bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?
Authors: Papadakos Stavros P. , Arvanitakis Konstantinos , Stergiou Ioanna E. , Lekakis Vasileios , Davakis Spyridon , Christodoulou Maria-Ioanna , Germanidis Georgios , Theocharis Stamatios
Published: May 2023

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.
Therapeutic Potential of BAY-117082, a Selective NLRP3 Inflammasome Inhibitor, on Metastatic Evolution in Human Oral Squamous Cell Carcinoma (OSCC)
Authors: Casili Giovanna , Scuderi Sarah Adriana , Lanza Marika , Filippone Alessia , Mannino Deborah , Giuffrida Raffaella , Colarossi Cristina , Mare Marzia , Capra Anna Paola , De Gaetano Federica , Portelli Marco , Militi Angela , Cuzzocrea Salvatore , Paterniti Irene , Esposito Emanuela
Published: May 2023

Oral squamous cell carcinoma (OSCC) is a commonly occurring head and neck cancer and it is characterized by a high metastasis grade. The aim of this study was to evaluate for the first time the effect of BAY-117082, a selective NLRP3 inflammasome inhibitor, in an in vivo orthotopic model of OSCC and its role in the invasiveness and metastasis processes in neighbor organs such as lymph node, lung, and spleen tissues. Our results demonstrated that BAY-117082 treatment, at doses of 2.5 mg/kg and 5 mg/kg, was able to significantly reduce the presence of microscopic tumor islands and nuclear pleomorphism in tongue tissues and modulate the NLRP3 inflammasome pathway activation in tongue tissues, as well as in metastatic organs such as lung and spleen. Additionally, BAY-117082 treatment modulated the epithelial–mesenchymal transition (EMT) process in tongue tissue as well as in metastatic organs such as lymph node, lung, and spleen, also reducing the expression of matrix metalloproteinases (MMPs), particularly MMP2 and MMP9, markers of cell invasion and migration. In conclusion, the obtained data demonstrated that BAY-117082 at doses of 2.5 mg/kg and 5 mg/kg were able to reduce the tongue tumor area as well as the degree of metastasis in lymph node, lung, and spleen tissues through the NLRP3 inflammasome pathway inhibition.
Results from Two HPV-Based Cervical Cancer Screening-Family Planning Integration Models in Malawi: A Cluster Randomized Trial
Authors: Tang Jennifer H. , Lee Fan , Chagomerana Maganizo B. , Ghambi Kachengwa , Mhango Patani , Msowoya Lizzie , Mkochi Tawonga , Magongwa Irene , Mhango Eneli , Mbendera Jacqueline , Mwandira Eunice , Schouten Erik , Gardner Leah , Smith Jennifer S. , Gadama Luis , Chinula Lameck
Published: May 2023

We conducted a cluster randomized trial of two models for integrating HPV self-collection into family-planning (FP) services at 16 health facilities in Malawi between March 2020–December 2021. Model 1 involved providing only clinic-based HPV self-collection, whereas Model 2 included both clinic-based and community-based HPV self-collection. An endline household survey was performed in sampled villages and households between October-December 2021 in the catchment areas of the health facilities. We analyzed 7664 surveys from 400 villages. Participants from Model 2 areas were more likely to have ever undergone cervical cancer screening (CCS) than participants from Model 1 areas, after adjusting for district, facility location (urban versus rural), and facility size (hospital versus health center) (adjusted odds ratio = 1.73; 95% CI: 1.29, 2.33). Among participants who had ever undergone CCS, participants from Model 2 were more likely to report having undergone HPV self-collection than participants from Model 1 (50.5% versus 22.8%, p = 0.023). Participants from Model 2 were more likely to be using modern FP (adjusted odds ratio = 1.01; 95% CI: 1.41, 1.98) than Model 1 participants. The integration of FP and HPV self-collection in both the clinic and community increases CCS and modern FP uptake more than integration at the clinic-level alone.
The Tumor Microenvironment in Classic Hodgkin’s Lymphoma in Responder and No-Responder Patients to First Line ABVD Therapy
Authors: Tamma Roberto , Ingravallo Giuseppe , Gaudio Francesco , d’Amati Antonio , Masciopinto Pierluigi , Bellitti Emilio , Lorusso Loredana , Annese Tiziana , Benagiano Vincenzo , Musto Pellegrino , Specchia Giorgina , Ribatti Domenico
Published: May 2023

Although classical Hodgkin lymphoma (CHL) is typically curable, 15–25% of individuals eventually experience a relapse and pass away from their disease. In CHL, the cellular microenvironment is constituted by few percent of H/RS (Hodgkin/Reed–Sternberg) tumor cells surrounded from a heterogeneous infiltration of inflammatory cells. The interplay of H/RS cells with other immune cells in the microenvironment may provide novel strategies for targeted immunotherapies. In this paper we analyzed the microenvironment content in CHL patients with responsive disease (RESP) and patients with relapsed/refractory disease to treatment (REL). Our results indicate the increase of CD68+ and CD163+ macrophages, the increase of PDL-1+ cells and of CD34+ microvessels in REL patients respective to RESP patients. In contrast we also found the decrease of CD3+ and of CD8+ lymphocytes in REL patients respective to RESP patients. Finally, in REL patients our results show the positive correlation between CD68+ macrophages and PDL-1+ cells as well as a negative correlation between CD163+ and CD3+.
Health-Related Quality of Life of Bone and Soft-Tissue Tumor Patients around the Time of Diagnosis
Authors: Kruiswijk Anouk A. , Dorleijn Desiree M. J. , Marang-van de Mheen Perla J. , van de Sande Michiel A. J. , van Bodegom-Vos Leti
Published: May 2023

