International Journal of Translational Medicine

A novel means of applying radiotherapy in cancer treatment is the application of a radiation dose at a very high intensity for a very short time in FLASH radiotherapy (FLASH-RT). This technique involves the exposure of tumors to >40 Gy/s, usually for less than one second. Studies conducted in cell and preclinical models suggest that FLASH-RT seems less damaging to normal tissues from adverse effects relative to the same overall dose of radiation administered in conventional therapy (CONV-RT), which involves the administration of lower levels of radiation repeated intermittently over a protracted period. In contrast, the susceptibility of tumor tissues to FLASH-RT is not diminished relative to CONV-RT. Within solid tumors, both modes of dispensation of radiation produce an equivalent degree of cell damage. The differential treatment between normal and malignant material has been found in isolated tissues, animal studies and, more recently, in clinical trials. However, the classic radiation concept is that high-energy linear transfer radiation (LET) is more damaging than the equivalent total dose of low LET. Thus, the susceptibility of cells should be greater after short-term exposure to high LET. This article discusses the potential reasons that may account for this discrepancy. While the relative protection given to untransformed tissues by FLASH-RT relative to tumor tissue is a major step forward in radiation therapy for cancer, the processes that lie behind this phenomenon are incompletely understood and are considered here. Full article

Background: In recent years, cystic fibrosis transmembrane regulator (CFTR) modulating therapy has made it possible to treat the underlying pathophysiological defect in children with cystic fibrosis (CF). Response to therapy varies among patients. We investigated the immune responses and exhaled breath profile changes after the initiation of CFTR modulator therapy to explore their potential as markers of therapy response. Methods: We performed a prospective, longitudinal proof-of-principle study, investigating immune responses and exhaled breath volatile organic component (VOC) profiles prior to and during the initiation of therapy with Lumacaftor/Ivacaftor in a cohort of 17 patients with CF aged 2 to 6 years old. Response to therapy was assessed based on clinical markers and the decrease in sweat chloride. Whole blood stimulation assays were performed at t = 0, 6 and 18 weeks, while VOC analysis was performed at t = 0 and 18 weeks. Results: A pattern of immune reconstitution was found in the first 4 months of therapy. The same pattern was found in responders and non-responders. Exhaled breath VOC profiles were significantly affected by therapy. A trend toward a significant difference was found between responders and non-responders. Conclusions: Pediatric CF patients show a pattern of immune reconstitution after the initiation of CFTR modulating therapy. We hypothesize that this could be explained by the need for a pro-inflammatory profile for a more effective clearance of latent airway pathogens in the initial phase. The exhaled breath profile also clearly changes after the initiation of therapy, indicating the therapy’s influence on airway inflammation and oxidative stress; thus, it might predict the response to therapy. Full article

The prevalence of patients on buprenorphine therapy presenting for elective surgery has increased. Buprenorphine is a widely used medication for the management of patients with chronic pain. It is also used as maintenance therapy for patients with a history of opioid use disorder (OUD). Due to the lack of a standardized protocol for managing patients on buprenorphine perioperatively, we performed a retrospective analysis to compare pain score outcomes and postoperative opiate requirements between patients who continued buprenorphine versus patients who discontinued buprenorphine. We identified 35 patients: 11 continued buprenorphine and 24 discontinued buprenorphine. The average Post-Anesthesia Care Unit (PACU) pain score was 5.59 for those who continued buprenorphine and 7.54 for those who discontinued preoperative buprenorphine (p value 0.0339). The average postoperative morphine milligram equivalent (MME) use was 86.13 for those who continued preoperative buprenorphine and 107.70 for those who discontinued buprenorphine (p value 0.6439). The results from our study correlate with several previous studies, which showed lower PACU pain scores in patients who continued buprenorphine. There is a benefit of decreased postoperative pain when preoperative buprenorphine is continued, and a decreased possibility for relapse in those with a history of OUD. Full article

