bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival Outcomes in T3 Laryngeal Cancers: Primary Total Laryngectomy vs. Concurrent Chemoradiation or Radiation Therapy—A Meta-Analysis
Authors: Rao Karthik Nagaraja , Pai Prathamesh S. , Dange Prajwal , Kowalski Luiz P. , Strojan Primož , Mäkitie Antti A. , Guntinas-Lichius Orlando , Robbins K. Thomas , Rodrigo Juan P. , Eisbruch Avraham , Takes Robert P. , de Bree Remco , Coca-Pelaz Andrés , Piazza Cesare , Chiesa-Estomba Carlos , López Fernando , Saba Nabil F. , Rinaldo Alessandra , Ferlito Alfio
Published: July 2023

Background: The management of cT3 laryngeal cancers remains controversial, with studies recommending surgical or non-surgical approaches. Despite the many papers that have been published on the subject, there is a lack of studies showing which treatment has better results in terms of survival. Objective: To determine the difference in survival outcomes following total laryngectomy (TL), concurrent chemoradiation (CRT) or radiation therapy (RT) alone in T3 laryngeal cancers. Methods: Search of PubMed, Scopus, and Google Scholar databases from 1995 to 2023 employing specific keywords and Boolean operators to retrieve relevant articles. Statistical analysis was conducted using a random-effects model, and heterogeneity was evaluated using the Q-test and I2 statistic. Funnel plot asymmetry was assessed using rank correlation and regression tests. Results: The qualitative data synthesis comprised 10,940 patients from 16 included studies. TL was performed in 2149 (19.4%), CRT in 6723 (61.5%), RT in 295 (2.7%), while non-surgical treatment was not specified in 1773 (16.2%) patients. The pooled 2-year overall survival (OS) rates were TL = 73%, CRT = 74.7%, RT = 57.9%, 3-year OS rates were TL = 64.3%, CRT = 62.9%, RT = 52.4%, and 5-year OS rates were TL = 54.2%, CRT = 52.7%, RT = 40.8%. There was a significant heterogeneity in the included studies. There was no statistically significant difference in 2-year OS (logOR= −0.88 (95% confidence interval (CI): −1.99 to 0.23), p = 0.12), 3-year OS (logOR = −0.6 (95% CI: −1.34 to 0.15), p = 0.11), and 5-year OS (logOR = −0.54 (95% CI: −1.29 to 0.21), p = 0.16) between TL and CRT. Instead, there was significant difference in 2-year OS (logOR= −1.2383 (95% CI: −2.1679 to −0.3087), p = 0.009), 3-year OS (−1.1262 (95% CI: −1.6166 to −0.6358), p < 0.001), and 5-year OS (−0.99 (95% CI: −1.44 to −0.53)), p < 0.001) between TL and RT alone. Conclusions and Significance: TL followed with adjuvant (chemo)radiation on indication and CRT with salvage surgery in reserve appear to have similar OS outcomes. Both resulted in better OS outcomes compared to RT alone in the treatment of T3 laryngeal cancers. If patients are unfit for chemotherapy, making CRT impossible, surgery may become the choice of treatment.
Myocardial RNA Sequencing Reveals New Potential Therapeutic Targets in Heart Failure with Preserved Ejection Fraction
Authors: Inácio José M. , Cristo Fernando , Pinheiro Miguel , Vasques-Nóvoa Francisco , Saraiva Francisca , Nunes Mafalda M. , Rosas Graça , Reis Andreia , Coimbra Rita , Oliveira José Luís , Moura Gabriela , Leite-Moreira Adelino , Belo José António
Published: July 2023

Heart failure with preserved ejection fraction (HFpEF) represents a global health challenge, with limited therapies proven to enhance patient outcomes. This makes the elucidation of disease mechanisms and the identification of novel potential therapeutic targets a priority. Here, we performed RNA sequencing on ventricular myocardial biopsies from patients with HFpEF, prospecting to discover distinctive transcriptomic signatures. A total of 306 differentially expressed mRNAs (DEG) and 152 differentially expressed microRNAs (DEM) were identified and enriched in several biological processes involved in HF. Moreover, by integrating mRNA and microRNA expression data, we identified five potentially novel miRNA–mRNA relationships in HFpEF: the upregulated hsa-miR-25-3p, hsa-miR-26a-5p, and has-miR4429, targeting HAPLN1; and NPPB mRNA, targeted by hsa-miR-26a-5p and miR-140-3p. Exploring the predicted miRNA–mRNA interactions experimentally, we demonstrated that overexpression of the distinct miRNAs leads to the downregulation of their target genes. Interestingly, we also observed that microRNA signatures display a higher discriminative power to distinguish HFpEF sub-groups over mRNA signatures. Our results offer new mechanistic clues, which can potentially translate into new HFpEF therapies.
Improving Oral Health with Fluoride-Free Calcium-Phosphate-Based Biomimetic Toothpastes: An Update of the Clinical Evidence
Authors: Limeback Hardy , Enax Joachim , Meyer Frederic
Published: July 2023

