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Second edition ICCR dataset for testicular germ cell tumours: a reporting guide for histopathological diagnosis of orchiectomy specimens
No full textTo summarise the content and significance of the recently published second edition International Collaboration on Cancer Reporting (ICCR) histopathology dataset for testicular germ cell tumours, covering the Orchiectomy specimen dataset. We highlight key updates from the first editions, including alignment with the 5th edition World Health Organization (WHO) Classification, revised staging criteria, clarified core data elements versus non-core elements and the evidentiary basis underpinning these changes. A review of the ICCR 2nd edition dataset for Orchiectomy specimens of primary testicular tumours was performed, focusing on their development by an international expert committee using a consensus-based approach. Core (required) and non-core (recommended) data elements were identified along with the level of evidence supporting each, following National Health and Medical Research Council (NHMRC) criteria. Changes from the first edition were extracted by comparing dataset content and notes, informed by up-to-date literature through July 2024. The 2nd edition Orchiectomy dataset provides an integrated, harmonised framework for reporting testicular germ cell tumours. The dataset incorporates the WHO 5th Edition Classification of Urinary and Male Genital Tumours. Pathological staging criteria have been updated to align with the 8th edition Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) definitions. The second edition of this dataset includes changes to align the dataset with the WHO Classification of Tumours, Urinary and Male Genital Tumours, 5th edition, 2022. The ICCR dataset includes the 5th edition Corrigenda, July 2024. It was agreed that this dataset is not suitable for non-germ cell tumours, with the hope that a new dataset, especially for sex-cord stromal tumours, would be developed. The 2nd edition Orchiectomy dataset represents an authoritative, up-to-date standard for pathology reporting of primary testicular germ cell tumours. By incorporating the WHO 5th edition classifications, current TNM staging and the latest evidence on prognostic factors, this dataset facilitates uniform reporting and prognostication. The ICCR dataset underscores core data required for patient management decisions (e.g., adjuvant therapy in Stage I disease, post-chemotherapy management) while providing flexibility through non-core elements for additional useful information. Adoption of this internationally vetted dataset will enhance consistency, assist multidisciplinary treatment planning and align pathology reports with modern consensus guidelines and classifications. The dataset can be used in both high-resource and limited-resource settings without compromising the essential reporting standards
Celebrating the 40-Year Milestone: NF-ĸB in Oncoimmunity
No full textSince its discovery by Dr. David Baltimore nearly 40 years ago, and in light of his recent passing, NF-κB has once again come into sharp focus as a central regulator of diverse cellular processes, including immune responses, inflammation, and cell survival. Its dysregulation is implicated in a wide range of human diseases, with mounting evidence highlighting its pivotal role in cancer and oncoimmunity. This review provides an integrated overview of NF-κB family members and their canonical and noncanonical signaling pathways, emphasizing how context-dependent activation orchestrates complex cellular outcomes. Within the tumor microenvironment (TME), NF-κB regulates crosstalk among cancer cells, immune subsets, and stromal components, promoting proliferation, metastasis, and immune evasion. We summarize FDA-approved and orphan-designated drugs targeting NF-κB, along with emerging therapeutics in clinical and preclinical development. Innovative strategies, including tumor-targeted delivery, immune checkpoint combination, nanocatalytic, and epigenetic modulation, are redefining NF-κB-directed therapy. Looking ahead, future efforts should focus on understanding context-specific NF-κB signaling, optimizing combination therapies, improving drug delivery and bioavailability, and identifying predictive biomarkers for patient stratification. Moreover, the emerging integration of artificial intelligence holds promise to accelerate discovery and personalize NF-κB-targeted therapies. Collectively, FDA-approved agents, experimental compounds, and novel strategies underscore NF-κB modulation as a versatile and promising avenue for cancer and immune disease therapy
Risk factors for mortality in children with hypoxemia in resource-constrained settings: a secondary analysis of Global Paediatric Acute Critical Illness Point Prevalence Study (PARITY)
No full textBackground: Hypoxemia, a mortality predictor and hallmark of pediatric acute respiratory distress syndrome (PARDS), is disproportionately common in resource-constrained settings (RCS). The burden of PARDS in RCS is likely substantial considering the high prevalence of known clinical triggers (e.g., sepsis, pneumonia, trauma), but it is challenging to diagnose due to limited diagnostic resources. We aimed to: (1) describe respiratory care resource availability in RCS hospitals and test whether availability was associated with mortality; (2) determine the proportion of children who presented to RCS hospitals with hypoxemia and their associated outcomes; and (3) test whether, in children with hypoxemia, having a PARDS trigger was associated with mortality.
Methods: We developed and applied operational definitions for five tiered respiratory care resource bundles. Through a secondary analysis of Global Paediatric Acute Critical Illness Point Prevalence Study (PARITY) data, we performed descriptive statistics, hypothesis testing (i.e., chi-square and Wilcoxon rank-sum tests), and logistic regression analyses.