Background: Bone and soft-tissue tumor patients experience long-lasting physical and psychological challenges. It is unknown to what extent Health-Related Quality of Life (HRQoL) is already affected during the diagnostic process. This study assesses the HRQoL of bone and soft-tissue tumor patients around time of diagnosis and explores which patient or tumor characteristics are associated with a reduced HRQoL. Methods: All patients with a suspected benign/malignant bone tumor (BT), benign soft-tissue tumor (STT), or malignant soft-tissue sarcoma (STS) visiting the Leiden University Medical Center between 2016 and 2020 were invited to complete the Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item profile questionnaire. Mean scores of all included patients and per diagnosis group were compared to mean scores of the general population using one-sample t-tests. Results: Overall, patients (n = 637) reported statistically significantly worse HRQoL-scores on anxiety (51.3 ± 9.6), pain (55.3 ± 10.1), physical functioning (46.0 ± 9.7), and social functioning (48.1 ± 10.8) with the difference in pain and physical functioning being clinically relevant (based on a 3-point difference on t-metric). HRQoL-scores differed between diagnosis subgroups, i.e., patients with malignant tumors had higher anxiety levels and experienced more pain, where patients with bone tumors had worse physical functioning. Conclusion: The HRQoL of patients with suspected bone and soft-tissue tumors is already affected during the diagnostic process.
Impact of Oocyte Extract Supplement on Quality of Life after Hepatectomy for Liver Tumours: A Prospective, Multicentre, Double-Blind Randomized Clinical Trial
Authors: Donadon Matteo , Palmisano Angela , Bizzarri Mariano , Ceriani Roberto , Veneroni Luigi , Donati Gabriele , Tassinari Davide , Viola Massimo Giuseppe , Tamburini Emiliano , Torzilli Guido
Published: May 2023

Background: Previous studies on oocyte extract supplementation showed benefits in patients with liver tumours. In this trial, we hypothesized that the oocyte extract supplement impacted the QoL after hepatectomy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Methods: This was a multicentre, double-blind, randomized clinical trial designed to assess the QoL of patients receiving a supplement of oocyte extract or placebo postoperatively. QoL was assessed using the Short Form-36 questionnaire in participants randomly assigned to treatment (Synchrolevels) or placebo. All study personnel and participants were masked to treatment assignment. The endpoint was the change in the QoL score. Results: Between June 2018 and September 2022, 66 of 128 expected patients were considered as per interim analysis, of which 33 were assigned to the treatment and 33 to the placebo group. Baseline and clinicopathological characteristics were similar between the two groups. In the treatment group, the health, mental and psychological status improved for many of the items considered, reaching statistical significance, while in the placebo group, those items either did not change or were impaired in comparison with the corresponding baseline. Conclusions: Supplementation with oocyte extract modifies QoL after liver surgery by enhancing functional recovery. Further in-depth studies are required to confirm this evidence.
Cholecystokinin Receptor Antagonist Induces Pancreatic Stellate Cell Plasticity Rendering the Tumor Microenvironment Less Oncogenic
Authors: Jolly Gurbani , Duka Tetyana , Shivapurkar Narayan , Chen Wenqiang , Bansal Sunil , Cheema Amrita , Smith Jill P.
Published: May 2023

CCK receptors are expressed on pancreatic cancer epithelial cells, and blockade with receptor antagonists decreases tumor growth. Activated pancreatic stellate cells or myofibroblasts have also been described to express CCK receptors, but the contribution of this novel pathway in fibrosis of the pancreatic cancer microenvironment has not been studied. We examined the effects of the nonselective CCK receptor antagonist proglumide on the activation, proliferation, collagen deposition, differential expression of genes, and migration in both murine and human PSCs. CCK receptor expression was examined using western blot analysis. Collagen production using activated PSCs was analyzed by mass spectroscopy and western blot. Migration of activated PSCs was prevented in vitro by proglumide and the CCK-B receptor antagonist, L365,260, but not by the CCK-A receptor antagonist L365,718. Proglumide effectively decreased the expression of extracellular matrix-associated genes and collagen-associated proteins in both mouse and human PSCs. Components of fibrosis, including hydroxyproline and proline levels, were significantly reduced in PSC treated with proglumide compared to controls. CCK peptide stimulated mouse and human PSC proliferation, and this effect was blocked by proglumide. These investigations demonstrate that targeting the CCK-B receptor signaling pathway with proglumide may alter the plasticity of PSC, rendering them more quiescent and leading to a decrease in fibrosis in the pancreatic cancer microenvironment.
Genomic and Transcriptomic Analyses of Malignant Pleural Mesothelioma (MPM) Samples Reveal Crucial Insights for Preclinical Testing
Authors: Laure Alexander , Rigutto Angelica , Kirschner Michaela B. , Opitz Lennart , Grob Linda , Opitz Isabelle , Felley-Bosco Emanuela , Hiltbrunner Stefanie , Curioni-Fontecedro Alessandra
Published: May 2023

