Biomedicines, Volume 12, Issue 5 (May 2024) – 205 articles

Abdominal imaging of autosomal dominant polycystic kidney disease (ADPKD) has historically focused on detecting complications such as cyst rupture, cyst infection, obstructing renal calculi, and pyelonephritis; discriminating complex cysts from renal cell carcinoma; and identifying sources of abdominal pain. Many imaging features of ADPKD are incompletely evaluated or not deemed to be clinically significant, and because of this, treatment options are limited. However, total kidney volume (TKV) measurement has become important for assessing the risk of disease progression (i.e., Mayo Imaging Classification) and predicting tolvaptan treatment’s efficacy. Deep learning for segmenting the kidneys has improved these measurements’ speed, accuracy, and reproducibility. Deep learning models can also segment other organs and tissues, extracting additional biomarkers to characterize the extent to which extrarenal manifestations complicate ADPKD. In this concept paper, we demonstrate how deep learning may be applied to measure the TKV and how it can be extended to measure additional features of this disease. Full article

Interproximal enamel reduction, also known as stripping, is a common orthodontic procedure that reduces the mesiodistal diameter of teeth, allowing for a balance of available space in dental arches. The aim of this study was to assess the enamel surface microhardness resulting from the application of currently available methods for interproximal reduction. Forty-two extracted human permanent teeth were divided into six different groups, each subjected to a therapeutic stripping procedure using various methods (i.e., diamond burs, abrasive strips of 90 μm, 60 μm, 40 μm, and 15 μm, and abrasive discs). Stripping was performed by a single individual in accordance with the manufacturers’ recommendations for the various systems used. One of the proximal faces of the tooth underwent IPR, while the other side remained untreated for control. The hardness of the enamel surface was measured using a Vickers hardness tester. The control group achieved the hardest enamel surface (354.4 ± 41.02 HV1), while the lowest was observed for enamel surfaces treated with 90 µm abrasive strips (213.7 ± 118.6). The only statistically significant difference was identified in comparisons between the values measured for the control group and those obtained after stripping with diamond burs (p = 0.0159). Enamel microhardness varied depending on the stripping instrument used, but no statistically significant differences were found (p > 0.05). Optimal microhardness values, close to those of healthy enamel, were achieved after mechanical treatment with 15 µm abrasive strips and abrasive discs. Dental stripping is a safe therapeutic procedure that has a relatively minor influence on the microhardness of surface enamel. Full article

The same sperm selection techniques in assisted reproduction clinics have remained largely unchanged despite their weaknesses. Recently, microfluidic devices have emerged as a novel methodology that facilitates the sperm selection process with promising results. A prospective case-control study was conducted in two phases: 100 samples were used to compare the microfluidic device with Density Gradient, and another 100 samples were used to compare the device with the Swim-up. In the initial phase, a significant enhancement in progressive motility, total progressive motile sperm count, vitality, morphology, and sperm DNA fragmentation were obtained for the microfluidic group compared to Density Gradient. Nevertheless, no statistically significant differences were observed in sperm concentration and chromatin structure stability. In the subsequent phase, the microfluidic group exhibited significant increases in sperm concentration, total progressive motile sperm count, and vitality compared to Swim-up. However, non-significant differences were seen for progressive motility, morphology, DNA structure stability, and DNA fragmentation. Similar trends were observed when results were stratified into quartiles. In conclusion, in a comparison of microfluidics with standard techniques, an improvement in sperm quality parameters was observed for the microfluidic group. However, this improvement was not significant for all parameters. Full article

Neuron damage by microglia, which act as macrophage cells in the brain, can result in various brain diseases. However, the function of pro-inflammatory or anti-inflammatory microglia in the neurons remains controversial. Guanylate-binding protein-2 (GBP2) is expressed and activated in the microglia in the early phase of the inflammatory response and plays an important role in controlling immune responses. In this study, we evaluated whether GBP2 initially reduces the immune response induced by microglia, and whether microglia induce pro-inflammatory functions in neurons via GBP2 expression. In lipopolysaccharide (LPS)-stimulated microglia, we assessed the expression of GBP2 and how it affects neurons via activated microglia. The biological functions of microglia due to the downregulation of the GBP2 gene were examined using short hairpin RNA (shRNA)-RNA-GBP2. Downregulated GBP2 affected the function of mitochondria in the microglia and showed reduced neuronal damage when compared to the control group in the co-culture system. Furthermore, this protein was observed to be highly expressed in the brains of dementia mice. Our results are the first to report that the downregulation of GBP2 in activated microglia has an anti-inflammatory function. This study suggests that the GBP2 gene can be used as a therapeutic target biomarker for inflammation-related neurodegenerative diseases. Full article

