bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward an Adapted Neurofeedback for Post-stroke Motor Rehabilitation: State of the Art and Perspectives
Authors: Le Franc Salomé , Herrera Altamira Gabriela , Guillen Maud , Butet Simon , Fleck Stéphanie , Lécuyer Anatole , Bougrain Laurent , Bonan Isabelle
Published: July 2022

Stroke is a severe health issue, and motor recovery after stroke remains an important challenge in the rehabilitation field. Neurofeedback (NFB), as part of a brain–computer interface, is a technique for modulating brain activity using on-line feedback that has proved to be useful in motor rehabilitation for the chronic stroke population in addition to traditional therapies. Nevertheless, its use and applications in the field still leave unresolved questions. The brain pathophysiological mechanisms after stroke remain partly unknown, and the possibilities for intervention on these mechanisms to promote cerebral plasticity are limited in clinical practice. In NFB motor rehabilitation, the aim is to adapt the therapy to the patient’s clinical context using brain imaging, considering the time after stroke, the localization of brain lesions, and their clinical impact, while taking into account currently used biomarkers and technical limitations. These modern techniques also allow a better understanding of the physiopathology and neuroplasticity of the brain after stroke. We conducted a narrative literature review of studies using NFB for post-stroke motor rehabilitation. The main goal was to decompose all the elements that can be modified in NFB therapies, which can lead to their adaptation according to the patient’s context and according to the current technological limits. Adaptation and individualization of care could derive from this analysis to better meet the patients’ needs. We focused on and highlighted the various clinical and technological components considering the most recent experiments. The second goal was to propose general recommendations and enhance the limits and perspectives to improve our general knowledge in the field and allow clinical applications. We highlighted the multidisciplinary approach of this work by combining engineering abilities and medical experience. Engineering development is essential for the available technological tools and aims to increase neuroscience knowledge in the NFB topic. This technological development was born out of the real clinical need to provide complementary therapeutic solutions to a public health problem, considering the actual clinical context of the post-stroke patient and the practical limits resulting from it.
Assessment of Low Back Pain in Helicopter Pilots Using Electrical Bio-Impedance Technique: A Feasibility Study
Authors: Wang Hang , Dai Jing , Wang Chunchen , Gao Zhijun , Liu Yang , Dai Meng , Zhao Zhanqi , Yang Lin , Tan Guodong
Published: July 2022

Low back pain (LBP) is known to pose a serious threat to helicopter pilots. This study aimed to explore the potential of electrical bio-impedance (EBI) technique with the advantages of no radiation, non-invasiveness and low cost, which is intended to be used as a daily detection tool to assess LBP in primary aviation medical units. The LBP scales (severity) in 72 helicopter pilots were assessed using a pain questionnaire, while the bilateral impedance measurements of the lumbar muscle were carried out with a high precision EBI measurement system. Results showed that the modulus of lumbar muscle impedance increased with LBP scale whereas the phase angle decreased. For different LBP scales, significant differences were found in the modulus of lumbar muscle impedance sum on both sides (Zsum), as well as in the modulus and phase angle of lumbar muscle impedance difference between both sides (Zdiffandϕdiff), respectively (P< 0.05). Moreover, Spearman’s correlation analysis manifested a strong correlation betweenZsumand LBP scale (R= 0.692,P< 0.01), an excellent correlation betweenZdiffand LBP scale (R= 0.86,P< 0.01), and a desirable correlation betweenϕdiffand LBP scale (R= −0.858,P< 0.01). In addition, receiver operator characteristic analysis showed that for LBP prediction, the area under receiver operator characteristic curve ofZsum,Zdiff, andϕdiffwere 0.931, 0.992, and 0.965, respectively. These findings demonstrated that EBI could sensitively and accurately detect the state of lumbar muscle associated with LBP, which might be the potential tool for daily detection of LBP in primary aviation medical units.
Deconvolution of Ears' Activity (DEA): A New Experimental Paradigm to Investigate Central Auditory Processing
Authors: Bardy Fabrice
Published: July 2022

A novel experimental paradigm, “deconvolution of ears' activity” (DEA), is presented which allows to disentangle overlapping neural activity from both auditory cortices when two auditory stimuli are presented closely together in time in each ear. Pairs of multi-tone complexes were presented either binaurally, or sequentially by alternating presentation order in each ear (i.e., first tone complex of the pair presented to one ear and second tone complex to the other ear), using stimulus onset asynchronies (SOAs) shorter than the neural response length. This timing strategy creates overlapping responses, which can be mathematically separated using least-squares deconvolution. The DEA paradigm allowed the evaluation of the neural representation in the auditory cortex of responses to stimuli presented at syllabic rates (i.e., SOAs between 120 and 260 ms). Analysis of the neuromagnetic responses in each cortex offered a sensitive technique to study hemispheric lateralization, ear representation (right vs. left), pathway advantage (contra- vs. ipsi-lateral) and cortical binaural interaction. To provide a proof-of-concept of the DEA paradigm, data was recorded from three normal-hearing adults. Results showed good test-retest reliability, and indicated that the difference score between hemispheres can potentially be used to assess central auditory processing. This suggests that the method could be a potentially valuable tool for generating an objective “auditory profile” by assessing individual fine-grained auditory processing using a non-invasive recording method.
Gene-Regulatory Potential of 25-Hydroxyvitamin D3 and D2
Authors: Hanel Andrea , Veldhuizen Cor , Carlberg Carsten
Published: July 2022

