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STK11 (serine-threonine kinase 11), also known as LKB1 (liver kinase B1) is a highly conserved master kinase that regulates cellular metabolism and polarity through a complex signaling network involving AMPK and 12 other AMPK-related kinases. Germline mutations in LKB1 have been causatively linked to Peutz-Jeghers Syndrome (PJS), an autosomal dominant hereditary disease with high cancer susceptibility. The identification of inactivating somatic mutations in LKB1 in different types of cancer further supports its tumor suppressive role. Deleterious mutations in LKB1 are frequently observed in patients with epithelial ovarian cancer. However, its inconsistent effects on tumorigenesis and cancer progression suggest that its functional impact is genetic context-dependent, requiring cooperation with other oncogenic lesions. In this review, we summarize the pleiotropic functions of LKB1 and how its altered activity in cancer cells is linked to oncogenic proliferation and growth, metastasis, metabolic reprogramming, genomic instability, and immune modulation. We also review the current mechanistic understandings of this master kinase as well as therapeutic implications with particular focus on the effects of LKB1 deficiency in ovarian cancer pathogenesis. Lastly, we discuss whether LKB1 deficiency can be exploited as an Achilles heel in ovarian cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kang, Gallucci, Pan, Oakhill and Sanij.)

Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-α-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFNα induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFNα-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Historically, the study of innate immune detection of bacterial infections has focused on the recognition of pathogen-associated molecular patterns (PAMPs) from bacteria growing as single cells in planktonic phase. However, over the past two decades, studies have highlighted an adaptive advantage of bacteria: the formation of biofilms. These structures are complex fortresses that stand against a hostile environment, including antibiotics and immune responses. Extracellular DNA (eDNA) is a crucial component of the matrix of most known biofilms. In this opinion article, I propose that eDNA is a universal PAMP that the immune system uses to recognize biofilms. Outstanding questions concern the discrimination between biofilm-associated eDNA and DNA from planktonic bacteria, the innate receptors involved, and the immune response to biofilms., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases and can manifest with a plethora of clinical signs and symptoms associated with a myriad of laboratory abnormalities. An infrequent but potentially lethal complication of SLE is macrophage activation syndrome (MAS). The diagnosis of MAS in SLE can be very challenging due to similarities in presentation of both flares and infections, such as fever, lymphadenopathy, splenomegaly, and cytopenias. These aggravating factors contribute to the increased risk of poor outcomes in SLE-associated MAS. Indeed, at the moment MAS remains invariably lethal if untreated and still has a high mortality rate with treatment. In this chapter, we discuss several aspects of MAS in the context of SLE and in particular, the pathogenesis of MAS in SLE, how MAS presents in pediatric versus adult SLE, and, finally, MAS treatment in SLE and future directions., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Inflammation and inflammasomes have been proposed as important regulators of the host-microorganism interaction, playing a key role in morbidity and mortality due to the coronavirus disease 2019 (COVID-19) in subjects with chronic conditions and compromised immune system. The inflammasome consists of a multiprotein complex that finely regulates the activation of caspase-1 and the production and secretion of potent pro-inflammatory cytokines such as IL-1β and IL-18. The pyrin containing NOD (nucleotide-binding oligomerization domain) like receptor (NLRP) is a family of intracellular receptors, sensing patterns associated to pathogens or danger signals and NLRP3 inflammasome is the most deeply analyzed for its involvement in the innate and adaptive immune system as well as its contribution to several autoinflammatory and autoimmune diseases. It is highly expressed in leukocytes and up-regulated in sentinel cells upon inflammatory stimuli. NLRP3 expression has also been reported in B and T lymphocytes, in epithelial cells of oral and genital mucosa, in specific parenchymal cells as cardiomyocytes, and keratinocytes, and chondrocytes. It is well known that a dysregulated activation of the inflammasome is involved in the pathogenesis of different disorders that share the common red line of inflammation in their pathogenetic fingerprint. Here, we review the potential roles of the NLRP3 inflammasome in cardiovascular events, liver damage, pulmonary diseases, and in that wide range of systemic inflammatory syndromes named as a cytokine storm.

