Biomedicines, Volume 11, Issue 7 (July 2023) – 315 articles

Background: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders. Methods: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership. Results: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes. Conclusions: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs. Full article

Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment. Full article

Cancer is one of the leading global causes of death and disease, and treatment options are constantly evolving. In this sense, the use of monoclonal antibodies (mAbs) in immunotherapy has been considered a fundamental aspect of modern cancer therapy. In order to avoid collateral damage, it is indispensable to identify specific molecular targets or biomarkers of therapy and/or diagnosis (theragnostic) when designing an appropriate immunotherapeutic regimen for any type of cancer. Furthermore, it is important to understand the currently employed mAbs in immunotherapy and their mechanisms of action in combating cancer. To achieve this, a comprehensive understanding of the biology of cancer cell antigens, domains, and functions is necessary, including both those presently utilized and those emerging as potential targets for the design of new mAbs in cancer treatment. This review aims to provide a description of the therapeutic targets utilized in cancer immunotherapy over the past 5 years, as well as emerging targets that hold promise as potential therapeutic options in the application of mAbs for immunotherapy. Additionally, the review explores the mechanisms of actin of the currently employed mAbs in immunotherapy. Full article

Cardiovascular diseases (CVD) are a global health concern, affecting millions of patients worldwide and being the leading cause of global morbidity and mortality, thus creating a major public health concern. Sodium/glucose cotransporter 2 (SGLT2) inhibitors have emerged as a promising class of medications for managing CVD. Initially developed as antihyperglycemic agents for treating type 2 diabetes, these drugs have demonstrated significant cardiovascular benefits beyond glycemic control. In our paper, we discuss the role of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and the relatively recently approved bexagliflozin, the class of SGLT-2 inhibitors, as potential therapeutic targets for cardiovascular diseases. All mentioned SGLT-2 inhibitors have demonstrated significant cardiovascular benefits and renal protection in clinical trials, in patients with or without type 2 diabetes. These novel therapeutic approaches aim to develop more effective treatments that improve patient outcomes and reduce the burden of these conditions. However, the major scientific achievements of recent years and the many new discoveries and mechanisms still require careful attention and additional studies. Full article

Androgen deprivation therapy (ADT) remains the cornerstone of advanced prostate cancer treatment. However, the progression towards castration-resistant prostate cancer is inevitable, as the cancer cells reactivate androgen receptor signaling and adapt to the castrate state through autoregulation of the androgen receptor. Additionally, the upfront use of novel hormonal agents such as enzalutamide and abiraterone acetate may result in long-term toxicities and may trigger the selection of AR-independent cells through “Darwinian” treatment-induced pressure. Therefore, it is crucial to develop new strategies to overcome these challenges. Bipolar androgen therapy (BAT) is one such approach that has been devised based on studies demonstrating the paradoxical inhibitory effects of supraphysiologic testosterone on prostate cancer growth, achieved through a variety of mechanisms acting in concert. BAT involves rapidly alternating testosterone levels between supraphysiological and near-castrate levels over a period of a month, achieved through monthly intramuscular injections of testosterone plus concurrent ADT. BAT is effective and well-tolerated, improving quality of life and potentially re-sensitizing patients to previous hormonal therapies after progression. By exploring the mechanisms and clinical evidence for BAT, this review seeks to shed light on its potential as a promising new approach to prostate cancer treatment. Full article

Background: Synthetic mesh material is of great importance for surgical incisional hernia repair. The physical and biochemical characteristics of the mesh influence mechanical stability and the foreign body tissue reaction. The influence on bacterial infections, however, remains ill-defined. The aim of the present study was to evaluate the influence of a modified mesh structure with variation in filament linking on the occurrence of bacterial infection that is indicated by the occurrence of CD68⁺, CD4⁺, and CD8⁺ cells in two different materials. Methods: A total of 56 male Sprague Dawley rats received a surgical mesh implant in a subcutaneous abdominal position. The mesh of two different polymers (polypropylene (PP) and polyvinylidenfluoride (PVDF)) and two different structures (standard structure and bold structure with higher filament linking) were compared. During the implantation, the meshes were infected with Staphylococcus (S.) aureus. After 7 and 21 days, meshes were explanted, and the early and late tissue responses to infection were histologically evaluated. Results: Overall, the inflammatory tissue response was higher at 7 days when compared to 21 days. At 7 days, PP meshes of the standard structure (PP-S) showed the strongest inflammatory tissue response in comparison to all the other groups. At 21 days, no statistically significant difference between different meshes was detected. CD8⁺ cytotoxic T cells showed a significant difference at 21 days but not at 7 days. PP meshes of both structures showed a higher infiltration of CD8⁺ T cells than PVDF meshes. CD4⁺ T helper cells differed at 7 days but not at 21 days, and PVDF meshes in a bold structure showed the highest CD4⁺ T cell count. The number of CD68⁺ macrophages was also significantly higher in PP meshes in a standard structure when compared to PVDF meshes at 21 days. Conclusion: The inflammatory tissue response to S. aureus infection appears to be highest during the early period after mesh implantation. PP meshes showed a higher inflammatory response than PVDF meshes. The mesh material appears to be more important for the risk of infection than the variation in filament linking. Full article