Human peripheral blood mononuclear cells (PBMCs) represent a highly responsive primary tissue that is composed of innate and adaptive immune cells. In this study, we compared modulation of the transcriptome of PBMCs by the vitamin D metabolites 25-hydroxyvitamin D3 (25(OH)D3), 25(OH)D2 and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Saturating concentrations of 1,25(OH)2D3, 25(OH)D3 and 25(OH)D2 resulted after 24 h stimulation in a comparable number and identity of target genes, but below 250 nM 25(OH)D3 and 25(OH)D2 were largely insufficient to affect the transcriptome. The average EC50 values of 206 common target genes were 322 nM for 25(OH)D3 and 295 nM for 25(OH)D2 being some 600-fold higher than 0.48 nM for 1,25(OH)2D3. The type of target gene, such as primary/secondary, direct/indirect or up-/down-regulated, had no significant effect on vitamin D metabolite sensitivity, but individual genes could be classified into high, mid and lower responders. Since the 1α-hydroxylase CYP27B1 is very low expressed in PBMCs and early (4 and 8 h) transcriptome responses to 25(OH)D3 and 25(OH)D2 were as prominent as to 1,25(OH)2D3, both vitamin D metabolites may directly control gene expression. In conclusion, at supra-physiological concentrations 25(OH)D3 and 25(OH)D2 are equally potent in modulating the transcriptome of PBMCs possibly by directly activating the vitamin D receptor.
Intraindividual Comparison Between [18F] PSMA-1007 PET/CT and Multiparametric MRI for Radiotherapy Planning in Primary Prostate Cancer Patients
Authors: Marinescu Ioana M. , Spohn Simon K. B. , Kiefer Selina , Bronsert Peter , Ceci Lara , Holzschuh Julius , Sigle August , Jilg Cordula A. , Rühle Alexander , Sprave Tanja , Nicolay Nils H. , Winzer Robert , Rehm Jana , Kotzerke Jörg , Hölscher Tobias , Grosu Anca L. , Ruf Juri , Benndorf Matthias , Zamboglou Constantinos
Published: July 2022

Introduction

Accurate detection and segmentation of the intraprostatic gross tumor volume (GTV) is pivotal for radiotherapy (RT) in primary prostate cancer (PCa) since it influences focal therapy target volumes and the patients’ cT stage. The study aimed to compare the performance of multiparametric resonance imaging (mpMRI) with [18F] PSMA-1007 positron emission tomography (PET) for intraprostatic GTV detection as well as delineation and to evaluate their respective influence on RT concepts.

Materials and Methods

In total, 93 patients from two German University Hospitals with [18F] PSMA-1007-PET/CT and MRI (Freiburg) or [18F] PSMA-1007-PET/MRI (Dresden) were retrospectively enrolled. Validated contouring techniques were applied for GTV-PET and -MRI segmentation. Absolute tumor volume and cT status were determined for each imaging method. The PCa distribution from histopathological reports based on biopsy cores and surgery specimen was used as reference in terms of laterality (unilateral vs. bilateral).

Results

In the Freiburg cohort (n = 84), mpMRI and PET detected in median 2 (range: 1–5) and 3 (range: 1–8) GTVs, respectively (p < 0.01). The median GTV-MRI was significantly smaller than the GTV-PET, measuring 2.05 vs. 3.65 ml (p = 0.0005). PET had a statistically significant higher concordance in laterality with surgery specimen compared to mpMRI (p = 0.04) and biopsy (p < 0.01), respectively. PSMA PET led to more cT2c and cT3b stages, whereas cT3a stage was more pronounced in mpMRI. Based on the cT stage derived from mpMRI and PET information, 21 and 23 as well as 59 and 60 patients, respectively, were intermediate- and high-risk according to the National Comprehensive Cancer Network (NCCN) v1.2022 criteria. In the Dresden cohort (n = 9), similar results were observed.

Conclusion

Intraprostatic GTV segmentation based on [18F] PSMA-1007 PET results in more and larger GTVs compared to mpMRI. This influences focal RT target volumes and cT stage definition, but not the NCCN risk group.
Phase II Study of ENZAlutamide Combined With Hypofractionated Radiation Therapy (ENZART) for Localized Intermediate Risk Prostate Cancer
Authors: Lara Pedro C. , Rodríguez-Melcón Juan I. , Palacios-Eito Amalia , Lozano Antonio , Hervás-Morón Asunción , Villafranca Elena , Gómez-Iturriaga Alfonso , Sancho Gemma , Maldonado Xavier
Published: July 2022

Background

Intermediate-risk prostate cancer (PCa) is usually treated by a combination of external beam radiation therapy (EBRT) and a short course of androgen deprivation therapy (ADT). ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, anti-androgen monotherapy is generally better tolerated in spite of higher rates of gynecomastia.

Objective

This study assessed the effectiveness of enzalutamide monotherapy combined with hypofractionated EBRT (Hypo-EBRT) for treating intermediate risk prostate cancer.

Method

This trial was a multicenter, open-label phase II study of 6 months of enzalutamide monotherapy combined with Hypo-EBRT for intermediate-risk prostate cancer. Hypo-EBRT was initiated 8–12 weeks after initiating enzalutamide. The primary endpoint was PSA decline >80% measured at the 25th week of enzalutamide administration. Secondary end-points included assessment of toxicity, changes in anthropomorphic body measurements, sexual hormones, and metabolic changes.