Results: Among the entire Global PARITY cohort (n = 7538), 763 (10.1%) were admitted with hypoxemia. Seventy percent (n = 531) were treated at a site with the intermediate or less respiratory care resource bundle available. Mortality was 6.8% (n = 52) and inversely associated with respiratory resource availability. The odds of mortality were higher for patients treated at sites with the intermediate bundle or less compared to those with the advanced or expert bundle available (adjusted odds ratio [OR] 18, 95% confidence interval [CI] 4.1-83). Fifty-six percent (n = 430) had a PARDS trigger, most commonly pneumonia (n = 256), bronchiolitis (n = 116), and sepsis (n = 58). There was no association between the presence of a PARDS trigger and mortality. Ninety-four percent of patients with a PARDS trigger (n = 405/430) had insufficient data available for a PARDS-related diagnosis according to the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines.
Conclusions: Children with hypoxemia treated at hospitals with respiratory care resource constraints in countries with lower socio-demographic index (SDI) had significantly higher mortality. These findings highlight the importance of ongoing work to improve resource availability, strengthen health systems, and support pediatric healthcare providers in identifying PARDS in order to help clinicians risk stratify children, focus resources, and tailor management to optimize outcomes
Magnesium modulates the stress responses of oral streptococci to environmental and antibiotic challenges by altering cell envelope and nutrient transport pathways
No full textBackground: Magnesium (Mg2+) is one of the most abundant metals in human teeth, second only to calcium. Demineralization of the tooth, caused by sugar intake or acid reflux, releases Mg2+ into the saliva. Mg2+ is also recommended as a dietary supplement for the prevention and treatment of chronic diseases. Oral streptococci, therefore, must regulate Mg2+ homeostasis to adapt to fluctuating levels of saliva in the human oral cavity.
Materials and methods: We determined the toxic concentration of MgCl2 for Streptococcus spp. and used a sub-toxic dose to assess its effect on osmotic and cation-excess stress tolerance. Growth assays, ICP-MS, proteomic analysis, and lipidomic analysis were performed on wild-type and mutant strains lacking a putative Mg2+ efflux pump homolog.
Results: Mg2+ supplementation enhanced tolerance to osmotic and cation-excess stress in both caries-associated and commensal streptococci. Homologs of the magnesium protection factor A (MpfA) were found across Streptococcus groups. Mutants lacking mpfA homologs (smu_1693 in S. mutans, and ssa1761 in S. sanguinis) showed MgCl2 sensitivity. Despite unchanged intracellular Mg2+ levels in Δsmu_1693, the mutant exhibited stress tolerance, consistent with the disruption of magnesium efflux pumps. Proteomic and lipidomic analyses revealed altered levels of amino acid transporters, cell envelope proteins, and an increase in long-chain unsaturated fatty acids. Furthermore, modulating intracellular Mg2+ concentration, either by MgCl2 supplementation or by eliminating HlyX, impacted the efficacy of multiple cell wall-targeting antibiotics.
Conclusion: This study highlights the role of Mg2+ in enhancing stress tolerance and modulating antibiotic sensitivity in streptococci, using S. mutans as a model
P-15 Peptide Enhanced Bone Graft Improves Time to Fusion in Transforaminal Lumbar Interbody Fusion: A Randomized, Controlled, Investigational Device Exemption Study
No full textStudy design: Prospective, multicenter, single-blind, randomized, and controlled pivotal study.
Objective: Compare time-to-fusion in patients treated with P-15L (PearlMatrix TM P-15 peptide enhanced bone graft) versus local autograft over 24 months and evaluate changes in pain and quality of life at 24 months relative to baseline.
Summary of background data: P-15L, an FDA-designated breakthrough device, is a composite bone graft with P-15, a 15-amino acid polypeptide that promotes cellular adhesion, proliferation, and differentiation to support bone formation.
Methods: Patients (22-80 y) with degenerative disc disease were randomized to the investigational (P-15L) or control (local autograft) group during single-level transforaminal lumbar interbody fusion (TLIF) with a PEEK cage and supplemental pedicle screw fixation. Fusion assessments occurred at 6, 12, and 24 months. Time-to-fusion was tested for superiority as compared with the control using Kaplan-Meier survival analysis. Back and leg pain were measured using the Visual Analog Scale (VAS) and quality of life was assessed using the Short Form Survey (SF-12).
