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Streptococcus pneumoniae is a Gram-positive, facultative anaerobic bacterium and a leading cause of community-acquired pneumonia, meningitis, bacteremia, and otitis media, responsible for an estimated 1.6 million deaths annually. Despite widespread polysaccharide and conjugate vaccine programs and decades of antibiotic therapy, pneumococcal disease continues to pose major public health challenges. These challenges are increasingly understood to reflect the organism's sophisticated capacity for adaptive recombination, allowing it to exploit every selective pressure applied through vaccination and antimicrobial treatment. This review aims to synthesize current understanding of pneumococcal molecular pathogenesis, virulence factor biology, vaccine evolution, antimicrobial resistance mechanisms, and novel therapeutic strategies, with explicit attention to unresolved questions and clinically consequential knowledge gaps that are inadequately addressed in existing literature. A comprehensive review of the primary and review literature was conducted. The review encompassed pneumococcal colonization biology, capsule and protein virulence factor mechanisms, pilus structure and host-cell interactions, the evolutionary trajectory of conjugate vaccines from PCV7 to PCV21, global antimicrobial resistance surveillance data, and the pharmacology and clinical trial evidence for recently approved antibiotics. Particular attention was given to serotype epidemiology in low- and middle-income country (LMIC) and Indigenous populations, and to resistance dynamics driven by vaccine-era lineage shifts and antimicrobial stewardship challenges. Pneumococcal pili-particularly the RrgA adhesin of pilus islet 1-mediate binding to PECAM-1/CD31 on human brain microvascular endothelial cells, providing mechanistic insight into blood-brain barrier penetration and bacteraemic complications. Capsule expression is dynamically regulated, and the paradox of serotype 1 (thick capsule, high invasiveness, rare carriage) remains unresolved with direct implications for surveillance-guided vaccine design. Analysis of conjugate vaccine evolution reveals that PCV21's deliberate omission of serotypes 4, 6A, 9 V, and 10A creates coverage gaps for Indigenous communities where serotype 4 has re-emerged. Post-vaccine resistance dynamics are coupled to serotype replacement. Multidrug-resistant lineages expressing serotypes 15A, 15C, and 35B are expanding in the post-PCV13 era. Ceftriaxone minimum inhibitory concentration creep among phenotypically susceptible isolates presents an underappreciated clinical risk, particularly in meningitis where cerebrospinal fluid penetration is inherently limited. Azithromycin mass drug administration programs in sub-Saharan Africa generate macrolide resistance prevalences exceeding 60% in treated communities within 12-24 months, with potential for international dissemination. Of the four novel agents approved for community-acquired bacterial pneumonia-ceftaroline, lefamulin, omadacycline, and delafloxacin-none have established pharmacokinetic or clinical efficacy data supporting use in pneumococcal meningitis. S. pneumoniae functions as an integrated adaptive system rather than a pathogen with independent resistance and evasion mechanisms. Iterative vaccine reformulation is approaching diminishing returns without parallel investment in serotype-independent protein vaccines and whole-genome sequencing surveillance. The mismatch between surveillance infrastructure in high-income countries and LMIC settings, where the greatest burden is concentrated, represents a structural inequity limiting global applicability of current policies. Priority areas include expansion of genomic surveillance to LMIC settings, clinical trials with mucosal protection endpoints for protein vaccine candidates, and explicit development of therapeutics with demonstrated cerebrospinal fluid penetration against multidrug-resistant pneumococci.
Hair follicle (HF) aging is a complex process involving gradual deterioration in the function and structure of the HF, adding to degenerative changes in the hair shaft caused by weathering. Despite growing research interest, hair aging remains inconsistently defined in clinical practice, with no universally accepted classification or management guidelines. This study aimed to define hair aging and achieve consensus on diagnostic and management of hair aging. A modified Delphi methodology was used. A European and USA-based scientific committee developed a structured questionnaire, which was distributed to a panel of 24 dermatologists in Europe. Each statement was rated on a 9-point Likert scale. Consensus was defined as a median score of 1-3 or 7-9 with < 1/3 of responses outside this range and an interquartile range (IQR) < 4. Of the 65 statements, 51 (78.5%) reached consensus. Experts agreed that hair aging includes both quantitative and qualitative changes involving pigment loss, hair follicle miniaturization, and declining hair fiber quality. Hair graying was attributed to oxidative stress, melanocyte depletion, and diminished pigmentation-related signaling. Several contributing risk factors were identified. Senescent alopecia was defined as diffuse hair thinning in both androgen-dependent and -nondependent areas. Although diagnostic overlap with androgenetic alopecia (AGA) was acknowledged, the panel emphasized distinct underlying pathophysiology for hair aging, with stem cell exhaustion, fibrosis, and immunosenescence as suspected key mechanisms. Preventative care through lifestyle modification and supportive hair care practices was widely endorsed. Minoxidil was the only pharmacologic therapy to receive consensus support, while other emerging therapies to slow HF aging require further investigation. This Delphi consensus provides a structured expert overview of hair aging, highlights areas of agreement and uncertainty, may assist in improving diagnostic accuracy and more consistent management strategies for age-related hair changes, and identifies potential new targets for therapeutic intervention. Graphical Abstract available for this article. Hair aging is a natural process where hair follicles (the skin structure where hair grows) lose function over time. This leads to graying, thinning, fragility, and sometimes hair loss. Although normal with age, early or severe changes can affect self-esteem and quality of life. This study was carried out in Europe by dermatologists from several countries. Experts in hair disorders aimed to describe what happens during the hair aging process, identify the main factors that can lead to premature hair aging, and offer practical recommendations for prevention and management. These conclusions are based on current scientific evidence and expert opinion. Five experts reviewed scientific studies about hair aging and then wrote 65 statements about hair aging. These statements were sent to 24 dermatologists across Europe. The dermatologists voted on the different statements over two rounds of voting to reach agreement (consensus). Experts agreed that hair aging involves both graying and structural changes in the follicle and hair shaft. Genetics, lifestyle, and environmental factors influence its severity. Signs may be partly reversible, and minoxidil may help in some cases. Cosmetic products can improve appearance, but effective therapies to reverse graying are not yet available. The study provides the first expert-based definition and guidance on hair aging. It highlights that hair aging is not just cosmetic but can affect well-being. Clearer definitions will help doctors counsel patients, guide treatment choices, and support future research into therapies.