Results

Sixty-two patients were included in the study from January 2018 to February 2020. A PSA decline of >80% was observed in all evaluable patients at the end of enzalutamide treatment and 92% achieved PSA values under 0.1 ngr/ml. All patients remain in PSA response (<80% reduction of the initial values) 6 months after the end of enzalutamide treatment. The most frequent adverse events were hypertension, asthenia, and gynecomastia. There were no significant changes in bone density, body mass index (BMI), or patient-reported outcomes (PROs).

Conclusion

Enzalutamide monotherapy is very effective along with hEBRT in reducing PSA levels for patients with intermediate-risk prostate cancer. Longer follow-up is needed to confirm the potential use of this combination in future randomized trials.
Neutron Radiation Dose Measurements in a Scanning Proton Therapy Room: Can Parents Remain Near Their Children During Treatment?
Authors: Mares Vladimir , Farah Jad , De Saint-Hubert Marijke , Domański Szymon , Domingo Carles , Dommert Martin , Kłodowska Magdalena , Krzempek Katarzyna , Kuć Michał , Martínez-Rovira Immaculada , Michaś Edyta , Mojżeszek Natalia , Murawski Łukasz , Ploc Ondrej , Romero-Expósito Maite , Tisi Marco , Trompier François , Van Hoey Olivier , Van Ryckeghem Laurent , Wielunski Marek , Harrison Roger M. , Stolarczyk Liliana , Olko Pawel
Published: July 2022

Purpose

This study aims to characterize the neutron radiation field inside a scanning proton therapy treatment room including the impact of different pediatric patient sizes.

Materials and Methods

Working Group 9 of the European Radiation Dosimetry Group (EURADOS) has performed a comprehensive measurement campaign to measure neutron ambient dose equivalent, H*(10), at eight different positions around 1-, 5-, and 10-year-old pediatric anthropomorphic phantoms irradiated with a simulated brain tumor treatment. Several active detector systems were used.

Results

The neutron dose mapping within the gantry room showed that H*(10) values significantly decreased with distance and angular deviation with respect to the beam axis. A maximum value of about 19.5 µSv/Gy was measured along the beam axis at 1 m from the isocenter for a 10-year-old pediatric phantom at 270° gantry angle. A minimum value of 0.1 µSv/Gy was measured at a distance of 2.25 m perpendicular to the beam axis for a 1-year-old pediatric phantom at 140° gantry angle.

The H*(10) dependence on the size of the pediatric patient was observed. At 270° gantry position, the measured neutron H*(10) values for the 10-year-old pediatric phantom were up to 20% higher than those measured for the 5-year-old and up to 410% higher than for the 1-year-old phantom, respectively.

Conclusions

Using active neutron detectors, secondary neutron mapping was performed to characterize the neutron field generated during proton therapy of pediatric patients. It is shown that the neutron ambient dose equivalent H*(10) significantly decreases with distance and angle with respect to the beam axis. It is reported that the total neutron exposure of a person staying at a position perpendicular to the beam axis at a distance greater than 2 m from the isocenter remains well below the dose limit of 1 mSv per year for the general public (recommended by the International Commission on Radiological Protection) during the entire treatment course with a target dose of up to 60 Gy. This comprehensive analysis is key for general neutron shielding issues, for example, the safe operation of anesthetic equipment. However, it also enables the evaluation of whether it is safe for parents to remain near their children during treatment to bring them comfort. Currently, radiation protection protocols prohibit the occupancy of the treatment room during beam delivery.
Sintilimab Combined with Lenvatinib for Advanced Intrahepatic Cholangiocarcinoma in Second-Line Setting—A Multi-Center Observational Study
Authors: Ding Xiaoyan , Li Guangxin , Sun Wei , Shen Yanjun , Teng Ying , Xu Yawen , Li Wendong , Liu Mei , Chen Jinglong
Published: July 2022

Background

Patients with advanced intrahepatic cholangiocarcinoma (iCCA) have a poor prognosis and a substantial unmet clinical need. The study was aimed to investigate the efficacy and safety of sintilimab combined with lenvatinib for advanced iCCA in second-line setting.

Methods

The patients at multiple centers, who progressed after the first-line chemotherapy or could not tolerate chemotherapy, were treated with the combination of sintilimab plus lenvatinib. The primary endpoint was time to progression (TTP), and the secondary endpoints included tumor objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Prognostic factors were analyzed using Cox regression analysis.

Results

A total of 41 patients with advanced iCCA were enrolled for this multi-center observational study. Under a median follow-up of 12.1 months, the median age was 59 years (range, 33–75 years). Sixteen patients died of disease progression, with a median TTP of 6.6 months (95% CI, 4.9–8.3). ORR and DCR were 46.3% and 70.3%, respectively. The patients with PD-L1 TPS ≥10% reported a significantly higher ORR compared to those with PD-L1 TPS <10%, 93.8% (15/16) vs. 16.0% (4/25), p<0.001. The median TTP was significantly improved in patients with PD-L1 TPS ≥10%, 16.9 months (95% CI, 7.5–26.3) vs. 4.1 months (95% CI, 1.8–6.4), p=0.001. Attaining treatment response predicts favorable TTP in a multivariate Cox model. Treatment-emergent adverse events occurred with 70.3% probability, and no treatment-related death had been reported.

