuclein aggregates are the molecular hallmarks of Parkinson’s disease. In vitro studies showed that α-synuclein aggregates in oligomeric structures of several 10th of monomers and into cylindrical structures (fibrils), comprising hundred to thousands of proteins, with polymorphic cross-β-sheet conformations. Oligomeric species, formed at the early stage of aggregation remain, however, poorly understood and are hypothezised to be the most toxic aggregates. Here, we studied the formation of wild-type (WT) and mutant (A30P, A53T, and E46K) dimers of α-synuclein using coarse-grained molecular dynamics. We identified two principal segments of the sequence with a higher propensity to aggregate in the early stage of dimerization: residues 36–55 and residues 66–95. The transient α-helices (residues 53–65 and 73–82) of α-synuclein monomers are destabilized by A53T and E46K mutations, which favors the formation of fibril native contacts in the N-terminal region, whereas the helix 53–65 prevents the propagation of fibril native contacts along the sequence for the WT in the early stages of dimerization. The present results indicate that dimers do not adopt the Greek key motif of the monomer fold in fibrils but form a majority of disordered aggregates and a minority (9–15%) of pre-fibrillar dimers both with intra-molecular and intermolecular β-sheets. The percentage of residues in parallel β-sheets is by increasing order monomer < disordered dimers < pre-fibrillar dimers. Native fibril contacts between the two monomers are present in the NAC domain for WT, A30P, and A53T and in the N-domain for A53T and E46K. Structural properties of pre-fibrillar dimers agree with rupture-force atomic force microscopy and single-molecule Förster resonance energy transfer available data. This suggests that the pre-fibrillar dimers might correspond to the smallest type B toxic oligomers. The probability density of the dimer gyration radius is multi-peaks with an average radius that is 10 Å larger than the one of the monomers for all proteins. The present results indicate that even the elementary α-synuclein aggregation step, the dimerization, is a complicated phenomenon that does not only involve the NAC region.
Molecular Modeling of ABHD5 Structure and Ligand Recognition
Authors: Shahoei Rezvan , Pangeni Susheel , Sanders Matthew A. , Zhang Huamei , Mladenovic-Lucas Ljiljana , Roush William R. , Halvorsen Geoff , Kelly Christopher V. , Granneman James G. , Huang Yu-ming M.
Published: June 2022

Alpha/beta hydrolase domain-containing 5 (ABHD5), also termed CGI-58, is the key upstream activator of adipose triglyceride lipase (ATGL), which plays an essential role in lipid metabolism and energy storage. Mutations in ABHD5 disrupt lipolysis and are known to cause the Chanarin-Dorfman syndrome. Despite its importance, the structure of ABHD5 remains unknown. In this work, we combine computational and experimental methods to build a 3D structure of ABHD5. Multiple comparative and machine learning-based homology modeling methods are used to obtain possible models of ABHD5. The results from Gaussian accelerated molecular dynamics and experimental data of the apo models and their mutants are used to select the most likely model. Moreover, ensemble docking is performed on representative conformations of ABHD5 to reveal the binding mechanism of ABHD5 and a series of synthetic ligands. Our study suggests that the ABHD5 models created by deep learning-based methods are the best candidate structures for the ABHD5 protein. The mutations of E41, R116, and G328 disturb the hydrogen bonding network with nearby residues and suppress membrane targeting or ATGL activation. The simulations also reveal that the hydrophobic interactions are responsible for binding sulfonyl piperazine ligands to ABHD5. Our work provides fundamental insight into the structure of ABHD5 and its ligand-binding mode, which can be further applied to develop ABHD5 as a therapeutic target for metabolic disease and cancer.
Biomaterial-Based Schwann Cell Transplantation and Schwann Cell-Derived Biomaterials for Nerve Regeneration
Authors: Rao Zilong , Lin Zudong , Song Panpan , Quan Daping , Bai Ying
Published: June 2022

Schwann cells (SCs) dominate the regenerative behaviors after peripheral nerve injury by supporting axonal regrowth and remyelination. Previous reports also demonstrated that the existence of SCs is beneficial for nerve regeneration after traumatic injuries in central nervous system. Therefore, the transplantation of SCs/SC-like cells serves as a feasible cell therapy to reconstruct the microenvironment and promote nerve functional recovery for both peripheral and central nerve injury repair. However, direct cell transplantation often leads to low efficacy, due to injection induced cell damage and rapid loss in the circulatory system. In recent years, biomaterials have received great attention as functional carriers for effective cell transplantation. To better mimic the extracellular matrix (ECM), many biodegradable materials have been engineered with compositional and/or topological cues to maintain the biological properties of the SCs/SCs-like cells. In addition, ECM components or factors secreted by SCs also actively contribute to nerve regeneration. Such cell-free transplantation approaches may provide great promise in clinical translation. In this review, we first present the current bio-scaffolds engineered for SC transplantation and their achievement in animal models and clinical applications. To this end, we focus on the physical and biological properties of different biomaterials and highlight how these properties affect the biological behaviors of the SCs/SC-like cells. Second, the SC-derived biomaterials are also reviewed and discussed. Finally, the relationship between SCs and functional biomaterials is summarized, and the trends of their future development are predicted toward clinical applications.
Speech Kinematics and Coordination Measured With an MEG-Compatible Speech Tracking System
Authors: Anastasopoulou Ioanna , van Lieshout Pascal , Cheyne Douglas O. , Johnson Blake W.
Published: June 2022