Recombinant biologics have transformed modern medicine but face persistent limitations, including high costs ($24,000-500,000 annually), injection burden, immunogenicity, manufacturing complexity ($200-500M in facility investments), and global barriers that limit access for billions worldwide. These challenges drive an urgent need for therapeutic alternatives. We evaluate six primary alternative modalities across FDA- and EMA-approved agents and pipeline candidates (2014-2025): oral small molecules targeting intracellular pathways, RNA therapeutics using gene silencing, CD36-mediated protein degraders (PROTACs), pharmacological chaperones, substrate-reduction therapies, and oral peptide formulations []. Clinical evidence from multiple FDA approvals demonstrates successful substitution: fitusiran achieves an 84-91% reduction in bleeding, iptacopan provides 61% transfusion independence, and deucravacitinib achieves 58.7% PASI-75 response. We identify four mechanistic principles-pathway convergence targeting, functional mimicry, allosteric modulation, and tissue-selective approaches-that can guide recombinant drug substitutions. Manufacturing analysis reveals potential for substantial cost advantages, although actual patient access requires policy intervention beyond market forces. Therapeutic alternatives represent a fundamental evolution in pharmaceutical medicine, with molecular targets rather than modalities determining potential. Success requires a mechanistic understanding, precision patient selection using pharmacogenomics (CYP2D6, CD36 expression), and modality-specific monitoring. While mRNA-based protein replacement currently faces dosing control challenges that limit its suitability for chronic diseases, advances in self-amplifying mRNA and modRNA with controllable expression kinetics may address these limitations. The future landscape will feature complementary modality use optimized for clinical scenarios, with AI-driven discovery and personalized selection potentially improving response rates from 30% to 60% to over 80%. Global access requires technology transfer, regulatory harmonization, and value-based pricing to bridge the gap between manufacturing cost advantages and realized patient benefits. Biologic medicines—complex proteins produced in living cells—have revolutionized treatment for conditions such as rheumatoid arthritis, cancer, and rare genetic diseases. However, these drugs are expensive (often $25,000–$500,000 per year), require injections or infusions, need refrigeration, and remain inaccessible to billions of people worldwide due to cost and infrastructure limitations. This review examines newer drug types that can replace biologics while offering essential advantages: many can be taken as pills, are easier to manufacture, more stable, and potentially more affordable. These alternatives include JAK inhibitors for inflammatory diseases, RNA-based therapies that silence disease-causing genes, drugs that help the body dispose of harmful proteins, and treatments that stabilize malfunctioning enzymes. We identify four scientific strategies that enable these substitutions: targeting shared cellular pathways rather than individual proteins, mimicking natural body processes, using novel drug-binding sites for greater precision, and designing drugs that concentrate in diseased tissues while sparing others. Clinical trials show that these alternatives can match or exceed the effectiveness of biologics—for example, achieving 60–90% improvement in bleeding disorders and skin conditions. While manufacturing costs are lower, patient prices often remain high, highlighting the need for policy changes to improve global access. These therapeutic alternatives represent a fundamental shift toward more accessible precision medicine.