The epithelial cell adhesion molecule (EpCAM) is a single transmembrane protein on the cell surface. Given its strong expression on epithelial cells and epithelial cell-derived tumors, EpCAM has been identified as a biomarker for circulating tumor cells (CTCs) and exosomes and a target for cancer therapy. As a cell adhesion molecule, EpCAM has a crystal structure that indicates that it forms a cis-dimer first and then probably a trans-tetramer to mediate intercellular adhesion. Through regulated intramembrane proteolysis (RIP), EpCAM and its proteolytic fragments are also able to regulate multiple signaling pathways, Wnt signaling in particular. Although great progress has been made, increasingly more findings have revealed the context-specific expression and function patterns of EpCAM and their regulation processes, which necessitates further studies to determine the structure, function, and expression of EpCAM under both physiological and pathological conditions, broadening its application in basic and translational cancer research. Full article

Aim: C1q/TNF-related protein 6 (CTRP6) is a novel adipokine involved in insulin resistance. Thus, we aim to investigate the expression profile of CTRP6 in the plasma, adipose tissue and placenta of GDM patients and mice. Methods: Chinese Han pregnant women (GDM n = 9, control n = 10) with a scheduled caesarean section delivery were recruited. A number of high-fat diet (HFD) induced-pregnancy C57BL/6 mice were chosen as an animal model of GDM. Circulating levels of CTRP6 and adiponectin were examined by ELISA. CTRP6 expression in adipose tissue and placenta were detected by real-time qPCR and WB. Result: Plasma CTRP6 levels were decreased during the first and second trimesters in mice, as well as the second and third trimesters in patients, while they were increased at delivery in GDM patients and mice. Plasma CTRP6 levels were significantly correlated with WBC, systolic pressure, diastolic pressure and fasting blood glucose. Moreover, CTRP6 mRNA expression in the subcutaneous (sWAT) and omental white adipose tissue (oWAT), as well as in the placenta, was significantly higher in GDM human patients at cesarean delivery. Furthermore, the mRNA expression of Ctrp6 was increased in the sWAT and visceral WAT (vWAT), whilst decreased in the interscapular brown adipose tissue (iBAT), of GDM mice at cesarean delivery. Conclusion: Dynamically expressed CTRP6 may be served as a candidate target for treatment of GDM. Full article

Background: Severe burns may induce hyperglycaemia in the absence of diabetes, but how glucose trajectories relate to burns outcomes is unclear. Aim: To assess incidence of hyperglycaemia following acute burn injury, and associations with diabetes history and length of stay (LOS). Methods: Retrospective cohort study of adults admitted with acute burns to tertiary centres. Blood glucose level (BGL), hyperglycaemic episodes (BGL ≥ 11.1 mmol/L) and hyperglycaemic days were recorded. Stress hyperglycaemia was defined as BGL ≥ 11.1 mmol/L without a diabetes history. Results: A total of 30 participants had a diabetes history and 260 did not. Participants with known diabetes had higher mean BGLs (9.7 vs. 9.0 mmol/L, p < 0.001), more hyperglycaemic episodes (28.0 vs. 17.2%, p < 0.001) and hyperglycaemic days (51 vs. 21%, p < 0.001), compared to those without diabetes, despite smaller burns (total body surface area 1.0 vs. 14.8%, p < 0.001). Fourteen participants with stress hyperglycaemia had similar BGLs (at admission 10.3 vs. 11.5 mmol/L; during inpatient stay 9.9 vs. 9.8 mmol/L), more severe burns (15.6% vs. 1.0% TBSA) and longer LOS (18 vs. 7 days, p < 0.001) compared to participants with known diabetes. Extent of burns, having NGT nutrition, age, having inpatient BGL monitoring in the setting of diabetes, or having inpatient BGL monitoring in the absence of diabetes were associated with longer LOS. Conclusions: In participants with known diabetes, small burn injuries were associated with hyperglycaemia. Stress hyperglycaemia can be triggered by major burn injuries, with early and sustained elevation of BGLs. Further research is warranted to improve inpatient management of BGL in patients with acute burn injury. Full article