Conclusion

The combination of sintilimab plus lenvatinib is effective and well tolerated for advanced iCCA in the second-line setting. PD-L1 TPS expression may predict the efficacy of the combination therapy. Further investigation is warranted to investigate this combination regimen in advanced iCCA.
Case Report: Monoclonal Gammopathies of Clinical Significance-Associated Myopathy: A Case-Based Review
Authors: Yu Hongbin , He Du , Zhang Qing , Cao Bei , Liu Weiping , Wu Yu
Published: July 2022

Monoclonal gammopathies of clinical significance (MGCS)-associated myopathy is a group of muscular MGCS-based rare manifestations. It mainly includes amyloid light chain (AL) amyloidosis and sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance. When myopathy manifests as the initial or sole clinical symptom, it can often be delayed or misdiagnosed as other myopathies. We report the case of a 60-year-old man who initially presented with fatigue and muscle weakness of the symmetric proximal lower limbs. Muscle biopsy did not reveal mononuclear cell infiltration, atrophy, necrosis, or positive Congo red staining results. The results of serum protein electrophoresis and immunofixation electrophoresis were negative. No specific diagnosis was established. After 1 year, the patient was diagnosed with AL amyloidosis after myocardial and fat pad biopsies were performed and myopathy was diagnosed as AL amyloidosis-associated myopathy after reassessment. The patient received CyBorD regime chemotherapy and achieved hematological and organ remission. Therefore, we reviewed the clinical and pathological manifestations of MGCS-associated myopathies. Based on published articles and the present case, we conclude that comprehensive screening for MGCS in unexplained myopathy is essential to avoid misdiagnosis or delayed diagnosis.
A “3S+f” Nephrometry Score System to Predict the Clinical Outcomes of Laparoscopic Nephron-Sparing Surgery
Authors: Zhang Shudong , Qin Zijian , Bi Hai , Tao Liyuan , Zhang Fan , Zhang Hongxian , Wang Wei , Wu Jitao , Huang Yi , Ma Lulin
Published: July 2022

Background

When we treat renal cell carcinoma by laparoscopic nephron-sparing surgery (NSS), it is essential to use an evaluation system to predict clinical outcomes. Hitherto, there are more than a dozen nephrometry score systems. In this study, through assessing the correlations between nephrometry score systems and clinical outcomes, we aim to provide a novel nephrometry score system—the “3S+f” score system—to simplify the evaluation of technical complexity of partial nephrectomy.

Methods

We retrospectively collected the data of 131 patients who underwent NSS, which was performed by a single surgeon (SZ) from January 2013 to July 2018 at Peking University Third Hospital. The “3S+f” score system contains four parameters: “size, side, site, and fat”, all of which can be obtained from preoperative imaging data. We evaluated the correlations between the “3S+f” score and clinical outcomes, and compared R.E.N.A.L. score and PADUA score.

Results

All the three nephrometry score systems were related to some clinical outcomes in univariate analyses. In multivariate regression models, the “3S+f” score, the R.E.N.A.L. score, and the PADUA score were significantly associated with operative time (p = 0.016, p = 0.035, and p = 0.001, respectively) and warm ischemia time (all p = 0.008, p < 0.001, and p < 0.001, respectively). “3S+f” was also significantly related to extubation time > 5 days (p = 0.018). In predicting operative time > 120 min and extubation time >5 days from ROC curves, the AUCs of the “3S+f” score (0.717 and 0.652, respectively) were larger than both the R.E.N.A.L (0.598 and 0.554, respectively) and PADUA (0.600 and 0.542, respectively) score systems.

Conclusion

A novel nephrometry score system—the “3S+f” score system—shows equivalent correlation and the ability in predicting clinical outcomes when compared to the R.E.N.A.L. score system and the PADUA score system, which can describe renal tumors.
Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance
Authors: Manzoor Shaista , Muhammad Jibran Sualeh , Maghazachi Azzam A. , Hamid Qutayba
Published: July 2022

Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.
DNA Demethylation Switches Oncogenic ΔNp63 to Tumor Suppressive TAp63 in Squamous Cell Carcinoma
Authors: Pokorna Zuzana , Hrabal Vaclav , Tichy Vlastimil , Vojtesek Borivoj , Coates Philip J.
Published: July 2022

