The diverse genetic origins of a Classical period Greek army.

Trade and colonization caused an unprecedented increase in Mediterranean human mobility in the first millennium BCE. Often seen as a dividing force, warfare is in fact another catalyst of culture contact. We provide insight into the demographic dynamics of ancient warfare by reporting genome-wide data from fifth-century soldiers who fought for the army of the Greek Sicilian colony of Himera, along with representatives of the civilian population, nearby indigenous settlements, and 96 present-day individuals from Italy and Greece. Unlike the rest of the sample, many soldiers had ancestral origins in northern Europe, the Steppe, and the Caucasus. Integrating genetic, archaeological, isotopic, and historical data, these results illustrate the significant role mercenaries played in ancient Greek armies and highlight how participation in war contributed to continental-scale human mobility in the Classical world.

Natural hazard risk analysis in the framework of water safety plans.

The available literature on natural hazard risk analysis focused on the implementation of water safety plans (WSPs) is surprisingly quite poor, despite the significant increase in the number and severity of disasters and adverse effects on drinking water supply systems generated by natural hazards. At the same time, WSPs that conveniently account for natural hazards with a comprehensive approach 'from source to tap' are still scarce as they typically occur at larger spatial scales and adequate prevention, mitigation and adaptation require efficient inter-institutional collaborations. The aim of this paper is to highlight the main bottlenecks for water utilities to include natural hazards in the development of their WSPs. The research adopted a stakeholders-oriented approach, involving a considerable number of water utilities (168), water sectoral agencies (15) and institutions (68) across the Adriatic-Ionian Region through a stepwise process that generated joint SWOT analysis, the development of a decision support system (DSS) focused on WSPs procedures and tabletop exercises. The final outcomes generated strategic documents (REWAS - Adrion Road map for resilient water supply) that highlighted the necessity for efficient cross-sectoral and inter-institutional cooperation in the development of well-founded and robust WSPs to address natural hazard risk analysis for water supply systems (DWSS).

Exploring cerebral laterality of writing and the relationship to handedness: a functional transcranial Doppler ultrasound investigation.

Cerebral lateralization of oral language has been investigated in a plethora of studies and it is well established that the left hemisphere is dominant for production tasks in the majority of individuals. However, few studies have focused on written language and even fewer have sampled left-handers. Writing comprises language and motor components, both of which contribute to cerebral activation, yet previous research has not disentangled. The aim of this study was to disentangle the language and motor components of writing lateralization. This was achieved through the comparison of cerebral activation during (i) written word generation and (ii) letter copying, as assessed by functional Transcranial Doppler (fTCD) ultrasound. We further assessed cerebral laterality of oral language. The sample was balanced for handedness. We preregistered the hypotheses that (i) cerebral lateralization of the linguistic component of writing would be weaker in left-handers compared to right-handers and (ii) oral language and the linguistic component of written language would not be correlated in terms of cerebral lateralization. No compelling evidence for either of our hypotheses was found. Findings highlight the complexity of the processes subserving written and oral language as well as the methodological challenges to isolate the linguistic component of writing.

Hand Preference in Stuttering: Meta-Analyses.

Reduced hemispheric asymmetries, as well as their behavioral manifestation in the form of atypical handedness (i.e., non-right, left-, or mixed-handedness), are linked to neurodevelopmental disorders, such as autism spectrum disorder, and several psychiatric disorders, such as schizophrenia. One neurodevelopmental disorder that is associated with reduced hemispheric asymmetries, but for which findings on behavioral laterality are conflicting, is stuttering. Here, we report a series of meta-analyses of studies that report handedness (assessed as hand preference) levels in individuals who stutter (otherwise healthy) compared to controls. For this purpose, articles were identified via a search in PubMed, Scopus, and PsycInfo (13 June 2023). On the basis of k = 52 identified studies totaling n = 2590 individuals who stutter and n = 17,148 controls, five random effects meta-analyses were conducted: four using the odds ratio [left-handers (forced choice); left-handers (extreme); mixed-handers; non-right-handers vs. total)] and one using the standardized difference in means as the effect size. We did not find evidence of a left (extreme)- or mixed-handedness difference or a difference in mean handedness scores, but evidence did emerge, when it came to left-handedness (forced-choice) and (inconclusively for) non-right-handedness. Risk-of-bias analysis was not deemed necessary in the context of these meta-analyses. Differences in hand skill or strength of handedness could not be assessed as no pertinent studies were located. Severity of stuttering could not be used s a moderator, as too few studies broke down their data according to severity. Our findings do not allow for firm conclusions to be drawn on whether stuttering is associated with reduced hemispheric asymmetries, at least when it comes to their behavioral manifestation.