Articulography and functional neuroimaging are two major tools for studying the neurobiology of speech production. Until recently, however, it has generally not been possible to use both in the same experimental setup because of technical incompatibilities between the two methodologies. Here we describe results from a novel articulography system dubbed Magneto-articulography for the Assessment of Speech Kinematics (MASK), which we used to derive kinematic profiles of oro-facial movements during speech. MASK was used to characterize speech kinematics in two healthy adults, and the results were compared to measurements from a separate participant with a conventional Electromagnetic Articulography (EMA) system. Analyses targeted the gestural landmarks of reiterated utterances /ipa/, /api/ and /pataka/. The results demonstrate that MASK reliably characterizes key kinematic and movement coordination parameters of speech motor control. Since these parameters are intrinsically registered in time with concurrent magnetoencephalographic (MEG) measurements of neuromotor brain activity, this methodology paves the way for innovative cross-disciplinary studies of the neuromotor control of human speech production, speech development, and speech motor disorders.
Lactobacillus paragasseri OLL2809 Improves Depression-Like Behavior and Increases Beneficial Gut Microbes in Mice
Authors: Hashikawa-Hobara Narumi , Otsuka Ami , Okujima Chihiro , Hashikawa Naoya
Published: June 2022

Lactobacillus paragasseri OLL2809 is a probiotic bacterial strain isolated from healthy human feces. While OLL2809 has been studied for its immunomodulatory activities, its effect on depressive-like behaviors remains unclear. In this study, we used a mouse model of social defeat stress (SDS) to investigate whether oral administration of OLL2809 ameliorates depressive-like behavior. C57BL6 male mice were administered OLL2809 for 2 weeks following a 4-week period of SDS. Although OLL2809 did not affect serum corticosterone levels, it ameliorated depression-like behaviors, and it induced neurite outgrowth in the hippocampal dentate gyrus. The 16S rRNA amplicon sequence analyses revealed that family level gut microbiota composition was affected by stress and OLL2809 administration. Additionally, Akkermansia muciniphila, Bifidobacterium, and Lactobacillus were significantly increased by OLL2809 treatment. LEfSe analysis suggested that the antidepressive effect of OLL2809 may be mediated by increases in other microorganisms, such as Erysipelotrichaceae uncultured. Our findings suggest that L. paragasseri OLL2809 may have potential in microbiome therapeutics.
The Impact of Non-caloric Sweeteners on Male Fertility: A Systematic Review and Narrative Synthesis in Rodent Models
Authors: Kearns Michelle L. , MacAindriu Fionn , Reynolds Clare M.
Published: June 2022

Understanding the factors which influence fertility is essential for developing appropriate nutritional recommendations for couples trying to conceive. Non-caloric sweeteners (NCS) are increasing in the food chain and despite being no/low calorie, several adverse metabolic consequences have been attributed to their consumption. Their effects on reproduction have been relatively under-researched, particularly in males. This review aims to systematically review the literature for evidence of the effect of NCS on male fertility in rodents, with sperm parameters (sperm quantity and quality) assessed as primary outcomes. Given the lack of information available in humans this review has been carried out using evidence from rodent models. Risk of bias assessment was carried out using the Syrcle risk of bias tool. Nine studies met the inclusion criteria. Forty-four percent showed a negative effect of NCS on male reproductive parameters compared with controls. The effects of NCS on fertility have been conflicting and selected studies have been heterogeneous in relation to study design. It is unclear if NCS has an impact on male reproductive function. There is a need for randomized controlled trials using a standardized protocol for analysis, to formulate a clear message in terms of male fertility.
Plant and Animal Protein Intakes Largely Explain the Nutritional Quality and Health Value of Diets Higher in Plants: A Path Analysis in French Adults
Authors: Perraud Elie , Wang Juhui , Salomé Marion , Huneau Jean-François , Lapidus Nathanaël , Mariotti François
Published: June 2022

Diets higher in plants are associated with lower risks of chronic diseases. However, animal foods, which are rich in protein, are also rich in some important minerals and vitamins. Using data from a representative survey in France (INCA3, n = 1,125), we used path analyses as a mediation-like approach to decipher the importance of plant and animal proteins in the relationship between the plant-based diet index (PDI) and diet quality. We used three types of diet quality scores, namely, nutrient security, positive nutrient adequacy, and long-term mortality risk of four diet-related diseases (i.e., coronary heart disease, stroke, type 2 diabetes, and colorectal cancer). We identified positive and negative mediations, i.e., changes in plant/animal protein intake that are associated with changes in PDI, and favor or limit the association with the diet quality score. The PDI was positively associated with the risk of long-term mortality but not significantly with nutrient adequacy or nutrient security. A positive mediation by plant protein was found for all diet quality scores (specific indirect effects (SIEs) ranging from 0.04 to 0.10 SD). Conversely, the association between PDI and nutrient adequacy (but not nutrient security) was negatively mediated by animal protein intake (SIE: −0.06 SD). In further detailed models, the association between PDI and diet quality was mainly positively mediated by protein foods from the fruit-vegetables-legumes group (0.01 SD for the nutrient security and 0.02 SD for the nutrient adequacy) and whole grains (0.02 SD for the nutrient adequacy). Our data suggest that the positive impact of plant-based diets on diet quality is largely driven by higher intakes of plant protein foods, especially from fruits-vegetables-legumes and whole grains. Conversely, lower animal protein intake tends to limit the positive impact of plant-based diets on overall positive nutrient adequacy but not security. Protein sources appear critical to healthy plant-based diets.
Circulating Tumor DNA in Identifying Resistant Sub-Clones Post EGFR Blockade: Implications for EGFR Rechallenge
Authors: Chennamadhavuni Adithya , Kasi Pashtoon Murtaza
Published: June 2022