The TP63 gene encodes two major protein variants; TAp63 contains a p53-like transcription domain and consequently has tumor suppressor activities whereas ΔNp63 lacks this domain and acts as an oncogene. The two variants show distinct expression patterns in normal tissues and tumors, with lymphocytes and lymphomas/leukemias expressing TAp63, and basal epithelial cells and some carcinomas expressing high levels of ΔNp63, most notably squamous cell carcinomas (SCC). Whilst the transcriptional functions of TAp63 and ΔNp63 isoforms are known, the mechanisms involved in their regulation are poorly understood. Using squamous epithelial cells that contain high levels of ΔNp63 and low/undetectable TAp63, the DNA demethylating agent decitabine (5-aza-2’-deoxycytidine, 5-dAza) caused a dose-dependent increase in TAp63, with a simultaneous reduction in ΔNp63, indicating DNA methylation-dependent regulation at the isoform-specific promoters. The basal cytokeratin KRT5, a direct ΔNp63 transcriptional target, was also reduced, confirming functional alteration of p63 activity after DNA demethylation. We also showed high level methylation of three CpG sites in the TAP63 promoter in these cells, which was reduced by decitabine. DNMT1 depletion using inducible shRNAs partially replicated these effects, including an increase in the ratio of TAP63:ΔNP63 mRNAs, a reduction in ΔNp63 protein and reduced KRT5 mRNA levels. Finally, high DNA methylation levels were found at the TAP63 promoter in clinical SCC samples and matched normal tissues. We conclude that DNA methylation at the TAP63 promoter normally silences transcription in squamous epithelial cells, indicating DNA methylation as a therapeutic approach to induce this tumor suppressor in cancer. That decitabine simultaneously reduced the oncogenic activity of ΔNp63 provides a “double whammy” for SCC and other p63-positive carcinomas. Whilst a variety of mechanisms may be involved in producing the opposite effects of DNA demethylation on TAp63 and ΔNp63, we propose an “either or” mechanism in which TAP63 transcription physically interferes with the ability to initiate transcription from the downstream ΔNP63 promoter on the same DNA strand. This mechanism can explain the observed inverse expression of p63 isoforms in normal cells and cancer.
Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Efficacy and Thoracic Toxicity in Non-Small-Cell Lung Cancer
Authors: He Kewen , Zhang Shaotong , Pang Jiaohui , Yin Jiani C. , Mu Dianbin , Wang Jun , Ge Hong , Ma Jie , Yang Zhe , Zheng Xiaoli , Dong Lihua , Zhang Junli , Chang Pengyu , Li Li , Tang Shanshan , Bao Hua , Wu Xue , Wang Xiaonan , Shao Yang , Yu Jinming , Yuan Shuanghu
Published: July 2022

Chemo-radiotherapy (CRT) remains the main treatment modality for non-small-cell lung cancer (NSCLC). However, its clinical efficacy is largely limited by individual variations in radio-sensitivity and radiotherapy-associated toxicity. There is an urgent need to identify genetic determinants that can explain patients’ likelihood to develop recurrence and radiotherapy-associated toxicity following CRT. In this study, we performed comprehensive genomic profiling, using a 474-cancer- and radiotherapy-related gene panel, on pretreatment biopsy samples from patients with unresectable stage III NSCLCs who underwent definitive CRT. Patients’ baseline clinical characteristics and genomic features, including tumor genetic, genomic and molecular pathway alterations, as well as single nucleotide polymorphisms (SNPs), were correlated with progression-free survival (PFS), overall survival (OS), and radiotherapy-associated pneumonitis and/or esophagitis development after CRT. A total of 122 patients were enrolled between 2014 and 2019, with 84 (69%) squamous cell carcinomas and 38 (31%) adenocarcinomas. Genetic analysis confirmed the association between the KEAP1-NRF2 pathway gene alterations and unfavorable survival outcome, and revealed alterations in FGFR family genes, MET, PTEN, and NOTCH2 as potential novel and independent risk factors of poor post-CRT survival. Combined analysis of such alterations led to improved stratification of the risk populations. In addition, patients with EGFR activating mutations or any oncogenic driver mutations exhibited improved OS. On the other hand, we also identified genetic markers in relation to radiotherapy-associated thoracic toxicity. SNPs in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis respectively. MTHFR (rs1801133) and NQO1 (rs1800566) were additional risk alleles related to higher susceptibility to pneumonitis and esophagitis overall. Moreover, through their roles in genome integrity and replicative fidelity, somatic alterations in ZNF217 and POLD1 might also serve as risk predictors of high-grade pneumonitis and esophagitis. Taken together, leveraging targeted next-generating sequencing, we identified a set of novel clinically applicable biomarkers that might enable prediction of survival outcomes and risk of radiotherapy-associated thoracic toxicities. Our findings highlight the value of pre-treatment genetic testing to better inform CRT outcomes and clinical actions in stage III unresectable NSCLCs.
Current Progress in Cancer Treatment Using Nanomaterials
Authors: Zhu Ruirui , Zhang Fangyuan , Peng Yudong , Xie Tian , Wang Yi , Lan Yin
Published: July 2022

The pathological processes of cancer are complex. Current methods used for chemotherapy have various limitations, such as cytotoxicity, multi-drug resistance, stem-like cells growth, and lack of specificity. Several types of nanomaterials are used for cancer treatment. Nanomaterials 1–100 nm in size have special optical, magnetic, and electrical characteristics. Nanomaterials have been fabricated for cancer treatments to overcome cytotoxicity and low specificity, and improve drug capacity and bioavailability. Despite the increasing number of related studies, few nanodrugs have been approved for clinical use. To improve translation of these materials, studies of targeted drug delivery using nanocarriers are needed. Cytotoxicity, enhanced permeability and retention effects, and the protective role of the protein corona remain to be addressed. This mini-review summarizes new nanomaterials manufactured in studies and in clinical use, analyses current barriers preventing their translation to clinical use, and describes the effective application of nanomaterials in cancer treatment.
The Prognostic Value of Tumor Size, Volume and Tumor Volume Reduction Rate During Concurrent Chemoradiotherapy in Patients With Cervical Cancer
Authors: Sun Chang , Wang Shubin , Ye Wenjing , Wang RanLin , Tan Mingyu , Zhang Hanyi , Zhou Jie , Li Minglun , Wei Lichun , Xu Peng , Zhu Guiquan , Lang Jinyi , Lu Shun
Published: July 2022

Objective

This study aimed to investigate the relationship between prognostic and tumor parameters of cervical cancer patients, such as tumor size (TS), tumor volume (TV), and tumor volume reduction rate (TVRR) after external beam radiotherapy.