Cell lines are extensively used to study cancer biology. However, the use of highly passaged commercial cell lines has to be questioned, as they do not closely resemble the originating tumor. To understand the reliability of preclinical models for Malignant pleural mesothelioma (MPM) studies, we have performed whole transcriptome and whole exome analyses of fresh frozen MPM tumors and compared them to cell lines generated from these tumors, as well as commercial cell lines and a preclinical MPM mouse model. Patient-derived cell lines were generated from digested fresh tumors and whole exome sequencing was performed on DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor samples, corresponding patient-derived cell lines, and normal tissue. RNA sequencing libraries were prepared from 10 fresh frozen tumor samples, the 10 corresponding patient-derived cell lines, and 7 commercial cell lines. Our results identified alterations in tumor suppressor genes such as FBXW7, CDKN2A, CDKN2B, and MTAP, all known to drive MPM tumorigenesis. Patient-derived cell lines correlate to a high degree with their originating tumor. Gene expressions involved in multiple pathways such as EMT, apoptosis, myogenesis, and angiogenesis are upregulated in tumor samples when compared to patient-derived cell lines; however, they are downregulated in commercial cell lines compared to patient-derived cell lines, indicating significant differences between the two model systems. Our results show that the genome and transcriptome of tumors correlate to a higher degree with patient-derived cell lines rather than commercial cell lines. These results are of major relevance for the scientific community in regard to using cell lines as an appropriate model, resembling the pathway of interest to avoid misleading results for clinical applications.
A Review of the Use of Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignancy in Pediatric Patients
Authors: Byrwa David J. , Twist Clare J. , Skitzki Joseph , Repasky Elizabeth , Ham P. Ben , Gupta Ajay
Published: May 2023

Hyperthermic intraperitoneal chemotherapy (HIPEC) can directly target microscopic peritoneal disease, has achieved regular consideration in the treatment of several adult cancer types, and is more recently being studied in pediatrics. This review paper provides an overview of the use of this modality in pediatrics in order to identify medication choice, discuss post-operative morbidity and mortality, and evaluate impact on overall survival. Four databases were searched including Scopus, PubMed, Embase, and CINAHL and ultimately 37 papers documenting the use of this modality comprising 264 pediatric patients were included. Malignancies treated include desmoplastic small round cell tumor, rhabdomyosarcoma, angiosarcoma, colorectal carcinoma, and mesothelioma, with several rarer tumor types. Cisplatin was the most commonly used drug for HIPEC at varying concentrations for 30–90 min in duration at temperatures of approximately 41–42 °C. Reported toxicities were generally self-limited and there was no post-operative mortality. The impact on overall survival versus systemic chemotherapy and debulking surgery is uncertain due to lack of clinical trials and very small sample size across tumor subsets and the overall pediatric population. The relationship between degree of tumor burden and extent of surgical debulking needs to be further clarified. Future directions include prospective clinical trials, establishment of patient databases to facilitate standardization of HIPEC in pediatric patients, and additional approaches to optimize HIPEC.
Single Fraction and Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, and Reduced Viability of Merlin-Deficient Schwann Cells
Authors: Dinh Christine T. , Chen Si , Nourbakhsh Aida , Padgett Kyle , Johnson Perry , Goncalves Stefania , Bracho Olena , Bas Esperanza , Bohorquez Jorge , Monje Paula V. , Fernandez-Valle Cristina , Elsayyad Nagy , Liu Xuezhong , Welford Scott M. , Telischi Fred
Published: May 2023

Background: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). Methods: Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. Results: Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. Conclusions: Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.
Association of Androgen Deprivation Therapy with Osteoporotic Fracture in Patients with Prostate Cancer with Low Tumor Burden Using a Retrospective Population-Based Propensity-Score-Matched Cohort
Authors: Kim Sung Han , Jeon Ye Jhin , Bak Jean Kyung , Yoo Bit-Na , Park Jung-Wee , Ha Yong-Chan , Lee Young-Kyun
Published: May 2023

This study evaluated the effect of androgen deprivation therapy (ADT) on osteoporotic fractures (OF) and its prognostic effect on overall survival in patients with localized or regional prostate cancer (PC) using the Korean National Insurance Dataset. A total of 8883 pairs of 1:1 propensity-score-matched patients with localized or regional PC were retrospectively enrolled between 2007 and 2016. All patients underwent at least 1 year of follow-up to evaluate therapeutic outcomes. Multivariate analysis was performed to determine the prognostic effect of ADT on OF. During a mean follow-up of 47.7 months, 977 (3.43%) patients developed OF, and the incidences of hip, spine, and wrist fractures were significantly different between ADT and non-ADT groups (p < 0.05). The ADT group had a significantly higher incidence of OF (hazard ratio 2.055, 95% confidence interval 1.747–2.417) than the non-ADT group (p < 0.05), and the incidence of spine/hip/wrist OF was significantly higher in the ADT group regardless of the PC stage (p < 0.05). Multivariate analysis failed to show any significant difference in overall survival between the two groups (p > 0.05). ADT resulted in a significantly higher incidence of OF among patients with localized and regional PC, but the overall survival did not differ between ADT and non-ADT groups.
T-Cell Engagers in Solid Cancers—Current Landscape and Future Directions
Authors: Shanshal Mohamed , Caimi Paolo F. , Adjei Alex A. , Ma Wen Wee
Published: May 2023