Depressive Symptoms and Anger Expression Among Survivors After Stroke.

INTRODUCTION: Stroke is a frequent cause of death and one of the most common causes of disability and depression in the countries of the Western world. Depression is associated with limited functionality, reduced self-care, and increased mortality in patients with stroke. Anger often occurs in these patients and may disrupt the course of their recovery. AIM: The investigation of the presence of depressive symptomatology, the expression of anger, and the degree of functioning/independence of patients after stroke. METHOD: One hundred and ten patients after stroke completed the Center for Epidemiological Studies-Depression (CES-D) scale, the State-Trait Anger Expression Inventory, and the Barthel Index. RESULTS: Patients who lived alone had a higher depressive symptomatology score than patients who did not live alone (p = 0.009). An increase in the total depressive symptomatology score was related to an increase in the anger expression score (p = 0.011), increase in anger-in score (p < 0.001), increase in anger-out score (p < 0.001), and decrease in anger control score (p = 0.001). Females had lower anger-in scores compared to men (p = 0.029). Individuals with a history of previous stroke had higher anger-out scores compared to people without a history of previous stroke (p = 0.025). An increase in the patient's functional/independence score was associated with an increase in anger control score (p = 0.015). CONCLUSIONS: Early detection and management of depression and anger will facilitate patient's compliance to the rehabilitation program in order to achieve optimal therapeutic results and ensure a better quality of life.

Genetic prediction of ICU hospitalization and mortality in COVID-19 patients using artificial neural networks.

There is an unmet need of models for early prediction of morbidity and mortality of Coronavirus disease-19 (COVID-19). We aimed to a) identify complement-related genetic variants associated with the clinical outcomes of ICU hospitalization and death, b) develop an artificial neural network (ANN) predicting these outcomes and c) validate whether complement-related variants are associated with an impaired complement phenotype. We prospectively recruited consecutive adult patients of Caucasian origin, hospitalized due to COVID-19. Through targeted next-generation sequencing, we identified variants in complement factor H/CFH, CFB, CFH-related, CFD, CD55, C3, C5, CFI, CD46, thrombomodulin/THBD, and A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS13). Among 381 variants in 133 patients, we identified 5 critical variants associated with severe COVID-19: rs2547438 (C3), rs2250656 (C3), rs1042580 (THBD), rs800292 (CFH) and rs414628 (CFHR1). Using age, gender and presence or absence of each variant, we developed an ANN predicting morbidity and mortality in 89.47% of the examined population. Furthermore, THBD and C3a levels were significantly increased in severe COVID-19 patients and those harbouring relevant variants. Thus, we reveal for the first time an ANN accurately predicting ICU hospitalization and death in COVID-19 patients, based on genetic variants in complement genes, age and gender. Importantly, we confirm that genetic dysregulation is associated with impaired complement phenotype.

