bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipoprotein(a) As a Potential Predictive Factor for Earlier Aortic Valve Replacement in Patients with Bicuspid Aortic Valve
Authors: Krzesińska Aleksandra , Nowak Maria , Mickiewicz Agnieszka , Chyła-Danił Gabriela , Ćwiklińska Agnieszka , Koper-Lenkiewicz Olga M. , Kamińska Joanna , Matowicka-Karna Joanna , Gruchała Marcin , Jankowski Maciej , Fijałkowski Marcin , Kuchta Agnieszka
Published: June 2023

Bicuspid aortic valve (BAV) affects 0.5–2% of the general population and constitutes the major cause of severe aortic valve stenosis (AVS) in individuals ≤70 years. The aim of the present study was to evaluate the parameters that may provide information about the risk of AVS developing in BAV patients, with particular emphasis on lipoprotein(a) (Lp(a)), which is a well-recognized risk factor for stenosis in the general population. We also analyzed the impact of autotaxin (ATX) and interleukin-6 (IL-6) as parameters potentially related to the pathomechanism of Lp(a) action. We found that high Lp(a) levels (>50 mg/dL) occurred significantly more frequently in patients with AVS than in patients without AVS, both in the group below and above 45 years of age (p = 0.036 and p = 0.033, respectively). Elevated Lp(a) levels were also strictly associated with the need for aortic valve replacement (AVR) at a younger age (p = 0.016). However, the Lp(a) concentration did not differ significantly between patients with and without AVS. Similarly, we observed no differences in ATX between the analyzed patient groups, and both ATX activity and concentration correlated significantly with Lp(a) level (R = 0.465, p < 0.001 and R = 0.599, p < 0.001, respectively). We revealed a significantly higher concentration of IL-6 in young patients with AVS. However, this observation was not confirmed in the group of patients over 45 years of age. We also did not observe a significant correlation between IL-6 and Lp(a) or between CRP and Lp(a) in any of the analyzed groups of BAV patients. Our results demonstrate that a high level of Lp(a), greater than 50 mg/dL, may be a significant predictive factor for earlier AVR. Lp(a)-related parameters, such as ATX and IL-6, may be valuable in providing information about the additional cardiovascular risks associated with developing AVS.
Classification of Breast Cancer Using Transfer Learning and Advanced Al-Biruni Earth Radius Optimization
Authors: Alhussan Amel Ali , Abdelhamid Abdelaziz A. , Towfek S. K. , Ibrahim Abdelhameed , Abualigah Laith , Khodadadi Nima , Khafaga Doaa Sami , Al-Otaibi Shaha , Ahmed Ayman Em
Published: June 2023

Breast cancer is one of the most common cancers in women, with an estimated 287,850 new cases identified in 2022. There were 43,250 female deaths attributed to this malignancy. The high death rate associated with this type of cancer can be reduced with early detection. Nonetheless, a skilled professional is always necessary to manually diagnose this malignancy from mammography images. Many researchers have proposed several approaches based on artificial intelligence. However, they still face several obstacles, such as overlapping cancerous and noncancerous regions, extracting irrelevant features, and inadequate training models. In this paper, we developed a novel computationally automated biological mechanism for categorizing breast cancer. Using a new optimization approach based on the Advanced Al-Biruni Earth Radius (ABER) optimization algorithm, a boosting to the classification of breast cancer cases is realized. The stages of the proposed framework include data augmentation, feature extraction using AlexNet based on transfer learning, and optimized classification using a convolutional neural network (CNN). Using transfer learning and optimized CNN for classification improved the accuracy when the results are compared to recent approaches. Two publicly available datasets are utilized to evaluate the proposed framework, and the average classification accuracy is 97.95%. To ensure the statistical significance and difference between the proposed methodology, additional tests are conducted, such as analysis of variance (ANOVA) and Wilcoxon, in addition to evaluating various statistical analysis metrics. The results of these tests emphasized the effectiveness and statistical difference of the proposed methodology compared to current methods.
An In Silico Analysis Reveals Sustained Upregulation of Neuroprotective Genes in the Post-Stroke Human Brain
Authors: Betto Federica , Chiricosta Luigi , Mazzon Emanuela
Published: June 2023

Ischemic stroke is a cerebrovascular disease caused by an interruption of blood flow to the brain, thus determining a lack of oxygen and nutrient supply. The ischemic event leads to the activation of several molecular signaling pathways involved in inflammation and the production of reactive oxygen species, causing irreversible neuronal damage. Several studies have focused on the acute phase of ischemic stroke. It is not clear if this traumatic event can influence some of the molecular processes in the affected area even years after the clinical event. In our study, we performed an in silico analysis using freely available raw data with the purpose of evaluating the transcriptomic state of post-mortem brain tissue. The samples were taken from non-fatal ischemic stroke patients, meaning that they suffered an ischemic stroke and lived for a period of about 2 years after the event. These samples were compared with healthy controls. The aim was to evaluate possible recovery processes useful to mitigating neuronal damage and the detrimental consequences of stroke. Our results highlighted differentially expressed genes codifying for proteins along with long non-coding genes with anti-inflammatory and anti-oxidant functions. This suggests that even after an amount of time from the ischemic insult, different neuroprotective mechanisms are activated to ameliorate brain conditions and repair post-stroke neuronal injury.
Excitatory Dorsal Lateral Prefrontal Cortex Transcranial Magnetic Stimulation Increases Social Anxiety
Authors: Minervini Anthony , LaVarco Adriana , Zorns Samantha , Propper Ruth , Suriano Christos , Keenan Julian Paul
Published: June 2023