The amyloid cascade hypothesis provided a compelling rationale for Alzheimer's disease (AD) drug development, but many amyloid-β (Aβ)-targeted agents failed to show benefit. The present review article evaluated emerging Aβ-directed therapies, focusing on mechanisms, clinical efficacy, safety, and regulatory progress. The recent approvals of lecanemab and donanemab offered the first convincing evidence that reducing Aβ burden can modestly slow cognitive decline in early AD. Beyond these first-generation monoclonal antibodies, the pipeline includes next-generation antibodies with enhanced brain penetration (trontinemab), therapies designed also for presymptomatic intervention (remternetug tested for secondary prevention), and novel approaches targeting galectin-3 to disrupt Aβ aggregation and neuroinflammation. Active immunotherapies like UB-311 and small molecules such as ALZ-801, avoiding amyloid-related imaging abnormalities (ARIA), broaden the therapeutic horizon with potentially safer and more accessible options, but with no proven efficacy. Clinical benefits for Aβ-centric therapies are modest, ARIA pose ongoing safety concerns, and high costs coupled with intensive monitoring limit accessibility. Regulators have begun to restrict approval to genetically defined subgroups according to apolipoprotein E genotype, underscoring the need for precision medicine. Therefore, while Aβ-centric therapies are incremental, they represent essential steps toward combination and precision strategies in the treatment of AD. Alzheimer’s disease (AD) is a growing global health problem, with no cure currently available. Most existing treatments only relieve symptoms and do not slow the underlying disease process. One of the earliest and most important biological changes in AD is the buildup of amyloid-β (Aβ), a protein that forms plaques in the brain. For this reason, many new drugs have been designed to remove Aβ or prevent it from accumulating. In recent years, several Aβ–targeting therapies have shown that they can successfully reduce amyloid plaques in the brain. These include monoclonal antibodies given by infusion or injection, vaccines that stimulate the immune system, and oral drugs designed to block the formation of toxic Aβ species. Some of these treatments have reached late-stage clinical trials, and a few have received regulatory approval in certain regions. However, while these drugs clearly reduce amyloid levels, their effects on memory and daily functioning are modest, especially when used after symptoms have already appeared. In addition, treatment can be associated with side effects such as brain swelling or small brain bleeds, requiring frequent medical monitoring, costly for healthcare systems. Most evidence so far comes from carefully controlled randomized clinical trials, and real-world experience remains limited. Current research is therefore shifting toward earlier treatment, including prevention in people at high risk, improved drug delivery methods, and combination approaches that also target other disease processes such as tau pathology, inflammation, and vascular or metabolic changes. New blood-based biomarkers are also making it easier to diagnose AD earlier and to select patients more precisely. Overall, Aβ–centered therapies represent an important scientific advance, but they are unlikely to be sufficient on their own. Future progress in AD treatment will depend on better understanding how amyloid may interact with other brain changes, identifying the right patients at the right time, and developing safer, more affordable, and more comprehensive therapeutic strategies.
Familial cancer test referral rates for rare tumors are suboptimal and follow a social gradient; while cancer registries are legally mandated to collect comprehensive clinical pathological data which could be used to inform clinical practice. We aimed to investigate consumer acceptability of and preferred approach for a cancer registry-driven familial cancer testing notification pathway. A qualitative study using semi-structured interviews informed by the Theoretical Framework of Acceptability was conducted. Nineteen individuals recently disclosed to the Victorian Cancer Registry diagnosed with a cancer meeting local familial cancer testing criteria were interviewed. Participants supported being notified directly by the cancer registry to inform them about familial cancer testing, as they welcomed using existing health data in new ways to optimize health care. Key considerations included the timing, tone, language, information provided in the registry communication, and minimizing the onus on the patient. Assuring data security and verifying the legitimacy of the registry were raised. Individuals diagnosed with cancer found the service model acceptable. Participants preferred either to action the findings independently, with supporting resources, or permit the cancer registry to directly inform treating clinicians. Ongoing and consumer-informed work is required to develop processes and resources including digital options. Cancer registries collect information about all new cancer diagnoses. This information could help identify people who might benefit from genetic testing, especially for rare cancers. However, not many people are currently referred for this testing. We wanted to know if people would be comfortable with cancer registries contacting them about genetic testing and how best to do this. We interviewed 19 people to get their thoughts. Most people were comfortable with the registry reaching out because they liked the idea of using health information to improve patient care. They had some important considerations including: making the contact easy to understand; taking care when and how to contact people after their diagnosis; including key information and helpful links; keeping it simple and not too much work for the patient; ensuring data is kept safe; and the registry is trustworthy. People thought this approach could help more patients and their families get genetic testing when needed. However, they felt it was important to do it in a way that respects patients’ feelings and privacy. We need to do more research with patients and clinicians to identify the best way for cancer registries to contact people about genetic testing. This could help improve care for people with rare cancers and their families.