At 2.3 megabases in length, the dystrophin gene is enormous: transcription of a single mRNA requires approximately 16 h. Principally expressed in skeletal muscle, the dystrophin protein product protects the muscle sarcolemma against contraction-induced injury, and dystrophin deficiency results in the fatal muscle-wasting disease, Duchenne muscular dystrophy. This gene is thus of key clinical interest, and therapeutic strategies aimed at eliciting dystrophin restoration require quantitative analysis of its expression. Approaches for quantifying dystrophin at the protein level are well-established, however study at the mRNA level warrants closer scrutiny: measured expression values differ in a sequence-dependent fashion, with significant consequences for data interpretation. In this manuscript, we discuss these nuances of expression and present evidence to support a transcriptional model whereby the long transcription time is coupled to a short mature mRNA half-life, with dystrophin transcripts being predominantly nascent as a consequence. We explore the effects of such a model on cellular transcriptional dynamics and then discuss key implications for the study of dystrophin gene expression, focusing on both conventional (qPCR) and next-gen (RNAseq) approaches. Full article

Background: Hepatocellular carcinoma is the sixth most diagnosed malignancy and the fourth most common cause of cancer-related mortality globally. Despite progress in the treatment of liver cancer, nonsurgical treatments remain unsatisfactory, and only 15% of early-stage cases are surgically operable. Radiotherapy (RT) is a non-surgical treatment option for liver cancer when other traditional treatment methods are ineffective. However, RT has certain limitations, including eliciting poor therapeutic effects in patients with advanced and recurrent tumors. Tumor-associated macrophages (TAMs) are major inflammatory cells in the tumor microenvironment that are key to tumor development, angiogenesis, invasion, and metastasis, and they play an essential role in RT responses. Methods: We used big data analysis to determine the potential of targeting CXCL6/CXCR2. We enrolled 50 patients with liver cancer who received RT at our hospital. Tumor tissue samples were examined for any relationship between CXCL6/CXCR2 activity and patient prognosis. Using a cell coculture system (Transwell), we cocultured Huh7 liver cancer cells and THP-1 monocytes with and without CXCL6/CXCR2 small interfering RNA for 72 h. Results: The overexpression of CXCL6/CXCR2 was highly correlated with mortality. Our tissue study indicated a positive correlation between CXCL6/CXCR2 and M2-TAMs subsets. The coculture study demonstrated that THP-1 monocytes can secrete CXCL6, which acts on the CXCR2 receptor on the surface of Huh7 cells and activates IFN-g/p38 MAPK/NF-κB signals to promote the epithelial–mesenchymal transition and radio-resistance. Conclusions: Modulating the TAM/CXCL6/CXCR2 tumor immune signaling axis may be a new treatment strategy for the effective eradication of radiotherapy-resistant hepatocellular carcinoma cells. Full article

Targeting folate receptors is a potential solution to low tumor selectivity concerning conventional chemotherapeutics. Apart from antibody–drug conjugates, folate-functionalized nanoparticle drug delivery systems are interesting to be explored due to many advantages, yet currently, none seems to enter the clinical trials. Multiple in vitro evidence is available to support its efficacy compared to the non-targeting carrier and free drug formulation. Additionally, several studies pointed out factors affecting its effectiveness, including surface properties and endosomal trapping. However, in vivo biodistribution studies revealed issues that may arise from folate receptor targeting, including rapid liver uptake, subsequently reducing the nanoparticles’ tumor uptake. This issue may be due to the folate receptor β expressed by the activated macrophages in the liver; route of administration and tumor location might also influence the targeting effectiveness. Moreover, it is perplexing to generalize nanoparticles reported from various publications, primarily due to the different formulations, lack of characterization, and experimental settings, making it harder to determine the accurate factor influencing targeting effectiveness. Full article

Castor zinc finger 1 (CASZ1) is a C2H2 zinc finger family protein that has two splicing variants, CASZ1a and CASZ1b. It is involved in multiple physiological processes, such as tissue differentiation and aldosterone antagonism. Genetic and epigenetic alternations of CASZ1 have been characterized in multiple cardiovascular disorders, such as congenital heart diseases, chronic venous diseases, and hypertension. However, little is known about how CASZ1 mechanically participates in the pathogenesis of these diseases. Over the past decades, at first glance, paradoxical influences on cell behaviors and progressions of different cancer types have been discovered for CASZ1, which may be explained by a “double-agent” role for CASZ1. In this review, we discuss the physiological function of CASZ1, and focus on the association of CASZ1 aberrations with the pathogenesis of cardiovascular diseases and cancers. Full article