Monoclonal antibody treatment initially heralded an era of molecularly targeted therapy in oncology and is now widely applied in modulating anti-cancer immunity by targeting programmed cell receptors (PD-1, PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and, more recently, lymphocyte-activation gene 3 (LAG3). Chimeric antigen receptor T-cell therapy (CAR-T) recently proved to be a valid approach to inducing anti-cancer immunity by directly modifying the host’s immune cells. However, such cell-based therapy requires extensive resources such as leukapheresis, ex vivo modification and expansion of cytotoxic T-cells and current Good Manufacturing Practice (cGMP) laboratories and presents significant logistical challenges. Bi-/trispecific antibody technology is a novel pharmaceutical approach to facilitate the engagement of effector immune cells to potentially multiple cancer epitopes, e.g., the recently approved blinatumomab. This opens the opportunity to develop ‘off-the-shelf’ anti-cancer agents that achieve similar and/or complementary anti-cancer effects as those of modified immune cell therapy. The majority of bi-/trispecific antibodies target the tumor-associated antigens (TAA) located on the extracellular surface of cancer cells. The extracellular antigens represent just a small percentage of known TAAs and are often associated with higher toxicities because some of them are expressed on normal cells (off-target toxicity). In contrast, the targeting of intracellular TAAs such as mutant RAS and TP53 may lead to fewer off-target toxicities while still achieving the desired antitumor efficacy (on-target toxicity). Here, we provide a comprehensive review on the emerging field of bi-/tri-specific T-cell engagers and potential therapeutic opportunities.
CO2 Electroreduction to Formate—Comparative Study Regarding the Electrocatalytic Performance of SnO2 Nanoparticles
Authors: Weinrich Henning , Rutjens Bastian , Basak Shibabrata , Schmid Bernhard , Camara Osmane , Kretzschmar Ansgar , Kungl Hans , Tempel Hermann , Eichel Rüdiger-A.
Published: May 2023

SnO2 nanoparticles have frequently been reported as effective electrocatalysts for CO2 electroreduction to formate. However, in the literature, there is little knowledge of SnO2 nanoparticles that guarantee superior electrocatalytic performance. Hence, in this study, several SnO2 nanoparticles are compared with respect to their material properties, and correlations to the electrocatalytic performance are established. For comparison, three custom-made SnO2-electrocatalysts were prepared, reproducing frequently cited procedures in literature. Based on the comparison, it is found that hydrothermal, sol-gel, and solid-state synthesis provide quite different electrocatalysts, particularly in terms of the particle size and crystal lattice defect structure. Desirably small nanoparticles with a comparatively high number of lattice defects are found for the nanoparticles prepared by hydrothermal synthesis, which also provide the best electrocatalytic performance in terms of Faradaic efficiency for the electroreduction of CO2 to formate. However, despite the considerably smaller surface area, the commercial reference also provides significant electrocatalytic performance, e.g., in terms of the overall produced amount of formate, which suggests a surprisingly high surface area-specific activity for this material that is low on defects. Thus, defects do not appear to be the preferred reaction site for the CO2 electroreduction to formate on SnO2 in this case.
Red Wine Extract Prevents Oxidative Stress and Inflammation in ARPE-19 Retinal Cells
Authors: Cornebise Clarisse , Perus Maude , Hermetet François , Valls-Fonayet Josep , Richard Tristan , Aires Virginie , Delmas Dominique
Published: May 2023

Age-related macular degeneration (AMD) is one of the most commonly occurring ocular diseases worldwide. This degenerative condition affects the retina and leads to the loss of central vision. The current treatments are focused on the late stage of the disease, but recent studies have highlighted the importance and benefits of preventive treatments and how good dietary habits can reduce the risk of progression to an advanced form of the disease. In this context, we studied whether resveratrol (RSV) or a polyphenolic cocktail, red wine extract (RWE), are able to prevent the initiating events of AMD (i.e., oxidative stress and inflammation) in human ARPE-19 retinal pigment epithelial (RPE) cells and macrophages. This study highlights that RWE and RSV can prevent hydrogen peroxide (H2O2) or 2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AAPH)-induced oxidative stress and can subsequently prevent DNA damage via the inhibition of the ATM (ataxia telangiectasia-mutated)/Chk2 (checkpoint kinase 2) or Chk1 signaling pathways, respectively. Moreover, ELISA assays show that RWE and RSV can prevent the secretion of proinflammatory cytokines in RPE cells and in human macrophages. Interestingly, RWE exhibits a greater protective impact compared to RSV alone, even though RSV was more concentrated when used alone than in the red wine extract. Our results suggest that RWE and RSV may have potential interest as preventive nutritional supplementations against AMD.
Functional Analysis of Pheromone Biosynthesis Activating Neuropeptide Receptor Isoforms in Maruca vitrata
Authors: Cha Wook Hyun , Kim Boyun , Lee Dae-Weon
Published: May 2023