Aberrant N-glycosylation has been associated with progression of the pediatric cancer neuroblastoma (NB) but remains understudied. Here we investigated oligomannose N-glycans in NB by genetic editing of MGAT1 in a human NB cell line, BE(2)-C, called BE(2)-C(MGAT1^−/−). Lectin binding studies confirmed that BE(2)-C(MGAT1^−/−) had decreased complex and increased oligomannose N-glycans. The relevance of 2D and 3D cell cultures was demonstrated for cell morphology, cell proliferation, and cell invasion, thereby highlighting the necessity for 3D cell culture in investigating cancerous properties. Western blotting revealed that oligomannosylated EGFR had increased autophosphorylation. Proliferation was decreased in BE(2)-C(MGAT1^−/−) using 2D and 3D cultures, but both cell lines had similar proliferation rates using 3D cultures without serum. Upon EGF treatment, BE(2)-C(MGAT1^−/−), but not BE(2)-C, showed increased proliferation, and furthermore, the mutant proliferated much faster than BE(2)-C under 3D conditions. Cell spheroid invasiveness was greatly increased in BE(2)-C(MGAT1^−/−) compared with BE(2)-C. Moreover, invasiveness was reduced in both cell lines with either EGF or RhoA activator treatment, regardless of the N-glycan population. Thus, this study further extends our earlier findings that oligomannose N-glycans enhance NB cell invasiveness, and that EGF stimulation of oligomannosylated EGFR greatly enhances cell proliferation rates, underlining the role of oligomannose N-glycans in the promotion of NB. Full article

Atherosclerosis, marked by plaque accumulation within arteries, results from lipid dysregulation, inflammation, and vascular remodeling. Plaque composition, including lipid-rich cores and fibrous caps, determines stability and vulnerability. Photodynamic therapy (PDT) has emerged as a promising treatment, leveraging photosensitizers to induce localized cytotoxicity upon light activation. PDT targets plaque components selectively, reducing burden and inflammation. Challenges remain in optimizing PDT parameters and translating preclinical success to clinical efficacy. Nonetheless, PDT offers a minimally invasive strategy for atherosclerosis management, promising personalized interventions for cardiovascular health. The objective of the current study was to present the findings from quantitative non-contrast MRI of atherosclerosis post-PDT by assessing relaxation times. The study aimed to utilize and optimize a 1.5T MRI system. Clinical scanners were used for MRI examinations. The research involved analyzing T1 and T2 relaxation times. Following treatment of the samples with Rose Bengal and exposure to pure oxygen, PDT irradiation was administered. The results indicated that the therapy impacted the crus, evidenced by a significant decrease in relaxation times in the MRI data. Full article

Immunoglobulin D (IgD) myeloma represents an uncommon subtype of multiple myeloma (MM), accounting for 1–2% of cases. Subjects affected by IgD MM have been demonstrated to have an inferior outcome and survival compared to those with other MM subtypes. A retrospective study was conducted on 15 patients (9 males and 6 females) diagnosed from 2008 to 2022 with IgD MM, in order to investigate the clinical and biochemical features at the moment of diagnosis, cytogenetic alterations, and survival times. The median age was 69 years, and higher frequencies of bone lesions, renal impairments, Bence–Jones proteinuria, and increased serum LDH were observed. Serum calcium levels were in the reference ranges. In the assessment of protein electrophoresis patterns, nine patients had a serum monoclonal protein that was not detectable. A cytogenetic analysis via fluorescence in situ demonstrated that the most common abnormalities were the deletion of 13q and IGH rearrangements. Patients treated with new chemotherapeutic drugs (immunomodulators, proteasome inhibitors), with or without autologous stem cell transplantation presented a higher median survival. The fundamental role of the laboratory in monoclonal IgD detection and the monitoring and studying of IgD MM cases enhances the knowledge of this disease, thus improving patient outcomes. Full article