In recent years, plant polyphenols have become a popular focus for the development of novel functional foods. Polyphenols, a class of bioactive compounds, including flavonoids, phenolic acids, and lignans, are commonly found in plant-based diets with a variety of biological actions, including antioxidant, anti-inflammatory, and anticancer effects. Unfortunately, polyphenols are not widely used in nutraceuticals since many of the chemicals in polyphenols possess poor oral bioavailability. Thankfully, polyphenols can be encapsulated and transported using bio-based nanocarriers, thereby increasing their bioavailability. Polyphenols’ limited water solubility and low bioavailability are limiting factors for their practical usage, but this issue can be resolved if suitable delivery vehicles are developed for encapsulating and delivering polyphenolic compounds. This paper provides an overview of the study of nanocarriers for the enhancement of polyphenol oral bioavailability, as well as a summary of the health advantages of polyphenols in the prevention and treatment of several diseases. Full article

Background: In many solid tumors, CD44 has been identified as a cancer stem cell marker as well as an important molecular in cancer progression and metastasis, making it attractive for potential therapeutic applications. However, our knowledge of the biological function and mechanism of CD44 in clear cell renal cell carcinoma (ccRCC) is limited. Methods: In this study, the expression, prognostic values and functional enrichment analysis of CD44 in ccRCC were analyzed using public databases. Quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemical (IHC) assays were taken to detect CD44 expression in ccRCC tissues. The effects of CD44 on the proliferation, migration and invasion of ccRCC cells were investigated by gain-of-function and loss-of-function experiments. Subcutaneous models further confirmed the role of CD44 in tumor growth. The relationship between CD44, HAS1 and MMP9 was investigated to uncover the regulatory mechanism of CD44 in ccRCC. Results: CD44 was significantly upregulated in ccRCC and associated with poor overall survival (OS). Based on the functional enrichment analysis and PPI network, we found that CD44 had associations with ECM interaction and focal adhesion pathway. Clinical ccRCC sample validation revealed that CD44 mRNA and protein expression were significantly increased in ccRCC tissues, and strong CD44 staining was observed in four metastatic ccRCC cases. In vitro experiments showed that CD44 overexpression promoted cell proliferation, migration and invasion. In vivo experiments also demonstrated that CD44 overexpression accelerated tumor formation in mice. Finally, we found that CD44 regulates the expression of HAS1 in ccRCC, which is essential for the secretion of MMP9 and cell migratory ability. Conclusion: The upregulation of CD44 mRNA and protein expressions in ccRCC is indicative of unfavorable clinical prognoses. The CD44/HAS1/MMP9 axis is believed to exert a significant influence on the regulation of ECM degradation and ccRCC metastasis. Full article

Patients with chronic kidney disease (CKD) often experience a high accumulation of protein-bound uremic toxins (PBUTs), specifically indoxyl sulfate (IS) and p-cresyl sulfate (pCS). In the early stages of CKD, the buildup of PBUTs inhibits bone and muscle function. As CKD progresses, elevated PBUT levels further hinder bone turnover and exacerbate muscle wasting. In the late stage of CKD, hyperparathyroidism worsens PBUT-induced muscle damage but can improve low bone turnover. PBUTs play a significant role in reducing both the quantity and quality of bone by affecting osteoblast and osteoclast lineage. IS, in particular, interferes with osteoblastogenesis by activating aryl hydrocarbon receptor (AhR) signaling, which reduces the expression of Runx2 and impedes osteoblast differentiation. High PBUT levels can also reduce calcitriol production, increase the expression of Wnt antagonists (SOST, DKK1), and decrease klotho expression, all of which contribute to low bone turnover disorders. Furthermore, PBUT accumulation leads to continuous muscle protein breakdown through the excessive production of reactive oxygen species (ROS) and inflammatory cytokines. Interactions between muscles and bones, mediated by various factors released from individual tissues, play a crucial role in the mutual modulation of bone and muscle in CKD. Exercise and nutritional therapy have the potential to yield favorable outcomes. Understanding the underlying mechanisms of bone and muscle loss in CKD can aid in developing new therapies for musculoskeletal diseases, particularly those related to bone loss and muscle wasting. Full article