Study Objectives: Narcolepsy is associated with cardiovascular risk factors; however, the risk of new-onset cardiovascular events in this population is unknown. This real-world study evaluated the excess risk of new-onset cardiovascular events in U.S. adults with narcolepsy., Methods: A retrospective cohort study using IBM MarketScan administrative claims data (2014-2019) was conducted. A narcolepsy cohort, comprising adults (≥18 years) with at least two outpatient claims containing a narcolepsy diagnosis, of which at least one was non-diagnostic, was matched to a non-narcolepsy control cohort (1:3) based on cohort entry date, age, sex, geographic region, and insurance type. The relative risk of new-onset cardiovascular events was estimated using a multivariable Cox proportional hazards model to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: The narcolepsy and matched non-narcolepsy control cohorts included 12 816 and 38 441 individuals, respectively. At baseline, cohort demographics were generally similar; however, patients with narcolepsy had more comorbidities. In adjusted analyses, the risk of new-onset cardiovascular events was higher in the narcolepsy cohort compared with the control cohort: any stroke (HR [95% CI], 1.71 [1.24, 2.34]); heart failure (1.35 [1.03, 1.76]); ischemic stroke (1.67 [1.19, 2.34]); major adverse cardiac event (1.45 [1.20, 1.74]); grouped instances of stroke, atrial fibrillation, or edema (1.48 [1.25, 1.74]); and cardiovascular disease (1.30 [1.08, 1.56])., Conclusion: Individuals with narcolepsy are at increased risk of new-onset cardiovascular events compared with individuals without narcolepsy. Physicians should consider cardiovascular risk in patients with narcolepsy when weighing treatment options., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Biofilms are communities of bacteria immersed in an extracellular matrix. Biofilms are considered a defensive strategy that protects bacteria from a hostile environment, including our immune system. Vidakovic et al. recently reported that Vibrio cholerae can build biofilms around immune cells and kill them, discovering an aggressive role for biofilms., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This paper assessed the variability of radiofrequency exposure among road users in urban settings due to vehicle-to-vehicle (V2V) communication operating at 5.9 GHz. The study evaluated the absorbed dose of radiofrequencies using whole-body specific absorption rate (SAR) in human models spanning different age groups, from children to adults. To overcome limitations of previous studies, we developed a novel hybrid procedure that combines deterministic and stochastic approaches, enabling assessment across multiple urban layouts. Real urban conditions and varying propagation scenarios were considered in SAR calculations. By varying the road user's position within 1.5-300 m from transmitting cars, the SAR distribution was determined. Median SAR remained consistently low, around 0.70 mW/kg, even with multiple transmitting cars and multiple emitting antennas, using maximum power allowed in US (44.8 dBm). The 99th percentile of SAR distribution varied based on body mass, decreasing for heavier models (typically adults) and increasing with the number of transmitting cars and antennas. The highest absorbed dose (73 mW/kg) occurred in a child model. The SAR consistently remained below the 80 mW/kg limit for whole-body exposure to electromagnetic fields in the 100 kHz-300 GHz range.

This study investigates the radio-frequency electromagnetic field exposure (RF-EMF) levels in pedestrians generated by vehicular communication technology. We specifically investigated exposure levels in children of different ages and both genders. This study also compares the children's exposure levels generated by such technology with those of an adult investigated in our previous study. The exposure scenario consisted of a 3D-CAD model of a vehicle equipped with two vehicular antennas operating at 5.9 GHz, each fed with 1 W power. Four child models were analyzed near the front and back of the car. The RF-EMF exposure levels were expressed as the Specific Absorption Rate (SAR) calculated over the whole body and 10 g mass (SAR 10g ) of the skin and 1 g mass (SAR 1g ) of the eyes. The maximum SAR 10g value of 9 mW/kg was found in the skin of the head of the tallest child. The maximum whole-body SAR was 0.18 mW/kg and was found in the tallest child. As a general result, it was found that children's exposure levels are lower than those of adults. All the SAR values are well below the limits recommended by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) in the general population.

Competing Interests: Competing interests: None declared.

