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Abstract Ventricular septal defect (VSD) is a serious complication of myocardial infarction (MI), with its global incidence significantly reduced in recent years due to advances in coronary reperfusion techniques. However, during the COVID-19 pandemic, there was an unexpected rise in the incidence of post-MI VSD, likely driven by delays in seeking treatment. This study retrospectively analyzed 10 cases of post-MI VSD treated at our hospitals from March 2018 to August 2023, comparing incidence rates across pre-pandemic, pandemic, and post-pandemic periods. The findings revealed a notable increase in VSD cases during the pandemic, with six cases occurring in two years, compared to only two cases in each of the pre-pandemic and post-pandemic periods. Despite these fluctuations, surgical intervention remained a crucial and effective treatment, with 60% of patients surviving the 30-day follow-up. The study underscores the impact of delayed treatment on VSD incidence during the pandemic and highlights the critical need for timely medical intervention to manage severe MI complications effectively.

Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion-mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat Prnp promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer's disease and other tau prion disorders.

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer's disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36-63 years of age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II-like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite its regulatory role and elevated function in ovarian and other solid tumors, another tumor-enriched death receptor called Fas (CD95) remained undervalued in cancer immunotherapy until recently, when its role in off-target tumor killing by CAR-T therapies was imperative. By comprehensively analyzing structure studies in the context of the binding epitope of FasL and various preclinical Fas agonist antibodies, we characterize a highly significant patch of positively charged residue epitope (PPCR) in its cysteine-rich domain 2 of Fas. PPCR engagement is indispensable for superior Fas agonist signaling and CAR-T bystander function in ovarian tumor models. A single-point mutation in FasL or Fas that interferes with the PPCR engagement inhibited apoptotic signaling in tumor cells and T cells. Furthermore, considering that clinical and immunological features of the autoimmune lymphoproliferative syndrome (ALPS) are directly attributed to homozygous mutations in FasL, we reveal differential mechanistic details of FasL/Fas clustering at the PPCR interface compared to described ALPS mutations. As Fas-mediated bystander killing remains vital to the success of CAR-T therapies in tumors, our findings highlight the therapeutic analytical design for potentially effective Fas-targeting strategies using death agonism to improve cancer immunotherapy in ovarian and other solid tumors.

Background: The ergogenic effects of caffeine intake on exercise performance are well-established, even if differences exist among individuals in response to caffeine intake. The genetic variation of a specific gene, human cytochrome P450 enzyme 1A2 (CYP1A2) (rs762551), may be one reason for this difference. This systematic review and meta-analysis aimed to comprehensively evaluate the influence of CYP1A2 gene types on athletes' exercise performance after caffeine intake. Methods: A literature search through 4 databases (Web of Science, PubMed, Scopus, and China National Knowledge Infrastructure) was conducted until March 2023. The effect size was expressed as the weighted mean difference (WMD) by calculating fixed effects meta-analysis if heterogeneity was not significant (I2 ≤ 50% and p ≥ 0.1). Subgroup analyses were performed based on AA and AC/CC genotype of CYP1A2. Results: The final number of studies meeting the inclusion criteria was 12 (n = 666 participants). The overall analysis showed that the cycling time trial significantly improved after caffeine intake (WMD = –0.48, 95% confidence interval (95%CI): –0.83 to –0.13, p = 0.007). In subgroup analyses, acute caffeine intake improved cycling time trial only in individuals with the A allele (WMD = –0.90, 95%CI: –1.48 to –0.33, p = 0.002), but not the C allele (WMD = –0.08, 95%CI: –0.32 to 0.17, p = 0.53). Caffeine supplementation did not influence the Wingate (WMD = 8.07, 95%CI: –22.04 to 38.18, p = 0.60) or countermovement jump test (CMJ) performance (WMD = 1.17, 95%CI: –0.02 to 2.36, p = 0.05), and these outcomes were not influenced by CYP1A2 genotype. Conclusion: Participants with the CYP1A2 genotype with A allele improved their cycling time trials after caffeine supplementation. However, compared to placebo, acute caffeine supplementation failed to increase the Wingate or CMJ performance, regardless of CYP1A2 genotype.