Accumulation of amyloid-beta is highly important in the development of Alzheimer's disease. Given the limitations of the amyloid cascade hypothesis and the repeated clinical failures of anti-amyloid-beta therapies, researchers are increasingly exploring the infection hypothesis. This review explores the dual behaviors of amyloid-beta in Alzheimer's disease, with a particular focus on its protective role against infection by microorganisms and its complicated connections with innate immune system. This new opinion holds that amyloid-beta can play an antimicrobial peptide role. During microbial invasion, its original role is to protect neural tissue, but prolonged accumulation leads to chronic deposition and involvement in pathological processes. Evidence from in vitro experiments, animal models, and clinical studies indicates that amyloid-beta may possess antiviral and antibacterial properties, particularly against infections such as (herps simplex virus) HSV, (human immunodeficiency virus) HIV, and Porphyromonas gingivalis. However, excessive accumulation of amyloid beta triggers a neuroinflammatory cascade that impairs neuronal regeneration and cognitive function. Despite substantial research into Alzheimer's disease, current treatments have not yielded significant clinical benefits. Although monoclonal antibodies such as Aducanumab, Lecanemab, and Donanemab have been approved for marketing, their strict indications and high costs pose challenges for widespread promotion. The infection hypothesis of amyloid-beta has spurred clinical trials investigating vaccines targeting specific pathogens to assess their potential in preventing or treating Alzheimer's disease. This highlights the need for further exploring the multifaceted role of amyloid-beta in Alzheimer's disease. In addition, microbial infections can also trigger or regulate genetic and epigenetic factors, accelerating amyloid beta deposition. Among them, the apolipoprotein E epsilon 4 allele is the strongest genetic risk factor for Alzheimer's disease, as it exacerbates the accumulation of amyloid beta and promotes neuroinflammation. Strategies targeting epigenetic regulation may provide novel approaches to inhibit Alzheimer's disease pathology. This review also integrates various technologies such as genomics, proteomics, and metabolomics. This provides a broader system-level understanding of the risk gene loci, protein interaction networks, and metabolic changes associated with amyloid beta under the influence of microbial infections. Such techniques may lead to the identification of new molecular targets, the development of individualized treatment strategies, and the creation of early biomarkers for use in clinical research. In conclusion, this review suggests that amyloid-beta is not merely a pathological by-product but an environmentally responsive molecule with dual functions. A deeper understanding of the dynamic regulation of amyloid-beta, considering infection status and disease stage, can provide new directions for treatment strategies aimed at the prevention and treatment of Alzheimer's disease.
Heart failure is not simply a pump that has grown tired; it is a tissue that adapts and then, too often, becomes locked into its adaptations. This review examines how epigenetic regulation - chromatin accessibility, histone modifications, DNA methylation and hydroxymethylation, and the reader complexes that interpret these marks - converts transient stress into durable transcriptional programs. We focus on the mechanisms by which the failing heart acquires regulatory "memory," and on the chromatin control nodes that are emerging as actionable targets for therapy and for biomarker development. Three lines of evidence are reshaping the field. First, the failing-heart transcriptome is increasingly governed by a tractable set of chromatin control points: acetylation balance [histone deacetylases (HDACs) versus histone acetyltransferases (HATs) such as p300/CREB-binding protein (CBP)] and acetyl-lysine readers [bromodomain and extraterminal (BET) proteins, including bromodomain-containing protein 4 (BRD4)] that amplify hypertrophic, inflammatory, and profibrotic programs. Second, the adult human myocardium is not epigenetically inert: reproducible disease-associated methylation signatures and regulatory shifts are detectable across cardiomyopathy and ischemic heart failure, with early signals that some features may move with physiologic recovery. Third, acute stress phenotypes are being reframed as chromatin-state problems: Takotsubo syndrome compresses stress-to-dysfunction into days, and emerging mechanistic work supports an acetylation/deacetylation axis as a tractable regulatory lever in Takotsubo-like injury. Epigenetics provides a mechanistic account of why cardiac injury can outlast its trigger and a rational route to intervention by targeting reader complexes, writer-eraser balance, and remodeler-mediated enhancer control. The translational mandate is precision: define causal regulatory nodes by cell type and disease phase and develop biomarkers that distinguish hemodynamic improvement from molecular reset.
As genetic testing becomes increasingly relevant to precision public health, understanding the preparedness of the public health workforce is essential. In the United Arab Emirates (UAE), national initiatives such as the Emirati Genome Program are progressing rapidly; however, the integration of genetic testing into public health training and practice remains limited. To examine the knowledge, attitudes, and training on genetic testing among public health professionals and students in the UAE, and to identify perceived barriers and enablers to its integration into public health practice. A qualitative descriptive design with embedded quantitative components was used. Semi‑structured interviews were conducted with 19 purposively selected public health stakeholders, including faculty members, postgraduate students, and public health professionals. Participants completed a brief pre‑interview survey capturing demographics, education, and self‑reported and objective knowledge on genetic testing. Qualitative data were analyzed using structured coding procedures, and quantitative data were summarized descriptively. Training on genetic testing was limited across undergraduate and postgraduate education, and most participants rated their knowledge as insufficient. Participants demonstrated moderate understanding of analytic validity, clinical validity, clinical utility, and the existence of international guidelines. However, some knowledge questions showed noticeably lower correct‑response rates. Despite these gaps, participants expressed positive attitudes toward the relevance of genetic testing for public health. Four themes emerged: recognition of genetic testing's value for disease prevention; sociocultural and ethical considerations influencing public acceptance; the need for enhanced education and institutional capacity; and cautious support for regulated consumer‑initiated genetic testing. Public health professionals and students who participated in the current study in the UAE show strong interest in genetic testing but report suboptimal training. Addressing these gaps will require systematic integration of genomics into public health curricula, targeted workforce development, and supportive policy frameworks aligned with national precision health initiatives.