Aging-related molecular and cellular alterations in the lung contribute to an increased susceptibility of the elderly to devastating diseases. Although the study of the aging process in the lung may benefit from the use of genetically modified mouse models and omics techniques, these approaches are still not available to most researchers and produce complex results. In this article, we review works that used naturally aged mouse models, together with immunohistochemistry (IHC) and quantitative morphologic (QM) methods in the study of the mechanisms of the aging process in the lung and its most commonly associated disorders: cancer, chronic obstructive pulmonary disease (COPD), and infectious diseases. The advantage of using naturally aged mice is that they present characteristics similar to those observed in human aging. The advantage of using IHC and QM methods lies in their simplicity, economic accessibility, and easy interpretation, in addition to the fact that they provide extremely important information. The study of the aging process in the lung and its associated diseases could allow the design of appropriate therapeutic strategies, which is extremely important considering that life expectancy and the number of elderly people continue to increase considerably worldwide. Full article

In this paper, a review of a rare case of paramacular choriocapillaris atrophy with a foveal-sparing phenotype is carried out. The 73-year-old patient stated that they had impaired vision and photophobia in both eyes during a regular ophthalmological examination, denying visual field defects and night blindness. A complete ophthalmological examination (best-corrected visual acuity, applanation tonometry, and biomicroscopy of anterior and posterior segments) and diagnostic tests, including fundus autofluorescence, fluorescein angiography, optical coherence tomography with angiography, computerized perimetry, and electroretinography, were carried out. The underlying genetic pattern is unclear, which points to paramacular choriocapillaris atrophy. According to recent research on histology, pathologies categorized as regional choroidal dystrophies are caused by alterations at the level of the retinal pigment epithelium. Despite the unresolved etiopathogenetic mechanism of foveal sparing in central choroidal and retinal dystrophies, a highly variable disease phenotype with spared fovea and central visual acuity present in a variety of heterogeneous dystrophies supports a disease-independent mechanism that allows the survival of foveal cones. The related preservation of BCVA has implications for individual prognosis and influences how treatment trials for choroidal and retinal dystrophies are designed. Full article

Anti-cancer therapy by iron chelation has been shown to inhibit many cellular processes including DNA replication, mitochondrial metabolism and oncogenic signalling pathways (e.g., EGFR). Iron chelator SK4 represents a double pronged approach towards treating cancer. SK4 enters through LAT1, a commonly overexpressed amino acid transporter in tumours, thus targeting iron addiction and LAT1 overexpression. The aim of this study was to characterise the mode of action of SK4 through proteomics, metabolomics, lipidomics and seahorse real-time analysis in ovarian cell line SKOV3 and triple negative breast cancer cell line MDA MB 231. Pathway enrichment of proteomics data showed an overrepresentation of metabolism related pathways. Metabolic change after SK4 exposure have been confirmed in investigations of changes in basal and maximal mitochondrial respiration using seahorse real-time analysis of mitochondrial metabolism. Metabolomics also showed an increase in AMP and glucose-1-phosphate. Interestingly, our lipidomics data show a decrease in phospholipid synthesis in the SKOV3 cells which is in contrast with previous data which showed an upregulation of ceramide driven apoptosis. In summary, our data highlight impairment of energy metabolism as a mechanism of action underlying SK4 apoptosis, but also suggest a potential role of ceramide induction in the phenotypic outcome of the cell model. Full article

Cellular senescence is a state of permanent cell cycle arrest triggered by various intrinsic and extrinsic stressors. Cellular senescence results in impaired tissue repair and remodeling, loss of physiological integrity, organ dysfunction, and changes in the secretome. The systemic accumulation of senescence cells has been observed in many age-related diseases. Likewise, cellular senescence has been implicated as a risk factor and driving mechanism in chronic obstructive pulmonary disease (COPD) pathogenesis. Airway epithelium exhibits hallmark features of senescence in COPD including activation of the p53/p21WAF1/CIP1 and p16INK4A/RB pathways, leading to cell cycle arrest. Airway epithelial senescent cells secrete an array of inflammatory mediators, the so-called senescence-associated secretory phenotype (SASP), leading to a persistent low-grade chronic inflammation in COPD. SASP further promotes senescence in an autocrine and paracrine manner, potentially contributing to the onset and progression of COPD. In addition, cellular senescence in COPD airway epithelium is associated with telomere dysfunction, DNA damage, and oxidative stress. This review discusses the potential mechanisms of airway epithelial cell senescence in COPD, the impact of cellular senescence on the development and severity of the disease, and highlights potential targets for modulating cellular senescence in airway epithelium as a potential therapeutic approach in COPD. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined as hepatic steatosis in combination with overweight, diabetes, or other metabolic risk factors. MAFLD affects a significant number of the global population and imposes substantial clinical and economic burdens. With no approved pharmacotherapy, current treatment options are limited to diet and exercise. Therefore, the development of medicines for MAFLD treatment or prevention is necessary. 20-Hydroxyecdysone (20E) is a natural steroid found in edible plants and has been shown to improve metabolism and dyslipidemia. Therefore, it may be useful for MAFLD treatment. Here, we aimed to determine how dietary supplementation with 20E affects fat accumulation and lipogenesis in the liver and adipose tissue of ovariectomized rats fed a high-fat, high-fructose diet (OHFFD). We found that 20E reduced hepatic triglyceride content and visceral fat deposition. 20E increased the phosphorylation of AMP-activated protein kinase and acetyl CoA carboxylase while reducing the expression of fatty acid synthase in the liver and adipose tissue. Additionally, 20E increased hepatic expression of carnitine palmitoyltransferase-1 and reduced adipose expression of sterol regulatory element-binding protein-1. In conclusion, 20E demonstrated beneficial effects in rats with OHFFD-induced MAFLD. These findings suggest that 20E may represent a promising option for MAFLD prevention or treatment. Full article