In recent years, germline mutations in the microRNA (miRNA) processor genes DICER1 and DGCR8 have been coupled to the development of thyroid follicular nodular disease (TFND), thereby casting new light on the etiology of this enigmatic, benign condition in non-iodine-deficient regions. Moreover, DICER1 and DGCR8 mutations have also been reported in rare subsets of follicular cell-derived thyroid carcinomas. Specifically, truncating germline or missense somatic DICER1 mutations have been reported in small subsets of pediatric and adolescent follicular thyroid carcinoma (FTC) and poorly differentiated thyroid carcinoma (PDTC). Similarly, a recurrent somatic mutation of the DGCR8 gene has been observed in highly aggressive FTCs and in some indolent cases of encapsulated follicular variant of papillary thyroid carcinoma. The reason why identical mutations in the same miRNA processor gene can lead to such a myriad of thyroid conditions, ranging from benign TFND to FTCs and PDTCs, remains unclear. This review highlights key features of miRNA regulator gene mutations in thyroid disease and explores their potential roles as drivers or progression events in tumor development.

The amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) of Guam is an endemic neurodegenerative disease that features widespread tau tangles, occasional α-synuclein Lewy bodies, and sparse β-amyloid (Aβ) plaques distributed in the central nervous system. Extensive studies of genetic or environmental factors have failed to identify a cause of ALS-PDC. Building on prior work describing the detection of tau and Aβ prions in Alzheimer's disease (AD) and Down syndrome brains, we investigated ALS-PDC brain samples for the presence of prions. We obtained postmortem frozen brain tissue from 26 donors from Guam with ALS-PDC or no neurological impairment and 71 non-Guamanian donors with AD or no neurological impairment. We employed cellular bioassays to detect the prion conformers of tau, α-synuclein, and Aβ proteins in brain extracts. In ALS-PDC brain samples, we detected high titers of tau and Aβ prions, but we did not detect α-synuclein prions in either cohort. The specific activity of tau and Aβ prions was increased in Guam ALS-PDC compared with sporadic AD. Applying partial least squares regression to all biochemical and prion infectivity measurements, we demonstrated that the ALS-PDC cohort has a unique molecular signature distinguishable from AD. Our findings argue that Guam ALS-PDC is a distinct double-prion disorder featuring both tau and Aβ prions.

In neurodegenerative diseases, proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations in situ. Here, we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid-binding dyes to identify six distinct different conformational strains in vitro, as well as amyloid-β (Aβ) deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in Aβ and tau deposits from Down syndrome, sporadic and familial Alzheimer's disease human brain slices. EMBER has in situ identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick's disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains.

Microglia are central to pathogenesis in many neurological conditions. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we show that CSF1R inhibitors given by multiple dosing paradigms in the Tg2541 tauopathy mouse model cause a sex-independent reduction in pathogenic tau and reversion of non-microglial gene expression patterns toward a normal wild type signature. Despite greater drug exposure in male mice, only female mice have functional rescue and extended survival. A dose-dependent upregulation of immediate early genes and neurotransmitter dysregulation are observed in the brains of male mice only, indicating that excitotoxicity may preclude functional benefits. Drug-resilient microglia in male mice exhibit morphological and gene expression patterns consistent with increased neuroinflammatory signaling, suggesting a mechanistic basis for sex-specific excitotoxicity. Complete microglial ablation is neither required nor desirable for neuroprotection and therapeutics targeting microglia must consider sex-dependent effects.