The Salmonella biofilm-associated amyloid protein, curli, is a dominant instigator of systemic inflammation and autoimmune responses following Salmonella infection. Systemic curli injections or infection of mice with Salmonella Typhimurium induce the major features of reactive arthritis, an autoimmune disorder associated with Salmonella infection in humans. In this study, we investigated the link between inflammation and microbiota in exacerbating autoimmunity. We studied C57BL/6 mice from two sources, Taconic Farms and Jackson Labs. Mice from Taconic Farms have been reported to have higher basal levels of the inflammatory cytokine IL - 17 than do mice from Jackson Labs due to the differences in their microbiota. When we systemically injected mice with purified curli, we observed a significant increase in diversity in the microbiota of Jackson Labs mice but not in that of the Taconic mice. In Jackson Labs, mice, the most striking effect was the expansion of Prevotellaceae . Furthermore, there were increases in the relative abundance of the family Akkermansiaceae and decreases in families Clostridiaceae and Muribaculaceae in Jackson Labs mice. Curli treatment led to significantly aggravated immune responses in the Taconic mice compared to Jackson Labs counterparts. Expression and production of IL - 1β, a cytokine known to promote IL - 17 production, as well as expression of Tnfa increased in the gut mucosa of Taconic mice in the first 24 hours after curli injections, which correlated with significant increases in the number of neutrophils and macrophages in the mesenteric lymph nodes. A significant increase in the expression of Ccl3 in colon and cecum of Taconic mice injected with curli was detected. Taconic mice injected with curli also had elevated levels of inflammation in their knees. Overall, our data suggest that autoimmune responses to bacterial ligands, such as curli, are amplified in individuals with a microbiome that promote inflammation.

(1) Background: This work aims to assess human exposure to EMF due to two different wearable antennas tuned to two 5G bands. (2) Methods: The first one was centered in the lower 5G band, around f = 3.5 GHz, whereas the second one was tuned to the upper 5G band, at 26.5 GHz. Both antennas were positioned on the trunk of four simulated human models. The exposure assessment was performed by electromagnetic numerical simulations. Exposure levels were assessed by quantifying the specific absorption rate averaged on 10 g of tissue (SAR 10g ) and the absorbed power density (S ab ), depending on the frequency of the wearable antenna. (3) Results: the higher exposure values that resulted were always mainly concentrated in a superficial area just below the antenna itself. In addition, these resulting distributions were narrowed around their peak values and tended to flatten toward lower values in farther anatomical body regions. All the exposure levels complied with ICNIRP guidelines when considering realistic input power. (4) Conclusions: This work highlights the importance of performing an exposure assessment when the antenna is placed on the human wearer, considering the growth of wearable technology and its wide variety of application, particularly regarding future 5G networks.

This study addressed an important but not yet thoroughly investigated topic regarding human exposure to radio-frequency electromagnetic fields (RF-EMF) generated by vehicular connectivity. In particular, the study assessed, by means of computational dosimetry, the RF-EMF exposure in road users near a car equipped with vehicle-to-vehicle (V2V) communication antennas. The exposure scenario consisted of a 3D numerical model of a car with two V2V antennas, each fed with 1 W, operating at 5.9 GHz and an adult human model to simulate the road user near the car. The RF-EMF dose absorbed by the human model was calculated as the specific absorption rate (SAR), that is, the RF-EMF power absorbed per unit of mass. The highest SAR was observed in the skin of the head (34.7 mW/kg) and in the eyes (15 mW/kg); the SAR at the torso (including the genitals) and limbs was negligible or much lower than in the head and eyes. The SAR over the whole body was 0.19 mW/kg. The SAR was always well below the limits of human exposure in the 100 kHz-6 GHz band established by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). The proposed approach can be generalized to assess RF-EMF exposure in different conditions by varying the montage/number of V2V antennas and considering human models of different ages.

(1) Background: Cooperative Intelligent Transportation Systems (C-ITS) will soon operate using 5G New-Radio (NR) wireless communication, overcoming the limitations of the current V2X (Vehicle-to-Everything) wireless communication technologies and increasing road-safety and driving efficiency. These innovations will also change the RF exposure levels of pedestrians and road-users in general. These people, in fact, will be exposed to additional RF sources coming from nearby cars and from the infrastructure. Therefore, an exposure assessment of people in the proximity of a connected car is necessary and urgent. (2) Methods: Two array antennas for 5G-V2X communication at 3.5 GHz were modelled and mounted on a realistic 3D car model for evaluating the exposure levels of a human model representing people on the road near the car. Computational simulations were conducted using the FDTD solver implemented in the Sim4Life platform; different positions and orientations between the car and the human model were assessed. The analyzed quantities were the Specific Absorption Rate on the whole body (SAR wb ), averaged over 10 g (SAR 10g ) in specific tissues, as indicated in the ICNIRP guidelines. (3) Results: the data showed that the highest exposure levels were obtained mostly in the head area of the human model, with the highest peak obtained in the configuration where the main beam of the 5G-V2X antennas was more direct towards the human model. Moreover, in all configurations, the dose absorbed by a pedestrian was well below the ICNIRP guidelines to avoid harmful effects. (4) Conclusions: This work is the first study on human exposure assessment in a 5G-V2X scenario, and it expands the knowledge about the exposure levels for the forthcoming use of 5G in connected vehicles.