Insect sex pheromones are volatile chemicals that induce mating behavior between conspecific individuals. In moths, sex pheromone biosynthesis is initiated when pheromone biosynthesis-activating neuropeptide (PBAN) synthesized in the suboesophageal ganglion binds to its receptor on the epithelial cell membrane of the pheromone gland. To investigate the function of PBAN receptor (PBANR), we identified two PBANR isoforms, MviPBANR-B and MviPBANR-C, in the pheromone glands of Maruca vitrata. These two genes belong to G protein-coupled receptors (GPCRs) and have differences in the C-terminus but share a 7-transmembrane region and GPCR family 1 signature. These isoforms were expressed in all developmental stages and adult tissues. MviPBANR-C had the highest expression level in pheromone glands among the examined tissues. Through in vitro heterologous expression in HeLa cell lines, only MviPBANR-C-transfected cells responded to MviPBAN (≥5 µM MviPBAN), inducing Ca2+ influx. Sex pheromone production and mating behavior were investigated using gas chromatography and a bioassay after MviPBANR-C suppression by RNA interference, which resulted in the major sex pheromone component, E10E12-16:Ald, being quantitatively reduced compared to the control, thereby decreasing the mating rate. Our findings indicate that MviPBANR-C is involved in the signal transduction of sex pheromone biosynthesis in M. vitrata and that the C-terminal tail plays an important role in its function.
A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)P2
Authors: Bura Ana , Čabrijan Sara , Đurić Iris , Bruketa Tea , Jurak Begonja Antonija
Published: May 2023

Phosphoinositides (PIs) are small, phosphorylated lipids that serve many functions in the cell. They regulate endo- and exocytosis, vesicular trafficking, actin reorganization, and cell mobility, and they act as signaling molecules. The most abundant PIs in the cell are phosphatidylinositol-4-monophosphate (PI4P) and phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. PI4P is mostly localized at the Golgi apparatus where it regulates the anterograde trafficking from the Golgi apparatus to the plasma membrane (PM), but it also localizes at the PM. On the other hand, the main localization site of PI(4,5)P2 is the PM where it regulates the formation of endocytic vesicles. The levels of PIs are regulated by many kinases and phosphatases. Four main kinases phosphorylate the precursor molecule phosphatidylinositol into PI4P, divided into two classes (PI4KIIα, PI4KIIβ, PI4KIIIα, and PI4KIIIβ), and three main kinases phosphorylate PI4P to form PI(4,5)P2 (PI4P5KIα, PI4P5KIβ, and PI4P5KIγ). In this review, we discuss the localization and function of the kinases that produce PI4P and PI(4,5)P2, as well as the localization and function of their product molecules with an overview of tools for the detection of these PIs.
The Role of FBXW7 in Gynecologic Malignancies
Authors: Di Fiore Riccardo , Suleiman Sherif , Drago-Ferrante Rosa , Subbannayya Yashwanth , Suleiman Sarah , Vasileva-Slaveva Mariela , Yordanov Angel , Pentimalli Francesca , Giordano Antonio , Calleja-Agius Jean
Published: May 2023

The F-Box and WD Repeat Domain Containing 7 (FBXW7) protein has been shown to regulate cellular growth and act as a tumor suppressor. This protein, also known as FBW7, hCDC4, SEL10 or hAGO, is encoded by the gene FBXW7. It is a crucial component of the Skp1-Cullin1-F-box (SCF) complex, which is a ubiquitin ligase. This complex aids in the degradation of many oncoproteins, such as cyclin E, c-JUN, c-MYC, NOTCH, and MCL1, via the ubiquitin-proteasome system (UPS). The FBXW7 gene is commonly mutated or deleted in numerous types of cancer, including gynecologic cancers (GCs). Such FBXW7 mutations are linked to a poor prognosis due to increased treatment resistance. Hence, detection of the FBXW7 mutation may possibly be an appropriate diagnostic and prognostic biomarker that plays a central role in determining suitable individualized management. Recent studies also suggest that, under specific circumstances, FBXW7 may act as an oncogene. There is mounting evidence indicating that the aberrant expression of FBXW7 is involved in the development of GCs. The aim of this review is to give an update on the role of FBXW7 as a potential biomarker and also as a therapeutic target for novel treatments, particularly in the management of GCs.
LPS-Induced Systemic Inflammation Affects the Dynamic Interactions of Astrocytes and Microglia with the Vasculature of the Mouse Brain Cortex
Authors: Xingi Evangelia , Koutsoudaki Paraskevi N. , Thanou Irini , Phan Minh-Son , Margariti Maria , Scheller Anja , Tinevez Jean-Yves , Kirchhoff Frank , Thomaidou Dimitra
Published: May 2023