The liver has a huge impact on the functioning of our body and the preservation of homeostasis. It is exposed to many serious diseases, which may lead to the chronic failure of this organ, which is becoming a global health problem today. Currently, the final form of treatment in patients with end-stage (acute and chronic) organ failure is transplantation. The proper function of transplanted organs depends on many cellular processes and immune and individual factors. An enormous role in the process of acceptance or rejection of a transplanted organ is attributed to, among others, the activation of the complement system. The aim of this study was the evaluation of the concentration of selected biomarkers’ complement system activation (C3a, C5a, and sC5b-9 (terminal complement complex)) in the serum of patients before and after liver transplantation (24 h, two weeks). The study was conducted on a group of 100 patients undergoing liver transplantation. There were no complications during surgery and no transplant rejection in any of the patients. All patients were discharged home 2–3 weeks after the surgery. The levels of all analyzed components of the complement system were measured using the ELISA method. Additionally, the correlations of the basic laboratory parameters—C-reactive protein (CRP), hemoglobin (Hb), total bilirubin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), and albumin—with the parameters of the complement system (C3a, C5a, and sC5b-9) were determined. In our study, changes in the concentrations of all examined complement system components before and after liver transplantation were observed, with the lowest values before liver transplantation and the highest concentration two weeks after. The direct increase in components of the complement system (C3a, C5a, and sC5b-9) 24 h after transplantation likely affects liver damage after ischemia-reperfusion injury (IRI), while their increase two weeks after transplantation may contribute to transplant tolerance. Increasingly, attention is being paid to the role of C3a and CRP as biomarkers of damage and failure of various organs. From the point of view of liver transplantation, the most interesting correlation in our own research was found exactly between CRP and C3a, 24 h after the transplantation. This study shows that changes in complement activation biomarkers and the correlation with CRP in blood could be a prognostic signature of liver allograft survival or rejection. Full article

Background: HPV is strongly related to cervical cancer. HPV lineages can contribute to a response to cervical cancer therapy. The aim of this research was to estimate the frequency of human papillomavirus (HPV)-16 lineages in specimens of cervical cancer, relate the pathological factors in these variants, and assess their response to treatment with radical chemoradiotherapy. Methods: Samples of cervical cancer were collected from women who were referred to a reference cancer hospital to test the presence of human papillomavirus-type DNA. The standard protocol of this service consisted of cisplatin-based chemotherapy of 40 mg/m², plus conventional pelvic irradiation in doses of 45–50.4 Gy and high dose-rate brachytherapy of 28–30 Gy to Point A. The response to chemotherapy was evaluated after three months in patients with the HPV-16 lineage. Results: HPV DNA was detected in 104 (88.1%) of the 118 patients. HPV-16 was present in 63 patients (53%). Lineages of HPV-16 were identified in 57 patients and comprised 33 instances of (57.8%) lineage A, 2 instances of lineage B (3.5%), 2 instances of lineage C (3.5%), and 20 instances of (35.0%) lineage D. The median age of the patients was 48.4 years (range 25–85 years). Squamous cell carcinoma was detected 48 times (84.2%). Adenocarcinoma was more likely to occur in lineage D, as three of the four cases occurred in this lineage. A total of 11 patients with the HPV-16 variant were treated with chemoradiotherapy. After three months, it was observed that nine of the eleven patients (81.8%) achieved a complete response, five with the lineage A type, two with the lineage C type, and two with the lineage D type. The two cases of partial response and disease progression, one of each, occurred in lineage A. Conclusions: In addition to the small number of patients and HPV variants, we noticed a better response in patients with the HPV-16 lineage A. Increasing the sample size could be helpful to better assess the impact of HPV variants on cervical cancer treatment. Full article