Social exclusion refers to the experience of rejection by one or more people during a social event and can induce pain-related sensations. Cyberball, a computer program, is one of the most common tools for analyzing social exclusion. Regions of the brain that underlie social pain include networks linked to the dorsal lateral prefrontal cortex (DLPFC). Specifically, self-directed negative socially induced exclusion is associated with changes in DLPFC activity. Direct manipulation of this area may provide a better understanding of how the DLPFC can influence the perception of social exclusion and determine a causal role of the DLPFC. Transcranial magnetic stimulation (TMS) was applied to both the left and right DLPFC to gauge different reactions to the Cyberball experience. It was found that there were elevated exclusion indices following right DLPFC rTMS; participants consistently felt more excluded when the right DLPFC was excited. This may relate to greater feelings of social pain when the right DLPFC is manipulated. These data demonstrate that direct manipulation of the DLPFC results in changes in responses to social exclusion.
Toxicity of Synthetic Cannabinoids in K2/Spice: A Systematic Review
Authors: de Oliveira Mariana Campello , Vides Mariana Capelo , Lassi Dângela Layne Silva , Torales Julio , Ventriglio Antonio , Bombana Henrique Silva , Leyton Vilma , Périco Cintia de Azevedo-Marques , Negrão André Brooking , Malbergier André , Castaldelli-Maia João Maurício
Published: June 2023

(1) Background: Synthetic cannabinoids (SCs) are emerging drugs of abuse sold as ‘K2’, ‘K9’ or ‘Spice’. Evidence shows that using SCs products leads to greater health risks than cannabis. They have been associated with greater toxicity and higher addiction potential unrelated to the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). Moreover, early cases of intoxication and death related to SCs highlight the inherent danger that may accompany the use of these substances. However, there is limited knowledge of the toxicology of Spice ingredients. This systematic review intends to analyze the toxicity of SCs compounds in Spice/K2 drugs. (2) Methods: Studies analyzing synthetic cannabinoid toxicity and dependence were included in the present review. We searched the PubMed database of the US National Library of Medicine, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. (3) Results: Sixty-four articles reporting the effects of synthetic cannabinoids in humans were included in our review. Ten original papers and fifty-four case studies were also included. Fourteen studies reported death associated with synthetic cannabinoid use, with AB-CHMINACA and MDMB-CHMICA being the main reported SCs. Tachycardia and seizures were the most common toxicity symptoms. The prevalence of neuropsychiatric symptoms was higher in third-generation SCs. (4) Conclusion: SCs may exhibit higher toxicity than THC and longer-lasting effects. Their use may be harmful, especially in people with epilepsy and schizophrenia, because of the increased risk of the precipitation of psychiatric and neurologic disorders. Compared to other drugs, SCs have a higher potential to trigger a convulsive crisis, a decline in consciousness, and hemodynamic changes. Therefore, it is crucial to clarify their potential harms and increase the availability of toxicology data in both clinical and research settings.
Audiovisual n-Back Training Alters the Neural Processes of Working Memory and Audiovisual Integration: Evidence of Changes in ERPs
Authors: Guo Ao , Yang Weiping , Yang Xiangfu , Lin Jinfei , Li Zimo , Ren Yanna , Yang Jiajia , Wu Jinglong
Published: June 2023

(1) Background: This study investigates whether audiovisual n-back training leads to training effects on working memory and transfer effects on perceptual processing. (2) Methods: Before and after training, the participants were tested using the audiovisual n-back task (1-, 2-, or 3-back), to detect training effects, and the audiovisual discrimination task, to detect transfer effects. (3) Results: For the training effect, the behavioral results show that training leads to greater accuracy and faster response times. Stronger training gains in accuracy and response time using 3- and 2-back tasks, compared to 1-back, were observed in the training group. Event-related potentials (ERPs) data revealed an enhancement of P300 in the frontal and central regions across all working memory levels after training. Training also led to the enhancement of N200 in the central region in the 3-back condition. For the transfer effect, greater audiovisual integration in the frontal and central regions during the post-test rather than pre-test was observed at an early stage (80–120 ms) in the training group. (4) Conclusion: Our findings provide evidence that audiovisual n-back training enhances neural processes underlying a working memory and demonstrate a positive influence of higher cognitive functions on lower cognitive functions.
Attention Aware Deep Learning Approaches for an Efficient Stress Classification Model
Authors: Zulqarnain Muhammad , Shah Habib , Ghazali Rozaida , Alqahtani Omar , Sheikh Rubab , Asadullah Muhammad
Published: June 2023