Methods

A total of 217 patients with advanced cervical cancer, classified as Federation of Gynecology and Obstetrics (FIGO) IIa–IVa, were enrolled in the study. Pre- and mid-RT pelvic magnetic resonance imaging (MRI) were performed twice, during RT and just before brachytherapy.

Results

The median follow-up time was 51 months (range, 7–111 months). The 5-year overall survival (OS), progression-free survival (PFS), and local failure-free survival (LFFS) rates were 81.3, 85.1, and 92.9%, respectively. Multivariate analysis revealed that tumor parameters including FIGO stage >II (Hazard Ratio, 2.377 and 95% confidence interval [CI], 1.091–5.182; P = 0.029), pre-RT TV >61.6 cm3 (HR, 0.417 and 95% CI, 0.188–0.926; P = 0.032), and mid-RT TV >11.38 cm3 (HR, 3.192 and 95% CI, 1.094–9.316; P = 0.034) were observably associated with OS. Univariate analysis showed that the tumor volume reduction rate (TVRR) was dramatically associated with overall survival (HR, 0.204 and 95% CI 0.033–1.282; P <0.001) and local failure-free survival (P = 0.050).

Conclusions

In this retrospective study, TVRR and mid-radiotherapy tumor volume are independent and strong prognostic parameters for patients with local advanced cervical cancer receiving CCRT.
Ononin Shows Anticancer Activity Against Laryngeal Cancer via the Inhibition of ERK/JNK/p38 Signaling Pathway
Authors: Ye Ben , Ma Jianhua , Li Zhaoxia , Li Yang , Han Xiaopan
Published: July 2022

Background

Laryngeal cancer is a type of head and neck tumor with a poor prognosis and survival rate. The new cases of laryngeal cancer increased rapidly with a higher mortality rate around the world.

Objective

The current research work was focused to unveil the in vitro antitumor effects of ononin against the laryngeal cancer Hep-2 cells.

Methodology

The cytotoxic effects of ononin against the laryngeal cancer Hep-2 cells and normal HuLa-PC laryngeal cells were studied using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The intracellular Reactive Oxygen Species (ROS) generation, apoptotic cell death, Mitochondrial Membrane Potential (MMP), and cell adhesion on the 25 and 50 µM ononin-treated Hep-2 cells were detected using respective staining assays. The levels of TBARS and antioxidants were assayed using specific kits. The expressions of c-Jun N-terminal kinase 1/2 (JNK1/2), Extracellular Signal-regulated Kinase 1/2 (ERK1/2), p38, Phosphatidylinositol-3 Kinase 1/2 (PI3K1/2), and protein kinase-B (Akt) in the ononin-treated Hep-2 cells were investigated using Reverse Transcription-Polymerase Chain Reaction (RT-PCR) assay.

Results

The ononin treatment effectively inhibited the Hep-2 cell viability but did not affect the viability of HuLa-PC cells. Furthermore, the ononin treatment effectively improved the intracellular ROS accumulation, depleted the MMP, and triggered apoptosis in Hep-2 cells. The Thiobarbituric acid reactive substances (TBARS) were improved, and Glutathione (GSH) levels and Superoxide dismutase (SOD) were depleted in the ononin-administered Hep-2 cells. The ononin treatment substantially inhibited the JNK/ERK/p38 axis in the Hep-2 cells.

Conclusion

Together, the outcomes of this exploration proved that the ononin has remarkable antitumor activity against laryngeal cancer Hep-2 cells.
Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer
Authors: Zhao Qiushi , Lin Xingyu , Wang Guan
Published: July 2022

Sterol regulatory element binding protein-1 (SREBP-1), a transcription factor with a basic helix–loop–helix leucine zipper, has two isoforms, SREBP-1a and SREBP-1c, derived from the same gene for regulating the genes of lipogenesis, including acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase. Importantly, SREBP-1 participates in metabolic reprogramming of various cancers and has been a biomarker for the prognosis or drug efficacy for the patients with cancer. In this review, we first introduced the structure, activation, and key upstream signaling pathway of SREBP-1. Then, the potential targets and molecular mechanisms of SREBP-1-regulated lipogenesis in various types of cancer, such as colorectal, prostate, breast, and hepatocellular cancer, were summarized. We also discussed potential therapies targeting the SREBP-1-regulated pathway by small molecules, natural products, or the extracts of herbs against tumor progression. This review could provide new insights in understanding advanced findings about SREBP-1-mediated lipogenesis in cancer and its potential as a target for cancer therapeutics.
Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers
Authors: Algorta Jaime , Krolewiecki Alejandro , Pinto Filipe , Gold Silvia , Muñoz Jose
Published: July 2022