Deposition of human amyloids is associated with complex human diseases such as Alzheimer's and Parkinson's. Amyloid proteins are also produced by bacteria. The bacterial amyloid curli, found in the extracellular matrix of both commensal and pathogenic enteric bacterial biofilms, forms complexes with extracellular DNA, and recognition of these complexes by the host immune system may initiate an autoimmune response. Here, we isolated early intermediate, intermediate, and mature curli fibrils that form throughout the biofilm development and investigated the structural and pathogenic properties of each. Early intermediate aggregates were smaller than intermediate and mature curli fibrils, and circular dichroism, tryptophan, and thioflavin T analyses confirmed the establishment of a beta-sheet secondary structure as the curli conformations matured. Intermediate and mature curli fibrils were more immune stimulatory than early intermediate fibrils in vitro. The intermediate curli was cytotoxic to macrophages independent of Toll-like receptor 2. Mature curli fibrils had the highest DNA content and induced the highest levels of Isg15 expression and TNFα production in macrophages. In mice, mature curli fibrils induced the highest levels of anti-double-stranded DNA autoantibodies. The levels of autoantibodies were higher in autoimmune-prone NZBWxF/1 mice than wild-type C57BL/6 mice. Chronic exposure to all curli forms led to significant histopathological changes and synovial proliferation in the joints of autoimmune-prone mice; mature curli was the most detrimental. In conclusion, curli fibrils, generated during biofilm formation, cause pathogenic autoimmune responses that are stronger when curli complexes contain higher levels of DNA and in mice predisposed to autoimmunity., Competing Interests: The authors have declared that no competing interests exist.

This study is based on the quantification of the influence of the presence of gold nanoparticles (Au NPs), of their geometry and their distance from cell membrane during time-varying electromagnetic fields cell membrane permeabilization on the pores opening dynamics. Results showed that the combined use of Au NPs and time-varying magnetic field can improve significantly the permeabilization of cell membrane. The presence of Au NPs allowed to reach transmembrane potential values enabling the cell membrane permeabilization only when placed at very short distance, equal to 20 nm. Both geometry and variability of the positioning in proximity of the cell membrane showed a strong influence on the probability of enabling pores opening. Clinical Relevance- This study provides a better comprehension about the mechanisms, still not completely understood, underlying cell membrane permeabilization by combining Au NPs and time-varying magnetic fields.

This work aimed to estimate the distribution of the electric field generated by a combined cerebellar and frontal transcranial direct current stimulation (tDCS) for treatment-resistant depression using electromagnetics computational techniques applied to a realistic head human model. Results showed that the stronger electric fields occur mainly in the cerebellum and in DLPFC areas, where the two pairs of electrodes were applied. Furthermore, the study demonstrated that the simultaneous use of the two pairs of electrodes did not imply a lower effectiveness of the tDCS technique, in fact the electric field distributions in the primarily targets of the anatomical regions (i.e., cerebellum and DLPFC) were very similar to when the pairs of electrodes were applied separately.

(1) Background: This work aims to assess the human exposure to the RF-EMFs emitted by a wearable antenna. (2) Methods: a wearable antenna tuned at f = 2.45 GHz was tested by placing it in six realistic configurations relative to a male and female human model. The exposure assessment was performed by means of computational methods to estimate the SAR 10g distributions at 1W of input power. (3) Results: (i) for all the configurations the SAR 10g distributions resulted always mainly concentrated on a superficial area immediately below the antenna itself; (ii) the obtained values have shown that the configuration with the highest exposure value was when the antenna was posed on the arm; (iii) the exposure tends to be higher for male model. (4) Discussion and Conclusions: This work highlights the importance of performing an exposure assessment when the antenna is placed on the human wearer considering the growth of the wearable technology and its wide variety of fields of application, e.g., medical and military.