Duplex kidney is a urinary tract anomaly commonly associated with a wide range of primary and secondary parenchymal structural abnormalities. We present a unique comparison of US and MRI findings with histopathology following partial resection of duplex kidneys due to nephropathy. We examined a group of 21 children with duplex kidneys who were qualified for heminephrectomy (24 kidney units (KU)). All patients underwent US and MRI prior to the surgery. The imaging results were compared with histopathologic findings. In 21/24 KU, dysplastic changes were found on histopathology, including all with obstructive nephropathy and 7/10 specimens with refluxing uropathy. The loss of corticomedullary differentiation on US and increased signal on T2-weighted images (T2WI) on MRI were the imaging findings that best correlated with fibrosis. In children with megaureter, there were no statistical differences in histopathological findings between primary megaureter, megaureter with ureterocele, and megaureter with ectopia (p > 0.05). The extent of dysplasia of the affected pole correlated negatively with residual function in MRI. Kidney dysplasia and inflammation in the kidney with obstructive nephropathy are the most important histopathologic findings of this study. US is a valuable screening tool, and MRI enables morphologic and functional assessments of the nephropathy in duplex kidneys. Full article

Tacrolimus (TAC) has a narrow therapeutic window and patient-specific pharmacokinetic variability. In our study, we analyzed the association between TAC exposure, metabolism, and kidney graft outcomes (function, rejection, and histological lesions). TAC trough (C₀), coefficient of variation (TAC CV), concentration/dose ratio (C/D), and biomarkers related to kidney injury molecule-1 (KIM-1) and neutrophil gelatinase lipocalin (NGAL) were analyzed. We examined 174 patients who were subjected to a triple immunosuppressive regimen and underwent kidney transplantation between 2017 and 2022. Surveillance biopsies were performed at the time of kidney implantation and at three and twelve months after transplantation. We classified patients based on their Tac C/D ratios, classifying them as fast (C/D ratio < 1.05 ng/mL × 1/mg) or slow (C/D ratio ≥ 1.05 ng/mL × 1/mg) metabolizers. TAC exposure/metabolism did not significantly correlate with interstitial fibrosis/tubular atrophy (IF/TA) progression during the first year after kidney transplantation. TAC CV third tertile was associated with a higher chronicity score at one-year biopsy. TAC C/D ratio at three months and Tac C₀ at six months were associated with rejection during the first year after transplantation. A fast TAC metabolism at six months was associated with reduced kidney graft function one year (OR: 2.141, 95% CI: 1.044–4.389, p = 0.038) and two years after transplantation (OR: 4.654, 95% CI: 1.197–18.097, p = 0.026), and TAC CV was associated with reduced eGFR at three years. uNGAL correlated with IF/TA and chronicity scores at three months and negatively correlated with TAC C₀ and C/D at three months and one year. Conclusion: Calculating the C/D ratio at three and six months after transplantation may help to identify patients at risk of suffering acute rejection and deterioration of graft function. Full article

Some glucagon-like peptide-1 receptor agonists (GLP-1 RAs), first used in the treatment of type 2 diabetes mellitus (T2DM), have been approved for the treatment of obesity in patients with or without T2DM (liraglutide—LIR, semaglutide—SEM, and tirzepatide—TIR). Social media had an important influence on the off-label use of GLP-1 RAs for obesity, especially for SEM. We analyzed the Google queries related to SEM to assess people’s interest in this drug. We also investigated the occurrence of adverse drug reactions (ADRs) by searching the EudraVigilance database (EV) for Individual Case Safety Reports (ICSRs) that reported SEM as the suspected drug and performed a descriptive and a disproportionality analysis. The data obtained for SEM were compared to other GLP-1 RAs. SEM had the highest proportions of searches on Google associated with the term “weight loss” and presented the lowest number of severe ADRs, but it also had the highest number of ICSRs reported in EV. Even though no unexpected safety issues have been reported for it until now, SEM has a hi3gh tendency for overdose reports. The most frequent off-label use was reported for SEM and TIR. In order to lower the risks of ADRs, the off-label use should be reduced and carefully monitored. Full article

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-β1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-β1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors’ expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-β1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-β1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-β1 and indicates independent prognostic significance of high FAS and TGF-β1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway. Full article