In today’s world, stress is a major factor for various diseases in modern societies which affects the day-to-day activities of human beings. The measurement of stress is a contributing factor for governments and societies that impacts the quality of daily lives. The strategy of stress monitoring systems requires an accurate stress classification technique which is identified via the reactions of the body to regulate itself to changes within the environment through mental and emotional responses. Therefore, this research proposed a novel deep learning approach for the stress classification system. In this paper, we presented an Enhanced Long Short-Term Memory(E-LSTM) based on the feature attention mechanism that focuses on determining and categorizing the stress polarity using sequential modeling and word-feature seizing. The proposed approach integrates pre-feature attention in E-LSTM to identify the complicated relationship and extract the keywords through an attention layer for stress classification. This research has been evaluated using a selected dataset accessed from the sixth Korea National Health and Nutrition Examination Survey conducted from 2013 to 2015 (KNHANES VI) to analyze health-related stress data. Statistical performance of the developed approach was analyzed based on the nine features of stress detection, and we compared the effectiveness of the developed approach with other different stress classification approaches. The experimental results shown that the developed approach obtained accuracy, precision, recall and a F1-score of 75.54%, 74.26%, 72.99% and 74.58%, respectively. The feature attention mechanism-based E-LSTM approach demonstrated superior performance in stress detection classification when compared to other classification methods including naïve Bayesian, SVM, deep belief network, and standard LSTM. The results of this study demonstrated the efficiency of the proposed approach in accurately classifying stress detection, particularly in stress monitoring systems where it is expected to be effective for stress prediction.
Amortization Transformer for Brain Effective Connectivity Estimation from fMRI Data
Authors: Zhang Zuozhen , Zhang Ziqi , Ji Junzhong , Liu Jinduo
Published: June 2023

Using machine learning methods to estimate brain effective connectivity networks from functional magnetic resonance imaging (fMRI) data has garnered significant attention in the fields of neuroinformatics and bioinformatics. However, existing methods usually require retraining the model for each subject, which ignores the knowledge shared across subjects. In this paper, we propose a novel framework for estimating effective connectivity based on an amortization transformer, named AT-EC. In detail, AT-EC first employs an amortization transformer to model the dynamics of fMRI time series and infer brain effective connectivity across different subjects, which can train an amortized model that leverages the shared knowledge from different subjects. Then, an assisted learning mechanism based on functional connectivity is designed to assist the estimation of the brain effective connectivity network. Experimental results on both simulated and real-world data demonstrate the efficacy of our method.
Molecular Characterization of Esophageal Squamous Cell Carcinoma Using Quantitative Proteomics
Authors: Mangalaparthi Kiran K. , Patel Krishna , Khan Aafaque Ahmad , Nair Bipin , Kumar Rekha V. , Prasad Thottethodi Subrahmanya Keshav , Sidransky David , Chatterjee Aditi , Pandey Akhilesh , Gowda Harsha
Published: June 2023

Esophageal squamous cell carcinoma (ESCC) is a heterogeneous cancer associated with a poor prognosis in advanced stages. In India, it is the sixth most common cause of cancer-related mortality. In this study, we employed high-resolution mass spectrometry-based quantitative proteomics to characterize the differential protein expression pattern associated with ESCC. We identified several differentially expressed proteins including PDPN, TOP2A, POSTN and MMP2 that were overexpressed in ESCC. In addition, we identified downregulation of esophagus tissue-enriched proteins such as SLURP1, PADI1, CSTA, small proline-rich proteins such as SPRR3, SPRR2A, SPRR1A, KRT4, and KRT13, involved in squamous cell differentiation. We identified several overexpressed proteins mapped to the 3q24-29 chromosomal region, aligning with CNV alterations in this region reported in several published studies. Among these, we identified overexpression of SOX2, TP63, IGF2BP2 and RNF13 that are encoded by genes in the 3q26 region. Functional enrichment analysis revealed proteins involved in cell cycle pathways, DNA replication, spliceosome, and DNA repair pathways. We identified the overexpression of multiple proteins that play a major role in alleviating ER stress, including SYVN1 and SEL1L. The SYVN1/SEL1L complex is an essential part of the ER quality control machinery clearing misfolded proteins from the ER. SYVN1 is an E3 ubiquitin ligase that ubiquitinates ER-resident proteins. Interestingly, there are also other non-canonical substrates of SYVN1 which are known to play a crucial role in tumor progression. Thus, SYVN1 could be a potential therapeutic target in ESCC.
Beyond PARP Inhibitors in Advanced Breast Cancer Patients with Germline BRCA1/2 Mutations: Focus on CDK4/6-Inhibitors and Data Review on Other Biological Therapies
Authors: Nerone Marta , Rossi Lorenzo , Condorelli Rosaria , Ratti Vilma , Conforti Fabio , Palazzo Antonella , Graffeo Rossella
Published: June 2023

We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first-line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in the overall survival (OS) and progression-free survival (PFS) in gBRCA1/2m patients compared to both the germinal BRCA1/2 wild type (gBRCA1/2wt) and the untested population. Regarding the efficacy of PI3Kα inhibitors, there are no subgroups or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2−) and both HR+ and HR− metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future, and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.
The Regulation of m6A Modification in Glioblastoma: Functional Mechanisms and Therapeutic Approaches
Authors: Deacon Simon , Walker Lauryn , Radhi Masar , Smith Stuart
Published: June 2023