Soil-transmitted helminths are intestinal worm diseases transmitted through the soil. Available treatments are albendazole and/or ivermectin. The co-administration of existing drugs is an appropriate strategy. A fixed-dose combination adds practical advantages mainly considering mass drug administration. The aim is to characterize pharmacokinetics and to evaluate the comparative bioavailability of an innovative fixed-dose combination of ivermectin/albendazole 18/400 mg compared with the marketed references. Seventy-eight healthy volunteers were included in this laboratory-blinded, randomized, three-treatment, three-period crossover study. Each subject received a single dose of ivermectin/albendazole 18/400 mg (1 tablet); ivermectin 3 mg (6 tablets); and albendazole 400 mg (1 tablet). Serial blood samples for the pharmacokinetic analysis were obtained pre-dose and up to 72 h post-dose. Plasma concentrations of ivermectin H2B1a, ivermectin H2B1b, albendazole, and albendazole sulfoxide were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated by a non-compartmental analysis and bioavailability compared through a bioequivalence analysis. Safety and tolerability were assessed throughout the study. Main pharmacokinetic parameters of the fixed combination were estimated for both, ivermectin [Cmax (mean, confidence interval): 86.40 (30.42–39.23) ng/ml; AUC0-72 (mean, CI): 1,040 (530–1,678) ng·h/mL; tmax (median, min., and max.); 4.50 (2.50–5.50)] and albendazole [Cmax (mean, CI): 22.27 (1.89–111.78) ng/ml; AUC0-72 (mean, CI): 94.65 (11.65–507.78) ng·h/mL; tmax (median, min., and max.): 2.50 (1.00–12.00) h]. The 90% confidence interval of the geometric mean ratios demonstrated the bioequivalence in the case of ivermectin (Cmax: 110.68%–120.49%; AUC0-72: 110.46%–119.60%) but not in the case of albendazole (Cmax: 53.10%–70.34%; AUC0-72: 61.13%–76.54%). The pharmacokinetic profile of a new fixed-dose combination of ivermectin and albendazole was characterized. The bioequivalence versus the reference ivermectin was demonstrated, though bioequivalence versus albendazole was not shown. The three medications analyzed were well tolerated. The results allow the advancement to the next phase of the clinical program to demonstrate efficacy and safety in patients affected by soil-transmitted helminths.

Clinical Trial Registration:https://www.clinicaltrialsregister.eu/ctr-search/search/, identifier Nr. 2020-003438-19
Epac: A Promising Therapeutic Target for Vascular Diseases: A Review
Authors: Pan Yunfeng , Liu Jia , Ren Jiahui , Luo Yun , Sun Xiaobo
Published: July 2022

Vascular diseases affect the circulatory system and comprise most human diseases. They cause severe symptoms and affect the quality of life of patients. Recently, since their identification, exchange proteins directly activated by cAMP (Epac) have attracted increasing scientific interest, because of their role in cyclic adenosine monophosphate (cAMP) signaling, a well-known signal transduction pathway. The role of Epac in cardiovascular disease and cancer is extensively studied, whereas their role in kidney disease has not been comprehensively explored yet. In this study, we aimed to review recent studies on the regulatory effects of Epac on various vascular diseases, such as cardiovascular disease, cerebrovascular disease, and cancer. Accumulating evidence has shown that both Epac1 and Epac2 play important roles in vascular diseases under both physiological and pathological conditions. Additionally, there has been an increasing focus on Epac pharmacological modulators. Therefore, we speculated that Epac could serve as a novel therapeutic target for the treatment of vascular diseases.
The potential mechanism of Longsheyangquan Decoction on the treatment of bladder cancer: Systemic network pharmacology and molecular docking
Authors: Cheng Zhang , Ye Fangdie , Xu Chenyang , Liang Yingchun , Zhang Zheyu , Chen Xinan , Dai Xiyu , Ou Yuxi , Mou Zezhong , Li Weijian , Chen Yiling , Zhou Quan , Zou Lujia , Mao Shanhua , Jiang Haowen
Published: July 2022

Our goal was to explore the bioactive constituents of Longsheyangquan (LSYQ) Decoction and elucidate its mechanisms on the treatment of bladder cancer (BCa). A total of 38 compounds were selected based on their pharmacokinetic properties in three large traditional Chinese medicine (TCM) databases. 654 putative targets of LSYQ Decoction were predicted using a structure-based, reverse-docking algorithm online, of which 343 overlapped with BCa-related protein-coding genes. The protein-protein interaction (PPI) network was constructed to perform module analysis for further Gene Ontology (GO) annotations and Kyoto Encyclopedia Genes and Genomes (KEGG) pathway enrichment analysis, which identified CDK2, EGFR, MMP9 and PTGS2 as hub targets. The TCM-compound-target network and compound-target-pathway network together revealed that quercetin, diosmetin, enhydrin and luteolin were the main components of LSYQ Decoction. Finally, molecular docking showed the affinity between the key compounds and the hub target proteins to verify the accuracy of drug target prediction in the first place. The present study deciphered the core components and targets of LSYQ Decoction on the treatment of BCa in a comprehensive systemic pharmacological manner.
P2X7 Purinoceptor Affects Ectopic Calcification of Dystrophic Muscles
Authors: Rumney Robin M. H. , Róg Justyna , Chira Natalia , Kao Alexander P. , Al-Khalidi Rasha , Górecki Dariusz C.
Published: July 2022