Impaired proprioception is a recognized complication in individuals with type 2 diabetes mellitus (T2DM), contributing to balance deficits and increased risk of falls. However, limited research has focused on lumbar proprioception in this population. This study aimed to investigate lumbar proprioception in individuals with T2DM, as well as healthy individuals. Additionally, this study aimed to examine the correlation between lumbar proprioception and glycated hemoglobin (HbA1c) levels, which is a marker of long-term glycemic control in T2DM. A cross-sectional study was conducted, comparing lumbar joint reposition errors (JRE) between a T2DM group (n = 85) and a healthy group (n = 85). Lumbar JRE was assessed in flexion, extension, lateral bending left, and lateral bending right using a dual inclinometer device. HbA1c levels were measured as an indicator of glycemic control. Significant differences in lumbar JRE were found between the T2DM and healthy groups, with individuals with T2DM exhibiting larger JRE values, indicating impaired lumbar proprioception (p < 0.001). The correlation analysis revealed significant positive associations between HbA1c levels and lumbar JRE. Higher HbA1c levels were correlated with greater joint JRE in flexion (r = 0.49, p < 0.001), extension (r = 0.51, p < 0.001), left lateral bending (r = 0.45, p < 0.001), and right lateral bending (r = 0.48, p < 0.001) in the T2DM group. This study provides evidence of impaired lumbar proprioception in individuals with T2DM, as evidenced by larger lumbar JRE compared to the healthy group. Full article

Squamous cell carcinoma (SCC) of the larynx in advanced stages is a challenging malignancy to treat with a high recurrence and death rate. An individualized approach to treatment is crucial in such patients. We present a 58-year-old male patient with SCC of the larynx in the T3N0M0 stage who was treated with concurrent radiochemotherapy. A total of 17 months after the radical treatment, the patient underwent a laryngectomy due to recurrence. A total of 11 months after the operation, local failure was diagnosed. In the next order, the patient received six cycles of palliative chemotherapy according to cisplatin 100 mg/m² and 5-fluorouracil 1000 mg/m². After three months, due to progression, Nivolumab-based immunotherapy was administered, ensuring disease stabilization. After the 56th cycle of Nivolumab, another progression was documented. The addition of stereotactic radiotherapy (18 Gy in three fractions) to immunotherapy led to significant regression of the disease and enabled the continuation of Nivolumab to the 70th cycle. The presented case demonstrates the usefulness of the combination of stereotactic radiotherapy with immunotherapy in prolonging the local control. Full article

The endoplasmic reticulum (ER) is a multifunctional organelle playing a vital role in maintaining cell homeostasis, and disruptions to its functions can have detrimental effects on cells. Dysregulated ER stress and the unfolded protein response (UPR) have been linked to various human diseases. For example, ER stress and the activation of the UPR signaling pathways in intestinal epithelial cells can either exacerbate or alleviate the severity of inflammatory bowel disease (IBD), contingent on the degree and conditions of activation. Our recent studies have shown that EPICERTIN, a recombinant variant of the cholera toxin B subunit containing an ER retention motif, can induce a protective UPR in colon epithelial cells, subsequently promoting epithelial restitution and mucosal healing in IBD models. These findings support the idea that compounds modulating UPR may be promising pharmaceutical candidates for the treatment of the disease. In this review, we summarize our current understanding of the ER stress and UPR in IBD, focusing on their roles in maintaining cell homeostasis, dysregulation, and disease pathogenesis. Additionally, we discuss therapeutic strategies that promote the cytoprotection of colon epithelial cells and reduce inflammation via pharmacological manipulation of the UPR. Full article

Background: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are common heart muscle disorders that are caused by pathogenic variants in sarcomere protein genes. In this study, we describe a variant in the MHY7 gene, segregating in a family having three different phenotypes of cardiomyopathies. MYH7 encodes for the myosin heavy-chain β (MHC-β) isoform involved in cardiac muscle contractility. Method and results: We present the case of a family with four members diagnosed with HCM and four members with DCM. The proband is a 42-year-old man diagnosed with HCM. He has an extended family of eight siblings; two of them are diagnosed with HCM and are implantable cardioverter–defibrillator (ICD) carriers. One of the siblings died at the age of 23 after suffering a sudden cardiac arrest and DCM of unknown etiology which was diagnosed at autopsy. Another brother was diagnosed with DCM during a routine echocardiographic exam. Genetic testing was performed for the proband and two of his siblings and a niece of the proband, who suffered a cardiac arrest at the age of nine, all being MYH7 mutation positive. For all four of them, cardiac imaging was performed with different findings. They are ICD carriers as well. Conclusions: Our results reveal three variants in phenotypes of cardiomyopathies in a family with MYH7 mutation associated with high SCD risk and ICD needed for primary and secondary prevention. Full article