As the demand for clinically effective fluoride-free oral care products for consumers increases, it is important to document which types of toothpastes have been shown in clinical studies to be effective in improving oral health. In this review, we included different indications, i.e., caries prevention, improving periodontal health, reducing dentin hypersensitivity, protecting against dental erosion, and safely improving tooth whitening in defining what constitutes improvement in oral health. While there are several professional and consumer fluoride-containing formulations fortified with calcium-phosphate-based ingredients, this review focuses on fluoride-free toothpastes containing biomimetic calcium-phosphate-based molecules as the primary active ingredients. Several databases were searched, and only clinical trials in human subjects were included; in vitro and animal studies were excluded. There were 62 oral health clinical trials on biomimetic hydroxyapatite (HAP), 57 on casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), 26 on calcium sodium phosphosilicate (CSPS, or so called Bioglass), and 2 on β-tricalcium phosphate (β-TCP). HAP formulations were tested the most in clinical trials for benefits in preventing caries, dentin hypersensitivity, improving periodontal health, and tooth whitening. Based on the current clinical evidence to date, fluoride-free HAP toothpaste formulations are the most versatile of the calcium phosphate active ingredients in toothpastes for improving oral health.
Predicting Fear Extinction in Posttraumatic Stress Disorder
Authors: Lewis Michael W. , Webb Christian A. , Kuhn Manuel , Akman Eylül , Jobson Sydney A. , Rosso Isabelle M.
Published: July 2023

Fear extinction is the basis of exposure therapies for posttraumatic stress disorder (PTSD), but half of patients do not improve. Predicting fear extinction in individuals with PTSD may inform personalized exposure therapy development. The participants were 125 trauma-exposed adults (96 female) with a range of PTSD symptoms. Electromyography, electrocardiogram, and skin conductance were recorded at baseline, during dark-enhanced startle, and during fear conditioning and extinction. Using a cross-validated, hold-out sample prediction approach, three penalized regressions and conventional ordinary least squares were trained to predict fear-potentiated startle during extinction using 50 predictor variables (5 clinical, 24 self-reported, and 21 physiological). The predictors, selected by penalized regression algorithms, were included in multivariable regression analyses, while univariate regressions assessed individual predictors. All the penalized regressions outperformed OLS in prediction accuracy and generalizability, as indexed by the lower mean squared error in the training and holdout subsamples. During early extinction, the consistent predictors across all the modeling approaches included dark-enhanced startle, the depersonalization and derealization subscale of the dissociative experiences scale, and the PTSD hyperarousal symptom score. These findings offer novel insights into the modeling approaches and patient characteristics that may reliably predict fear extinction in PTSD. Penalized regression shows promise for identifying symptom-related variables to enhance the predictive modeling accuracy in clinical research.
Elastic Local Buckling of I-Sections under Axial Compression Incorporating Web–Flange Interaction
Authors: Zhang Qianjing , Zhang Lei , Zhang Yujia , Liu Yufei , Zhou Jia
Published: July 2023

The local buckling of I-section columns is investigated in this paper, where the interaction between the web and flanges is taken into account. An analytical method is first developed based on the classical theory of the elastic buckling of thin plates, with which the main parameters affecting the interaction between the web and flanges are analyzed. The interactive behaviors of the buckling deformations of the I-section with different parameters are then revealed by employing finite element analyses. Simple approximate solutions for the buckling coefficients of the web and flanges are proposed using the energy method, which is capable of providing very accurate predictions compared to the analytical results. Using the simple solutions for buckling coefficients, the limits for the width-to-thickness ratio of I-section columns are proposed. Comparisons between the existing solutions and provisions in design codes indicate that the proposed limits for width-to-thickness ratio are capable of precisely considering the web–flange interaction at the local buckling of I-section columns.
Evaluating Reduction in Thermal Energy Consumption across Renovated Buildings in Latvia and Lithuania
Authors: Prozuments Aleksejs , Borodinecs Anatolijs , Zaharovs Sergejs , Banionis Karolis , Monstvilas Edmundas , Norvaišienė Rosita
Published: July 2023

Currently, the optimization of thermal energy consumption in buildings is considered a suitable alternative in the construction of new buildings, as a result of which the overall energy efficiency of the building increases. Thus, this study examined the efficiency and efficacy of different building renovation packages conducted across several buildings in Latvia and in Lithuania (across a larger building stock). In the first section of this study, 13 multi-apartment residential houses with 3 building renovation packages have been investigated in the city of Daugavpils, Latvia, in order to determine the actual reduction in heat energy consumption across each of the renovation implementation packages. The study findings indicate that changes in Latvian building regulations regarding insulation thickness did not significantly impact thermal energy consumption in fully renovated buildings. However, the combination of facade renovations, upgraded heating systems, and improved ventilation systems resulted in substantial energy savings, with an average reduction of 50.59% in thermal energy consumption for space heating across the reviewed multi-apartment residential building stock. In the following section of this study, the impact of the Energy Performance of Buildings Directive (EPBD) on building energy efficiency in Lithuania has been examined. The results show that over a 10-year period in the 2000s, Lithuanian building stock experienced a 20% increase in energy efficiency, followed by an additional 6.3% increase between 2010 and 2016. The mandatory requirement for renovated buildings to achieve a minimum energy efficiency class has resulted in significant reductions in energy consumption for heating purposes. The findings underscore the effectiveness of building renovation packages and the EPBD regulations in enhancing energy efficiency and promoting sustainable building practices. The importance of heat metering, consideration of indoor air temperature, and the need to address indoor air quality during renovations were also highlighted.
Characterization of DoTc2 4510—Identifying HPV16 Presence in a Cervical Carcinoma Cell Line Previously Considered to Be HPV-Negative
Authors: Vučković Nika , Hoppe-Seyler Karin , Riemer Angelika B.
Published: July 2023