For patients with metastatic RAS/RAF wild-type refractory colorectal cancer, the question of anti-EGFR therapy rechallenge often comes up after initial use. However, not all patients derive benefit. It is now well known that these tumors acquire mechanisms of resistance in the mitogen-activated protein kinase (MAPK) pathway, which can be detected on circulating tumor DNA (ctDNA)-based testing. We present a series of patients who had serial testing post-EGFR blockade showing its feasibility and value. This would have implications for EGFR rechallenge. We reviewed records for patients who were initially noted to be RAS/RAF wild-type on tissue, who received prior anti-EGFR therapy and then subsequently had at least one circulating tumor DNA-based testing. These patients also had tissue-based genomic testing obtained earlier as part of their standard of care, alongside serial ctDNA-based testing that was done later when subsequent lines of therapy were being decided. The median duration of initial prior anti-EGFR therapy was around 10 months. Known acquired mechanisms of resistance were noted in 100% of the cases. These included KRAS, NRAS, extracellular domain mutations in EGFR, and BRAF mutations. Interestingly, the levels of the sub-clones expressed in variant allele fraction percentage varied and decreased over time in relation to timing of the prior EGFR exposure. Additionally, these were noted to be polyclonal, and the number of clones also varied including some disappearing over time during non-EGFR-based therapy (EGFR holiday). Patients’ post-EGFR blockade may have multiple mechanisms of acquired resistance that can be easily detected on non-invasive liquid biopsies. These patients do not benefit from EGFR rechallenge based on the results of the recently reported CRICKET (NCT02296203) and CAVE (NCT04561336) clinical trials. Furthermore, excluding these patients from EGFR rechallenge is already being adopted in prospectively done clinical trials, e.g., the CHRONOS study (NCT03227926). Rechecking the liquid biopsy plasma RAS/RAF status is one thing that may be incorporated into practice with EGFR rechallenge only a consideration if acquired mechanisms of resistance are absent.
Towards Photodynamic Image-Guided Surgery of Head and Neck Tumors: Photodynamic Priming Improves Delivery and Diagnostic Accuracy of Cetuximab-IRDye800CW
Authors: Bhandari Chanda , Fakhry John , Eroy Menitte , Song Jane Junghwa , Samkoe Kimberley , Hasan Tayyaba , Hoyt Kenneth , Obaid Girgis
Published: June 2022

Fluorescence image-guided surgery (IGS) using antibody conjugates of the fluorophore IRDye800CW have revolutionized the surgical debulking of tumors. Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, conjugated to IRDye800CW (Cet-IRDye800) is the first molecular targeted antibody probe to be used for IGS in head and neck cancer patients. In addition to surgical debulking, Cetuximab-targeted photodynamic therapy (photoimmunotherapy; PIT) is emerging in the clinic as a powerful modality for head and neck tumor photodestruction. A plethora of other photoactivable agents are also in clinical trials for photodynamic-based therapies of head and neck cancer. Considering the vascular and stromal modulating effects of sub-therapeutic photodynamic therapy, namely photodynamic priming (PDP), this study explores the potential synergy between PDP and IGS for a novel photodynamic image-guided surgery (P-IGS) strategy. To the best of our knowledge, this is the first demonstration that PDP of the tumor microenvironment can augment the tumor delivery of full-length antibodies, namely Cet-IRDye800. In this study, we demonstrate a proof-of-concept that PDP primes orthotopic FaDu human head and neck tumors in mice for P-IGS by increasing the delivery of Cet-IRDye800 by up to 138.6%, by expediting its interstitial accumulation by 10.5-fold, and by increasing its fractional tumor coverage by 49.5% at 1 h following Cet-IRDye800 administration. Importantly, PDP improves the diagnostic accuracy of tumor detection by up to 264.2% with respect to vicinal salivary glands at 1 h. As such, PDP provides a time-to-surgery benefit by reducing the time to plateau 10-fold from 25.7 h to 2.5 h. We therefore propose that a pre-operative PDP regimen can expedite and augment the accuracy of IGS-mediated surgical debulking of head and neck tumors and reduce the time-to-IGS. Furthermore, this P-IGS regimen, can also enable a forward-looking post-operative protocol for the photodestruction of unresectable microscopic disease in the surgical bed. Beyond this scope, the role of PDP in the homogenous delivery of diagnostic, theranostic and therapeutic antibodies in solid tumors is of considerable significance to the wider community.
Use of Laparoscopic and Laparotomic J-Plasma Handpiece in Gynecological Malignancies: Results From A Pilot Study in A Tertiary Care Center
Authors: Gueli Alletti Salvatore , Rosati Andrea , Capozzi Vito Andrea , Pavone Matteo , Gioè Alessandro , Cianci Stefano , Chiantera Vito , Vizzielli Giuseppe , Scaglione Giulia , Fagotti Anna , Scambia Giovanni
Published: June 2022

Introduction

The J-Plasma has recently been introduced into the surgical community with different intrinsic characteristics aimed to further reduce the thermal effect and enhance precision when compared to standard radiofrequency. This study aimed to investigate the role of this new technology in different conditions of gynecological carcinomatosis characterized by the indication for regional peritonectomy and/or ablation, either in laparotomy (LPT) or in laparoscopy (LPS), in the context of a modern personalized approach to the surgical management of gynecological malignancies.