TNF inhibitors are widely used to treat inflammatory diseases; however, 30%-50% of treated patients develop new autoantibodies, and 0.5%-1% develop secondary autoimmune diseases, including lupus. TNF is required for formation of germinal centers (GCs), the site where high-affinity autoantibodies are often made. We found that TNF deficiency in Sle1 mice induced TH17 T cells and enhanced the production of germline encoded, T-dependent IgG anti-cardiolipin antibodies but did not induce GC formation or precipitate clinical disease. We then asked whether a second hit could restore GC formation or induce pathogenic autoimmunity in TNF-deficient mice. By using a range of immune stimuli, we found that somatically mutated autoantibodies and clinical disease can arise in the setting of TNF deficiency via extrafollicular pathways or via atypical GC-like pathways. This breach of tolerance may be due to defects in regulatory signals that modulate the negative selection of pathogenic autoreactive B cells.

The recent deployment of 5G networks is bringing benefits to the population but it is also raising public concern about human RF-EMF exposure levels. This is particularly relevant considering the next 5G mobile devices, which are placed in close proximity to the subjects. Therefore, the aim of the following paper is focused on expanding the knowledge of the exposure levels in 5G exposure scenarios, specifically for mobile applications, using computational methods. The mobile antenna was designed considering the 5G technology innovations (i.e., mm-wave spectrum, beamforming capability, high gain and wide coverage), resulting in a phased-array antenna with eight elements at the working frequency of 27 GHz. To assess the exposure levels, different types of skin models with different grades of details and layers were considered. Furthermore, not only was the presence of a mobile phone user simulated, but also that of a person in their proximity, who could be hit by the main beam of the phased-array antenna. All the simulations were conducted in Sim4Life platform, where the exposure levels were assessed in terms of absorbed power density averaged over 4 cm 2 and 1 cm 2 , following the ICNIRP guidelines. The results highlighted that the use of the homogeneous skin model led to the absorbed power density peaks being greatly underestimated, with respect to those obtained in multilayer skin models. Furthermore, interestingly, we found that the exposure levels obtained for the person passing nearby were slightly higher than those experienced by the mobile phone user himself. Finally, using the allowed input power for real mobile applications, all the values remained below the limits indicated by the ICNIRP guidelines.

(1) Background: Radiofrequency radiations are used in most devices in current use and, consequently, the assessment of the human exposure to the radiofrequency radiations has become an issue of strong interest. Even if in the military field there is wide use of radiofrequency devices, a clear picture on the exposure assessment to the electromagnetic field of the human beings in the military scenario is still missing. (2) Methods: a review of the scientific literature regarding the assessment of the exposure of the military personnel to the RF specific to the military environment, was performed. (3) Results: the review has been performed grouping the scientific literature by the typology of military devices to which the military personnel can be exposed to. The military devices have been classified in four main classes, according to their intended use: communication devices, localization/surveillance devices, jammers and EM directed-energy weapons. (4) Discussion and Conclusions: The review showed that in the exposure conditions here evaluated, there were only occasional situations of overexposure, whereas in the majority of the conditions the exposure was below the worker exposure limits. Nevertheless, the limited number of studies and the lack of exposure assessment studies for some devices prevent us to draw definitive conclusions and encourage further studies on military exposure assessment.

In recent years the introduction of 5G networks is causing a drastically change of human exposure levels in the radio frequency range. The aim of this paper is on expanding the knowledge on this issue, assessing the exposure levels for a particular case of indoor 5G scenario, where the presence of an Access Point (AP) was simulated. Coupling the traditional deterministic computational method with an innovative stochastic approach, called Polynomial Chaos Kriging, allowed to evaluate the exposure variability of an user considering the 3D beamforming capability of the antenna. The exposure levels, expressed in terms of specific absorption rate (SAR) in specific tissues, showed low values compared to ICNIRP guidelines.

The feasibility of using time-varying magnetic field as a contactless cells permeabilization method was demonstrated by experimental results, but the underlying mechanism is still poorly understood. In this study a numerical analysis of the transmembrane potential (TMP) at cell membranes during permeabilization by time-varying magnetic fields was proposed, and a first quantification of mechanical stress induced by the magnetic and electric fields and hypothesized to play an important role in the permeabilization mechanism was carried out. TMP values induced by typical in-vitro experimental conditions were far below the values needed for membrane permeabilization, with a strong dependence on distance of the cell from the coil. The preliminary assessment of the mechanical pressure and potential deformation of cells showed that stress values evaluated in conditions in which TMP values were too low to cause membrane permeabilization were comparable to those known to influence the pore opening mechanisms.Clinical Relevance- Results represent a significant step towards a better comprehension of the mechanism underlying cell membrane permeabilization by time-varying magnetic fields.