Diffuse noxious inhibitory controls (DNICs), or the pain inhibits pain phenomenon, refer to reduced pain-like behaviors that are displayed following a noxious conditioning stimulus located far from the test stimulus and have also been referred to as “descending control of nociception” when measured in awake-behaving animals. In this study, we sought to determine the impact of moderate long-term exercise on the DCN response and determine if this effect differed across age and sex. After a six-week exercise program consisting of 30 min of moderate treadmill running 5 days a week, the animals’ forepaws were injected with capsaicin, and DCN responses were assessed using thermal withdrawal latencies of the hind paw. Young, exercised male and female rats displayed prolonged DCN responses relative to their sedentary counterparts, with the young exercised male group displaying longer-lasting DCN facilitation than the young exercised females. Exercise did not impact DCN responses in either male or female aged rats. Additionally, the serum testosterone levels did not change following exercise in any group. Importantly, the levels of corticosterone did not change following the exercise program, indicating that changes in the DCN response are not due to stress-induced analgesia. Our findings suggest that moderate exercise can facilitate the DCN response in young animals, even when this exercise does not change the levels of serum testosterone. Full article

Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug indicated as monotherapy for adults with newly diagnosed epilepsy and as adjunctive therapy for the treatment of partial seizures. Our aim was to assess the effectiveness and safety of both acute and repeated ESL administration against reflex audiogenic seizures, as shown by the Genetic Audiogenic Seizures Hamster from Salamanca (GASH/Sal). Animals were subject to the intraperitoneal administration of ESL, applying doses of 100, 150 and 200 mg/kg for the acute study, whereas a daily dose of 100 mg/kg was selected for the subchronic study, which lasted 14 days. In both studies, the anticonvulsant effect of the therapy was evaluated using neuroethological methods. To assess the safety of the treatment, behavioral tests were performed, hematological and biochemical liver profiles were obtained, and body weight was monitored. In addition, the ESL levels in blood were measured after the acute administration of a 200 mg/kg dose. Treatment with ESL caused a reduction in seizure severity. No statistically significant differences were detected between the selected doses or between the acute or repeated administration of the drug. To summarize, the intraperitoneal administration of ESL is safe and shows an anticonvulsant effect in the GASH/Sal. Full article

Lactoferrin (Lf), which is particularly abundant in human breast milk during the early stages of lactation, provides protection against a variety of infections, including viral infections, and has demonstrated activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The objective of this study was to measure the concentrations of Lf in the colostrum of mothers with active coronavirus disease 2019 (COVID-19) infections during delivery, in mothers with a history of COVID-19 during pregnancy, and in non-infected controls. In this cross-sectional study, colostrum samples from 41 lactating mothers with a confirmed history of SARS-CoV-2 infection (asymptomatic or symptomatic) (both active and past infections) were collected. Twenty-eight colostrum samples collected during the pre-pandemic period served as a control group. An enzyme-linked immunosorbent assay was performed to analyze the Lf concentrations. Concentrations of Lf in the colostrum samples were closely related to virus infection. Colostrum samples from mothers with confirmed SARS-CoV-2 infections contained higher concentrations of lactoferrin compared with samples from mothers from the control group. The highest concentrations of Lf were found in the colostrum samples of mothers with active SARS-CoV-2 infection during delivery when compared with the post-infection and control samples. This observed increase in lactoferrin suggests that it may be an important protective factor for breastfed infants, a finding which was particularly relevant during the pandemic period and remains relevant whenever a breastfeeding mother is infected. Full article

Ustekinumab (UST) is an anti–IL-12/23p40 monoclonal antibody used to treat inflammatory bowel disease. The aim of this retrospective, multicenter study was to investigate the effectiveness of UST administration in achieving remission in patients with ulcerative colitis (UC) and to determine patient characteristics that influence its effectiveness. Of 88 UC patients who received UST from March 2020 to August 2023, 47 with traceable data and for whom 56 weeks had elapsed since the start of treatment received UST to induce remission. The remission rates at 8 weeks were 66% overall, 73.7% for Bio Naïve (never used biologics/JAK inhibitors), and 60.7% for Bio Failure (used biologics/JAK inhibitors) groups. Remission rates at 56 weeks were 70.2% overall, 73.7% for Bio Naïve, and 67.9% for Bio Failure groups. Ustekinumab showed good mid-to-long-term results in the induction of remission of UC in both Bio Naïve and Bio Failure groups. The group showing remission at 8 weeks had a significantly higher non-relapse or continuation rate (proportion of patients with no worsened symptoms necessitating surgery/drug change) at 56 weeks. Predictive factors for achieving remission after UST in UC were female gender, low body mass index, and low lymphocyte-to-monocyte ratio. Thus, UST is effective for moderate-to-severe UC. Full article