Teachers play a crucial role in fostering supportive environments for all students. However, research indicates that their knowledge and attitudes toward stuttering are often similar to those of the general population. The primary aim of this study is to examine the attitudes of teachers at different educational levels in Spain toward stuttering and to explore how these attitudes relate to specific sociodemographic variables. A cross-sectional, self-report design was employed with a sample of 250 teachers from various educational levels and teaching roles across Spain. Participants completed the Public Opinion Survey on Human Attributes-Stuttering (POSHA-S). Overall, the attitudes of teachers in Spain toward stuttering were generally positive and exceeded those observed in other comparison groups, except for the Knowledge Source component. Positive attitudes toward stuttering were strongly associated with factors reflecting experience and knowledge, such as training in stuttering, teaching students who stutter, current teaching role, and self-identification as a person who stutters. Our findings highlight the importance of providing teachers with targeted training and direct experience with students who stutter to foster supportive attitudes. What is already known on the subject Attitudes toward stuttering can significantly affect the wellbeing and development of people who stutter. While these attitudes have been studied internationally, no research has examined teachers' attitudes in Spain toward students who stutter. What this paper adds to existing knowledge This study shows that teachers in Spain-including School-Based Speech-Language Pathologists (SLPs) and Special Education Teachers-generally hold more positive attitudes than those reported in previous studies. However, some harmful beliefs remain, such as underestimating genetic factors or perceiving students who stutter as shy, introverted or incapable of demanding tasks. What are the potential or actual clinical implications of this work? The lack of experience, training and information about stuttering, along with the better attitudes of specialized teachers, highlights the need to prioritize stuttering in the SEN agenda to address biased beliefs and reactions toward students who stutter.
Heart pumping weakness occurs progressively in all patients with Duchenne muscular dystrophy (DMD), but symptoms only occur very late in the process. Regular imaging assessments of heart function are needed to see how the heart is 'doing' and how well it is responding to treatment with heart drugs. Echocardiography (echo) has been the standard type of imaging used for these assessments in the UK. It is widely available but has limitations. Cardiac MRI (CMR), although less readily available and more expensive, is better able to detect tissue changes in the heart before there is any reduction of heart pump function and retains accuracy in all measures even as DMD progresses. An expert panel of cardiologists, muscle specialists and patient representatives was set up to review evidence and provide expert guidance on how to use both echo and CMR best to the benefit of patients with DMD, Becker muscular dystrophy (BMD) and females affected by DMD-gene abnormalities ('female gene carriers').The working group concluded that echo should remain the predominant method used in heart checks for patients with DMD in the UK. However, wider use of CMR, performed at times individualised to key decision points after about the age of 10 years, would allow earlier detection of those heart changes prompting the introduction and changes in heart therapies. Similarly, greater use of CMR could contribute to improving cardiac management of males with BMD and females with DMD-gene variations._______________________ OBJECTIVE: To provide guidance on the use of cardiac MRI (CMR) in the UK in paediatric and adult patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) as well as recommendations for screening and monitoring females with dystrophin-gene variations. Specifically, to examine the 'added value' of CMR over echocardiography at selected time points in the assessment of individuals with or at risk of developing cardiac dystrophinopathy. METHODS: Initiated by an expert working group of UK-based and US-based imaging cardiologists, neuromuscular clinicians and DMD-patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK cardiologists, consensus was reached on the optimal use of CMR in clinical decision-making about therapy. RESULTS AND CONCLUSIONS: Echocardiography should remain the predominant modality for cardiac surveillance and to guide therapy for patients with DMD in the UK. However, when tolerated, wider use of CMR at key stages in patients with DMD, older than age 10 years, and for males with BMD and females with DMD-gene variations would allow earlier detection of those with cardiac involvement and inform the earlier initiation of regimes of cardiac medications. In this way, greater use of CMR could contribute to improving cardiac health in each of these patient groups.
Stroma areactive invasion front area (SARIFA) was recently defined and introduced as a histomorphological, prognostic biomarker for various carcinomas. Current state of research and prospects for future developments. Report on the results of the consensus meeting. Evaluation of the available literature and the results of the consensus meeting. SARIFA has been successfully established as a strong prognostic biomarker. Its advantages include rapid, almost cost-neutral determination and excellent low interobserver variability. SARIFA correlates with increased expression ofproteinases and lipid metabolism proteins and genes. The immune response, by contrast, is downregulated in SARIFA-positive tumours. The consensus experts confirm the prognostic relevance in gastric and colorectal carcinomas and advocate routine reporting. The role of the biological background should be investigated in further studies and the name should be reconsidered and, if necessary, adapted. SARIFA is a prognostically relevant and robust biomarker. The evidence is particularly strong for gastric and colorectal carcinomas. HINTERGRUND: SARIFA („stroma areactive invasion front area“) wurde kürzlich als histomorphologischer, prognostischer Biomarker für verschiedene Karzinomentitäten definiert und eingeführt. Der gegenwärtige Stand der Forschung und die Aussicht auf künftige Entwicklungen werden dargestellt. Außerdem wird ein Bericht über die Ergebnisse der stattgefundenen Konsensuskonferenz gegeben. Verfügbare Literatur und der Ergebnisse der Konsensuskonferenz wurden ausgewertet. SARIFA konnte als prognostischer starker Biomarker erfolgreich etabliert werden. Vorteile ist die schnelle und nahezu kostenneutrale Erhebung mit exzellenter Reproduzierbarkeit. SARIFA korreliert mit einer gesteigerten Expression von Proteinasen- und Lipidstoffwechselproteinen sowie Proteinasen- und Lipidstoffwechselgenen. Die Immunantwort hingegen ist in SARIFA-positiven Tumoren herunterreguliert. Die Konsensexperten bestätigen die prognostische Relevanz in Magen- und kolorektalen Karzinomen und befürworten die routinemäßige Erhebung des SARIFA-Status. Die Rolle der zugrundeliegenden biologischen Mechanismen soll in weiteren Studien untersucht und die Namensgebung überdacht und gegebenenfalls angepasst werden. SARIFA ist ein prognostisch relevanter und robuster Biomarker. Besonders hoch ist die Evidenz für Magenkarzinome und kolorektale Karzinome.