Material and Methods

From January 2019 to April 2019, 12 patients were selected for this prospective pilot study at the Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. In this single surgeon experience, the inclusion criteria were: histologically proven advanced ovarian/endometrial cancer, primary or interval debulking surgery, and intraoperative indication for regional peritonectomy. Six patients were treated by LPS (Group 1) and 6 by LPT (Group 2).

Results

In Group 1 the indication for debulking surgery was in 4 cases an interval debulking surgery and 2 advanced endometrial cancer. All patients in Group 2 underwent primary debulking surgery for advanced ovarian cancer. The whole cohort achieved a complete tumor excision after surgery. The median OT and median EBL were 195 min and 100 ml in Group 1, and 420 min and 500 ml in Group 2. The median hospital stay was 4 days in Group 1 and 13 days in Group 2, respectively. No intra and postoperative complications were registered within 60 days after surgery.

Conclusions

J-Plasma allows to approach delicate maneuvers on viscera, mesentery, and blood vessels with a high degree of safety and precision thanks to its limited vertical and lateral thermal spread, favoring the surgeon to push ever higher the cytoreduction/morbidity tradeoff. The use of J-Plasma in cytoreductive surgery could also increase the range of possible minimally invasive procedures, narrowing the technical distance with the open technique and thus contributing to designing a personalized surgical strategy for each patient in different scenarios of peritoneal carcinomatosis.
Comparison of T790M Acquisition After Treatment With First- and Second-Generation Tyrosine-Kinase Inhibitors: A Systematic Review and Network Meta-Analysis
Authors: Hsieh Po-Chun , Wu Yao-Kuang , Huang Chun-Yao , Yang Mei-Chen , Kuo Chan-Yen , Tzeng I-Shiang , Lan Chou-Chin
Published: June 2022

Background

Lung adenocarcinoma is a common disease with a high mortality rate. Epidermal growth factor receptor (EGFR) mutations are found in adenocarcinomas, and oral EGFR-tyrosine kinase inhibitors (EGFR-TKIs) show good responses. EGFR-TKI therapy eventually results in resistance, with the most common being T790M. T790M is also a biomarker for predicting resistance to first- and second-generation EGFR-TKIs and is sensitive to osimertinib. The prognosis was better for patients with acquired T790M who were treated with osimertinib than for those treated with chemotherapy. Therefore, T790M mutation is important for deciding further treatment and prognosis. Previous studies based on small sample sizes have reported very different T790 mutation rates. We conducted a meta-analysis to evaluate the T790M mutation rate after EGFR-TKI treatment.

Methods

We systematic reviewed the electronic databases to evaluate the T790M mutation rate after treatment with first-generation (gefitinib, erlotinib, and icotinib) and second-generation (afatinib and dacomitinib) EGFR-TKIs. Random-effects network meta-analysis and single-arm meta-analysis were conducted to estimate the T790M mutation rate of the target EGFR-TKIs.

Results

A total of 518 studies were identified, of which 29 were included. Compared with afatinib, a higher odds ratio (OR) of the T790M mutation rate was observed after erlotinib [OR = 1.48; 95% confidence interval (CI):1.09–2.00] and gefitinib (OR = 1.45; 95% CI: 1.11–1.90) treatments. An even OR of the T790M mutation rate was noted after icotinib treatment (OR = 0.91, 95% CI: 0.46–1.79) compared with that after afatinib. The T790M mutation rate was significantly lower with afatinib (33%) than that with gefitinib (49%) and erlotinib treatments (47%) (p < 0.001). The acquired T790M mutation rate in all participants was slightly lower in Asians (43%) than that in Caucasians (47%).

Conclusions

Erlotinib and gefitinib had a higher OR for the T790M mutation than afatinib. The T790M mutation rate was significantly lower in afatinib than in gefitinib and erlotinib. T790M is of great significance because osimertinib shows a good prognosis in patients with T790M mutation.

Systematic Review Registration

PROSPERO, identifier CRD42021257824.
An Orthotopic Patient-Derived Xenograft (PDX) Model Allows the Analysis of Metastasis-Associated Features in Colorectal Cancer
Authors: De Angelis Maria Laura , Francescangeli Federica , Nicolazzo Chiara , Xhelili Eljona , La Torre Filippo , Colace Lidia , Bruselles Alessandro , Macchia Daniele , Vitale Sara , Gazzaniga Paola , Baiocchi Marta , Zeuner Ann
Published: June 2022

Metastasis is the primary cause of death in patients with colorectal cancer (CRC), urging the need for preclinical models that recapitulate the metastatic process at the individual patient level. We used an orthotopic patient-derived xenograft (PDX) obtained through the direct implantation of freshly dissociated CRC cells in the colon of immunocompromised mice to model the metastatic process. Ortho-PDX engraftment was associated to a specific set of molecular features of the parental tumor, such as epithelial-to-mesenchymal transition (EMT), TGF-β pathway activation, increased expression of stemness-associated factors and higher numbers of circulating tumor cells (CTCs) clusters expressing the metastatic marker CD44v6. A parallel analysis of orthotopic/metastatic xenografts and organoids showed that tumor cells underwent mesenchymal-to-epithelial transition at the metastatic site and that metastasis-derived organoids had increased chemotherapy resistance. These observations support the usefulness of ortho-PDX as a preclinical model to study metastasis-related features and provide preliminary evidence that EMT/stemness properties of primary colorectal tumors may be crucial for orthotopic tumor engraftment.
Comprehensive Analysis of a Ferroptosis-Related lncRNA Signature for Predicting Prognosis and Immune Landscape in Osteosarcoma
Authors: Zhang Yiming , He Rong , Lei Xuan , Mao Lianghao , Yin Zhengyu , Zhong Xinyu , Cao Wenbing , Zheng Qiping , Li Dapeng
Published: June 2022