Cervical cancer is the fourth leading cause of cancer deaths in women, with over 340,000 women dying from this disease in 2020. Almost all cases have an underlying persistent infection with an oncogenic high-risk type of human papillomavirus (HPV), mainly HPV16. While cervical squamous cell carcinoma is hardly ever HPV-negative, a small subset of adenocarcinoma exhibits absence of HPV, even after disproval of false-negative testing results due to low viral load. This proportion is evident in many cervical cancer studies and is reflected in the repertoire of model cell lines commonly used in research. As the viral origin of cervical cancer makes it a disease preventable and potentially treatable by immunotherapeutic approaches, it is the focus of many studies. For pertinent research, both a broad set of HPV-infected cervical carcinoma models are required, as well as stringent negative controls. A ubiquitously used HPV-negative cervical adenocarcinoma cell line is C-33A. Another cervical cancer cell line is available for purchase from the American Type Culture Collection (ATCC), namely DoTc2 4510, described to be HPV-negative and thus as a model for a rare gynecological malignancy. Here, we present findings proving that DoTc2 4510 is, in fact, an HPV16-positive cell line. This we assessed using a highly sensitive nested multiplex PCR protocol adapted for the identification of 12 carcinogenic HPV types and a second PCR targeting the HPV16 oncogenes E6 and E7. Subsequently, the protein expression of E6 and E7 was examined, as well as the expression of their target proteins p53, p21, and p16INK4a, to assess E6/E7 functionality. Finally, to attest to the survival dependence of DoTc2 4510 cells on HPV16, we performed an HPV16 E6/E7-targeted siRNA knock-down, which indeed led to senescence induction. Together, these findings demonstrate that DoTc2 4510 is an HPV16-transformed cell line.
Clinical Management of Patients with Gastric MALT Lymphoma: A Gastroenterologist’s Point of View
Authors: Matysiak-Budnik Tamara , Priadko Kateryna , Bossard Céline , Chapelle Nicolas , Ruskoné-Fourmestraux Agnès
Published: July 2023

Gastric mucosa-associated lymphoid tissue (MALT) lymphomas (GML) are non-Hodgkin lymphomas arising from the marginal zone of the lymphoid tissue of the stomach. They are usually induced by chronic infection with Helicobacter pylori (H. pylori); however, H. pylori-negative GML is of increasing incidence. The diagnosis of GML is based on histological examination of gastric biopsies, but the role of upper endoscopy is crucial since it is the first step in the diagnostic process and, with currently available novel endoscopic techniques, may even allow an in vivo diagnosis of GML per se. The treatment of GML, which is usually localized, always includes the eradication of H. pylori, which should be performed even in H. pylori-negative GML. In the case of GML persistence after eradication of the bacteria, low-dose radiotherapy may be proposed, while systemic treatments (immunochemotherapy) should be reserved for very rare disseminated cases. In GML patients, at diagnosis but even after complete remission, special attention must be paid to an increased risk of gastric adenocarcinoma, especially in the presence of associated gastric precancerous lesions (gastric atrophy and gastric intestinal metaplasia), which requires adequate endoscopic surveillance of these patients.
Effects of Hyaluronan on Breast Cancer Aggressiveness
Authors: Parnigoni Arianna , Moretto Paola , Viola Manuela , Karousou Evgenia , Passi Alberto , Vigetti Davide
Published: July 2023

The expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells is critical for determining tumor aggressiveness and targeting therapies. The presence of such receptors allows for the use of antagonists that effectively reduce breast cancer growth and dissemination. However, the absence of such receptors in triple-negative breast cancer (TNBC) reduces the possibility of targeted therapy, making these tumors very aggressive with a poor outcome. Cancers are not solely composed of tumor cells, but also include several types of infiltrating cells, such as fibroblasts, macrophages, and other immune cells that have critical functions in regulating cancer cell behaviors. In addition to these cells, the extracellular matrix (ECM) has become an important player in many aspects of breast cancer biology, including cell growth, motility, metabolism, and chemoresistance. Hyaluronan (HA) is a key ECM component that promotes cell proliferation and migration in several malignancies. Notably, HA accumulation in the tumor stroma is a negative prognostic factor in breast cancer. HA metabolism depends on the fine balance between HA synthesis by HA synthases and degradation yielded by hyaluronidases. All the different cell types present in the tumor can release HA in the ECM, and in this review, we will describe the role of HA and HA metabolism in different breast cancer subtypes.
Evaluation of Nutritional Status and the Impact of Nutritional Treatment in Patients with Pancreatic Cancer
Authors: Mękal Dominika , Sobocki Jacek , Badowska-Kozakiewicz Anna , Sygit Katarzyna , Cipora Elżbieta , Bandurska Ewa , Czerw Aleksandra , Deptała Andrzej
Published: July 2023