Glioblastoma is the most prevalent primary brain tumour and invariably confers a poor prognosis. The immense intra-tumoral heterogeneity of glioblastoma and its ability to rapidly develop treatment resistance are key barriers to successful therapy. As such, there is an urgent need for the greater understanding of the tumour biology in order to guide the development of novel therapeutics in this field. N6-methyladenosine (m6A) is the most abundant of the RNA modifications in eukaryotes. Studies have demonstrated that the regulation of this RNA modification is altered in glioblastoma and may serve to regulate diverse mechanisms including glioma stem-cell self-renewal, tumorigenesis, invasion and treatment evasion. However, the precise mechanisms by which m6A modifications exert their functional effects are poorly understood. This review summarises the evidence for the disordered regulation of m6A in glioblastoma and discusses the downstream functional effects of m6A modification on RNA fate. The wide-ranging biological consequences of m6A modification raises the hope that novel cancer therapies can be targeted against this mechanism.
Assessing the Needs of Those Who Serve the Underserved: A Qualitative Study among US Oncology Clinicians
Authors: Patel Manali I. , Hinyard Leslie , Hlubocky Fay J. , Merrill Janette K. , Smith Kimberly T. , Kamaraju Sailaja , Carrizosa Daniel , Kalwar Tricia , Fashoyin-Aje Lola , Gomez Scarlett L. , Jeames Sanford , Florez Narjust , Kircher Sheetal M. , Tap William D.
Published: June 2023

Background: The American Society of Clinical Oncology established the ‘Supporting Providers Serving the Underserved’ (SUS) Task Force with a goal to develop recommendations to support cancer clinicians who deliver care for populations at risk for cancer disparities. As a first step, the Task Force explored barriers and facilitators to equitable cancer care delivery. Methods: Clinicians across the United States who deliver care predominantly for low-income and racially and ethnically minoritized populations were identified based on lists generated by the Task Force and the Health Equity Committee. Through purposive sampling based on geographical location, clinicians were invited to participate in 30-60 min semi-structured interviews to explore experiences, barriers, and facilitators in their delivery of cancer care. Interviews were recorded, transcribed, imported into qualitative data management software, and analyzed using thematic analysis. Results: Thematic analysis revealed three major themes regarding barriers (lack of executive leadership recognition of resources; patient-related socio-economic needs; clinician burnout) and two major themes regarding facilitators (provider commitment, experiential training). Conclusions: Findings reveal modifiable barriers and potential solutions to facilitate equitable cancer care delivery for populations at risk for cancer disparities.
The Biological Role and Translational Implications of the Long Non-Coding RNA GAS5 in Breast Cancer
Authors: Grossi Ilaria , Marchina Eleonora , De Petro Giuseppina , Salvi Alessandro
Published: June 2023

The lncRNA GAS5 plays a significant role in tumorigenicity and progression of breast cancer (BC). In this review, we first summarize the role of GAS5 in cell biology, focusing on its expression data in human normal tissues. We present data on GAS5 expression in human BC tissues, highlighting its downregulation in all major BC classes. The main findings regarding the molecular mechanisms underlying GAS5 dysregulation are discussed, including DNA hypermethylation of the CpG island located in the promoter region of the gene. We focused on the action of GAS5 as a miRNA sponge, which is able to sequester microRNAs and modulate the expression levels of their mRNA targets, particularly those involved in cell invasion, apoptosis, and drug response. In the second part, we highlight the translational implications of GAS5 in BC. We discuss the current knowledge on the role of GAS5 as candidate prognostic factor, a responsive molecular therapeutic target, and a circulating biomarker in liquid biopsies with clinical importance in BC. The findings position GAS5 as a promising druggable biomolecule and stimulate the development of strategies to restore its expression levels for novel therapeutic approaches that could benefit BC patients in the future.
The Role of an MRI-Based Radiomic Signature in Predicting Malignancy of Parotid Gland Tumors
Authors: Muntean Delia Doris , Dudea Sorin Marian , Băciuț Mihaela , Dinu Cristian , Stoia Sebastian , Solomon Carolina , Csaba Csutak , Rusu Georgeta Mihaela , Lenghel Lavinia Manuela
Published: June 2023