The Neurovascular Unit (NVU), composed of glia (astrocytes, oligodendrocytes, microglia), neurons, pericytes and endothelial cells, is a dynamic interface ensuring the physiological functioning of the central nervous system (CNS), which gets affected and contributes to the pathology of several neurodegenerative diseases. Neuroinflammation is a common feature of neurodegenerative diseases and is primarily related to the activation state of perivascular microglia and astrocytes, which constitute two of its major cellular components. Our studies focus on monitoring in real time the morphological changes of perivascular astrocytes and microglia, as well as their dynamic interactions with the brain vasculature, under physiological conditions and following systemic neuroinflammation triggering both microgliosis and astrogliosis. To this end, we performed 2-photon laser scanning microscopy (2P-LSM) for intravital imaging of the cortex of transgenic mice visualizing the dynamics of microglia and astroglia following neuroinflammation induced by systemic administration of the endotoxin lipopolysaccharide (LPS). Our results indicate that following neuroinflammation the endfeet of activated perivascular astrocytes lose their close proximity and physiological cross-talk with vasculature, an event that most possibly contributes to a loss of blood–brain barrier (BBB) integrity. At the same time, microglial cells become activated and exhibit a higher extent of physical contact with the blood vessels. These dynamic responses of perivascular astrocytes and microglia are peaking at 4 days following LPS administration; however, they still persist at a lower level at 8 days after LPS injection, revealing incomplete reversal of inflammation affecting the glial properties and interactions within the NVU.
Fibroblast Activation Protein-Targeting Minibody-IRDye700DX for Ablation of the Cancer-Associated Fibroblast with Photodynamic Therapy
Authors: Smeets Esther M. M. , Dorst Daphne N. , Franssen Gerben M. , van Essen Merijn S. , Frielink Cathelijne , Stommel Martijn W. J. , Trajkovic-Arsic Marija , Cheung Phyllis F. , Siveke Jens T. , Wilson Ian , Mascioni Alessandro , Aarntzen Erik H. J. G. , van Lith Sanne A. M.
Published: May 2023

Fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, is a target for diagnosis and therapy in multiple tumour types. Strategies to systemically deplete FAP-expressing cells show efficacy; however, these induce toxicities, as FAP-expressing cells are found in normal tissues. FAP-targeted photodynamic therapy offers a solution, as it acts only locally and upon activation. Here, a FAP-binding minibody was conjugated to the chelator diethylenetriaminepentaacetic acid (DTPA) and the photosensitizer IRDye700DX (DTPA-700DX-MB). DTPA-700DX-MB showed efficient binding to FAP-overexpressing 3T3 murine fibroblasts (3T3-FAP) and induced the protein’s dose-dependent cytotoxicity upon light exposure. Biodistribution of DTPA-700DX-MB in mice carrying either subcutaneous or orthotopic tumours of murine pancreatic ductal adenocarcinoma cells (PDAC299) showed maximal tumour uptake of 111In-labelled DTPA-700DX-MB at 24 h post injection. Co-injection with an excess DTPA-700DX-MB reduced uptake, and autoradiography correlated with FAP expression in the stromal tumour region. Finally, in vivo therapeutic efficacy was determined in two simultaneous subcutaneous PDAC299 tumours; only one was treated with 690 nm light. Upregulation of an apoptosis marker was only observed in the treated tumours. In conclusion, DTPA-700DX-MB binds to FAP-expressing cells and targets PDAC299 tumours in mice with good signal-to-background ratios. Furthermore, the induced apoptosis indicates the feasibility of targeted depletion of FAP-expressing cells with photodynamic therapy.
A Novel Approach to Optimize the Industrial Process of Membrane Concentration of Grape Musts
Authors: Bianchi Biagio , Molino Bruno , Catalano Filippo , Giametta Ferruccio , Molino Antonio Jacopo , Ambrosone Luigi
Published: May 2023

Nanofiltration and reverse osmosis are used in the concentration of grape musts in winemaking. Both technologies offer an effective way to concentrate the grape musts, reducing the volume and the solids content to achieve desired characteristics in the final wine. The choice between nanofiltration and reverse osmosis depends on the specific needs of the winemaker and the desired characteristics. It is important to carefully consider the properties of the grape musts and the performance of the selected membranes to optimize the concentration process and ensure the desired outcome. Herein, we present a novel approach that allows us to choose a suitable membrane for an optimal industrial process for the concentration of musts, both in reverse osmosis and nanofiltration. The proposed method consists of combining the fitting equations of laboratory results with the balance equations on the industrial plant. Specifically, a full-scale plant has been designed and assembled with which grape musts of Trebbiano, Verdeca, Black Bombino, and White Bombino varieties have been concentrated through the selected best-performing membranes. Results of the proposed approach show that grape musts with sugar content commercially appreciated when the membranes work at high pressure can be obtained.
Direct Electrochemical Analysis in Seawater: Evaluation of Chloride and Bromide Detection
Authors: Chen Yuqi , Compton Richard
Published: May 2023

Chloride and bromide are two of the most abundant anions found in seawater, and knowledge of their concentrations is essential for environmental monitoring. However, the analysis of chloride and bromide in seawater is challenging due to the complex nature of the seawater matrix. From an electrochemical perspective, we investigate the suitability of three types of electrode (Au, glassy carbon and Pt) for the analysis of Cl− and/or Br− in seawater. With the understanding of their electrochemical behaviours in artificial seawater (ASW), optimal voltammetric procedures for their detection are developed. The results show that the Au electrode is unsuitable for use as a Cl− and/or Br− sensor due to its dissolution and passivation in ASW. The use of glassy carbon resulted in poorly defined chloride and bromide signals. Finally, platinum was found to be a good candidate for chloride detection in artificial seawater using square wave voltammetry, and the results obtained in natural seawater via electrochemical measurement were in good agreement with those obtained via ion chromatography. Platinum electrodes are also recommended for bromide analysis.
Evolution of Youth’s Mental Health and Quality of Life during the COVID-19 Pandemic in South Tyrol, Italy: Comparison of Two Representative Surveys
Authors: Barbieri Verena , Wiedermann Christian J. , Piccoliori Giuliano , Mahlknecht Angelika , Plagg Barbara , Ausserhofer Dietmar , Ravens-Sieberer Ulrike , Engl Adolf
Published: May 2023