SARS-CoV-2, the causative agent of the COVID-19 pandemic, has had a global impact, affecting millions over the last three years. Pre-existing lung diseases adversely affect the prognosis of infected COVID-19 patients, and agricultural workers routinely exposed to inhalable organic dusts have substantial increased risk for developing chronic lung diseases. In previous studies, we characterized the protein kinase C (PKC)-dependent airway inflammation mediated by organic dust extract (ODE) derived from dust collected from swine confinement facilities in in vitro and in vivo models. Here, we studied the effect of ODE on SARS-CoV-2 pseudoviral infection in mice and human bronchial epithelial cells (BEAS-2B). In wild-type (WT) and transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor (SARS-CoV-2 entry receptor), ODE increased ACE2 shedding by ADAM-17 in the lungs. After repeated ODE treatments, the increased soluble ACE2 correlated to higher pseudovirus titer in the mouse lungs. In the human bronchial epithelial cells, ODE augmented PKCα activity in WT cells, and membrane ACE2 expression was diminished in PKCα-dominant negative cells. Unlike in the mice, increasing membrane ACE2 levels by treating with PKCα or ADAM-17 inhibitors and a low dose of ODE enhanced pseudoviral entry in vitro. Following viral entry, IL-8 secretion by the cells was diminished in a PKCα- and ADAM-17-independent manner. Together, the complex mechanisms involved in the synergistic effects of agricultural dust and SARS-CoV-2 highlight the importance of studying dust-mediated changes to immunity against circulating pathogens. Full article

Cancer stem cells (CSCs) are a dynamic population of tumor cells characterized by long-term self-renewal, high tumorigenicity, resistance to conventional therapies such as radio- and chemotherapy, and capacity to recapitulate the tumor heterogeneity. Similar to other tumor cells, CSCs need to carry critical mutations and epigenetic changes to acquire their aberrant phenotype. Confirmed in various hematologic and solid malignancies, the critical need to deepen our understanding of CSC biology, including identification of CSC biomarkers, and develop novel CSC-targeted therapies has been clearly recognized. Here, we review the L1 cell adhesion molecule (L1CAM) as a CSC-associated biomarker in ovarian cancer. Furthermore, we inform on the promising potential of anti-L1CAM radioimmunotherapy with ¹⁶¹Tb as a novel CSC-targeted therapeutic approach to overcome CSC radioresistance in comparison to ¹⁷⁷Lu. Full article

It is well known that mental illness is often the result of genetic susceptibility combined with environmental factors. In this context, it is useful to consider the role that changes in DNA expression, known as epigenetic, can play in the development and progression of psychiatric disorders. Accordingly, psychotherapy, a form of pharmacological strategy that often targets dysfunctional emotions and behaviors, may also improve the symptoms of mental illness via epigenetic changes. This article reviews the current literature on epigenetic changes induced by psychotherapy in psychiatric disorders, pointing out encouraging findings for borderline personality disorder (BPD), post-traumatic stress disorder (PTSD), anxiety disorders and obsessive–compulsive disorder (OCD). It focuses on genes that are more commonly associated with epigenetic changes and paves the way for further research. Full article

Many anti-tumor effects of group-specific component-derived macrophage-activating factors (GcMAFs) have been reported; however, the specific mechanisms remain unclear. Controlling tumor-associated macrophages (TAMs) in the tumor microenvironment is essential for cancer treatment. This study assessed the role of GcMAF in macrophage activation, elucidated the mechanisms by which it exerts its anti-tumor effects, and determined its effects on TAMs in the tumor microenvironment. GcMAF-stimulated RAW264.7 macrophages and EMT6 breast tumor cells were co-cultured in a 0.4 µm pore cell culture insert, and gene and protein expression and cell viability were evaluated. DNA microarray analysis of GcMAF-stimulated RAW264.7 cells was conducted. The induction of M2 RAW264.7 cells by interleukin (IL)-4 and IL-13 was analyzed. GcMAF stimulation increased the tumor necrosis factor-α and inducible nitric oxide synthase mRNA and protein levels in RAW264.7 cells but decreased the viability of co-cultured EMT6 cells. Although the details of the receptor or signal pathway of GcMAF are still unclear, these results were confirmed in the M2 RAW264.7 cells, suggesting that GcMAF exerts anti-tumor effects by inducing the differentiation of macrophages into the M1 type and reprogramming M2 macrophages to the M1 type. The anti-tumor activity of GcMAF via M2-to-M1 macrophage reprogramming could aid in developing novel cancer immunotherapies. Full article