The aim of this study was to assess the ability of MRI radiomic features to differentiate between benign parotid gland tumors (BPGT) and malignant parotid gland tumors (MPGT). This retrospective study included 93 patients who underwent MRI examinations of the head and neck region (78 patients presenting unique PGT, while 15 patients presented double PGT). A total of 108 PGT with histological confirmation were eligible for the radiomic analysis and were assigned to a training group (n = 83; 58 BPGT; 25 MPGT) and a testing group (n = 25; 16 BPGT; 9 MPGT). The radiomic features were extracted from 3D segmentations of the PGT on the T2-weighted and fat-saturated, contrast-enhanced T1-weighted images. Following feature reduction techniques, including LASSO regression analysis, a radiomic signature (RS) was built with five radiomic features. The RS presented a good diagnostic performance in differentiating between PGT, achieving an area under the curve (AUC) of 0.852 (p < 0.001) in the training set and 0.786 (p = 0.017) in the testing set. In both datasets, the RS proved to have lower values in the BPGT group as compared to MPGT group (p < 0.001 and p = 0.023, respectively). The multivariate analysis revealed that RS was independently associated with PGT malignancy, together with the ill-defined margin pattern (p = 0.031, p = 0.001, respectively). The complex model, using clinical data, MRI features and the RS, presented a higher diagnostic performance (AUC of 0.976) in comparison to the RS alone. MRI-based radiomic features could be considered potential additional imaging biomarkers able to discriminate between benign and malignant parotid gland tumors.
The Assessment of White Matter Integrity Alteration Pattern in Patients with Brain Tumor Utilizing Diffusion Tensor Imaging: A Systematic Review
Authors: Manan Aiman Abdul , Yahya Noorazrul Azmie , Taib Nur Hartini Mohd , Idris Zamzuri , Manan Hanani Abdul
Published: June 2023

Alteration in the surrounding brain tissue may occur in the presence of a brain tumor. The present study aims to assess the characteristics and criteria of the pattern of white matter tract microstructure integrity alteration in brain tumor patients. The Scopus, PubMed/Medline, and Web of Science electronic databases were searched for related articles based on the guidelines established by PRISMA. Twenty-five studies were selected on the morphological changes of white matter tract integrity based on the differential classification of white matter tract (WMT) patterns in brain tumor patients through diffusion tensor imaging (DTI). The characterization was based on two criteria: the visualization of the tract—its orientation and position—and the DTI parameters, which were the fractional anisotropy and apparent diffusion coefficient. Individual evaluations revealed no absolute, mutually exclusive type of tumor in relation to morphological WMT microstructure integrity changes. In most cases, different types and grades of tumors have shown displacement or infiltration. Characterizing morphological changes in the integrity of the white matter tract microstructures is vital in the diagnostic and prognostic evaluation of the tumor’s progression and could be a potential assessment for the early detection of possible neurological defects that may affect the patient, as well as aiding in surgery decision-making.
The Impact of Metastasectomy on Survival Outcomes of Renal Cell Carcinoma: A 10-Year Single Center Experience
Authors: Ferriero Mariaconsiglia , Cacciatore Loris , Ochoa Mario , Mastroianni Riccardo , Tuderti Gabriele , Costantini Manuela , Anceschi Umberto , Misuraca Leonardo , Brassetti Aldo , Guaglianone Salvatore , Bove Alfredo Maria , Papalia Rocco , Gallucci Michele , Simone Giuseppe
Published: June 2023

Objectives: The role of surgical metastasectomy (MST) in solitary or oligometastasis from renal cell carcinoma (RCC) and its impact on survival outcomes remains poorly addressed. We evaluated the impact of MST on overall survival (OS) in patients with oligometastatic (m)RCC. Materials and methods: The institutional renal cancer prospective database was examined for cases treated with partial or radical nephrectomy who developed metastatic disease during follow-up. Patients with evidence of clinical metastasis at first diagnosis were excluded. Patients considered unfit for MST received systemic treatment (ST); all others received MST. The impact of MST vs. the ST only cohort was assessed with the Kaplan–Meier method. Age, gender, bilaterality, histology, AJCC stage of primary tumor, surgical margins, local vs. distant metastasis and MST were included in univariable and multivariable regression analyses to assess the predictors of OS. Results: Overall, at a median follow-up of 16 months after primary treatment, 168 patients with RCC developed asynchronous metastasis at the adrenal gland, lung, liver, spleen, peritoneal, renal fossa, bone, nodes, brain and thyroid gland. Nine patients unfit for any treatment were excluded. The site of metastasis was treated with surgical MST (77/159, 48.4%), with or without previous or subsequent ST, while 82/159 cases (51.2%) received ST only. The 2-year, 5-year and 10-year OS probabilities were 93.8%, 82.8% and 79.5%, respectively. After multivariable analysis, MST and the primary tumor AJCC stage were independent predictors of OS probabilities (p = 0.019 and p = 0.035, respectively). After Kaplan–Meier analysis, MST significantly improved OS probabilities versus patients receiving ST (p < 0.001). Limitations: The main drawbacks of our research were the small sample size from a single-tertiary referral institution, as well as the absent or different ST lines in the cohort of patients receiving MST. Conclusions: When an NED status is achievable, surgical MST of mRCC significantly impacts OS, delaying and not precluding further subsequent ST.
Evaluating the Harms of Cancer Testing—A Systematic Review of the Adverse Psychological Correlates of Testing for Cancer and the Effectiveness of Interventions to Mitigate These
Authors: Kwong Fong Lien , Davenport Clare , Sundar Sudha
Published: June 2023