IL-19 is a cytokine discovered by homologous searching with IL-10 and is produced by non-immune cells, such as keratinocytes, in addition to immune cells, such as macrophages. Liver fibrosis results from the inflammation and activation of hepatic stellate cells via chronic liver injury. However, the participation of IL-19 in liver fibrosis remains to be sufficiently elucidated. Our group studied the immunological function of IL-19 in a mouse model of carbon tetrachloride (CCl₄)-induced liver fibrosis. IL-19 gene-deficient (KO) mice and body weight-matched wild-type (WT) mice were used. A liver fibrosis mouse model was created via CCl₄ administration (two times per week) for 8 weeks. In CCl₄-induced liver fibrosis, serum analysis revealed that IL-19 KO mice had higher ALT levels compared to WT mice. IL-19 KO mice had worse fibrosis, as assessed by morphological evaluation of total area stained positive with Azan and Masson trichrome. In addition, the expression of α-SMA was increased in liver tissues of IL-19 KO mice compared to WT mice. Furthermore, mRNA expression levels of TGF-β and α-SMA were enhanced in IL-19 KO mice compared to WT mice. In vitro assays revealed that IL-19-high expressing RAW264.7 cells inhibited the migration of NIH3T3 cells via the inhibited expression of CCL2 in the presence of CCl₄ and IL-4. These findings indicate that IL-19 plays a critical role in liver fibrosis by affecting TGF-β signaling and the migration of hepatic stellate cells during liver injury. Enhancement of the IL-19 signaling pathway is a potential treatment for liver fibrosis. Full article

Background: Hemorheology is a field of science which often becomes interesting to researchers studying impairments related to blood flow disturbances. Clinically silent vascular cerebral lesions (CSVCLs) are considered a problem of great importance in neurology. Objective: This work aimed to analyze the interdependencies of the rheological and biochemical parameters of the blood. Methods: The group of patients included persons with clinically silent multifocal vascular cerebral lesions diagnosed using neuroimaging. The control group had no symptoms in the central nervous system (CNS). We analyzed hemorheological profiles in 69 patients with CSVCLs diagnosed via magnetic resonance imaging (MR) or 64-row computer tomography measurements. Rheological data were acquired using a rotary-oscillating rheometer, the Contraves LS-40, an instrument dedicated to blood viscosity measurements. For each sample, the hematocrit value was measured using the standard method. Analysis of erythrocytes’ aggregability and deformability was performed using the rheological model of Quemada. Biochemical tests of blood were also performed. Results: The results of rheological and biochemical studies were compared with those obtained in the control group. Special attention was paid to the correlation analysis of rheological and biochemical parameters. Conclusions: Such correlations were found, e.g., between the red cells’ deformability and the fibrinogen level. The results improve our understanding of blood flow hemodynamics by analyzing the shear-dependent behavior of the aggregation and deformability of red blood cells. Full article

Germline pathogenic variants (PVs) in the Ataxia Telangiectasia mutated (ATM) gene (MIM* 607585) increase the risk for breast, pancreatic, gastric, and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. We describe a family presenting early-onset gastric cancer and harboring a heterozygous pathogenic ATM variant. The proband had gastric cancer (age 45) and reported a sister deceased due to diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next generation sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, and TP53) was performed. Molecular analysis identified the truncating c.5944C>T, p.(Gln1982*) variant in the ATM (NM_000051.3; NP_000042.3) in the proband. The variant had segregated in the living affected sister and in the unaffected daughter of the deceased affected sister. Familial early-onset gastric cancer is an unusual presentation for ATM-related malignancies. Individual variants may result in different specific risks. Genotype–phenotype correlations are challenging given the low penetrance and variable expressivity. Careful family history assessments are pivotal for prevention planning and are strengthened by the availability of molecular diagnoses. Full article

Several epidemiological studies have described childhood obesity as a risk factor for atopic disease, particularly asthma. At the same time, this association seems to be more conflicting for allergic rhinitis, atopic dermatitis, and chronic urticaria. This article aims to deepen the possibility of a relationship between childhood obesity and allergic diseases. As regards asthma, the mechanical and inflammatory effects of obesity can lead to its development. In addition, excess adiposity is associated with increased production of inflammatory cytokines and adipokines, leading to low-grade systemic inflammation and an increased risk of asthma exacerbations. Allergic rhinitis, atopic dermatitis, food allergies, and chronic urticaria also seem to be related to this state of chronic low-grade systemic inflammation typical of obese children. Vitamin D deficiency appears to play a role in allergic rhinitis, while dyslipidemia and skin barrier defects could explain the link between obesity and atopic dermatitis. Starting from this evidence, it becomes of fundamental importance to act on body weight control to achieve general and allergic health, disentangling the detrimental link between obesity allergic diseases and childhood obesity. Further studies on the association between adiposity and atopy are needed, confirming the biologically active role of fat tissue in the development of allergic diseases and exploring the possibility of new therapeutic strategies. Full article