Patients with pancreatic cancer who develop irreversible cancer cachexia have a life expectancy of less than 3 months. Therefore, it is extremely important to evaluate the patient’s nutritional status as early as possible and to implement an appropriate nutritional intervention in order to reduce the risk of further weight loss and/or muscle loss, which affect the outcomes of cancer treatment and the correct nutritional treatment in patients with pancreatic cancer. A literature review was performed by using the PubMed and Cochrane quick search methodology. The main purpose of this review was to present the current approach to nutritional treatment in pancreatic cancer. The review included publications, most of which concerned clinical nutrition as part of the phase of treatment of patients with pancreatic cancer, nutritional and metabolic disorders in pancreatic cancer, and the period after pancreatic resection. Some of the publications concerned various nutritional interventions in patients with pancreatic cancer undergoing chemotherapy or surgical treatment (nutritional support before surgery, after surgery, or during palliative treatment). There is an unmet need for integrated nutritional therapy as a key part of the comprehensive care process for PC patients. Nutritional counseling is the first line of nutritional treatment for malnourished cancer patients, but pancreatic enzyme replacement therapy also constitutes the cornerstone of nutritional treatment for relieving symptoms of indigestion and maintaining or improving nutritional status.
Effects on the Hypothalamo-Pituitary Axis in Patients with CNS or Head and Neck Tumors following Radiotherapy
Authors: Bouter Jordan , Reznik Yves , Thariat Juliette
Published: July 2023

Background: Knowledge about the precise effects of radiotherapy on hypothalamo-pituitary functions is limited. Reduction of side effects is a major goal of advanced radiotherapy modalities. We assessed strategies for monitoring and replacement of hormone deficiencies in irradiated patients. Methods: A search strategy was systematically conducted on PubMed®. Additional articles were retrieved to describe endocrine mechanisms. Results: 45 studies were evaluated from 2000 to 2022. They were predominantly retrospective and highly heterogeneous concerning patient numbers, tumor types, radiotherapy technique and follow-up. Endocrine deficiencies occurred in about 40% of patients within a median follow-up of 5.6 years without a clear difference between radiotherapy modalities. Somatotropic and thyrotropic axes were, respectively, the most and least radiosensitive. Conclusions: Current pituitary gland dose constraints may underestimate radiation-induced endocrine deficiencies, thus impairing quality of life. Little difference might be expected between radiation techniques for PG tumors. For non-PG tumors, dose constraints should be applied more systematically.
Health Outcomes with Curative and Palliative Therapies in Real World: Role of the Quality of Life Summary Score in Thoracic Oncology Patients
Authors: Tournoy Kurt G. , Adam Valerie , Muylle Inge , De Rijck Helene , Everaert Ellen , Eqlimi Ehsan , van Meerbeeck Jan P. , Vercauter Piet
Published: July 2023

Background: For patients receiving therapy with curative or palliative intent for a thoracic malignancy, prediction of quality of life (QOL), once therapy starts, remains challenging. The role of health assessments by the patient instead of the doctor herein remains ill-defined. Aims: To assess the evolution of QOL in patients with thoracic malignancies treated with curative and palliative intent, respectively. To identify factors that determine QOL one year after the start of cancer therapy. To identify factors that affect survival. Methods: We prospectively included consecutive patients with a thoracic malignancy who were starting anti-cancer therapy and measured QOL with QLQ-C30 before the start of therapy, and thereafter at regular intervals for up to 12 months. A multivariate regression analysis of the global health score (GHS) and QOL summary scores (QSS) one year after the start of therapy was conducted. A proportional hazards Cox regression was conducted to investigate the effects of case-mix variables on survival. Results: Of 587 new patients, 375 started different forms of therapy. Most had non-small cell lung cancer (n = 298), 35 had small cell lung cancer, and 42 had other thoracic malignancies or were diagnosed on imaging alone. There were 203 who went for a curative intent and 172 for a palliative intent strategy. The WHO score of 0–1 was more prevalent in the former group (p = 0.02), and comorbidities were equally distributed. At baseline, all QOL indices were better in the curative group (p < 0.05). The curative group was characterized by a significant worsening of GHS and QSS (p < 0.05). The palliative group was characterized by an improvement in GHS and emotional health (p < 0.05), while other dimensions of functioning remained stable. GHS at 12 months was estimated in a multivariate linear regression model (R2 = 0.23—p < 0.001) based on baseline GHS, QSS, and comorbidity burden. QSS at 12 months was estimated (R2 = 0.31—p < 0.001) by baseline QSS and therapeutic intent strategy (curative vs. palliative). The prognostic factors for overall survival were the type of therapy (curative vs. palliative intent, p < 0.001) and occurrence of early toxicity-related hospitalization (grade ≥ 3, p = 0.001). Conclusion: Patients with thoracic malignancies treated with curative intent experience a worsening of their QOL in the first year, whereas those receiving palliative anti-cancer therapy do not. QOL one year after the start of therapy depends on the baseline health scores as determined by the patient, comorbidity burden, and therapeutic strategy. Survival depends on therapeutic strategy and early hospitalization due to toxicity.
Mutational Profile Enables the Identification of a High-Risk Subgroup in Myelodysplastic Syndromes with Isolated Trisomy 8
Authors: Toribio-Castelló Sofía , Castaño Sandra , Villaverde-Ramiro Ángela , Such Esperanza , Arnán Montserrat , Solé Francesc , Díaz-Beyá Marina , Díez-Campelo María , del Rey Mónica , González Teresa , Hernández-Rivas Jesús María
Published: July 2023