(1) Background: Several studies have described the psychological harms of testing for cancer. However, most were conducted in asymptomatic subjects and in cancers with a well-established screening programme. We sought to establish cancers in which the literature is deficient, and identify variables associated with psychological morbidity and interventions to mitigate their effect. (2) Methods: Electronic bibliographic databases were searched up to December 2020. We included quantitative studies reporting on variables associated with psychological morbidity associated with cancer testing and primary studies describing interventions to mitigate these. (3) Results: Twenty-six studies described individual, testing-related, and organisational variables. Thirteen randomised controlled trials on interventions were included, and these were categorised into five groups, namely the use of information aids, music therapy, the use of real-time videos, patient navigators and one-stop clinics, and pharmacological or homeopathic therapies. (4) Conclusions: The contribution of some factors to anxiety in cancer testing and their specificity of effect remains inconclusive and warrants further research in homogenous populations and testing contexts. Targeting young, unemployed patients with low levels of educational attainment may offer a means to mitigate anxiety. A limited body of research suggests that one-stop clinics and patient navigators may be beneficial in patients attending for diagnostic cancer testing.
Functional Imaging of Hypoxia: PET and MRI
Authors: Perez Ryan C. , Kim DaeHee , Maxwell Aaron W. P. , Camacho Juan C.
Published: June 2023

Molecular and functional imaging have critical roles in cancer care. Existing evidence suggests that noninvasive detection of hypoxia within a particular type of cancer can provide new information regarding the relationship between hypoxia, cancer aggressiveness and altered therapeutic responses. Following the identification of hypoxia inducible factor (HIF), significant progress in understanding the regulation of hypoxia-induced genes has been made. These advances have provided the ability to therapeutically target HIF and tumor-associated hypoxia. Therefore, by utilizing the molecular basis of hypoxia, hypoxia-based theranostic strategies are in the process of being developed which will further personalize care for cancer patients. The aim of this review is to provide an overview of the significance of tumor hypoxia and its relevance in cancer management as well as to lay out the role of imaging in detecting hypoxia within the context of cancer.
Predicting Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Receiving Finite Periods of Antiviral Therapy
Authors: Lin Chih-Lang , Wu Szu-Yuan , Lai Ming-Wei , Hsu Chao-Wei , Chen Wan-Ming , Jao An-Tzu , Chien Cheng-Hung , Hu Ching-Chih , Chien Rong-Nan , Yeh Chau-Ting
Published: June 2023

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most severe complications in chronic hepatitis B virus (HBV) infection. HCC can still develop in patients with chronic HBV (CHB) infection undergoing antiviral therapy. Several effective scoring systems for the prediction of HCC risk in CHB patients have been established. However, very few of them are designed for CHB patients receiving nucleos(t)ide analogues (NAs) therapy. Furthermore, none are available for HCC risk prediction in CHB patients receiving finite periods of antiviral therapy. METHODS: This study enrolled 790 consecutive treatment-naïve patients with CHB infection who had visited our liver clinics from 2008 to 2012 for pretreatment assessment before receiving antiviral therapies. The treatments were provided at finite periods according to the National Health Insurance Policy in Taiwan. The last follow-up date was 31 December 2021. We analyzed the virological and clinical factors in these 790 CHB patients receiving finite periods of NA treatments and identified the most significant risk factors for HCC to establish a novel predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. RESULTS: Our predictive scoring system included five independent variables: genotype C (adjusted HR [aHR] = 2.23), NA-withdraw-related hepatitis relapse (aHR = 6.96), male (aHR = 4.19), liver cirrhosis (aHR = 11.14), and T1768A core promoter mutation (aHR = 3.21). This model revealed significant differences in HCC incidence among the three risk groups. The 5-year cumulative HCC risk significantly differed among the three risk groups (low risk: 1.33%, moderate risk: 4.99%, and high risk: 17.46%), with log-rank test p < 0.001. CONCLUSION: Our predictive scoring system is a promising tool for the prediction of HCC in CHB patients receiving finite NA treatments. Genotype C, NA-withdraw-related hepatitis relapse, male gender, liver cirrhosis, and the T1768A HBV core promoter mutation were significant independent risk factors.
The Current State of Neoadjuvant Therapy in Resectable Advanced Stage Melanoma
Authors: Bushara Omar , Tidwell Jerica , Wester James R. , Miura John
Published: June 2023

The advent of effective immunotherapy and targeted therapy has significantly improved outcomes in advanced-stage resectable melanoma. Currently, the mainstay of treatment of malignant melanoma is surgery followed by adjuvant systemic therapies. However, recent studies have shown a potential role for neoadjuvant therapy in the treatment of advanced-stage resectable melanoma. Mechanistically, neoadjuvant immunotherapy may yield a more robust response than adjuvant immunotherapy, as the primary tumor serves as an antigen in this setting rather than only micrometastatic disease after the index procedure. Additionally, targeted therapy has been shown to yield effective neoadjuvant cytoreduction, and oncolytic viruses may also increase the immunogenicity of primary tumors. Effective neoadjuvant therapy may serve to decrease tumor size and thus reduce the extent of required surgery and thus morbidity. It also allows for assessment of pathologic response, facilitating prognostication as well as tailoring future therapy. The current literature consistently supports that neoadjuvant therapy, even as little as one dose, is associated with improved outcomes and is well-tolerated. Some patients with a complete pathological response may even avoid surgery completely. These results challenge the current paradigm of a surgery-first approach and provide further evidence supporting neoadjuvant therapy in advanced-stage resectable melanoma. Further research into the optimal treatment schedule and dose timing is warranted, as is the continued investigation of novel therapies and combinations of therapies.
Acute Lymphoblastic Leukemia Immunotherapy Treatment: Now, Next, and Beyond
Authors: Aureli Anna , Marziani Beatrice , Venditti Adriano , Sconocchia Tommaso , Sconocchia Giuseppe
Published: June 2023