Vaccinated and Convalescent Donor-Derived Severe Acute Respiratory Syndrome Coronavirus 2-Specific T Cells as Adoptive Immunotherapy for High-Risk Coronavirus Disease 2019 Patients.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an urgent need for the development of effective therapies for coronavirus disease 2019 (COVID-19). METHODS: We first tested SARS-CoV-2-specific T-cell (CοV-2-ST) immunity and expansion in unexposed donors, COVID-19-infected individuals (convalescent), asymptomatic polymerase chain reaction (PCR)-positive subjects, vaccinated individuals, non-intensive care unit (ICU) hospitalized patients, and ICU patients who either recovered and were discharged (ICU recovered) or had a prolonged stay and/or died (ICU critical). CoV-2-STs were generated from all types of donors and underwent phenotypic and functional assessment. RESULTS: We demonstrate causal relationship between the expansion of endogenous CoV-2-STs and the disease outcome; insufficient expansion of circulating CoV-2-STs identified hospitalized patients at high risk for an adverse outcome. CoV-2-STs with a similarly functional and non-alloreactive, albeit highly cytotoxic, profile against SARS-CoV-2 could be expanded from both convalescent and vaccinated donors generating clinical-scale, SARS-CoV-2-specific T-cell products with functional activity against both the unmutated virus and its B.1.1.7 and B.1.351 variants. In contrast, critical COVID-19 patient-originating CoV-2-STs failed to expand, recapitulating the in vivo failure of CoV-2-specific T-cell immunity to control the infection. CoV-2-STs generated from asymptomatic PCR-positive individuals presented only weak responses, whereas their counterparts originating from exposed to other seasonal coronaviruses subjects failed to kill the virus, thus disempowering the hypothesis of protective cross-immunity. CONCLUSIONS: Overall, we provide evidence on risk stratification of hospitalized COVID-19 patients and the feasibility of generating powerful CoV-2-ST products from both convalescent and vaccinated donors as an "off-the shelf" T-cell immunotherapy for high-risk patients.

Genetic justification of severe COVID-19 using a rigorous algorithm.

Recent studies suggest excessive complement activation in severe coronavirus disease-19 (COVID-19). The latter shares common characteristics with complement-mediated thrombotic microangiopathy (TMA). We hypothesized that genetic susceptibility would be evident in patients with severe COVID-19 (similar to TMA) and associated with disease severity. We analyzed genetic and clinical data from 97 patients hospitalized for COVID-19. Through targeted next-generation-sequencing we found an ADAMTS13 variant in 49 patients, along with two risk factor variants (C3, 21 patients; CFH,34 patients). 31 (32%) patients had a combination of these, which was independently associated with ICU hospitalization (p = 0.022). Analysis of almost infinite variant combinations showed that patients with rs1042580 in thrombomodulin and without rs800292 in complement factor H did not require ICU hospitalization. We also observed gender differences in ADAMTS13 and complement-related variants. In light of encouraging results by complement inhibitors, our study highlights a patient population that might benefit from early initiation of specific treatment.

Non-transplantable cord blood units as a source for adoptive immunotherapy of leukaemia and a paradigm of circular economy in medicine.

Advances in immunotherapy with T cells armed with chimeric antigen receptors (CAR-Ts), opened up new horizons for the treatment of B-cell lymphoid malignancies. However, the lack of appropriate targetable antigens on the malignant myeloid cell deprives patients with refractory acute myeloid leukaemia of effective CAR-T therapies. Although non-engineered T cells targeting multiple leukaemia-associated antigens [i.e. leukaemia-specific T cells (Leuk-STs)] represent an alternative approach, the prerequisite challenge to obtain high numbers of dendritic cells (DCs) for large-scale Leuk-ST generation, limits their clinical implementation. We explored the feasibility of generating bivalent-Leuk-STs directed against Wilms tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) from umbilical cord blood units (UCBUs) disqualified for allogeneic haematopoietic stem cell transplantation. By repurposing non-transplantable UCBUs and optimising culture conditions, we consistently produced at clinical scale, both cluster of differentiation (CD)34+ cell-derived myeloid DCs and subsequently polyclonal bivalent-Leuk-STs. Those bivalent-Leuk-STs contained CD8+ and CD4+ T cell subsets predominantly of effector memory phenotype and presented high specificity and cytotoxicity against both WT1 and PRAME. In the present study, we provide a paradigm of circular economy by repurposing unusable UCBUs and a platform for future banking of Leuk-STs, as a 'third-party', 'off-the-shelf' T-cell product for the treatment of acute leukaemias.

l-selenomethionine supplementation in children and adolescents with autoimmune thyroiditis: A randomized double-blind placebo-controlled clinical trial.