Background and Objective: Effective cerebral perfusion monitoring is essential in aortic arch surgery, particularly when employing the Kazui technique under moderate hypothermia. Near-infrared spectroscopy (NIRS) provides real-time regional oxygen saturation (rSO2) measurements, while the continuous monitoring of venous drainage flow and oxygen extraction ratio (ERiO2) delivers additional insights into cerebral oxygenation and metabolic balance. This study investigates the correlation between NIRS-derived rSO2, venous drainage flow, and ERiO2 during selective antegrade cerebral perfusion (SACP) to better understand their interplay and clinical significance. Materials and Methods: This retrospective study analyzed data from 10 patients undergoing aortic arch surgery with the Kazui technique, including 4 patients with type I A dissections and 6 with aortic arch aneurysms. Bilateral NIRS (Masimo system) was used to measure rSO2, while venous drainage flow and ERiO2 were continuously monitored using the Landing system. Intraoperative parameters such as cardiopulmonary bypass (CPB) time, cooling and rewarming duration, venous return flow, and perfusion delivery rates were collected and analyzed. The correlations between rSO2, venous drainage flow, and ERiO2 were statistically evaluated. Results: The mean CPB time was 182 ± 15 min, with a mean cross-clamp time of 98 ± 12 min. Cooling to 20 °C was achieved in 29 ± 3 min, followed by a controlled rewarming phase of 10 ± 1.5 min. The venous return flow averaged 570 ± 25 mL/min, while the perfusion delivery rates exceeded 600 ± 30 mL/min. Bilateral NIRS monitoring revealed stable rSO2 values averaging 65 ± 5%, while ERiO2 averaged 28 ± 4%. A strong correlation (r = 0.91, p < 0.01) was observed between rSO2 and ERiO2, with venous drainage flow playing a critical role in maintaining this relationship. Conclusions: This study demonstrates a robust correlation between NIRS-derived rSO2, continuous venous drainage flow, and ERiO2 during SACP in aortic arch surgery.

Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer's disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aβ and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aβ and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aβ and tau prions increased with age. In contrast to DS brains, the levels of Aβ and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.

Background and Objectives: In coronary artery bypass grafting (CABG) on pump, achieving optimal visualization is critical for surgical precision and safety. The use of blowers to clear the CABG anastomosis poses risks, including the formation of micro-embolic gas bubbles, which can be insidious and increase the risk of cerebral or myocardial complications. This retrospective study compares the effectiveness of the use of irrigation mist and CO2 versus a direct CO2 blower without irrigation in terms of visualization, postoperative fibrillation, and micro-embolic gas activity. Materials and Methods: The study involved 40 patients who underwent on-pump CABG, with 20 patients assigned to the irrigation mist and CO2 group (ClearView™) and 20 to the direct CO2 blower group. Primary outcomes included the quality of intraoperative visualization, the incidence of fibrillation at aortic de-clamping, and the presence of micro-embolic gas activity detected via transesophageal echocardiography (TEE) in the cardiac chambers. Results: Patients in the irrigation mist and CO2 group experienced superior visualization and reduced tissue desiccation. Fibrillation at the time of aortic de-clamping occurred in two patients (10%) using the irrigation mist and CO2, compared to eight patients (40%) using the direct CO2 blower. Additionally, TEE monitoring revealed lower levels of micro-embolic gas activity in the irrigation mist and CO2 group, indicating a potential reduction in gas embolization risk. Conclusions: The irrigation mist and CO2 system not only provides enhanced visualization during CABG but also significantly reduces the incidence of fibrillation during aortic de-clamping and micro-embolic gas activity. These findings suggest improved patient safety and outcomes, highlighting the irrigation mist and CO2 system as a potentially safer alternative to direct CO2 blowing in the context of myocardial revascularization.