Acute liver failure (ALF) is a serious inflammatory disorder with high mortality rates, which poses a significant threat to human health. The IL-33/ST2 signal is a crucial regulator in inflammation responses associated with lipopolysaccharide (LPS)-induced macrophages. The IL-17A signaling pathway promotes the release of chemokines and inflammatory cytokines, recruiting neutrophils and T cells under LPS stimulation, thus facilitating inflammatory responses. Here, the potential therapeutic benefits of neutralizing the IL-17A signal and modulating the IL-33/ST2 signal in ALF were investigated. A novel dual-functional fusion protein, anti-IL-17A-sST2, was constructed, which displayed high purity and biological activities. The administration of anti-IL-17A-sST2 resulted in significant anti-inflammatory benefits in ALF mice, amelioration of hepatocyte necrosis and interstitial congestion, and reduction in TNF-α and IL-6. Furthermore, anti-IL-17A-sST2 injection downregulated the expression of TLR4 and NLRP3 as well as important molecules such as MyD88, caspase-1, and IL-1β. The results suggest that anti-IL-17A-sST2 reduced the secretion of inflammatory factors, attenuated the inflammatory response, and protected hepatic function by regulating the TLR4/MyD88 pathway and inhibiting the NLRP3 inflammasome, providing a new therapeutic approach for ALF. Full article

Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement in survival outcomes; however, metastatic GC remains a lethal malignancy and amongst the leading causes of cancer-related mortality worldwide. Importantly, the ongoing molecular characterisation of GCs continues to uncover potentially actionable molecular targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs in approximately 3–11% of GCs. However, whilst several inhibitors of FGFR have been clinically tested to-date, there are currently no approved FGFR-directed therapies for GC. In this review, we summarise the significance of FGFR2 as an actionable therapeutic target in GC, examine the recent pre-clinical and clinical data supporting the use of small-molecule inhibitors, antibody-based therapies, as well as novel approaches such as proteolysis-targeting chimeras (PROTACs) for targeting FGFR2 in these tumours, and discuss the ongoing challenges and opportunities associated with their clinical development. Full article

Background: Recent evidence has identified great promise for the novel whole-body photobiomodulation therapy (PBMT) for individuals with fibromyalgia (FM). However, currently no evidence has documented the experiences of participants. The objective of this study was to qualitatively assess treatment experience and response in a group of participants with FM undergoing a course of whole-body PBMT. Methods: An interpretive hermeneutic phenomenological study situated within the worldview of pragmatism was undertaken. A convenience sample of individuals with FM were included if they had undertaken a novel 6-week trial of PBMT. Individuals undertook semi-structured interviews exploring treatment experience and multidimensional treatment responses during Week 3 and Week 6. Results: Sixteen trial participants (47.3 ± 10.9 years) took part in this study. The analysis produced three overarching themes that were previously identified from a baseline study (namely, ‘Body Structure & Function’, ‘Activities & Participation’, and ‘Environment’) with an additional five sub-themes that highlighted the intervention experience. Subsequently, four important processes were observed and identified: increased motivation; feeling proud; improved confidence; feeling like ‘old self’. This ultimately culminated in the identification of a positive spiral, which we have termed ‘recomposition’. Conclusions: We believe our study is the first in the field of chronic pain management to utilise qualitative methodology to directly assess the acceptability and efficacy of a specific medical intervention in a clinical trial, and the first study to qualitatively assess whole-body PBMT experience. The findings are compelling and warrant further work to support the introduction of this device into the National Health Service (NHS). Full article

Biologics are widely used to treat moderate-to-severe psoriasis. However, we have unmet needs for predicting individual patient responses to biologics before starting psoriasis treatment. We investigate a reliable platform and biomarkers for predicting individual patient responses to biologics. In a cohort study between 2018 and 2023 from a referral center in Taiwan, twenty psoriasis patients with or without psoriatic arthritis who had ever experienced two or more biologics were enrolled. Peripheral blood mononuclear cells obtained from these patients were treated with Streptococcus pyogenes and different biologics. The PASI reduction rate was strongly correlated with the reduction rate in the IL-13 level (p = 0.001) and the ratios of IFN-γ to IL-13 (p < 0.001), IFN-γ to IL-4 (p = 0.019), and IL-17A to IL-13 (p = 0.001). The PASI reduction difference was strongly correlated with the difference in the IFN-γ level (p = 0.002), the difference in the ratios of IFN-γ to IL-4 (p = 0.041), the difference in the ratios of IFN-γ to IL-13 (p = 0.006), the difference in the ratios of IL-17A to IL-4 (p = 0.011), and the difference in the ratios of IL-17A to IL-13 (p = 0.029). The biomarkers IFN-γ, IL-13, IFN-γ/IL4, IFN-γ/IL13, IL-17A/IL-4, and IL-17A/IL-13 are representative of the effectiveness of psoriasis treatment. Full article