Background: The coronavirus disease 2019 pandemic has led to an increase in youth mental health problems worldwide. Studies have revealed substantial variation in the incidence of these problems across different regions. Longitudinal studies of children and adolescents in Italy are lacking. This study aimed to investigate the development of health-related quality of life (HRQoL) and mental health in Northern Italy by comparing surveys conducted in June 2021 and in March 2022. Methods: A representative, large cross-sectional, online survey investigated HRQoL, psychosomatic complaints, and symptoms of anxiety and depression among 5159 and 6675 children and adolescents in 2021 and 2022, respectively, using the KIDSCREEN-10 index, HBSC symptom checklist, SCARED, CES-DC, and PHQ-2 instruments. Statistical analyses included a multivariate linear regression analysis. Results: Baseline characteristics showed significant differences in demographic variables between the two surveys. Girls and their parents reported a significantly lower HRQoL in 2021 than in 2022. Psychosomatic complaints differed significantly between sexes, and the results showed no decrease in psychosomatic complaints, anxiety, or depression between 2021 and 2022. Predictors of HRQoL, anxiety, depressive symptoms, and psychosomatic complaints in 2022 differed from those in 2021. Conclusions: The characteristics of the 2021 pandemic, including lockdowns and home schooling, may have contributed to the differences between the two surveys. As most pandemic restrictions ended in 2022, the results confirm the need for measures to improve the mental and physical health of children and adolescents after the pandemic.
Translating Precision Health for Pediatrics: A Scoping Review
Authors: Subasri Mathushan , Cressman Celine , Arje Danielle , Schreyer Leighton , Cooper Erin , Patel Komal , Ungar Wendy J. , Barwick Melanie , Denburg Avram , Hayeems Robin Z.
Published: May 2023

Precision health aims to personalize treatment and prevention strategies based on individual genetic differences. While it has significantly improved healthcare for specific patient groups, broader translation faces challenges with evidence development, evidence appraisal, and implementation. These challenges are compounded in child health as existing methods fail to incorporate the physiology and socio-biology unique to childhood. This scoping review synthesizes the existing literature on evidence development, appraisal, prioritization, and implementation of precision child health. PubMed, Scopus, Web of Science, and Embase were searched. The included articles were related to pediatrics, precision health, and the translational pathway. Articles were excluded if they were too narrow in scope. In total, 74 articles identified challenges and solutions for putting pediatric precision health interventions into practice. The literature reinforced the unique attributes of children and their implications for study design and identified major themes for the value assessment of precision health interventions for children, including clinical benefit, cost-effectiveness, stakeholder values and preferences, and ethics and equity. Tackling these identified challenges will require developing international data networks and guidelines, re-thinking methods for value assessment, and broadening stakeholder support for the effective implementation of precision health within healthcare organizations. This research was funded by the SickKids Precision Child Health Catalyst Grant.
Hidradenitis Suppurativa: Molecular Etiology, Pathophysiology, and Management—A Systematic Review
Authors: Diaz Michael Joseph , Aflatooni Shaliz , Abdi Parsa , Li Rina , Anthony Michelle Robert , Neelam Sphurti , Farkouh Chris , Tran Jasmine Thuy , Svoboda Steven , Forouzandeh Mahtab , Valdes Rodriguez Rodrigo H.
Published: May 2023

Hidradenitis suppurativa is a chronic inflammatory skin condition that affects the hair follicles in areas of the body with apocrine glands. The condition is characterized by recurrent, painful nodules, abscesses, and draining sinuses that can lead to scarring and disfigurement. In this present study, we provide a focused evaluation of recent developments in hidradenitis suppurativa research, including novel therapeutics and promising biomarkers that may facilitate clinical diagnosis and treatment. We conducted a systematic review of controlled trials, randomized controlled trials, meta-analyses, case reports, and Cochrane Review articles in accordance with the PRISMA guidelines. The Cochrane Library, PubMed, EMBASE, and Epistemonikos databases were queried via Title/Abstract screen. Eligibility criteria included the following: (1) has a primary focus on hidradenitis suppurativa, (2) includes measurable outcomes data with robust comparators, (3) details the sample population, (4) English language, and (5) archived as full-text journal articles. A total of 42 eligible articles were selected for review. Qualitative evaluation identified numerous developments in our understanding of the disease’s multiple potential etiologies, pathophysiology, and treatment options. It is important for individuals with hidradenitis suppurativa to work closely with a healthcare provider to develop a comprehensive treatment plan that addresses their individual needs and goals. To meet this objective, providers must keep current with developments in the genetic, immunological, microbiological, and environmental factors contributing to the disease’s development and progression.
Brassica napus Haploid and Double Haploid Production and Its Latest Applications
Authors: Starosta Ewa , Szwarc Justyna , Niemann Janetta , Szewczyk Katarzyna , Weigt Dorota
Published: May 2023