Background: Tissue factor pathway inhibitors (TFPI1 and TFPI2) are ubiquitously distributed in humans and exhibit inhibitory activity against serine proteinases. TFPI1 inhibits the tissue factor (TF)-dependent extrinsic coagulation pathway, while TFPI2 modulates extracellular matrix remodeling. TFPI2 has been reported to be an epigenetically silenced tumor suppressor and independent prognostic factor in various human cancers. However, elevated serum levels of TFPI2 have been observed in ovarian and endometrial cancers compared to healthy controls, with increased levels correlating with poor prognosis in endometrial cancer. This raises the question of why the tumor suppressor TFPI2 is elevated in the blood of patients with gynecological cancers and is associated with adverse outcomes. Methods: A comprehensive literature search was performed in PubMed and Google Scholar without time restriction. Results: TFPI2 gene expression may be influenced by both cancer cell-specific gene expression profiles (e.g., oncogenic signaling pathways) and epigenetic modifications (e.g., DNA methylation, histone modifications, and non-coding RNAs). Although TFPI2 generally exhibits an anti-invasion effect in most human cancers, it has been reported to have a paradoxical pro-invasive effect in certain cancers. TFPI2 facilitates cancer invasion through aberrant alternative splicing or through a pathophysiological process known as angiotropism or vasculogenic mimicry. The overproduction of TFPI2 in the tumor microenvironment may reinforce the extracellular matrix, thereby enhancing tumor cell adhesion and invasion. Conclusion: This review summarizes the current understanding of the seemingly contradictory functions of TFPI2 in human malignancies, primarily focusing on the mechanisms regulating its expression and function, and discusses future prospects for translational research. Full article

While existing local therapies partially restore vision loss from diabetic retinopathy (DR), there is currently no reliable treatment to prevent the onset or stop the progression of the disease. This review seeks to explore the inflammatory molecular mechanisms underpinning DR pathogenesis, which have not been targeted by current interventions. Specifically, this review explores the role of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) inflammasome in DR onset and progression. Evidence through clinical trials has begun to note that specific drugs (fenofibrate, metformin) appear effective in slowing DR progression independent of lipid or glucose-lowering, respectively, suggesting that other mechanisms are at play. Novel therapeutics that inhibit the activation of the NLRP3 inflammasome pathway may provide a novel treatment for halting DR progression. Full article

Gastric gastrointestinal stromal tumors (GIST) are rare, neuroectodermal tumors primarily residing in the stomach with characteristic genetic mutations. They are often identified using ultrasound and cross-sectional imaging, or they are noted during endoscopy. Localized gastric GISTs are commonly treated with surgical resection, with the possible use of neoadjuvant or adjuvant medical therapies as they are considered to have malignant potential. The use of tyrosine kinase inhibitors (TKI) such as imatinib has been shown to successfully reduce pre-operative tumor burden, recurrence, and disease progression. Surgical resection considerations vary depending on tumor size, location, and malignant potential. Neoadjuvant and adjuvant TKI therapy dosing varies in response to the type of GIST mutation present and greatly influences prognosis. Novel cooperative minimally invasive surgical techniques and targeted therapies are currently in development to address challenges in GIST treatment for tumors in challenging locations or with significant potential for progression. The management of localized gastric GISTs continues to rapidly evolve; each case should be managed individually, where care is taken in considering details, including tumor location, tumor size, and the molecular genetic profile, before embarking on a course of treatment. Full article