Background: Frailty has been proven to be associated with mortality after orthotopic heart transplantation (OHT). The aim of our study was to determine the impact of frailty on mortality in the current era using pretransplant mechanical cardiac support (MCS). Methods: We retrospectively calculated the frailty scores of 471 patients undergoing OHT in a single institution between January 2012 and August 2022. The outcome was all-cause mortality. Results: The median survival time was 1987 days (IQR: 1487 days) for all patients. In total, 266 (56.5%) patients were categorized as nonfrail, 179 (38.0%) as prefrail, and 26 (5.5%) as frail. The survival rates were 0.73, 0.54, and 0.28 for nonfrail, prefrail, and frail patients, respectively. The frailty score was associated with mortality [HR: 1.34 (95% CI: 1.22–1.47, p < 0.001)]. Among the components of the frailty score, age above 50 years, creatinine ≥ 3.0 mg/dL or prior dialysis, and hospitalization before OHT were independently associated with mortality. Continuous-flow left ventricular assist devices (CF-LVAD) were associated with an increased risk for all-cause mortality [AHR: 1.80 (95% CI: 1.01–3.24, p = 0.047)]. Conclusions: The components of the frailty score were not equally associated with mortality. Frailty and pretransplant MCS should be included in the risk estimation. Full article

In patients with acute coronary syndrome (ACS), lipid-lowering therapy plays an important role in the prevention of the recurrence of cardiovascular disease. Recent guidelines recommend the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with ACS if their low-density lipoprotein cholesterol (LDL-C) levels are not adequately controlled with statins and ezetimibe. Based on this, we report a case in which administering a PCSK9 inhibitor successfully lowered the patient’s LDL-C level to the target level and managed the coronary artery disease (CAD) recurrence. A 39-year-old man who was taking statins presented to the hospital with chest pain and was diagnosed with unstable angina. He started taking maximum doses of statins and ezetimibe to lower his LDL-C. However, the patient’s unstable angina recurred 1 year later, and a de novo lesion with plaque rupture was demonstrated via coronary angiography. The LDL-C failed to reach the target level despite maintaining the maximum dose of statin and ezetimibe. Accordingly, evolocumab was initiated in addition to rosuvastatin/ezetimibe 20/10 mg daily. Subsequently, coronary angiography was performed twice, and on follow-up, the patient remained free of CAD recurrence. This case highlights the efficacy of lipid-lowering therapy with evolocumab in high-risk patients with repeated ACS. Full article

Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes. The clinical picture and family history are crucial to formulating the diagnostic hypothesis, but only the identification of the genetic defect allows the correct classification. In the attempt to molecularly classify 17 unrelated Italian patients referred with congenital nonsyndromic ichthyosis, we performed massively parallel sequencing of over 50 ichthyosis-related genes. Genetic data of 300 Italian unaffected subjects were also analyzed to evaluate frequencies of putative disease-causing alleles in our population. For all patients, we identified the molecular cause of the disease. Eight patients were affected by autosomal recessive congenital ichthyosis associated with ALOX12B, NIPAL4, and TGM1 mutations. Three patients had biallelic loss-of-function variants in FLG, whereas 6/11 males were affected by X-linked ichthyosis. Among the 24 different disease-causing alleles we identified, 8 carried novel variants, including a synonymous TGM1 variant that resulted in a splicing defect. Moreover, we generated a priority list of the ichthyosis-related genes that showed a significant number of rare and novel variants in our population. In conclusion, our comprehensive molecular analysis resulted in an effective first-tier test for the early classification of ichthyosis patients. It also expands the genetic, mutational, and phenotypic spectra of inherited ichthyosis and provides new insight into the current understanding of etiologies and epidemiology of this group of rare disorders. Full article

The management of renal cell carcinoma (RCC) has been revolutionized over the past two decades with several practice-changing treatments. Treatment for RCC often requires a multimodal approach: Local treatment, such as surgery or ablation, is typically recommended for patients with localized tumors, while stage IV cancers often require both local and systemic therapy. The treatment of advanced RCC heavily relies on immunotherapy and targeted therapy, which are highly contingent upon histological subtypes. Despite years of research on biomarkers for RCC, the standard of care is to choose systemic therapy based on the risk profile according to the International Metastatic RCC Database Consortium and Memorial Sloan Kettering Cancer Centre models. However, many questions still need to be answered. Should we consider metastatic sites when deciding on treatment options for metastatic RCC? How do we choose between dual immunotherapy and combinations of immunotherapy and tyrosine kinase inhibitors? This review article aims to answer these unresolved questions surrounding the concept of personalized medicine. Full article