WHAT IS KNOWN AND OBJECTIVE: Although a beneficial effect of selenium (Se) administration has been proposed in adults with autoimmune thyroiditis (AT), there is a paucity of similar data in children and adolescents. The purpose of the study was to investigate whether administration of a high dose of organic Se (200 µg daily as l-selenomethionine) has an effect on antithyroid antibody titres in children and adolescents with AT. METHODS: Seventy-one (71) children and adolescents, with a mean age of 11.3 ± 0.3 years (range 4.5-17.8), diagnosed with AT (antibodies against thyroid peroxidase [anti-TPO] and/or thyroglobulin [anti-Tg] ≥60 IU/mL, euthyroidism or treated hypothyroidism and goitre in thyroid gland ultrasonography) were randomized to receive 200 µg l-selenomethionine or placebo daily for 6 months. Blood samples were drawn for measurement of serum fT4, TSH, anti-TPO and anti-Tg levels, and thyroid gland ultrasonography was performed at the entry to the study and after 6 months of treatment. RESULTS AND DISCUSSION: At the end of the study, a statistically significantly higher reduction in anti-Tg levels was observed in the Se group compared to the placebo group (Δ: -70.9 ± 22.1 vs -6.7 ± 60.6 IU/mL, P = 0.021). Although anti-TPO levels were also decreased in the Se group, this change was not statistically different from that of the control group (Δ: -116.2 ± 68.4 vs +262.8 ± 255.5 IU/mL, P = 0.219). No significant difference in thyroid gland volume was observed between the two study groups (P > 0.05). WHAT IS NEW AND CONCLUSION: In this original study, organic Se supplementation appears to reduce anti-Tg levels in children and adolescents with AT.

The ex vivo toll-like receptor 7 tolerance induction in donor lymphocytes prevents murine acute graft-versus-host disease.

BACKGROUND AIMS: Acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation, mediated by alloreactive donor T cells. Toll-like receptors (TLRs), a family of conserved pattern-recognition receptors (PRRs), represent key players in donors' T-cell activation during aGVHD; however, a regulatory, tolerogenic role for certain TLRs has been recognized in a different context. We investigated whether the ex vivo-induced TLR-2,-4,-7 tolerance in donor cells could prevent alloreactivity in a mismatched transplantation model. METHODS: TLR-2,-4,-7 tolerance was induced in mouse splenocytes, after stimulation with low doses of corresponding ligands. Cellular and molecular changes of the TLR-tolerant splenocytes and purified T cells were assessed by immunophenotypic and gene expression analyses. Incidence of aGVHD was evaluated by the clinical score and survival as well as histopathology of target tissues. RESULTS: Only the R848-induced TLR7 tolerance prevented aGVHD. The TLR7 ligand-induced tolerance lasted for a critical post-transplant period and was associated with distinct cellular and molecular signatures characterized by induction of regulatory T cells, reduced alloreactivity and balanced regulation of inflammatory signaling and innate immune responses. The TLR7-tolerant T cells preserved the immunological memory and generated in vitro virus-specific T cells upon antigen stimulation. The anti-aGVHD tolerization effect was direct and specific to TLR7 and required the receptor-ligand interaction; TLR7-/- T cells isolated from B6 TLR7-/- mice presented a distinct gene expression profile but failed to prevent aGVHD. DISCUSSION: We propose an effective and clinically applicable ex vivo approach for aGVHD prevention through a transient and reversible immune reprogramming exerted by TLR7-tolerant donor lymphocytes.

High density of tryptase-positive mast cells in patients with multiple myeloma: correlation with parameters of disease activity.