Background: The impact of prolonged digital device exposure on physical and mental health in children has been widely investigated by the scientific community. Additionally, the lockdown periods due to the COVID-19 pandemic further exposed children to screen time for e-learning activities. The aim of this systematic review (PROSPERO Registration: CRD42022315596) was to evaluate the effect of digital device exposure on children’s health. The impact of the COVID-19 pandemic was additionally explored to verify the further exposure of children due to the e-learning environment. Methods: Available online databases (PubMed, Google Scholar, Semantic Scholar, BASE, Scopus, Web of Science, and SPORTDiscus) were searched for study selection. The PICO model was followed by including a target population of children aged 2 to 12 years, exposed or not to any type of digital devices, while evaluating changes in both physical and mental health outcomes. The quality assessment was conducted by using the Joanna Briggs Institute (JBI) Critical Appraisal Tool. Synthesis without meta-analysis (SWiM) guidelines were followed to provide data synthesis. Results: Forty studies with a total sample of 75,540 children were included in this systematic review. The study design was mainly cross-sectional (n = 28) and of moderate quality (n = 33). Overall, the quality score was reduced due to recall, selection, and detection biases; blinding procedures influenced the quality score of controlled trials, and outcome validity reduced the quality score of cohort studies. Digital device exposure affected physical activity engagement and adiposity parameters; sleep and behavioral problems emerged in children overexposed to digital devices. Ocular conditions were also reported and associated with higher screen exposure. Home confinement during COVID-19 further increased digital device exposure with additional negative effects. Conclusions: The prolonged use of digital devices has a significant negative impact on children aged 2 to 12, leading to decreased physical activity, sleep disturbances, behavioral issues, lower academic performance, socioemotional challenges, and eye strain, particularly following extended online learning during lockdowns.

The saphenous vein graft (SVG) has been a cornerstone of coronary bypass surgery, but its long-term patency is limited by accelerated atherosclerosis. Recent advancements, including the no-touch technique and the use of SVG as a limb of the left internal thoracic artery (LITA), have shown promise in improving outcomes. Both approaches enhance nitric oxide (NO) availability, a key factor in promoting endothelial stability and arterial-like behavior in the SVG. Among these, the LITA-SVG connection may offer superior long-term benefits due to sustained NO supplementation. This paper argues that the SVG, with proper strategies, can indeed achieve outcomes comparable to arterial grafts.

The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble (sTREM2) form. Mutations in TREM2 have been linked to increased risk of Alzheimer's disease (AD). A prominent neuropathological component of AD is deposition of the amyloid-β (Aβ) into plaques, particularly Aβ40 and Aβ42. While the membrane-bound form of TREM2 is known to facilitate uptake of Aβ fibrils and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar Aβ, has been less clear. Our results demonstrate that sTREM2 does not bind to monomeric Aβ40 and Aβ42, even at a high micromolar concentration, while it does bind to fibrillar Aβ42 and Aβ40 with equal affinities (2.6 ± 0.3 µM and 2.3 ± 0.4 µM). Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of Aβ, while having little effect on the primary nucleation pathway. Furthermore, binding of sTREM2 to fibrils markedly enhanced uptake of fibrils into human microglial and neuroglioma derived cell lines. The disease-associated sTREM2 mutant, R47H, displayed little to no effect on fibril nucleation and binding, but it decreased uptake and functional responses markedly. We also probed the structure of the WT sTREM2-Aβ fibril complex using integrative molecular modeling based primarily on the cross-linking mass spectrometry data. The model shows that sTREM2 binds fibrils along one face of the structure, leaving a second, mutation-sensitive site free to mediate cellular binding and uptake.

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.

Amyloid beta (Aβ) is thought to play a critical role in the pathogenesis of Alzheimer's disease (AD). Prion-like Aβ polymorphs, or "strains", can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of Aβ that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and Aβ strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various Aβ and tau species and used conformation-sensitive fluorescent probes to detect differences in Aβ strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of Aβ emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sporadic AD.