Hypersensitivity pneumonitis (HP) represents the third common interstitial lung disease caused by an exaggerated immune response following the inhalation of organic and/or chemical environmental antigens. The aim of this study was to determine the cut-off values of specific IgG antibodies (named precipitins) and their association with clinical data in the diagnosis of HP. In this 10-year retrospective study, the IgG concentrations against six antigens, Penicillium chrysogenum/notatum, Aspergillus fumigatus, Alternaria alternata, Aspergillus niger, Micropolyspora faeni, and pigeon droppings, were retrieved. The controlled group was made of 1516 healthy subjects without diagnosis of lung pathologies, while the case group consisted of 54 individuals affected by HP. Considering all six IgG antibodies together and the 97.5% percentiles determined in the control group, 30 of 54 subjects (56%) had one or more positive precipitins. In these patients, the major frequencies found were IgG antibodies against pigeon droppings, followed by Penicillium chrysogenum/notatum and Aspergillus niger. Although the sensitivity of serum precipitins depends on the population enrolled and the method used, the cut-off values determined in this study can be a valuable tool for clinicians in the diagnosis of HP, in eliminating the antigens responsible from the environment, and in establishing more specific IgG panels. Full article

High-density lipoprotein cholesterol (HDL) has long been regarded as a protective factor against cardiovascular disease (CVD). However, recent research challenges this notion, suggesting that HDL functionality rather than its quantity may be a more accurate predictor of CVD risk. While epidemiological studies have traditionally found that higher HDL levels are associated with reduced CVD risk, intervention trials aiming to elevate HDL levels have yielded inconsistent results. Moreover, observational studies have reported that unusually high HDL levels are associated with increased mortality rates. These discrepancies underscore the complexity of the role of HDL in CVD. Reverse cholesterol transport, facilitated by HDL, plays a crucial role in preventing atherosclerosis by removing cholesterol from peripheral tissues. Additionally, HDL exhibits anti-inflammatory properties by inhibiting endothelial adhesion molecules and suppressing pro-inflammatory cytokines. Recent studies have highlighted the importance of HDL particle number, size, and functionality in assessing CVD risk. For instance, increased HDL particle number and larger particle size have been associated with reduced CVD risk, independent of HDL cholesterol levels. Furthermore, HDL’s cholesterol efflux capacity has emerged as a promising biomarker for predicting CVD risk, with higher efflux capacity correlating with lower CVD incidence and mortality. This article reviews the latest findings regarding the role of HDL in CVD risk assessment, emphasizing the need to focus on HDL quantity and HDL quality. Full article

Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), increase the survival of chronic myeloid leukemia (CML) patients but do not eradicate the disease as leukemia stem cells (LSCs) with primitive and quiescent signatures persist after TKI monotherapy, driving disease relapse. Using single-cell publicly available transcriptomic data, we investigated potentially tractable vulnerabilities in this persistent CML LSC population. GAS2 is significantly upregulated when comparing LSCs from CML patients in remission to normal hematopoietic stem cells (HSCs). A topoisomerase IIβ inhibitor, XK469, was proposed to be repurposed as a candidate small-molecule inhibitor of GAS2, and its effect was investigated in cell line models in combination with IM in vitro. Alone, XK469 could induce cell cycle arrest/differentiation in CML cells and reduce cell viability. In combination with IM, XK469 significantly increased CML cell apoptosis and reduced CML cell clonogenic capacity. These results suggest that GAS2 is a targetable vulnerability in CML LSCs and that using XK469 in combination with TKI potentiates the sensitivity of CML cells to IM. Full article