Trisomy 8 (+8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated with clinical heterogeneity and intermediate cytogenetic risk when found in isolation. The presence of gene mutations in this group of patients and the prognostic significance has not been extensively analyzed. Targeted deep sequencing was performed in a cohort of 79 MDS patients showing isolated +8. The most frequently mutated genes were: TET2 (38%), STAG2 (34.2%), SRSF2 (29.1%) and RUNX1 (26.6%). The mutational profile identified a high-risk subgroup with mutations in STAG2, SRSF2 and/or RUNX1, resulting in shorter time to acute myeloid leukemia progression (14 months while not reached in patients without these mutations, p < 0.0001) and shorter overall survival (23.7 vs. 46.3 months, p = 0.001). Multivariate analyses revealed the presence of mutations in these genes as an independent prognostic factor in MDS showing +8 isolated (HR: 3.1; p < 0.01). Moreover, 39.5% and 15.4% of patients classified as low/intermediate risk by the IPSS-R and IPSS-M, respectively, were re-stratified as a high-risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n = 2494). In summary, this study validates the prognosis significance of somatic mutations shown in IPSS-M and adds STAG2 as an important mutated gene to consider in this specific subgroup of patients. The mutational profile in isolated +8 MDS patients could, therefore, offer new insights for the correct management of patients with a higher risk of leukemic transformation.
A Systematic Review of Mesenchymal Epithelial Transition Factor (MET) and Its Impact in the Development and Treatment of Non-Small-Cell Lung Cancer
Authors: Bodén Embla , Sveréus Fanny , Olm Franziska , Lindstedt Sandra
Published: July 2023

Lung cancer represents the leading cause of annual cancer-related deaths worldwide, accounting for 12.9%. The available treatment options for patients who experience disease progression remain limited. Targeted therapeutic approaches are promising but further understanding of the role of genetic alterations in tumorigenesis is imperative. The MET gene has garnered great interest in this regard. The aim of this systematic review was to analyze the findings from multiple studies to provide a comprehensive and unbiased summary of the evidence. A systematic search was conducted in the reputable scientific databases Embase and PubMed, leading to the inclusion of twenty-two articles, following the PRISMA guidelines, elucidating the biological role of MET in lung cancer and targeted therapies. The systematic review was registered in PROSPERO with registration ID: CRD42023437714. MET mutations were detected in 7.6–11.0% of cases while MET gene amplification was observed in 3.9–22.0%. Six studies showed favorable treatment outcomes utilizing MET inhibitors compared to standard treatment or placebo, with increases in PFS and OS ranging from 0.9 to 12.4 and 7.2 to 24.2 months, respectively, and one study reporting an increase in ORR by 17.3%. Furthermore, patients with a higher mutational burden may derive greater benefit from treatment with MET tyrosine kinase inhibitors (TKIs) than those with a lower mutational burden. Conversely, two studies reported no beneficial effect from adjunctive treatment with a MET targeted therapy. Given these findings, there is an urgent need to identify effective therapeutic strategies specifically targeting the MET gene in lung cancer patients.
A Radiomics-Clinical Model Predicts Overall Survival of Non-Small Cell Lung Cancer Patients Treated with Immunotherapy: A Multicenter Study
Authors: Yolchuyeva Sevinj , Giacomazzi Elena , Tonneau Marion , Ebrahimpour Leyla , Lamaze Fabien C. , Orain Michele , Coulombe François , Malo Julie , Belkaid Wiam , Routy Bertrand , Joubert Philippe , Manem Venkata S. K.
Published: July 2023

Background: Immune checkpoint inhibitors (ICIs) are a great breakthrough in cancer treatments and provide improved long-term survival in a subset of non-small cell lung cancer (NSCLC) patients. However, prognostic and predictive biomarkers of immunotherapy still remain an unmet clinical need. In this work, we aim to leverage imaging data and clinical variables to develop survival risk models among advanced NSCLC patients treated with immunotherapy. Methods: This retrospective study includes a total of 385 patients from two institutions who were treated with ICIs. Radiomics features extracted from pretreatment CT scans were used to build predictive models. The objectives were to predict overall survival (OS) along with building a classifier for short- and long-term survival groups. We employed the XGBoost learning method to build radiomics and integrated clinical-radiomics predictive models. Feature selection and model building were developed and validated on a multicenter cohort. Results: We developed parsimonious models that were associated with OS and a classifier for short- and long-term survivor groups. The concordance indices (C-index) of the radiomics model were 0.61 and 0.57 to predict OS in the discovery and validation cohorts, respectively. While the area under the curve (AUC) values of the radiomic models for short- and long-term groups were found to be 0.65 and 0.58 in the discovery and validation cohorts. The accuracy of the combined radiomics-clinical model resulted in 0.63 and 0.62 to predict OS and in 0.77 and 0.62 to classify the survival groups in the discovery and validation cohorts, respectively. Conclusions: We developed and validated novel radiomics and integrated radiomics-clinical survival models among NSCLC patients treated with ICIs. This model has important translational implications, which can be used to identify a subset of patients who are not likely to benefit from immunotherapy. The developed imaging biomarkers may allow early prediction of low-group survivors, though additional validation of these radiomics models is warranted.
Brain Re-Irradiation Robustly Accounting for Previously Delivered Dose
Authors: Thompson Christopher , Pagett Christopher , Lilley John , Svensson Stina , Eriksson Kjell , Bokrantz Rasmus , Ödén Jakob , Nix Michael , Murray Louise , Appelt Ane
Published: July 2023