Acute lymphoblastic leukemia (ALL) is a blood cancer that primarily affects children but also adults. It is due to the malignant proliferation of lymphoid precursor cells that invade the bone marrow and can spread to extramedullary sites. ALL is divided into B cell (85%) and T cell lineages (10 to 15%); rare cases are associated with the natural killer (NK) cell lineage (<1%). To date, the survival rate in children with ALL is excellent while in adults continues to be poor. Despite the therapeutic progress, there are subsets of patients that still have high relapse rates after chemotherapy or hematopoietic stem cell transplantation (HSCT) and an unsatisfactory cure rate. Hence, the identification of more effective and safer therapy choices represents a primary issue. In this review, we will discuss novel therapeutic options including bispecific antibodies, antibody–drug conjugates, chimeric antigen receptor (CAR)-based therapies, and other promising treatments for both pediatric and adult patients.
Effect of the Lipid Landscape on the Efficacy of Cell-Penetrating Peptides
Authors: Zakany Florina , Mándity István M. , Varga Zoltan , Panyi Gyorgy , Nagy Peter , Kovacs Tamas
Published: June 2023

Every cell biological textbook teaches us that the main role of the plasma membrane is to separate cells from their neighborhood to allow for a controlled composition of the intracellular space. The mostly hydrophobic nature of the cell membrane presents an impenetrable barrier for most hydrophilic molecules larger than 1 kDa. On the other hand, cell-penetrating peptides (CPPs) are capable of traversing this barrier without compromising membrane integrity, and they can do so on their own or coupled to cargos. Coupling biologically and medically relevant cargos to CPPs holds great promise of delivering membrane-impermeable drugs into cells. If the cargo is able to interact with certain cell types, uptake of the CPP–drug complex can be tailored to be cell-type-specific. Besides outlining the major membrane penetration pathways of CPPs, this review is aimed at deciphering how properties of the membrane influence the uptake mechanisms of CPPs. By summarizing an extensive body of experimental evidence, we argue that a more ordered, less flexible membrane structure, often present in the very diseases planned to be treated with CPPs, decreases their cellular uptake. These correlations are not only relevant for understanding the cellular biology of CPPs, but also for rationally improving their value in translational or clinical applications.
Beyond the Complement Cascade: Insights into Systemic Immunosenescence and Inflammaging in Age-Related Macular Degeneration and Current Barriers to Treatment
Authors: Khan Adnan H. , Chowers Itay , Lotery Andrew J.
Published: June 2023

Landmark genetic studies have revealed the effect of complement biology and its regulation of the pathogenesis of age-related macular degeneration (AMD). Limited phase 3 clinical trial data showing a benefit of complement inhibition in AMD raises the prospect of more complex mediators at play. Substantial evidence supports the role of para-inflammation in maintaining homeostasis in the retina and choroid. With increasing age, a decline in immune system regulation, known as immunosenescence, has been shown to alter the equilibrium maintained by para-inflammation. The altered equilibrium results in chronic, sterile inflammation with aging, termed ‘inflammaging’, including in the retina and choroid. The chronic inflammatory state in AMD is complex, with contributions from cells of the innate and adaptive branches of the immune system, sometimes with overlapping features, and the interaction of their secretory products with retinal cells such as microglia and retinal pigment epithelium (RPE), extracellular matrix and choroidal vascular endothelial cells. In this review, the chronic inflammatory state in AMD will be explored by immune cell type, with a discussion of factors that will need to be overcome in the development of curative therapies.
Activation Ratio Correlates with IQ in Female Carriers of the FMR1 Premutation
Authors: Protic Dragana , Polli Roberta , Hwang Ye Hyun , Mendoza Guadalupe , Hagerman Randi , Durbin-Johnson Blythe , Hayward Bruce E. , Usdin Karen , Murgia Alessandra , Tassone Flora
Published: June 2023

Carriers of the FMR1 premutation (PM) allele are at risk of one or more clinical conditions referred to as FX premutation-associated conditions (FXPAC). Since the FMR1 gene is on the X chromosome, the activation ratio (AR) may impact the risk, age of onset, progression, and severity of these conditions. The aim of this study was to evaluate the reliability of AR measured using different approaches and to investigate potential correlations with clinical outcomes. Molecular and clinical assessments were obtained for 30 PM female participants, and AR was assessed using both Southern blot analysis (AR-Sb) and methylation PCR (AR-mPCR). Higher ARs were associated with lower FMR1 transcript levels for any given repeat length. The higher AR-Sb was significantly associated with performance, verbal, and full-scale IQ scores, confirming previous reports. However, the AR-mPCR was not significantly associated (p > 0.05) with these measures. Similarly, the odds of depression and the number of medical conditions were correlated with higher AR-Sb but not correlated with a higher AR-mPCR. This study suggests that AR-Sb may be a more reliable measure of the AR in female carriers of PM alleles. However, further studies are warranted in a larger sample size to fully evaluate the methylation status in these participants and how it may affect the clinical phenotype.
Dependency of Tamoxifen Sensitive and Resistant ER+ Breast Cancer Cells on Semaphorin 3C (SEMA3C) for Growth
Authors: Bhasin Satyam , Dusek Christopher , Peacock James W. , Cherkasov Artem , Wang Yuzhuo , Gleave Martin , Ong Christopher J.
Published: June 2023