Research on the implications of ferroptosis in tumors has increased rapidly in the last decades. There are evidences that ferroptosis is involved in several aspects of cancer biology, including tumor progression, metastasis, immunomodulation, and therapeutic response. Nonetheless, the interaction between ferroptosis-related lncRNAs (FRLs) and the osteosarcoma immune microenvironment is poorly understood. In this study, a risk model composed of FRLs was developed using univariate and LASSO Cox regression analyses. On the basis of this model, FRL scores were calculated to systematically explore the role of the model in predicting the prognosis and immune characteristics of osteosarcoma patients. Survival analysis showed that osteosarcoma samples with lower FRL-score had better overall survival. After predicting the abundance of immune cells in osteosarcoma microenvironment by single-sample gene-set enrichment analysis (ssGSEA) and ESTIMATE analysis, we found that the FRL-score could distinguish immune function, immune score, stromal score, tumor purity, and tumor infiltration of immune cells in different osteosarcoma patients. In addition, FRL-score was also associated with immune checkpoint gene expression and half-maximal inhibitory concentration of chemotherapeutic agents. Finally, we confirmed that knockdown of RPARP-AS1 suppressed the malignant activity of osteosarcoma cells in vitro experiments. In general, the FRL-based prognostic signature could promote our understanding of the immune microenvironment characteristics of osteosarcoma and guide more effective treatment regimens.
Subclinical Left Ventricular Dysfunction Detected by Speckle-Tracking Echocardiography in Breast Cancer Patients Treated With Radiation Therapy: A Six-Month Follow-Up Analysis (MEDIRAD EARLY‐HEART study)
Authors: Locquet Médéa , Spoor Daan , Crijns Anne , van der Harst Pim , Eraso Arantxa , Guedea Ferran , Fiuza Manuela , Santos Susana Constantino Rosa , Combs Stephanie , Borm Kai , Mousseaux Elie , Gencer Umit , Frija Guy , Cardis Elisabeth , Langendijk Hans , Jacob Sophie
Published: June 2022

Background

In the case of breast cancer (BC), radiotherapy (RT) helps reduce locoregional recurrence and BC-related deaths but can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular events. It is therefore of primary importance to early detect subclinical left ventricular (LV) dysfunction in BC patients after RT and to determine the dose–response relationships between cardiac doses and these events.

Methods

Within the frame of the MEDIRAD European project (2017–2022), the prospective multicenter EARLY‐HEART study (ClinicalTrials.gov Identifier: NCT03297346) included chemotherapy naïve BC women aged 40–75 years and treated with lumpectomy and adjuvant RT. Myocardial strain analysis was provided using speckle‐tracking echocardiography performed at baseline and 6 months following RT. A global longitudinal strain (GLS) reduction >15% between baseline and follow-up was defined as a GLS-based subclinical LV dysfunction. Individual patient dose distributions were obtained using multi-atlas-based auto-segmentation of the heart. Dose-volume parameters were studied for the whole heart (WH) and left ventricle (LV).

Results

The sample included 186 BC women (57.5 ± 7.9 years, 64% left-sided BC). GLS-based subclinical LV dysfunction was observed in 22 patients (14.4%). These patients had significantly higher cardiac exposure regarding WH and LV doses compared to patients without LV dysfunction (for mean WH dose: 2.66 ± 1.75 Gy versus 1.64 ± 0.96 Gy, p = 0.01). A significantly increased risk of subclinical LV dysfunction was observed with the increase in the dose received to the WH [ORs from 1.13 (V5) to 1.74 (Dmean); p <0.01] and to the LV [ORs from 1.10 (V5) to 1.46 (Dmean); p <0.01]. Based on ROC analysis, the LV-V5 parameter may be the best predictor of the short-term onset of subclinical LV dysfunction.

Conclusion

These results highlighted that all cardiac doses were strongly associated with the occurrence of subclinical LV dysfunction arising 6 months after BC RT. Whether measurements of GLS at baseline and 6 months after RT combined with cardiac doses can early predict efficiently subclinical events occurring 24 months after RT remains to be investigated.
Yiqi Jianpi Huayu Jiedu Decoction Inhibits Metastasis of Colon Adenocarcinoma by Reversing Hsa-miR-374a-3p/Wnt3/β-Catenin-Mediated Epithelial–Mesenchymal Transition and Cellular Plasticity
Authors: Zhuang Yuwen , Zhou Jinyong , Liu Shenlin , Wang Qiong , Qian Jun , Zou Xi , Peng Haiyan , Xue Tian , Jin Zhichao , Wu Cunen
Published: June 2022