(1) Background: The STRIDeR (Support Tool for Re-Irradiation Decisions guided by Radiobiology) planning pathway aims to facilitate anatomically appropriate and radiobiologically meaningful re-irradiation (reRT). This work evaluated the STRIDeR pathway for robustness compared to a more conservative manual pathway. (2) Methods: For ten high-grade glioma reRT patient cases, uncertainties were applied and cumulative doses re-summed. Geometric uncertainties of 3, 6 and 9 mm were applied to the background dose, and LQ model robustness was tested using α/β variations (values 1, 2 and 5 Gy) and the linear quadratic linear (LQL) model δ variations (values 0.1 and 0.2). STRIDeR robust optimised plans, incorporating the geometric and α/β uncertainties during optimisation, were also generated. (3) Results: The STRIDeR and manual pathways both achieved clinically acceptable plans in 8/10 cases but with statistically significant improvements in the PTV D98% (p < 0.01) for STRIDeR. Geometric and LQ robustness tests showed comparable robustness within both pathways. STRIDeR plans generated to incorporate uncertainties during optimisation resulted in a superior plan robustness with a minimal impact on PTV dose benefits. (4) Conclusions: Our results indicate that STRIDeR pathway plans achieved a similar robustness to manual pathways with improved PTV doses. Geometric and LQ model uncertainties can be incorporated into the STRIDeR pathway to facilitate robust optimisation.
Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients
Authors: Stögbauer Fabian , Geß Barbara , Brambs Christine , Lautizi Manuela , Kacprowski Tim , Ourailidis Iordanis , Bronger Holger , Kiechle Marion , Noske Aurelia , Keller Gisela , Jesinghaus Moritz , Poremba Christopher , Weichert Wilko , Boxberg Melanie
Published: July 2023

The molecular characterization of endometrial endometrioid adenocarcinomas has provided major advances in its prognostic stratification. However, risk assessment of microsatellite instability (MSI) and copy-number (CN)-low cases remains a challenge. Thus, we aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification of these cases. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor–stroma ratio (as a quantitative description of stromal desmoplasia), tumor-infiltrating lymphocytes (TIL), “microcystic, elongated, fragmented” (MELF) pattern) were analyzed in resection specimens of the TCGA-UCEC cohort (n = 228). For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. Associations with survival outcomes were calculated in univariate and multivariate analysis and validated in two independent cohorts. In MSI tumors, only TB remained an independent prognostic factor. TB (≥3 buds/high-power field) was associated with inferior outcomes and with lymph node metastases. The prognostic significance of TB was confirmed in two validation cohorts. For CN-low tumors, established grading defined by the WHO was independently prognostic with inferior outcomes for high-grade tumors. The evaluation of TB might help in identifying MSI-patients with unfavorable prognosis who, e.g., could benefit from lymphadenectomy. WHO-based grading facilitates independent prognostic stratification of CN-low endometrioid adenocarcinomas. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management.
Association of Tumor Microenvironment with Biological and Chronological Age in Head and Neck Cancer
Authors: van der Kamp Martine Froukje , Hiddingh Eric , de Vries Julius , van Dijk Boukje Annemarie Cornelia , Schuuring Ed , Slagter-Menkema Lorian , van der Vegt Bert , Halmos Gyorgy Bela
Published: July 2023

There is often a mismatch between the chronological and biological age of head and neck squamous cell carcinoma (HNSCC) patients. Treatment is based on chronological age, while biological age seems to be a better prognosticator for treatment toleration. This study investigated whether tumor characteristics are associated with chronological and biological age. The relation with survival was also assessed. Prospectively collected data from 164 newly diagnosed HNSCC patients enrolled in the OncoLifeS database were analyzed. Biological age was assessed by a multidomain geriatric assessment. Several immunological markers were tested by immunohistochemistry on tissue microarray sections from the tumor. Disease-free survival (DFS), adjusted for chronological- and biological age, was assessed by univariable and bivariable analyses. In biologically old patients, a lower infiltration of CD163+ macrophages (p = 0.036) as well as CD4+ (p = 0.019) and CD8+ (p = 0.026) lymphocytes was found in the tumor microenvironment. Chronological older patients showed significantly lower PD-L1 combined positive scores (p = 0.030). Advanced tumor stage and perineural growth were related to a worse DFS. None of the immunological markers showed a significant association with DFS. Biological age might have a stronger influence on tumor microenvironment than chronological age. These findings should initiate clinical studies investigating the response to specific treatment regimens (e.g., immunotherapy) according to the biological age.
Precision Medicine: Disease Subtyping and Tailored Treatment
Authors: Wang Richard C. , Wang Zhixiang
Published: July 2023