Takotsubo syndrome (TTS) is associated with inflammatory response, therefore the aim of the study was to evaluate the presence and dynamics of inflammatory-associated forms of cell death, necroptosis, and pyroptosis in the female rat model of isoprenaline (ISO)-induced TTS. TTS was induced in female Sprague Dawley rats (n = 36) by ISO 150 mg/kg intraperitoneally. Animals were divided into four groups: TTSO (TTS+ovariectomy; n = 10), TTSP (TTS+sham operation; n = 10), CO (0.9% NaCl+ovariectomy; n = 8), CP (0.9% NaCl+sham operation; n = 8). Histopathological analysis, evaluation of plasma concentration, and myocardial expression of pyroptosis- and necroptosis-associated proteins were performed. TTSO and TTSP groups had higher plasma concentrations of interleukin-1β in comparison with the controls. Low myocardial protein expression of mixed lineage kinase domain-like pseudokinase (MLKL), caspase-1 (Casp-1), and calcium/calmodulin-dependent kinase type II isoform delta (CAMKIIδ) was visible 6 and/or 12 h post-ISO. Twenty-four hours post-ISO, high myocardial and vascular protein expression of CAMKIIδ was visible in TTSO but not TTSP rats, while high myocardial expression of MLKL and Casp-1 was visible both in TTSO and TTSP rats. The course of TTS is associated with activation of inflammatory-associated programmed cell death, necroptosis, and pyroptosis, therefore inflammation may be a primary response occurring simultaneously with cardiomyocyte death in TTS. Full article

Tumors of the parathyroid glands, when associated with PTH (parathyroid hormone) excess, display a large area of complications; in addition to the classical clinical picture of primary hyperparathyroidism (PHP), a complex panel of other symptoms/signs can be identified, including memory and cognitive impairment, chronic asthenia/fatigue, reduced muscle functionality, depressive mood, non-specific bone pain, and loss of sleep quality. The perception of quality of life (QoL) can be supplementarily enhanced by their progressive onset, which makes many patients not be fully aware of them. Their improvement was reported very early after parathyroidectomy (PTx), yet the level of statistical evidence does not qualify these non-classical elements as standalone indications for PTx. Our objective is introducing an up-to-date on QoL scores with regards to the patients diagnosed with PHP, particularly taking into consideration PHP management from baseline to post-operatory outcome, including in cases with multiple endocrine neoplasia. This is a narrative review of literature. We revised full-length papers published in English through PubMed research conducted between January 2018 and May 2023 by using the key words “quality of life” and “primary hyperparathyroidism”. We particularly looked at data on self-reported QoL (through questionnaires). We excluded from the search the studies focused on non-PTH related hypercalcemia, secondary, and/or renal/tertiary hyperparathyroidism, and vitamin D supplementation. Overall, we identified 76 papers and selected for the final analysis 16 original studies on QoL and PHP (a total of 1327 subjects diagnosed with syndromic and non-syndromic PHP). The studies with the largest number of individuals were of 92, 104, 110, 134, 159, as well as 191. A few cohorts (n = 5) were of small size (between 20 and 40 patients in each of them). Concerning the study design, except for 2 papers, all the mentioned studies provided longitudinal information, particularly the timeframe from baseline (before PTx) and after surgery. The post-operatory follow-up was of 3–6 months, but mostly between 1 and 3 years (maximum a decade of surveillance). The age of the patients varies between medians of 56, 62, 64, and 68 years. Most frequent questionnaires were SF-36, PHPQoL, and PAS. Despite not being unanimously similar, an overall reduced score of QoL in patients with PHP versus controls was registered, as well as general improvement following PTx. Variations of QoL results might have a multifactorial background from different comorbidities, studied populations, technical aspects of collecting the data, etc. QoL scores in PHP represents a complex heterogeneous picture, from their correlation with clinical features and lab assays (e.g., the level of serum calcium), the associated comorbidities (such as multiple endocrine neoplasia syndromes), up to the assessment of the QoL improvement after parathyroidectomy (PTx). While current studies do not unanimously agree on each QoL domain, the assessment of QoL might represent a supplementary argument to consider when deciding for PTx, especially in asymptomatic cases and in patients who do not fit into well-known categories of surgery candidates, according to current guidelines, thus assessing QoL in PHP is part of a current research gap. QoL evaluation in PHP remains an open issue, towards which awareness should be cultivated by both endocrinologists and surgeons. The introduction of a routine evaluation of the QoL scores in patients, as well as the selection of the most appropriate questionnaire(s), represents an open chapter thus awareness in mandatory. Full article