Hemostasis disorders require particular attention in dental treatment. Dental implants are a very widespread and valid method for total rehabilitation. Flapless dental implant surgery is a minimally invasive treatment that allows the implants to be placed in the jaw bones with minimal surgical trauma. The aim of this study is to report the bleeding incidence in a group of patients with bleeding disorders treated with flapless implants. A total of 52 patients with bleeding disorders (46 in anticoagulant therapy; 4 with hemophilia; 2 with von Willebrandt disease) were treated with 188 flapless implant surgeries Anticoagulants were not discontinued. Patients with hemophilia and VWD were treated following specific protocols. Four late, easy to treat bleeding complications were reported (three mild bleeding, one ecchymosis). No additional sutures or other hemostatic measures were taken, no further infusions or transfusions were reported, and no severe bleeding complications requiring more than easy on-chair treatment, were reported. In conclusion, with adequate knowledge of the procedure and the pathology, dental implantology can be safely performed in patients with bleeding disorders. Full article

Background: Intravenous (IV) flecainide is recommended for the pharmacological cardioversion of recent-onset atrial fibrillation (AF). The aim of this study was to study the efficacy and safety of IV flecainide, co-administered with oral b-blockers, for the cardioversion of paroxysmal AF. Methods: Single-center registry, initiated in the “Skylitseion” General Hospital of Chios in January 2020. The main inclusion criterion was IV flecainide administration plus oral b-blocker for recent-onset AF (≤48 h). The primary outcome was conversion to sinus rhythm at 2 h. Results: A total of 121 (73 males and 48 females, with mean age 61.4 years) consecutive, unselected patients who complied with the study protocol were included. A successful conversion to sinus rhythm at 2 h was achieved in 99 patients (success rate: 81.8%). The median conversion time was 11.7 min (varied from 3 to 23 min). Duration of hospitalization was significantly shorter in patients who were successfully cardioverted with IV flecainide (10.9 vs. 30.7 h, p < 0.001). No serious adverse events were recorded. Conclusion: This is one of the largest registries worldwide, evaluating the effectiveness and safety of IV flecainide co-administered with a b-blocker in the acute management of recent-onset AF. The successful conversion rate at 2 h is very high and quick with no serious adverse events. Full article

Many ailments can be diagnosed while they are asymptomatic, meaning that the patient has no signs or symptoms of a progressing disease. If caught in their initial stage of formation, these disorders can be effectively treated, leading to successful outcomes; curative therapies can halt illnesses from advancing, thus improving the quality of life and long-term survival of the patient. Still, cutting-edge upgrades in precision technologies are necessary for early, reliable, affordable, and rapid disease detection, but also vital for the well-being of people and the future of global public health. The emerging role and utility of non-invasive and repeatable diagnostic test approaches for the detection of health conditions have been exemplified by liquid biopsies based on genomic biomarkers. As such, biological fluids permit any measurable molecular indicator or signature (e.g., proteins) to provide valuable information on an individual’s wellness and/or disease. Among the bodily secretions used for non-invasive diagnostics is sputum, a complex viscous gel-like biopolymeric network that has gained growing recognition as a rich source of biomarkers of airway infections and pulmonary diseases, and serves as a determinant to reveal other illnesses. As per the World Health Organization, the burden of respiratory conditions is exacerbated by factors ranging from considerable subjection to air pollution and occupational contaminants to tobacco smoking and second-hand smoke, in addition to poor socio-economic status. Due to the likely increase in these determinants, respiratory tract ailments are on the rise, affecting the health of many individuals, in addition to putting stress on healthcare facilities and services worldwide. The aim of this study was to perform a narrative review of sputum constituents with an emphasis on proteins and glycoproteins assessed as possible biomarkers of lung and other organ diseases. A search was conducted using mucus, sputum proteomics, sputum biomarkers, and point-of-care testing as keywords employing Google, PubMed (MEDLINE), and Web of Science, selecting the most referenced and related papers of the last decade. We, therefore, highlight the need to use expectorated or induced sputum specimens as a routine sample source for testing valuable protein biomarkers to diagnose these chronic disorders, predict inflammation and disease progression, as well as monitor the effectiveness of treatments. Further, we discuss the urgent need for fast and reliable point-of-care methods to detect and quantify crucial protein biomarkers in sputum specimens, and the limitations faced when dealing with their complex matrices. Full article