The evolutionarily conserved nonsense-mediated mRNA decay (NMD) pathway is a quality control mechanism that degrades aberrant mRNA containing one or more premature termination codons (PTCs). Recent discoveries indicate that NMD also differentially regulates mRNA from wild-type protein-coding genes despite lacking PTCs. Together with studies showing that NMD is involved in development and adaptive responses that influence health and longevity, these findings point to an expanded role of NMD that adds a new layer of complexity in the post-transcriptional regulation of gene expression. However, the extent of its control, whether different types of NMD play different roles, and the resulting physiological outcomes remain unclear and need further elucidation. Here, we review different branches of NMD and what is known of the physiological outcomes associated with this type of regulation. We identify significant gaps in the understanding of this process and the utility of genetic tools in accelerating progress in this area. Full article

This systematic review evaluates the clinical outcomes and molecular predictors of response to pembrolizumab in patients with advanced and metastatic cervical cancer. We adhered to the PRISMA guidelines for systematic reviews, conducting a database search in PubMed, Scopus, and Embase. The eligibility criteria centered on clinical outcomes, including the overall survival (OS), progression-free survival (PFS), and immune-related biomarkers post-pembrolizumab therapy. We included both prospective and retrospective studies that detailed clinical outcomes and molecular characteristics predictive of therapeutic response. Our search yielded six studies involving 846 patients treated with pembrolizumab from 2017 to 2022. The meta-analysis of these studies showed that pembrolizumab, used as monotherapy or in combination with chemotherapy, extended the OS by a weighted median of 10.35 months and the PFS by 8.50 months. The treatment demonstrated a pooled objective response rate (ORR) of 22.39%, although the I² test result of 67.49% showed a high heterogeneity among the studies. Notably, patients with high PD-L1 expression (CPS ≥ 10) experienced improved outcomes in terms of the PFS and OS. The most common complications were fatigue, diarrhea, and immune-related adverse events. Pembrolizumab significantly enhances clinical outcomes in metastatic cervical cancer, particularly among patients with high PD-L1 expression. The drug maintains a good safety profile, reinforcing its treatment potential for patients with advanced and metastatic cervical cancer. Future studies should explore long-term effects and strategies to integrate pembrolizumab optimally into current treatment regimens, aiming to maximize patient benefits and effectively manage side effects. Full article

Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median [interquartile range]) were significantly higher in ILD patients than in controls (1.05 [0.75–1.51] ng/mL versus 0.81 [0.65–0.98] ng/mL in healthy controls; p < 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 [0.80–1.72] ng/mL versus 0.99 [0.66–1.32] ng/mL; p = 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of OPN polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes. Full article

Background: Alzheimer’s disease (AD) presents a significant global health concern, characterized by neurodegeneration and cognitive decline. Neuroinflammation is a crucial factor in AD development and progression, yet effective pharmacotherapy remains elusive. Sulforaphane (SFN), derived from cruciferous vegetables and mainly from broccoli, has shown a promising effect via in vitro and in vivo studies as a potential treatment for AD. This study aims to investigate the possible prophylactic mechanisms of SFN against prefrontal cortex (PFC)-related recognition memory impairment induced by lipopolysaccharide (LPS) administration. Methodology: Thirty-six Swiss (SWR/J) mice weighing 18–25 g were divided into three groups (n = 12 per group): a control group (vehicle), an LPS group (0.75 mg/kg of LPS), and an LPS + SFN group (25 mg/kg of SFN). The total duration of the study was 3 weeks, during which mice underwent treatments for the initial 2 weeks, with daily monitoring of body weight and temperature. Behavioral assessments via novel object recognition (NOR) and temporal order recognition (TOR) tasks were conducted in the final week of the study. Inflammatory markers (IL-6 and TNF), antioxidant enzymes (SOD, GSH, and CAT), and pro-oxidant (MDA) level, in addition to acetylcholine esterase (AChE) activity and active (caspase-3) and phosphorylated (AMPK) levels, were evaluated. Further, PFC neuronal degeneration, Aβ content, and microglial activation were also examined using H&E, Congo red staining, and Iba1 immunohistochemistry, respectively. Results: SFN pretreatment significantly improved recognition memory performance during the NOR and TOR tests. Moreover, SFN was protected from neuroinflammation and oxidative stress as well as neurodegeneration, Aβ accumulation, and microglial hyperactivity. Conclusion: The obtained results suggested that SFN has a potential protective property to mitigate the behavioral and biochemical impairments induced by chronic LPS administration and suggested to be via an AMPK/caspase-3-dependent manner. Full article