Colon adenocarcinoma (COAD) accounts for 95% of colon cancer cases, with the 5-year survival rate significantly affected by local or distant metastases. Yiqi Jianpi Huayu Jiedu decoction (YJHJD), based on the theory of “nourish qi, invigorate the spleen, remove blood stasis, and detoxify”, has long been applied and shown to be remarkable in the prevention and treatment of gastrointestinal tumors. However, the underlying therapeutic mechanisms of YJHJD have not been fully elucidated. Herein, we first confirmed hsa-miR-374a-3p as a tumor suppressor based on its lower expression in the plasma of patients with COAD with liver metastasis and association with more advanced local progression. We also verified WNT3 as a potential target of hsa-miR-374a-3p and observed its increased expression in COAD tissues. Furthermore, we showed that the hsa-miR-374a-3p/Wnt3/β-catenin axis was responsible for epithelial–mesenchymal transition (EMT) and cellular plasticity in COAD, as well as poorer patient prognosis. Our results showed that YJHJD inhibited motility and colony potential in vitro, as well as liver metastasis of COAD in vivo. Moreover, YJHJD induced a reversal of EMT and cellular plasticity-related molecular expression, increased hsa-miR-374a-3p, and decreased Wnt3 and β-catenin levels. In addition, silencing of hsa-miR-374a-3p weakened YJHJD inhibition, whereas the β-catenin inhibitor XAV939 partially repaired it. Taken together, these results demonstrated that YJHJD suppressed the EMT and cellular plasticity of COAD by regulating hsa-miR-374a-3p/Wnt3/β-catenin signaling.
Microsatellite Instable Colorectal Adenocarcinoma Diagnostics: The Advent of Liquid Biopsy Approaches
Authors: Ceccon Carlotta , Angerilli Valentina , Rasola Cosimo , Procaccio Letizia , Sabbadin Marianna , Bergamo Francesca , Malapelle Umberto , Lonardi Sara , Fassan Matteo
Published: June 2022

The introduction of immunotherapy has revolutionized the oncological targeted therapy paradigm. Microsatellite instability (MSI) identifies a subgroup of colorectal cancers (CRCs) which respond to treatment with immune checkpoint inhibitors. Tissue biopsy is currently the gold standard for the assessment of MSI/Mismatch Repair deficiency (MMRd) by means immunohistochemistry or molecular assays. However, the application of liquid biopsy in the clinic may help to overcome several limitations of tissue analysis and may provide great benefit to the diagnostic scenario and therapeutic decision-making process. In the context of MSI/MMRd CRC, the use of liquid biopsy may allow to establish MSI/MMR status if tissue sampling cannot be performed or in case of discordant tissue biopsies. Liquid biopsy may also become a powerful tool to monitor treatment response and the onset resistance to immunotherapy over time and to stratify of MSI/MMRd patients according to their risk of relapse and metastases. The aim of this review is to summarize the main technical aspects and clinical applications, the benefits, and limitations of the use of liquid biopsy in MSI/MMRd colorectal cancer patients.
Radiomic Machine Learning and External Validation Based on 3.0 T mpMRI for Prediction of Intraductal Carcinoma of Prostate With Different Proportion
Authors: Yang Ling , Li Zhengyan , Liang Xu , Xu Jingxu , Cai Yusen , Huang Chencui , Zhang Mengni , Yao Jin , Song Bin
Published: June 2022

Purpose

To assess the association of radiomics features based on multiparametric MRI (mpMRI) with the proportion of intraductal carcinoma of prostate (IDC-P) and validate the predictive models.

Materials and Methods

We retrospectively included pre-treatment MR images of prostate cancer (PCa) with IDC components of high proportion (≥10%, hpIDC-P), low proportion (<10%, lpIDC-P), and pure acinar adenocarcinoma (PAC) from our institution for training and internal validation and cooperated cohort for external validation. Normalized images of T2WI, diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) map, and dynamic contrast enhanced (DCE) sequences were used for radiomics modeling. The clinical model was built based on serum total prostate specific antigen (tPSA) and Gleason score (GS), and the integrated model was the combination of Rad-score and clinicopathological data. The discrimination ability was assessed by area under the receiver operating characteristic curve (ROC-AUC) in the internal and external validation sets and compared by DeLong test.

Results

Overall, 97 patients with hpIDC-P, 87 lpIDC-P, and 78 PAC were included for training and internal validation, and 11, 16, and 19 patients for external validation. The integrated model for predicting hpIDC-P got the best ROC-AUC of 0.88 (95%CI = 0.83-0.93) in internal and 0.86 (95%CI = 0.72-1.0) in external validation, which both outperformed clinical models (AUC=0.78, 95% CI = 0.72-0.85, AUC=0.69, 95% CI = 0.5-0.85, respectively) based solely on GS, and the radiomics model (AUC=0.85, 95% CI = 0.79-0.91) was slightly inferior to the integrated model and better than the clinical model in internal dataset. The integrated model for predicting lpIDC-P outperformed both radiomics and clinical models in the internal dataset, while slightly inferior to the integrated model for predicting hpIDC-P.