Ectopic calcification (EC) of myofibers is a pathological feature of muscle damage in Duchenne muscular dystrophy (DMD). Mineralisation of muscle tissue occurs concomitantly with macrophage infiltration, suggesting a link between ectopic mineral deposition and inflammation. One potential link is the P2X7 purinoceptor, a key trigger of inflammation, which is expressed on macrophages but also up-regulated in dystrophic muscle cells. To investigate the role of P2X7 in dystrophic calcification, we utilised the Dmdmdx-βgeo dystrophin-null mouse model of DMD crossed with a global P2X7 knockout (P2rx7−/−) or with our novel P2X7 knockin-knockout mouse (P2x7KiKo), which expresses P2X7 in macrophages but not muscle cells. Total loss of P2X7 increased EC, indicating that P2X7 overexpression is a protective mechanism against dystrophic mineralisation. Given that muscle-specific P2X7 ablation did not affect dystrophic EC, this underlined the role of P2X7 receptor expression on the inflammatory cells. Serum phosphate reflected dystrophic calcification, with the highest serum phosphate levels found in genotypes with the most ectopic mineral. To further investigate the underlying mechanisms, we measured phosphate release from cells in vitro, and found that dystrophic myoblasts released less phosphate than non-dystrophic cells. Treatment with P2X7 antagonists increased phosphate release from both dystrophic and control myoblasts indicating that muscle cells are a potential source of secreted phosphate while macrophages protect against ectopic mineralisation. Treatment of cells with high phosphate media engendered mineral deposition, which was decreased in the presence of the P2X7 agonist BzATP, particularly in cultures of dystrophic cells, further supporting a protective role for P2X7 against ectopic mineralisation in dystrophic muscle.
Inhibition of HDAC6 With CAY10603 Ameliorates Diabetic Kidney Disease by Suppressing NLRP3 Inflammasome
Authors: Hou Qing , Kan Shuyan , Wang Zhuang , Shi Jinsong , Zeng Caihong , Yang Dahai , Jiang Song , Liu Zhihong
Published: July 2022

Background: Diabetic nephropathy (DN) is one of the leading causes of chronic kidney disease (CKD) worldwide, tubular injury is the driving force during the pathogenesis and progression of DN. Thus, we aim to utilize the connectivity map (CMap) with renal tubulointerstitial transcriptomic profiles of biopsy-proven DN to identify novel drugs for treating DN.

Methods: We interrogated the CMap profile with tubulointerstitial transcriptomic data from renal biopsy-proven early- and late-stage DN patients to screen potential drugs for DN. Therapeutic effects of candidate drug were assessed in Murine model of diabetic kidney disease (STZ-induced CD-1 mice), and HK-2 cells and immortalized bone marrow-derived macrophages (iBMDMs).

Results: We identified CAY10603, a specific inhibitor of histone deacetylase 6 (HDAC6), as a potential drug that could significantly reverse the altered genes in the tubulointerstitial component. In DN patients and mice, upregulation of HDAC6 was mainly observed in renal tubular cells and infiltrated macrophages surrounding the diluted tubules. In both early- and late-onset diabetic mice, daily CAY10603 administration effectively alleviated renal dysfunction and reduced macrophage infiltration, tubular injury and tubulointerstitial fibrosis. Mechanistically, CAY10603 suppressed NLRP3 activation in both HK-2 cells and iBMDMs.

Conclusion: CAY10603 exhibited therapeutic potential for DN by suppressing NLRP3 inflammasome activation in both tubular cells and macrophages.
Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle
Authors: Hernández-Camacho Juan Diego , Fernández-Ayala Daniel J. M. , Vicente-García Cristina , Navas-Enamorado Ignacio , López-Lluch Guillermo , Oliva Clara , Artuch Rafael , Garcia-Villoria Judith , Ribes Antonia , de Cabo Rafael , Carvajal Jaime J. , Navas Plácido
Published: July 2022

ADCK2 haploinsufficiency-mediated mitochondrial coenzyme Q deficiency in skeletal muscle causes mitochondrial myopathy associated with defects in beta-oxidation of fatty acids, aged-matched metabolic reprogramming, and defective physical performance. Calorie restriction has proven to increase lifespan and delay the onset of chronic diseases associated to aging. To study the possible treatment by food deprivation, heterozygous Adck2 knockout mice were fed under 40% calorie restriction (CR) and the phenotype was followed for 7 months. The overall glucose and fatty acids metabolism in muscle was restored in mutant mice to WT levels after CR. CR modulated the skeletal muscle metabolic profile of mutant mice, partially rescuing the profile of WT animals. The analysis of mitochondria isolated from skeletal muscle demonstrated that CR increased both CoQ levels and oxygen consumption rate (OCR) based on both glucose and fatty acids substrates, along with mitochondrial mass. The elevated aerobic metabolism fits with an increase of type IIa fibers, and a reduction of type IIx in mutant muscles, reaching WT levels. To further explore the effect of CR over muscle stem cells, satellite cells were isolated and induced to differentiate in culture media containing serum from animals in either ad libitum or CR diets for 72 h. Mutant cells showed slower differentiation alongside with decreased oxygen consumption. In vitro differentiation of mutant cells was increased under CR serum reaching levels of WT isolated cells, recovering respiration measured by OCR and partially beta-oxidation of fatty acids. The overall increase of skeletal muscle bioenergetics following CR intervention is paralleled with a physical activity improvement, with some increases in two and four limbs strength tests, and weights strength test. Running wheel activity was also partially improved in mutant mice under CR. These results demonstrate that CR intervention, which has been shown to improve age-associated physical and metabolic decline in WT mice, also recovers the defective aerobic metabolism and differentiation of skeletal muscle in mice caused by ADCK2 haploinsufficiency.