Multiple myeloma (MM) is a plasma cell neoplasm characterized by bone marrow infiltration from malignant plasma cells. Mast cells play an important role in inflammation and angiogenesis in malignant diseases. The aim of the study was to evaluate the mast cell density in bone marrow of untreated MM patients with markers of disease activity such as serum interleukin-6 (IL-6), B2M, and C-reactive protein (CRP), the grade of bone marrow infiltration, and the levels of produced paraprotein. We studied 86 newly diagnosed MM patients (46 males, 40 females, mean age 59 ± 13.7 years). Thirty of them reached plateau phase after chemotherapy and 20 healthy volunteers. According to the criteria of International Staging System (ISS) staging system, 23 patients had stage I, 30 had stage II, and 33 had stage III. The serum concentrations of CRP, B2M, and IL-6, and the mast cell density (MCD) values were significantly higher in MM patients' group (1.6 ± 1.8, 4.3 ± 2.9, 7.1 ± 5.1, and 9 ± 4.8), in comparison with those found in control group (0.4 ± 0.1, 1.5 ± 0.6, 1.1 ± 0.5, and 1.9 ± 0.7; p < 0.001 in all the cases). Significant differences were found between the grade of infiltration in bone marrow, and the paraprotein values in patients' serum before and after chemotherapy. Furthermore, there was a significant correlation between the MCD values and the prognostic markers CRP (r = 0.452, p < 0.0001), IL-6 (r = 0.475, p < 0.0001), bone marrow infiltration (r = 0.333, p < 0.0002), and serum paraprotein levels(r = 0.221, p < 0.04). High MCD values strengthen the hypothesis that mast cells participate in the pathogenesis of disease progression and may be used as an indicator of the disease activity.

Systemic inflammatory response syndrome after administration of unmodified T lymphocytes.

Systemic inflammatory response syndrome (SIRS) is a rare systemic inflammatory response associated with fever, tachycardia, profound hypotension, and respiratory distress, which has been reported in cancer patients receiving T cells genetically modified with chimeric antigen receptors to retarget their specificity to tumor-associated antigens. The syndrome usually occurs following significant in vivo expansion of the infused cells and has been associated with tumor destruction/lysis. Analysis of patient plasma has shown elevated cytokine levels, and resolution of symptoms has been reported after administration of steroids and/or antibodies (such as anti-tumor necrosis factor and anti-interleukin (IL)-6 receptor antibodies) that interfere with cytokine responses.To date, SIRS has not been reported in subjects receiving genetically unmodified T cells with native receptors directed against tumor antigens, in which greater physiological control of T-cell activation and expansion may occur. Here, however, we report a patient with bulky refractory Epstein-Barr virus (EBV)-associated lymphoma, who developed this syndrome 2 weeks after receiving T cells directed against EBV antigens through their native receptors. She was treated with steroids and etanercept, with rapid resolution of symptoms. SIRS may therefore occur even when T cells recognize antigens physiologically through their "wild-type" native receptors and should be acknowledged as a potential complication of this therapy.

Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant.

Adoptive transfer of virus-specific T cells can prevent and treat serious infections with Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenovirus (Adv) after allogeneic hematopoietic stem cell transplant. It has, however, proved difficult to make this approach widely available since infectious virus and viral vectors are required for T cell activation, followed by an intensive and prolonged culture period extending over several months. We now show that T cells targeting a range of viral antigens derived from EBV, CMV, and Adv can be reproducibly generated in a single culture over a 2-3-week period, using methods that exclude all viral components and employ a much-simplified culture technology. When administered to recipients of haploidentical (n = 5), matched unrelated (n = 3), mismatched unrelated (n = 1) or matched related (n = 1) transplants with active CMV (n = 3), Adv (n = 1), EBV (n = 2), EBV+Adv (n = 2) or CMV+Adv (n = 2) infections, the cells produced complete virological responses in 80%, including all patients with dual infections. In each case, a decrease in viral load correlated with an increase in the frequency of T cells directed against the infecting virus(es); both immediate and delayed toxicities were absent. This approach should increase both the feasibility and applicability of T cell therapy. The trial was registered at www.clinicaltrials.gov as NCT01070797.