Insect polyphenisms are an extreme form of phenotypic plasticity that arises when environmental cues are transduced into endocrine signals that redirect development, producing discrete morphs from a single genome. Aphid wing polyphenisms have been important to establishing this framework. In asexual females, stress-inducing conditions result in winged daughters, whereas benign environments yield wingless offspring. Classic work emphasized juvenile hormone, but recent evidence points to a causal role for ecdysone. Upstream neurotransmitter pathways, including glutamate and possibly dopamine, translate tactile crowding into endocrine responses, while downstream processes such as autophagy, Transforming growth factor (TGF-β) signaling, and insulin signaling shape wing development. Epigenetic mechanisms, including microRNAs and chromatin modifiers, stabilize morph-specific transcriptional states. Collectively, these studies outline a multi-step process, from environmental sensing to neuroendocrine integration, hormonal signaling, and epigenetic maintenance, that governs aphid wing plasticity. Emerging genomic and chromatin profiling tools now position aphids as a powerful model for dissecting environmentally induced developmental plasticity.
This review summarises recent findings from the past decade on infraoccluded primary molars, focusing on diagnosis, aetiology, prevalence, associated findings and clinical consequences, and to compare these with earlier literature to support improved clinical management. A systematic literature search was conducted according to PRISMA guidelines, evaluating MEDLINE (PubMed), Cochrane Library, Web of Science, and Embase from 2014 to 2025. Randomized controlled trials (RCT), non-randomized studies of interventions (NRSI), cohort studies, case-control studies and cross-sectional studies published in English and German were included. Case series, case reports, expert opinions and commentaries were excluded. Of 2816 publications identified, 30 met the inclusion criteria after screening and full-text review. These studies addressed prevalence (n = 17), retained molars (n = 4), retained molars without successors (n = 5), aetiology (n = 1), diagnosis (n = 1), mandibular growth impact (n = 1), and interventions (n = 1). Current evidence provides new insights into the aetiology and clinical management of infraoccluded primary molars. Genetic factors, particularly those related to epithelial development and inflammatory signalling pathways, are increasingly recognised. Conservative treatment approaches have gained traction, emphasizing alveolar preservation over orthodontic considerations of craniofacial growth. Most cases are mild and occur unilaterally in mandibular first primary molars. Early-onset infraocclusion is linked to a less favourable prognosis. Root resorption shows age-related variability. However, conflicting evidence exists regarding the association of infraocclusion with root resorption, especially in cases of tooth agenesis, and its correlation with mandibular growth rotation. Additionally, prevalence data remain inconsistent due to heterogenous classification, underscoring the need for further research.
IMNN-001 is designed for local and durable delivery of a pluripotent anti-tumor cytokine, IL-12, using an expression plasmid and a synthetic lipopolymer delivery system. IMNN-001, delivered intraperitoneally in combination with chemotherapy, is currently in a Phase 3 trial for the front-line treatment of advanced epithelial ovarian cancer. This report details IMNN-001 preclinical and clinical development, demonstrating local and durable production of IL-12, minimal systemic exposure and manageable safety profile, as well as its antitumoral effects in a total of six completed trials in ovarian cancer. In the OVATION-2 Phase 2 randomized trial, neo- and adjuvant chemotherapy combined with IMNN-001 produced a numerical 13 month increase in overall survival, with even greater benefit in tumors that lacked DNA homologous repair activity. In translational studies, IMNN-001-induced changes in the tumor microenvironment are consistent with the observed induction of IL-12 and IFN-γ levels at the tumor site and support the hypothesis that IMNN-001 treatment alters the tumor microenvironment in favor of broad immune stimulation and inhibition of immunosuppressive mechanisms. IMNN-001 gene therapy could add clinically meaningful IL-12-driven immunotherapy to newly diagnosed ovarian cancer patients. IMNN-001 holds promise for synergistic combinations with immunotherapies requiring intrinsic immune activity. The recent ability to harness a patient’s own immune system to control or destroy a tumor has revolutionized the care and outcomes in many types of cancers. Unfortunately, up to this time, such efforts have been unsuccessful in ovarian cancer, where the standard of care has not improved for 25 or more years. The barrier in ovarian cancer is that the tumor is not recognized by the body’s defense mechanism. IMNN-001 represents a new and promising approach to this problem. IMNN-001 is designed to stimulate tumor cells and the cells surrounding the tumor to make IL-12, a natural molecule which strongly activates the body’s natural response against the tumor, resulting in the destruction of the malignant cells. In previous and ongoing studies, beneficial outcomes of IMNN-001 on tumor response and survival have been observed with a manageable safety profile. A large clinical trial is ongoing, with the hope that IMNN-001 could provide a new, safe, and novel treatment for women with advanced ovarian cancer.