Estrogen receptor positive (ER+) breast cancer (BCa) accounts for the highest proportion of breast cancer-related deaths. While endocrine therapy is highly effective for this subpopulation, endocrine resistance remains a major challenge and the identification of novel targets is urgently needed. Previously, we have shown that Semaphorin 3C (SEMA3C) is an autocrine growth factor that drives the growth and treatment resistance of various cancers, but its role in breast cancer progression and endocrine resistance is poorly understood. Here, we report that SEMA3C plays a role in maintaining the growth of ER+ BCa cells and is a novel, tractable therapeutic target for the treatment of ER+ BCa patients. Analyses of publicly available clinical datasets indicate that ER+ BCa patients express significantly higher levels of SEMA3C mRNA than other subtypes. Furthermore, SEMA3C mRNA expression was positively correlated with ESR1 mRNA expression. ER+ BCa cell lines (MCF7 and T47D) expressed higher levels of SEMA3C mRNA and protein than a normal mammary epithelial MCF10A cell line. ER siRNA knockdown was suppressed, while dose-dependent beta-estradiol treatment induced SEMA3C expression in both MCF7 and T47D cells, suggesting that SEMA3C is an ER-regulated gene. The stimulation of ER+ BCa cells with recombinant SEMA3C activated MAPK and AKT signaling in a dose-dependent manner. Conversely, SEMA3C silencing inhibited Estrogen Receptor (ER) expression, MAPK and AKT signaling pathways while simultaneously inducing apoptosis, as monitored by flow cytometry and Western blot analyses. SEMA3C silencing significantly inhibited the growth of ER+ BCa cells, implicating a growth dependency of ER+ BCa cells on SEMA3C. Moreover, the analysis of tamoxifen resistant (TamR) cell models (TamC3 and TamR3) showed that SEMA3C levels remain high despite treatment with tamoxifen. Tamoxifen-resistant cells remained dependent on SEMA3C for growth and survival. Treatment with B1SP Fc fusion protein, a SEMA3C pathway inhibitor, attenuated SEMA3C-induced signaling and growth across a panel of tamoxifen sensitive and resistant ER+ breast cancer cells. Furthermore, SEMA3C silencing and B1SP treatment were associated with decreased EGFR signaling in TamR cells. Here, our study implicates SEMA3C in a functional role in ER+ breast cancer signaling and growth that suggests ER+ BCa patients may benefit from SEMA3C-targeted therapy.
Expression of pY397-FAK and Its miR Regulators Drive Dedifferentiation in the Thyroid Neoplasia Spectrum
Authors: Ignjatović Jocić Valentina , Janković Miljuš Jelena , Išić Denčić Tijana , Živaljević Vladan , Tatić Svetislav , Đorić Ilona , Šelemetjev Sonja
Published: June 2023

Thyroid carcinomas are growing malignancies worldwide. They encompass several diagnostic categories with varying degrees of dedifferentiation. Focal adhesion kinase is involved in cellular communication and locomotion. It is regulated on a posttranscriptional level by miR-7, miR-135a, and miR-138 and on a posttranslational level by autophosphorylation at Y397 (pY397-FAK). We related regulators of FAK with histologic dedifferentiation, clinicopathological factors, and differential diagnosis in the thyroid neoplasia spectrum. We classified 82 cases into 5 groups with increasing aggressiveness: healthy tissue, follicular and classical variants of papillary thyroid carcinoma (PTC), dedifferentiated PTC, and anaplastic carcinoma. MiRs were analyzed by RT-qPCR. Protein expression of pY397-FAK was analyzed by immunohistochemistry (separately in the membrane, cytoplasm, and nuclear compartment) and Western blot. All three miRs were upregulated in healthy tissue compared to malignant, while pY397-FAK was downregulated. MiRs and pY397-FAK were not mutually correlated. MiR-135a-5p was decreasing while membranous and cytoplasmic pY397-FAK increased with dedifferentiation. Neither miR correlated with clinicopathological factors. MiR-135a-5p, miR-138-5p, and membranous and cytoplasmic pY397-FAK discriminated the follicular from the classical variant of PTC. Disturbances of FAK regulation on different levels contribute to neoplastic dedifferentiation. pY397-FAK exerts its oncogenic role in the membrane and cytoplasm. Diagnostically, miRs-135a-5p, miR-138-5p, and membranous and cytoplasmic pY397-FAK differentiated between classical and follicular PTC.