Conclusions

Radiomics signature improved differentiation of both hpIDC-P and lpIDC-P versus PAC when compared with the clinical model based on Gleason score, and was validated in an external cohort.
Shifting the Balance: How Top-Down and Bottom-Up Input Modulate Pain via the Rostral Ventromedial Medulla
Authors: Chen Qiliang , Heinricher Mary M.
Published: June 2022

The sensory experience of pain depends not only on the transmission of noxious information (nociception), but on the state of the body in a biological, psychological, and social milieu. A brainstem pain-modulating system with its output node in the rostral ventromedial medulla (RVM) can regulate the threshold and gain for nociceptive transmission. This review considers the current understanding of how RVM pain-modulating neurons, namely ON-cells and OFF-cells, are engaged by “top-down” cognitive and emotional factors, as well as by “bottom-up” sensory inputs, to enhance or suppress pain.
Spontaneous Rupture of Rhabdomyosarcoma of the Testis With Unilateral Ptosis: A Case Report and Literature Review
Authors: Wu Ronghua , Liu Xing , Song Yajun , Yi Shanhong , Chen Wei , Fu Wanlei , Zhu Jingzhen
Published: June 2022

Spontaneous rupture of testicular rhabdomyosarcoma is very rare. We report a case of spontaneous testicular rupture that was pathologically confirmed as rhabdomyosarcoma with unilateral blepharoptosis. The patient, a 19-year-old male, and his father had weakness of the left eyelid muscle. The patient was suspected to have a right inguinal hernia by a family doctor but was not treated further. 2 days later, there was skin itching in the right inguinal area, accompanied by redness, swelling and discomfort of the right scrotum, and the patient went to the local hospital again. Ultrasound examination showed that a contusion of the right testis may have been complicated with orchitis. Oral levofloxacin was ineffective. In addition, the swelling of scrotal increased significantly. He came to the emergency room of our hospital and also was treated with levofloxacin, but the pain was still not relieved. CT and ultrasound examination could not identify the cause of the disease. Exploration of the right scrotum was performed under general anesthesia and confirmed that the right testis had spontaneously ruptured. The pathological diagnosis was rhabdomyosarcoma of the right testis. Testicular rhabdomyosarcoma is clinically rare, and spontaneous rupture is even rarer. The pathogenesis of the disease needs to be further studied, and the diagnosis should be made on a case-by-case basis. Overall, the prognosis of testicular rhabdomyosarcoma is poor. As seen in this case, further study is required to determine whether there is some association between testicular rhabdomyosarcoma and ptosis. Unfortunately, the patient's family rejected a genetic examination because of financial difficulty. We only report a single case of this rare phenomenon here.
Communicating Risk for Obesity in Early Life: Engaging Parents Using Human-Centered Design Methodologies
Authors: Cheng Erika R. , Moore Courtney , Parks Lisa , Taveras Elsie M. , Wiehe Sarah E. , Carroll Aaron E.
Published: June 2022

Objective

Pediatricians are well positioned to discuss early life obesity risk, but optimal methods of communication should account for parent preferences. To help inform communication strategies focused on early life obesity prevention, we employed human-centered design methodologies to identify parental perceptions, concerns, beliefs, and communication preferences about early life obesity risk.

Methods

We conducted a series of virtual human-centered design research sessions with 31 parents of infants <24 months old. Parents were recruited with a human intelligence task posted on Amazon's Mechanical Turk, via social media postings on Facebook and Reddit, and from local community organizations. Human-centered design techniques included individual short-answer activities derived from personas and empathy maps as well as group discussion.

Results

Parents welcomed a conversation about infant weight and obesity risk, but concerns about health were expressed in relation to the future. Tone, context, and collaboration emerged as important for obesity prevention discussions. Framing the conversation around healthy changes for the entire family to prevent adverse impacts of excess weight may be more effective than focusing on weight loss.

Conclusions

Our human-centered design approach provides a model for developing and refining messages and materials aimed at increasing parent/provider communication about early life obesity prevention. Motivating families to engage in obesity prevention may require pediatricians and other health professionals to frame the conversation within the context of other developmental milestones, involve the entire family, and provide practical strategies for behavioral change.
Study on the Antipyretic and Anti-inflammatory Mechanism of Shuanghuanglian Oral Liquid Based on Gut Microbiota-Host Metabolism
Authors: Gao Yan , Liu Lu , Li Chen , Liang Yu-Ting , Lv Jing , Yang Long-Fei , Zhao Bo-Nian
Published: June 2022

Nowadays, there has been increased awareness that the therapeutic effects of natural medicines on inflammatory diseases may be achieved by regulating the gut microbiota. Shuanghuanglian oral liquid (SHL), the traditional Chinese medicine preparation, has been shown to be effective in clearing heat-toxin, which is widely used in the clinical treatment of respiratory tract infection, mild pneumonia, and common cold with the wind-heat syndrome. Yet the role of gut microbiota in the antipyretic and anti-inflammatory effects is unclear. In this study, a new strategy of the 16S rRNA gene sequencing and serum metabolomics that aims to explore the role of SHL in a rat model of the systemic inflammatory response induced by lipopolysaccharide would be a major advancement. Our results showed that the gut microbiota structure was restored in rats with inflammation after oral administration of SHL, thereby reducing inflammation. Specifically, SHL increased the relative abundance of Bacteroides and Faecalibacterium and decreased the abundance of Bifidobacterium, Olsenella, Aerococcus, Enterococcus, and Clostridium in the rat model of inflammatory disease. Serum metabolomic profile obtained by the orbitrap-based high-resolution mass spectrometry revealed significant differences in the levels of 39 endogenous metabolites in the inflammatory model groups, eight metabolites of which almost returned to normal levels after SHL treatment. Correlation analysis between metabolite, gut microbiota, and inflammatory factors showed that the antipyretic and anti-inflammatory effects of SHL were related to the recovery of the abnormal levels of the endogenous metabolites (N-acetylserotonin and 1-methylxanthine) in the tryptophan metabolism and caffeine metabolism pathway. Taken together, these findings suggest that the structural changes in the gut microbiota are closely related to host metabolism. The regulation of gut microbiota structure and function is of great significance for exploring the potential mechanism in the treatment of lipopolysaccharide-induced inflammatory diseases with SHL.
Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases
Authors: Wang Zhicheng , Bian Weikang , Yan Yufeng , Zhang Dai-Min
Published: June 2022