Macular edema (ME) remains a primary cause of visual deterioration in uveitis. Visual acuity (VA) can often be maintained using corticosteroid depot systems. This study evaluated the efficacy of a fluocinolone acetonide (FAc) intravitreal implant (ILUVIEN^®) in treating non-infectious uveitis using real-world data. This retrospective analysis included 135 eyes subdivided into responders and non-responders. Central retinal thickness (CRT), VA, and intraocular pressure (IOP) were followed over time. A significant decrease in CRT and an increase in VA were observed in all eyes throughout the follow-up period (p < 0.01). An IOP increase (p = 0.028) necessitated treatment in 43% of eyes by Month 6. Non-responders were older (p = 0.004) and had been treated with more dexamethasone (DEX) implants (p = 0.04); 89.3% had a defect in the external limiting membrane (ELM) and inner/outer segment (IS/OS) zone (p < 0.001). Immunomodulatory therapy had no impact on treatment response. Pars plana vitrectomy (PPV) patients had a mean CRT reduction of 47.55 µm and a reduced effect by Month 24 (p = 0.046) versus non-PPV patients. We conclude that the FAc implant achieves long-term control of CRT and improves VA. Increases in IOP were manageable. Eyes with a previous PPV showed milder results. Data showed a correlation between older age, a damaged ELM and IS/OS zone, frequent DEX inserts, and poorer outcome measures. Full article

Neutrophils play a crucial role in host defense against infection. Aberrant neutrophil activation may induce tissue damage via sterile inflammation. Neutrophil accumulation has been identified as a feature of the inflammatory response observed in metabolic dysfunction-associated steatohepatitis (MASH) and has been associated with liver fibrosis and cirrhosis. Here, we performed the transcriptomic analysis of circulating neutrophils from mild and advanced MASH patients to identify the potential mechanism behind neutrophil contribution to MASH progression. Our findings demonstrated that circulating neutrophils from mild and advanced MASH display an increased activated transcriptional program, with the expression of pro-inflammatory factors and an amplified lifespan compared to cells from non-diseased controls. Our results also suggest that MASH progression is associated with a dynamic shift in the profile of circulating neutrophils. In the early stages of MASH, mature neutrophils predominate in the bloodstream. As hepatic inflammation and fibrosis progress, the premature release of immature neutrophils into the circulation occurs. These immature neutrophils exhibit a pro-inflammatory profile that may exacerbate inflammation and promote fibrosis in MASH. Full article

Hospital-acquired infections (HAIs) pose a significant risk to global health, impacting millions of individuals globally. These infections have increased rates of morbidity and mortality due to the prevalence of widespread antimicrobial resistance (AMR). Graphene-based nanoparticles (GBNs) are known to possess extensive antimicrobial properties by inflicting damage to the cell membrane, suppressing virulence, and inhibiting microbial biofilms. Developing alternative therapies for HAIs and addressing AMR can be made easier and more affordable by combining nanoparticles with medicinal plants harboring antimicrobial properties. Hence, this study was undertaken to develop a novel graphene–silver nanocomposite via green synthesis using Trillium govanianum plant extract as a reducing agent. The resulting nanocomposite comprised silver nanoparticles embedded in graphene sheets. The antibacterial and antifungal properties of graphene–silver nanocomposites were investigated against several nosocomial pathogens, namely, Candida auris, Candida glabrata, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The nanocomposite displayed broad-range antimicrobial potential against the test pathogens, with minimum inhibitory concentrations (MICs) ranging between 31.25 and 125.0 µg/mL, and biofilm inhibition up to 80–96%. Moreover, nanocomposite-functionalized urinary catheters demonstrated hemocompatibility towards sheep erythrocytes and imparted anti-fouling activity to the biomaterial, while also displaying biocompatibility towards HEK 293 cells. Collectively, this investigation highlights the possible application of green-synthesized GBNs as an effective alternative to conventional antibiotics for combating multidrug-resistant pathogens. Full article