Background: The advantages of mechanical assistance during ventricular tachycardia (VT) ablation have not been clinically demonstrated. We propose and discuss a technique, set up by us, that makes use of minimally invasive extra-corporeal circulation (MiECC) type III associated with a venous reservoir system, which allows complete cardiac flow support and blood oxygenation as well as hemodynamic stability during long-lasting procedures. Methods: We present a retrospective case series of ten patients with valvular heart disease and unresponsive Ventricular Tachycardia (VT) who underwent VT ablation with MiECC support. The mean age of the patients was 72 ± 8 years and the left ventricular ejection fraction was 36 ± 12%. All patients underwent a clinical evaluation to identify the cause of VT unresponsiveness (e.g., ischemic heart disease). Results: A total of 140 min, the following parameters were evaluated and recorded for 140 min. Central venous pressure (CVP) was used to evaluate excess volume. During the first 5 min, the mean was 15 mmHg, with a pump flow of 1.5 L/min and a mean systemic arterial pressure of 100 mmHg while setting up the circulation support. Following drainage in a volumetric bag of 1 L of blood, CVP was reduced to a value of 5 mmHg with a flow rate of 5 L/min and a mean systemic arterial pressure of 65 mmHg. In the case of small and low-weight patients our “1 L protocol” can be modified. Conclusions: In this preliminary retrospective case series, the MiECC type III system may represent the ideal support system during VT ablation, and further studies are needed to support this preliminary report.

Background: Successful radioiodine treatment of differentiated thyroid canc er requires iodine avidity: that is, the concentration and retention of iodine in cancer tissue. Several parameters have previously been linked with lower iodine avidity. However, a comprehensive analysis of which factors best predict iodine avidity status, and the magnitude of their impact, is lacking. Methods: Quantitative measurements of iodine avidity in surgical specimens (primary tumour and lymph node metastases) of 28 patients were compared to immunohistochemical expression of the thyroid-stimulating hormone receptor, thyroid peroxidase (TPO), pendrin, sodium–iodide symporter (NIS) and mutational status of BRAF and the TERT promoter. Regression analysis was used to identify independent predictors of poor iodine avidity. Results: Mutations in BRAF and the TERT promoter were significantly associated with lower iodine avidity for lymph node metastases (18-fold and 10-fold, respectively). Membranous NIS localisation was found only in two cases but was significantly associated with high iodine avidity. TPO expression was signific antly correlated with iodine avidity (r = 0.44). The multivariable modelling showed that tumour tissue localisation (primary tumour or lymph node metastasis), histological subtype, TPO and NIS expression and TERT promoter mutation were each independent predictors of iodine avidity that could explain 68% of the observed variation of iodine avidity. Conclusions: A model based on histological subtype, TPO and NIS expression and TERT promoter mutation, all evaluated on initial surgical material, can predict iodine avidity in thyroid cancer tissue ahead of treatment. This could inform early adaptation with respect to expected treatment effect.

Cancer is a complex disease that affects millions of people and remains a major public health problem worldwide. Conventional cancer treatments, including surgery, chemotherapy, immunotherapy, and radiotherapy, have limited achievements and multiple drawbacks, among which are healthy tissue damage and multidrug-resistant phenotype onset. Increasing evidence shows that many plants’ natural products, as well as their bioactive compounds, have promising anticancer activity and exhibit minimal toxicity compared to conventional anticancer drugs. However, their widespread use in cancer therapy is severely restricted by limitations in terms of their water solubility, absorption, lack of stability, bioavailability, and selective targeting. The use of nanoformulations for plants’ natural product transportation and delivery could be helpful in overcoming these limitations, thus enhancing their therapeutic efficacy and providing the basis for improved anticancer treatment strategies. The present review is aimed at providing an update on some phytocompounds (curcumin, resveratrol, quercetin, and cannabinoids, among others) and their main nanoformulations showing antitumor activities, both in vitro and in vivo, against such different human cancer types as breast and colorectal cancer, lymphomas, malignant melanoma, glioblastoma multiforme, and osteosarcoma. The intracellular pathways underlying phytocompound anticancer activity and the main advantages of nanoformulation employment are also examined. Finally, this review critically analyzes the research gaps and limitations causing the limited success of phytocompounds’ and nanoformulations’ clinical translation.