ATP-sensitive potassium channels (KATP channels) play pivotal roles in excitable cells and link cellular metabolism with membrane excitability. The action potential converts electricity into dynamics by ion channel-mediated ion exchange to generate systole, involved in every heartbeat. Activation of the KATP channel repolarizes the membrane potential and decreases early afterdepolarization (EAD)-mediated arrhythmias. KATP channels in cardiomyocytes have less function under physiological conditions but they open during severe and prolonged anoxia due to a reduced ATP/ADP ratio, lessening cellular excitability and thus preventing action potential generation and cell contraction. Small active molecules activate and enhance the opening of the KATP channel, which induces the repolarization of the membrane and decreases the occurrence of malignant arrhythmia. Accumulated evidence indicates that mutation of KATP channels deteriorates the regulatory roles in mutation-related diseases. However, patients with mutations in KATP channels still have no efficient treatment. Hence, in this study, we describe the role of KATP channels and subunits in angiocardiopathy, summarize the mutations of the KATP channels and the functional regulation of small active molecules in KATP channels, elucidate the potential mechanisms of mutant KATP channels and provide insight into clinical therapeutic strategies.
Shen-Ling-Bai-Zhu-San (SL) and SL Derived-Polysaccharide (PL) Ameliorate the Severity of Diarrhea-Induced by High Lactose via Modification of Colonic Fermentation
Authors: Xue Hong , Ma Jinxin , Wang Yitian , Lu Mengxiong , Wang Fengyun , Tang Xudong
Published: June 2022

In our previous study, we demonstrated that Shen-ling-bai-zhu-san (SL), a classical Chinese herbal formula, could alleviate lactose-induced diarrhea. However, little is known about the mechanism underlying SL action or the efficacy of the polysaccharide (PL) derived from SL. In this study, we investigated the effect of SL and PL on improving the dysregulated luminal and mucosal microbiota in rats with high lactose diet using 16S rRNA analysis. The concentrations of lactose, lactic acid in cecum and short-chain fatty acids (SCFAs) in cecum and portal vein were measured, meanwhile the expression of ion transporters were ascertained. Our data suggest that the SL, PL and cecal microbiota transplantation (CMT) significantly decreased fecal water content and water intake. In the luminal microbiota there was a significant increase in Akkermansia, Bifidobacterium and Blautia and a lower abundance of Lactobacillus, Escherichia-Shigella, and Dubosiella, while the mucosal microbiota showed a significant increase in Bifidobacterium, Akkermansia, Albaculum, Bilophila, and Coriobacteriaceae_UCG-002 and a lower abundance of Enterococcus, Helicobacter, Dubosiella, and Collinsella. Furthermore, the treatments enhanced lactose fermentation and SCFA production, which may be related to the modulation of the luminal microbial community. A lower ratio of phosphorylation Na/H exchanger3/Na/H exchanger3 (pNHE3/NHE3) and a higher sodium monocarboxylate1 (sMCT1) expression were found in the treatment group than in the model group, which may be related to the changes in the mucosal microbial community. Also, the treatments may restore the impacted metabolic pathways of gut microbiota. These results provide an important foundation for mechanism of SL action and developing PL-based treatment for lactose-induced diarrhea.
Cost-Effectiveness of Pharmacogenomics-Guided Prescribing to Prevent Gene-Drug-Related Deaths: A Decision-Analytic Model
Authors: van der Wouden Cathelijne H. , Marck Heiralde , Guchelaar Henk-Jan , Swen Jesse J. , van den Hout Wilbert B.
Published: June 2022

Aim: Prospective studies support the clinical impact of pharmacogenomics (PGx)-guided prescribing to reduce severe and potentially fatal adverse effects. Drug-gene interactions (DGIs) preventing potential drug-related deaths have been categorized as “essential” by the Dutch Pharmacogenetics Working Group (DPWG). The collective clinical impact and cost-effectiveness of this sub-set is yet undetermined. Therefore, we aim to assess impact and cost-effectiveness of “essential” PGx tests for prevention of gene-drug-related deaths, when adopted nation-wide.

Methods: We used a decision-analytic model to quantify the number and cost per gene-drug-related death prevented, from a 1-year Dutch healthcare perspective. The modelled intervention is a single gene PGx-test for CYP2C19, DPYD, TPMT or UGT1A1 to guide prescribing based on the DPWG recommendations among patients in the Netherlands initiating interacting drugs (clopidogrel, capecitabine, systemic fluorouracil, azathioprine, mercaptopurine, tioguanine or irinotecan).

Results: For 148,128 patients initiating one of seven drugs in a given year, costs for PGx-testing, interpretation, and drugs would increase by €21.4 million. Of these drug initiators, 35,762 (24.1%) would require an alternative dose or drug. PGx-guided prescribing would relatively reduce gene-drug related mortality by 10.6% (range per DGI: 8.1–14.5%) and prevent 419 (0.3% of initiators) deaths a year. Cost-effectiveness is estimated at €51,000 per prevented gene-drug-related death (range per DGI: €-752,000–€633,000).

Conclusion: Adoption of PGx-guided prescribing for “essential” DGIs potentially saves the lives of 0.3% of drug initiators, at reasonable costs.