Inflammatory bowel disease (IBD) arises from dysregulated interactions between the immune system and the intestinal microenvironment. Finding new therapeutic targets could help to develop treatments that attenuate its severity. The present study investigated the immunomodulatory potential of bioaccessible sulforaphane (SFN, 0.100 μg/mL) from broccoli by-products. Interestingly, the main results evidenced that at this physiological concentration, SFN contributed to reducing the secretion of pro-inflammatory interleukins (IL-1β, IL-6, IL-17, IL-18, IL-23, TNF-α) by intestinal epithelium up to ~56%, whereas enhancing anti-inflammatory cytokines (IL-10, IL-4, IL-13) between ~24% and ~71%. These changes adjusted the proportion of CD86+ and CD206+ during macrophage differentiation, associated with the prevention of immune-mediated IBD. In addition, a reduction in the expression of macrophage-dependent pro-inflammatory cytokines and an augmentation of the tolerogenic classes were observed. The combined use of intestinal epithelial (Caco-2) and monocytic (THP-1) cell lines established an in vitro model of the epithelium-macrophage crosstalk, thereby enhancing the physiological relevance of our findings. These results were confirmed using a pure SFN-based model system, which demonstrated SFN's contribution to the anti-inflammatory properties of broccoli stalk and bridged the gap between in vitro findings and potential dietary/therapeutic applications. Thereby, this work demonstrated that dietary SFN contributes to a large extent to the reshaping capacity of the phytochemical burden of broccoli stalks, on the interleukin profile secreted by epithelium and macrophages, as well as the macrophage differentiation, thus supporting the valorisation of broccoli by-products for preventing and managing inflammatory conditions, such as IBD.
Addictive behaviors-including the misuse of tobacco, alcohol, illicit substances, and compulsive activities such as gambling, overeating, and sexual excess-remain widespread and profoundly burdensome on both individuals and societies. Their impact is multifaceted, encompassing adverse health outcomes, increased criminal activity, and significant economic costs due to lost productivity. Addiction is a highly complex condition shaped by genetic predispositions, environmental influences, and behavioral factors, all of which contribute to disruptions in neural regulation and compulsive decision-making. While advances have been made in identifying the genetic and biochemical underpinnings of addiction and related psychiatric disorders, progress in developing broadly effective therapies has been limited. Addiction is often characterized by feelings of fragmentation, helplessness, and existential despair-phenomena that may reflect a deeper, unmet need for personal integration, purpose, and transformation. This perspective supports the notion that spiritual yearning can be an integral part of the recovery process. Efforts to address addiction have frequently overlooked the potential therapeutic value of spirituality in fostering healing. If one accepts the premise that the brain governs both conscious and unconscious experience-including religious and spiritual phenomena-it follows that addiction, and mental illness may involve disrupted neural systems that regulate reward and suffering. We propose that individuals may have differing capacities for spiritual resilience or growth based on a dynamic interplay between their genetic architecture and epigenetic factors (e.g. life experiences, trauma, social environment). This expert opinion presents current evidence supporting this hypothesis and highlights the relevance of the Hierarchical Neuro-Spiritual Model (HNSM) as a novel framework for understanding the spiritual dimension in the pathophysiology and treatment of addiction.
The International Neonatal Consortium Seizure Working Group of the Critical Path Institute provides an update to the original recommendations for design of clinical trials to treat neonatal seizures based on recent experiences from several trials and developments in the field. Although there aren't sufficient new data to inform definitions of optimal efficacy endpoints, the Working Group recommended inclusion of alternate measures of seizure burden reduction as secondary or exploratory endpoints, to elucidate clinically meaningful efficacy endpoints for future trials. It was recommended to include additional key covariates, such as timing of seizure onset/cessation, randomization, and ASM administration. There are new recommendations regarding potential for unmasked or single-masked trials, and reporting of concomitant medications and adverse events, and genetic testing. Importantly, specific recommendations were added regarding improved strategies for recruitment and consent, including the use of novel technologies and the involvement of patient advocacy groups. Recommendations regarding trial infrastructure and operational feasibility were included to facilitate trial initiation and conduct, given the many logistical challenges of conducting neonatal seizure treatment trials. Finally, the recommendations consider accommodations for local or national regulations and resources, to ensure that trials are conducted as appropriate to the setting in which the patients are treated. IMPACT: This review provides an update to the initial recommendations for neonatal seizure treatment trial design, with recommendations regarding: (1) exploratory endpoints to inform future trials, (2) additional key covariates to include, (3) considerations regarding masking of investigators, (3) inclusion of concomitant medications and adverse events, (4) genetic testing, (5) strategies for recruitment and consent, and (6) infrastructure and operational feasibility.