Rapeseed is one of the most important oil crops in the world. Increasing demand for oil and limited agronomic capabilities of present-day rapeseed result in the need for rapid development of new, superior cultivars. Double haploid (DH) technology is a fast and convenient approach in plant breeding as well as genetic research. Brassica napus is considered a model species for DH production based on microspore embryogenesis; however, the molecular mechanisms underlying microspore reprogramming are still vague. It is known that morphological changes are accompanied by gene and protein expression patterns, alongside carbohydrate and lipid metabolism. Novel, more efficient methods for DH rapeseed production have been reported. This review covers new findings and advances in Brassica napus DH production as well as the latest reports related to agronomically important traits in molecular studies employing the double haploid rapeseed lines.
Question of Liability for Emissions from Land Development in Relation to New York State Climate Change Plan
Authors: Mikhailova Elena A. , Lin Lili , Hao Zhenbang , Zurqani Hamdi A. , Post Christopher J. , Schlautman Mark A. , Post Gregory C. , Shepherd George B.
Published: May 2023

The question of liability (responsibility) for loss and damage (L&D) associated with climate change often ignores the liability for L&D from greenhouse gas (GHG) emissions which are the source of climate change-related impacts. New York State (NYS) recognizes its responsibility regarding climate change as documented in the NYS Climate Leadership and Community Protection Act (CLCPA) (Senate Bill S6599), which put forward the goal of reducing greenhouse gas emissions from all anthropogenic sources 100% over 1990 levels by the year 2050, with an incremental target of at least a 40% reduction in climate pollution by the year 2030. The current NYS carbon footprint (CF) does not include soil-based GHG emissions from land developments, preventing the state from reaching its net-zero emission goals. The current study addresses this shortcoming by quantifying the “realized” social costs of CO2 (SC-CO2) emissions for NYS from all land developments (12,037.5 km2, midpoint 1.7 × 1011 of total soil carbon (TSC) losses with midpoint $28.5B (where B = billion = 109, USD)) in social costs of carbon dioxide emissions, SC-CO2) and “new” land developments (485.2 km2) in the period from 2001 to 2016, which caused a complete loss of midpoint 6.6 × 109 kg of TSC resulting in midpoint $1.1B SC-CO2. All NYS’s counties experienced land conversions, with most of the developments, TSC losses, and SC-CO2 occurred near the existing urban areas of New York City (NYC), Long Island, and Albany. Land conversion to developments creates additional liability by the loss of future GHG sequestration potential in developed areas. In addition, there is a substantial future liability in NYS from climate change impacts, such as the projected sea-level rises will impact 17 of NY’s 62 counties, which will cause high costs of adaptation. Incorporation of land use/land cover change (LULCC) analysis can help better quantify the CF and identify ways to reduce GHG emissions and the associated liabilities and compensations to help achieve some of the United Nations (UN) Sustainable Development Goals (SDGs).
Quality of Life in Patients Undergoing Percutaneous Coronary Intervention
Authors: Tsoulou Vasiliki , Vasilopoulos Georgios , Kapadochos Theodore , Pavlatou Niki , Kalogianni Antonia , Toulia Georgia , Dousis Evangellos , Panoutsopoulos George , Kourakos Michael , Polikandrioti Maria
Published: May 2023

Introduction: Percutaneous coronary intervention (PCI) is a non-surgical invasive procedure to treat coronary artery occlusion. The quality of life (QoL) is a way to measure the impact of illness and additionally its treatments to traditional measures of clinical outcomes. Purpose: The aim of the present study was to explore the levels of QoL pre-PCI, 6 and 12 months after PCI, as well as the factors associated with the QoL pre-PCI. Methods: In the present study, 100 patients undergoing PCI were enrolled. Data were collected through the completion of the SF-36 Health Survey (SF-36), which included participants’ characteristics. The statistical significance level was p < 0.05. Results: Patients had moderate levels of QoL at baseline, with a median general health score of 45 (IQR: 30–65). A gradual statistically significant increase in scores was observed in all subcategories of the patients’ QoL at 6 and 12 months after PCI (p < 0.001). A greater increase in scores was observed in physical functioning, physical role, emotional role and social functionality. In terms of the pre-PCI phase, it was found that physical functionality was statistically significantly associated with educational level (p = 0.005), occupation (p = 0.026) and whether the patients had children (p = 0.041). The physical and emotional role was significantly associated with gender (p = 0.046 and p = 0.040) and educational level (p = 0.030 and p = 0.001). Energy–fatigue was significantly associated with gender (p = 0.001), age (p = 0.028), marital status (p = 0.001), educational level (p = 0.001), whether the patients had children (p= 0.012) and other diseases (p = 0.001). Emotional well-being was significantly associated with family history of coronary artery disease (p = 0.011) and the frequency of physical exercise (p = 0.001). Social functioning was significantly associated with gender (p = 0.033), marital status (p = 0.034) and educational level (p = 0.002). Pain was not found to be significantly associated with patients’ demographics. General health was significantly associated with gender (p = 0.003), age (p = 0.043), educational level (p = 0.001), other diseases (p = 0.005) and the frequency of physical exercise (p = 0.001). Conclusion: Information about the QoL of PCI and its determinants is important to define an effective and comprehensive care plan.