The genomics-based concept of precision medicine began to emerge following the completion of the Human Genome Project. In contrast to evidence-based medicine, precision medicine will allow doctors and scientists to tailor the treatment of different subpopulations of patients who differ in their susceptibility to specific diseases or responsiveness to specific therapies. The current precision medicine model was proposed to precisely classify patients into subgroups sharing a common biological basis of diseases for more effective tailored treatment to achieve improved outcomes. Precision medicine has become a term that symbolizes the new age of medicine. In this review, we examine the history, development, and future perspective of precision medicine. We also discuss the concepts, principles, tools, and applications of precision medicine and related fields. In our view, for precision medicine to work, two essential objectives need to be achieved. First, diseases need to be classified into various subtypes. Second, targeted therapies must be available for each specific disease subtype. Therefore, we focused this review on the progress in meeting these two objectives.
Advancements in MRI-Based Radiomics and Artificial Intelligence for Prostate Cancer: A Comprehensive Review and Future Prospects
Authors: Chaddad Ahmad , Tan Guina , Liang Xiaojuan , Hassan Lama , Rathore Saima , Desrosiers Christian , Katib Yousef , Niazi Tamim
Published: July 2023

The use of multiparametric magnetic resonance imaging (mpMRI) has become a common technique used in guiding biopsy and developing treatment plans for prostate lesions. While this technique is effective, non-invasive methods such as radiomics have gained popularity for extracting imaging features to develop predictive models for clinical tasks. The aim is to minimize invasive processes for improved management of prostate cancer (PCa). This study reviews recent research progress in MRI-based radiomics for PCa, including the radiomics pipeline and potential factors affecting personalized diagnosis. The integration of artificial intelligence (AI) with medical imaging is also discussed, in line with the development trend of radiogenomics and multi-omics. The survey highlights the need for more data from multiple institutions to avoid bias and generalize the predictive model. The AI-based radiomics model is considered a promising clinical tool with good prospects for application.
Development and External Validation of 18F-FDG PET-Based Radiomic Model for Predicting Pathologic Complete Response after Neoadjuvant Chemotherapy in Breast Cancer
Authors: Lim Chae Hong , Choi Joon Young , Choi Joon Ho , Lee Jun-Hee , Lee Jihyoun , Lim Cheol Wan , Kim Zisun , Woo Sang-Keun , Park Soo Bin , Park Jung Mi
Published: July 2023

The aim of our retrospective study is to develop and externally validate an 18F-FDG PET-derived radiomics model for predicting pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer patients. A total of 87 breast cancer patients underwent curative surgery after NAC at Soonchunhyang University Seoul Hospital and were randomly assigned to a training cohort and an internal validation cohort. Radiomic features were extracted from pretreatment PET images. A radiomic-score model was generated using the LASSO method. A combination model incorporating significant clinical variables was constructed. These models were externally validated in a separate cohort of 28 patients from Soonchunhyang University Buscheon Hospital. The model performances were assessed using area under the receiver operating characteristic (AUC). Seven radiomic features were selected to calculate the radiomic-score. Among clinical variables, human epidermal growth factor receptor 2 status was an independent predictor of pCR. The radiomic-score model achieved good discriminability, with AUCs of 0.963, 0.731, and 0.729 for the training, internal validation, and external validation cohorts, respectively. The combination model showed improved predictive performance compared to the radiomic-score model alone, with AUCs of 0.993, 0.772, and 0.906 in three cohorts, respectively. The 18F-FDG PET-derived radiomic-based model is useful for predicting pCR after NAC in breast cancer.
Functional Diversity of Mammalian Small Heat Shock Proteins: A Review
Authors: Gu Chaoguang , Fan Xinyi , Yu Wei
Published: July 2023

The small heat shock proteins (sHSPs), whose molecular weight ranges from 12∼43 kDa, are members of the heat shock protein (HSP) family that are widely found in all organisms. As intracellular stress resistance molecules, sHSPs play an important role in maintaining the homeostasis of the intracellular environment under various stressful conditions. A total of 10 sHSPs have been identified in mammals, sharing conserved α-crystal domains combined with variable N-terminal and C-terminal regions. Unlike large-molecular-weight HSP, sHSPs prevent substrate protein aggregation through an ATP-independent mechanism. In addition to chaperone activity, sHSPs were also shown to suppress apoptosis, ferroptosis, and senescence, promote autophagy, regulate cytoskeletal dynamics, maintain membrane stability, control the direction of cellular differentiation, modulate angiogenesis, and spermatogenesis, as well as attenuate the inflammatory response and reduce oxidative damage. Phosphorylation is the most significant post-translational modification of sHSPs and is usually an indicator of their activation. Furthermore, abnormalities in sHSPs often lead to aggregation of substrate proteins and dysfunction of client proteins, resulting in disease. This paper reviews the various biological functions of sHSPs in mammals, emphasizing the roles of different sHSPs in specific cellular activities. In addition, we discuss the effect of phosphorylation on the function of sHSPs and the association between sHSPs and disease.
Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy
Authors: Bagyinszky Eva , Hulme John , An Seong Soo A.
Published: July 2023