Potassium conductances regulate neuronal excitability across heterogeneous disorders, controlling thresholds, repolarization, adaptation, and bursting at a low energetic cost. However, translating this biology into therapeutic stratification remains incompletely validated. This reviewdistinguishes established potassium-channel mechanisms from conceptual integration and future-facing translational proposals. Based on the literature identified through searches for PubMed/MEDLINE, Embase, Web of Science Core Collection, and Scopus (inception-May 2026), this review advances an 'excitability fingerprint' translational framework, linking microdomain-resolved gating to network stability and future biomarker-enriched therapeutic development. Voltage-gated potassium channels, big- and small-conductance Ca2+ -activated K+ channels , inwardly rectifying , ATP-sensitive and two-pore domain potassium channels are gated by phosphatidylinositol 4,5-bisphosphate (PIP2), Ca2+, redox, and pH across neural and glial microdomains. A tri-axial fingerprint is defined: electroencephalography (EEG)/high-frequency oscillation (HFO) and transcranial magnetic stimulation (TMS) metrics; microdomain tone (PIP2/redox); and astroglial K+ buffering, modulated by age, sex, genetics, and metabolic-inflammatory comorbidities. Biomarker-anchored titration uses electrophysiology, molecular panels of redox and acid-base status, and patient-derived induced pluripotent stem cell (iPSC) assays of PIP2-dependent M-current rescue. Fingerprint-guided K+ modulation can compress time-to-response and manage network-level risk, supporting standardized pipelines, practical microdomain assays, and response-adaptive trials to implement individualized therapeutic windows.
Despite licensing many new antiseizure drugs over the last few decades, the proportion of pharmacoresistant epileptic seizures has remained largely unchanged at about 30%. However, recent progress in genetics has revealed new and more specific therapeutic targets that can be addressed through improved drug design and advancements in gene therapy, such as improved antisense oligonucleotide chemistry. Furthermore, many of these developing new precision therapies hold the promise of shifting from purely symptomatic toward disease-modifying treatment, particularly in the field of developmental and epileptic encephalopathies. This article focuses on novel potential therapeutic targets, including those encoded by causative genes for epileptic syndromes and those that show promise for favorably impacting common epilepsies or epileptogenesis. The covered areas are organized according to different molecular protein targets. Therapy in the near future will likely be based predominantly on specific small molecules or gene therapies, such as antisense oligonucleotides. Among currently used allele-specific therapeutic designs, only some loss- or gain-of-function pathological variants are expected to profit from them. Allele-specific gene therapy may be a promising treatment for those diseases that would not benefit from currently used allele-nonspecific designs. Over the last 30 years, the success rate for stopping seizures has not changed much. However, new discoveries in genetics have helped us identify many new proteins responsible for inherited epilepsies. This knowledge can be used to design new therapies that do more than just stop seizures. They may also treat other symptoms, such as intellectual disability, behavioral issues, movement problems, or feeding difficulties. Because these new treatments are designed to target the exact disease mechanism of a patient’s epilepsy, they are called personalized or precision medicine. This approach is expected to have fewer side effects and better tolerability than casual anti-seizure medications, since those usually also have other targets and are less specific. These treatments are only possible thanks to breakthroughs in chemistry that allow us to create drugs that were previously impossible to develop. One important category involves therapies based on small pieces of genetic material (DNA or RNA). We expect to see many new drugs in this specific area. In this article, we have listed the most promising new therapies. While most are designed for inherited epilepsies, some may also work for more common types of the condition. We have organized these new targets based on how they function within a cell. The coming years will show whether these new therapies can fulfill our hopes of not just treating epilepsy, but perhaps even curing it.
Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in CTNS, which encodes cystinosin, a H+/cystine symporter that mediates cystine efflux from lysosomes. Defective cystinosin leads to accumulation of cystine in lysosomes and the formation of cystine crystals in most tissues. In its more severe and frequent form, infantile nephropathic cystinosis, patients present with renal Fanconi syndrome in the first 2 years of life, which progresses to chronic kidney disease. Since the 1970s, cysteamine therapy and improvements in dialysis and transplantation have substantially improved patient outcomes, and currently most patients survive into adulthood. Consequently, the diagnosis and management of extra-renal complications that develop later in life have become increasingly important. In addition to the kidneys, commonly affected organs include the eyes, the musculoskeletal system, the central nervous system, exocrine glands and endocrine organs. Cystinosis therefore requires integrated care that involves multiple medical specialties and a structured transition plan from paediatric to adult care. Herein, we present evidence-based and expert opinion-based clinical practice recommendations, developed by a team of international specialists and patient representatives following the GRADE methodology, to improve the diagnosis and management of cystinosis in children and adults.