Perspectives for the Use of Umbilical Cord Blood in Transplantation and Beyond: Initiatives for an Advanced and Sustainable Public Banking Program in Greece.

The umbilical cord blood (UCB) donated in public UCB banks is a source of hematopoietic stem cells (HSC) alternative to bone marrow for allogeneic HSC transplantation (HSCT). However, the high rejection rate of the donated units due to the strict acceptance criteria and the wide application of the haploidentical HSCT have resulted in significant limitation of the use of UCB and difficulties in the economic sustainability of the public UCB banks. There is an ongoing effort within the UCB community to optimize the use of UCB in the field of HSCT and a parallel interest in exploring the use of UCB for applications beyond HSCT i.e., in the fields of cell therapy, regenerative medicine and specialized transfusion medicine. In this report, we describe the mode of operation of the three public UCB banks in Greece as an example of an orchestrated effort to develop a viable UCB banking system by (a) prioritizing the enrichment of the national inventory by high-quality UCB units from populations with rare human leukocyte antigens (HLA), and (b) deploying novel sustainable applications of UCB beyond HSCT, through national and international collaborations. The Greek paradigm of the public UCB network may become an example for countries, particularly with high HLA heterogeneity, with public UCB banks facing sustainability difficulties and adds value to the international efforts aiming to sustainably expand the public UCB banking system.

Metabolome and transcriptome reprogramming underlying tomato drought resistance triggered by a Pseudomonas strain.

Although amelioration of drought stress by Plant Growth Promoting Rhizobacteria (PGPR) is a well-documented phenomenon, the combined molecular and metabolic mechanisms governing this process remain unclear. In these lines, the present study aimed to provide new insights in the underlying drought attenuating mechanisms of tomato plants inoculated with a PGP Pseudomonas putida strain, by using a combination of metabolomic and transcriptomic approaches. Following Differentially Expressed Gene analysis, it became evident that inoculation resulted in a less disturbed plant transcriptome upon drought stress. Untargeted metabolomics highlighted the differential metabolite accumulation upon inoculation, as well as the less metabolic reprograming and the lower accumulation of stress-related metabolites for inoculated stressed plants. These findings were in line with morpho-physiological evidence of drought stress mitigation in the inoculated plants. The redox state modulation, the more efficient nitrogen assimilation, as well as the differential changes in amino acid metabolism, and the induction of the phenylpropanoid biosynthesis pathway, were the main drought-attenuating mechanisms in the SAESo11-inoculated plants. Shifts in pathways related to hormonal signaling were also evident upon inoculation at a transcript level and in conjunction with carbon metabolism regulation, possibly contributed to a drought-attenuation preconditioning. The identified signatory molecules of SAESo11-mediated priming against drought included aspartate, myo-inositol, glutamate, along with key genes related to trehalose, tryptophan and cysteine synthesis. Taken together, SAESo11-inoculation provides systemic effects encompassing both metabolic and regulatory functions, supporting both seedling growth and drought stress amelioration.

Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond.

Adoptive immunotherapy with virus-specific cytotoxic T cells (VSTs) has evolved over the last three decades as a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after solid organ or allogeneic hematopoietic cell-transplantation (allo-HCT). Since the early proof-of-principle studies demonstrating that seropositive donor-derived T cells, specific for the commonest pathogens post transplantation, namely cytomegalovirus or Epstein-Barr virus (EBV) and generated by time- and labor-intensive protocols, could effectively control viral infections, major breakthroughs have then streamlined the manufacturing process of pathogen-specific T cells (pSTs), broadened the breadth of target recognition to even include novel emerging pathogens and enabled off-the-shelf administration or pathogen-naive donor pST production. We herein review the journey of evolution of adoptive immunotherapy with nonengineered, natural pSTs against infections and virus-associated malignancies in the transplant setting and briefly touch upon recent achievements using pSTs outside this context.