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5–10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder are sporadic (sporadic ALS, sALS). At least 50 genes have been identified as causative or risk factors for ALS. Established pathogenic variants include superoxide dismutase type 1 (SOD1), chromosome 9 open reading frame 72 (c9orf72), TAR DNA Binding Protein (TARDBP), and Fused In Sarcoma (FUS); additional ALS-related genes including Charged Multivesicular Body Protein 2B (CHMP2B), Senataxin (SETX), Sequestosome 1 (SQSTM1), TANK Binding Kinase 1 (TBK1) and NIMA Related Kinase 1 (NEK1), have been identified. Mutations in these genes could impair different mechanisms, including vesicle transport, autophagy, and cytoskeletal or mitochondrial functions. So far, there is no effective therapy against ALS. Thus, early diagnosis and disease risk predictions remain one of the best options against ALS symptomologies. Proteomic biomarkers, microRNAs, and extracellular vehicles (EVs) serve as promising tools for disease diagnosis or progression assessment. These markers are relatively easy to obtain from blood or cerebrospinal fluids and can be used to identify potential genetic causative and risk factors even in the preclinical stage before symptoms appear. In addition, antisense oligonucleotides and RNA gene therapies have successfully been employed against other diseases, such as childhood-onset spinal muscular atrophy (SMA), which could also give hope to ALS patients. Therefore, an effective gene and biomarker panel should be generated for potentially “at risk” individuals to provide timely interventions and better treatment outcomes for ALS patients as soon as possible.
Circular and Circulating DNA in Inflammatory Bowel Disease: From Pathogenesis to Potential Molecular Therapies
Authors: Di Vincenzo Federica , Yadid Ylenia , Petito Valentina , Emoli Valeria , Masi Letizia , Gerovska Daniela , Araúzo-Bravo Marcos Jesus , Gasbarrini Antonio , Regenberg Birgitte , Scaldaferri Franco
Published: July 2023

Inflammatory bowel diseases (IBD), including Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic multifactorial disorders which affect the gastrointestinal tract with variable extent. Despite extensive research, their etiology and exact pathogenesis are still unknown. Cell-free DNAs (cfDNAs) are defined as any DNA fragments which are free from the origin cell and able to circulate into the bloodstream with or without microvescicles. CfDNAs are now being increasingly studied in different human diseases, like cancer or inflammatory diseases. However, to date it is unclear how IBD etiology is linked to cfDNAs in plasma. Extrachromosomal circular DNA (eccDNA) are non-plasmidic, nuclear, circular and closed DNA molecules found in all eukaryotes tested. CfDNAs appear to play an important role in autoimmune diseases, inflammatory processes, and cancer; recently, interest has also grown in IBD, and their role in the pathogenesis of IBD has been suggested. We now suggest that eccDNAs also play a role in IBD. In this review, we have comprehensively collected available knowledge in literature regarding cfDNA, eccDNA, and structures involving them such as neutrophil extracellular traps and exosomes, and their role in IBD. Finally, we focused on old and novel potential molecular therapies and drug delivery systems, such as nanoparticles, for IBD treatment.
Impact of Physical Activity Counselling on Children with Medical Conditions and Disabilities and Their Families
Authors: Cummings Hannah C. , Merkas Jordan , Yaraskavitch Jenna , Longmuir Patricia E.
Published: July 2023

Physical activity counselling can target cognitive-affective participation barriers, but counselling benefits for children with medical conditions/disabilities were unknown. This study investigated successes, challenges, and the impact of physical activity counselling on children and their families. One-on-one semi-structured interviews were completed with 7 patients (2 male/5 female, aged 13–17) and 4 parents who participated in 2–8 weekly counselling sessions (2015–2020). Interviews were recorded and transcribed verbatim for inductive thematic analyses. Counselling encouraged positive mindset changes (viewing physical activity more holistically, making it “more fun and manageable”, helping them to “learn how to love moving and doing sports”). Participants felt strong support (feeling heard, validated, and provided with “hope… that we can still achieve things… even though it may seem like there’s limitations”). Counselling was viewed positively. The intent to improve active lifestyle attitudes and confidence was reflected in positive, primarily cognitive-affective (motivation for activity, “more general skills of having a positive attitude towards physical activity and the willingness to try new things”) outcomes. More sessions, additional resources to keep, and follow-up after counselling completion were recommended to support behaviour change. Future research should evaluate enhanced counselling services and comparing children who have and have not received such counselling.
Onset of the Non-Medical Use of Prescription and Over-the-Counter Medications during Early Adolescence: Comparison with Alcohol, Tobacco, and Marijuana
Authors: Khan Sarosh , Griffin Kenneth W. , Botvin Gilbert J.
Published: July 2023

This study examined the prevalence and psychosocial predictors of the non-medical use of prescription and over-the-counter (OTC) medications and compared these to cigarette, marijuana, and alcohol use in a cohort of early adolescents (N = 1887) aged 11 to 13, a critical risk period for the initiation of substance use. Participants were students attending 22 middle schools in the northeastern United States. Participants completed surveys in the classroom, the first in the sixth grade and a second in the seventh grade, and the rate of overall substance use more than doubled from 5.5% to 11.9% over this period. Predictors of the onset of non-medical prescription and over-the-counter drug misuse overlapped substantially with those for marijuana and other substances. The perception of friends’ substance use and the belief that substance use can help you deal with problems predicted the onset of marijuana use, OTC medication misuse, and prescription drug misuse. Decision-making skills were protective for the onset of all substance use outcomes. The findings of this study have important implications for prevention and suggest that a single comprehensive approach may be sufficient for preventing multiple forms of substance use onset during early adolescence.