Administration of the Second Dose of mRNA COVID-19 Vaccine to a Woman With Immediate Reaction to the First Dose.

Vaccines constitute the most effective public health intervention as they prevent the spread of infectious diseases and reduce disease severity and mortality. Allergic reactions can occur during vaccination. Systemic anaphylaxis is a severe, life-threatening allergic reaction which can rarely occur after vaccination. There is limited data suggesting that the majority of the patients with immediate and potentially allergic reactions after the first dose of coronavirus disease 2019 (COVID-19) can receive the second dose. A 39-year-old woman was admitted to our department after presenting anaphylactic reaction following the first dose of mRNA COVID-19 vaccine (BNT162b2). A few days later, she contacted our department and was admitted for an allergy work-up on mRNA COVID-19 vaccine and its compound polyethylene glycol (PEG). Thereafter, she completed the vaccination procedure having received pretreatment under our guidance. Confirmed allergic reactions to vaccines are customarily attributed to the inactive ingredients, or excipients like PEG and polysorbate. The latest are used to improve water-solubility in vaccines. PEG itself has not been previously used in a vaccine but polysorbate has been identified as a rare cause of allergic reactions to vaccines. It has been reported that the interaction of the immune system with lipidic nanoparticle therapeutics could result in hypersensitivity reactions (HSRs), referred to as complement activation related pseudoallergy (CARPA), which is classified as non-IgE-mediated pseudoallergy caused by the activation of the complement system.

Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy.

Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis by inhibiting immune responses to self-antigens and preventing the excessive activation of the immune system. Their functions extend beyond immune surveillance and subpopulations of tissue-resident Treg cells can also facilitate tissue repair and homeostasis. The unique ability to regulate aberrant immune responses has generated the concept of harnessing Tregs as a new cellular immunotherapy approach for reshaping undesired immune reactions in autoimmune diseases and allo-responses in transplantation to ultimately re-establish tolerance. However, a number of issues limit the broad clinical applicability of Treg adoptive immunotherapy, including the lack of antigen specificity, heterogeneity within the Treg population, poor persistence, functional Treg impairment in disease states, and in vivo plasticity that results in the loss of suppressive function. Although the early-phase clinical trials of Treg cell therapy have shown the feasibility and tolerability of the approach in several conditions, its efficacy has remained questionable. Leveraging the smart tools and platforms that have been successfully developed for primary T cell engineering in cancer, the field has now shifted towards "next-generation" adoptive Treg immunotherapy, where genetically modified Treg products with improved characteristics are being generated, as regards antigen specificity, function, persistence, and immunogenicity. Here, we review the state of the art on Treg adoptive immunotherapy and progress beyond it, while critically evaluating the hurdles and opportunities towards the materialization of Tregs as a living drug therapy for various inflammation states and the broad clinical translation of Treg therapeutics.

Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming.

T-cell-based, personalized immunotherapy can nowadays be considered the mainstream treatment for certain blood cancers, with a high potential for expanding indications. Chimeric antigen receptor T cells (CAR-Ts), an ex vivo genetically modified T-cell therapy product redirected to target an antigen of interest, have achieved unforeseen successes in patients with B-cell hematologic malignancies. Frequently, however, CAR-T cell therapies fail to provide durable responses while they have met with only limited success in treating solid cancers because unique, unaddressed challenges, including poor persistence, impaired trafficking to the tumor, and site penetration through a hostile microenvironment, impede their efficacy. Increasing evidence suggests that CAR-Ts' in vivo performance is associated with T-cell intrinsic features that may be epigenetically altered or dysregulated. In this review, we focus on the impact of epigenetic regulation on T-cell differentiation, exhaustion, and tumor infiltration and discuss how epigenetic reprogramming may enhance CAR-Ts' memory phenotype, trafficking, and fitness, contributing to the development of a new generation of potent CAR-T immunotherapies.