Results: The analysis included 290 patients from 33 sites; 141 (48.6%) received P-15L and 149 (51.3%) received local autograft. At randomization, at least one risk factor for pseudoarthrosis (obesity, nicotine use, or diabetes) was reported in 58.9% (83/141) of the investigational group and 60.4% (90/149) of the control group. More patients in the investigational group than the control group achieved fusion at 6 months (Kaplan-Meier fusion rates 57.6% vs. 26.9%, respectively), 12 months (68.8% vs. 41.5%, respectively), and 24 months (81.1% vs. 54.9%, respectively). P-15L was statistically superior to autograft for time-to-fusion (hazard ratio=1.87, 95% CI: 1.47-2.38; P < 0.0001). There was marked improvement in VAS and SF-12 relative to baseline in both groups at 24 months.
Conclusion: P-15L promotes statistically superior earlier time-to-fusion than local autograft in instrumented TLIF. Both treatments resulted in clinically meaningful improvements in pain and quality of life at 24 months
Propyl Gallate Attenuates Methylglyoxal-Induced Alzheimer-like Cognitive Deficits and Neuroinflammation in Mice
No full textMethylglyoxal (MG), a reactive dicarbonyl metabolite associated with diabetes and metabolic disorders, contributes to carbonyl stress, neuroinflammation, and Alzheimer-like neurodegeneration. This study investigated the neuroprotective effects of propyl gallate (PG), a phenolic antioxidant widely used as a food additive, against MG-induced cognitive impairment in mice. Male C57BL/6J mice were exposed to 1% MG in drinking water for eight weeks and orally administered PG (20, 40, or 100 mg/kg/d). Behavioral tests demonstrated that PG significantly improved spatial learning and recognition memory and alleviated anxiety-like behavior induced by MG. Histological and biochemical analyses revealed that PG reduced hippocampal neuronal damage, suppressed tau hyperphosphorylation and amyloid-β (Aβ) accumulation, and attenuated the overexpression of pro-inflammatory cytokines TNF-α and IL-6. Furthermore, PG increased PI3K expression and Akt phosphorylation while reducing activation of GSK-3β, counteracting the MG-induced suppression of this pathway and aligning with reduced tau hyperphosphorylation. These findings indicate that PG protects against MG-related cognitive dysfunction through modulation of neuroinflammatory responses and survival-related signaling pathways, highlighting its potential as a neuroprotective dietary antioxidant for metabolic stress-associated neurodegenerative disorders
Efficacy and Efficiency of In‐House Clear Aligners in Limited Orthodontic Treatment
No full textObjective: To evaluate the efficacy and efficiency of in-house digital software and fabrication of clear aligners.
Materials and methods: This retrospective study analysed pre-treatment, predicted and post-treatment digital scans of 61 patients (42 females, 19 males) to assess the accuracy of predicted tooth movements. Planned and final scans were superimposed using best-fit analysis in Geomagic Design X (Hexagon AB, Stockholm, Sweden). Distoincisal (DI), mesioincisal (MI) and gingival zenith (Z) landmarks were measured perpendicularly from the mid-facial aspect, with differences < 0.5 mm deemed clinically acceptable. Data were analysed using repeated-measures ANOVA with logarithmic transformation, and clinically acceptable movements were compared between groups using generalised estimating equations (GEE).
Results: When evaluated individually, 91% of mandibular and 95% of maxillary landmarks showed clinically acceptable movement. When all three landmarks per tooth were below the threshold, 84% of mandibular and 88% of maxillary teeth met this criterion. At the case level, 48% of mandibular and 50% of maxillary cases achieved overall clinically acceptable movement. The greatest discrepancies were observed at the Z point on maxillary teeth (p < 0.05). Mandibular canine movements were more predictable than those of mandibular incisors (p < 0.05).
Conclusion: In-house aligner planning and fabrication demonstrated effective and efficient outcomes for limited treatment cases. Tooth movement was generally more predictable in the maxilla than in the mandible, with canines showing greater predictability than incisors. Torque movements in the maxilla exhibited the lowest accuracy
Acute anti‐Aβ antibody exposure induces microglial changes and significantly alters chemokine signaling
No full textIntroduction: While the anti-amyloid-lowering immunotherapies provide the first disease-targeting therapies for the treatment of Alzheimer's disease, there remain harmful adverse events causing hesitation among patients, families, physicians, and regulatory bodies. Though these drugs have been repeatedly proven to lower brain amyloid plaque burden, the specific cellular mechanisms and pathways by which the immunotherapy impacts the brain remain unclear.
Methods: This study aimed to transcriptionally profile the brain's immediate immune response to anti-amyloid beta (anti-Aβ) antibodies. To evaluate acute cellular priorities, we intracranially injected anti-Aβ antibody (3D6) or an isotype-matched control immunoglobulin G (IgG) antibody and performed single-cell sequencing analysis after 3 days.
Results: We found reduced numbers of a motile microglia cluster and homeostatic microglia in the 3D6 antibody-injected cortex compared to the IgG-injected cortex. It was also found that chemokine/cytokine signaling was enriched across homeostatic-proinflammatory microglia, interferon-responding microglia, and disease-associated microglia 2 (DAM2) following 3D6 antibody injection. We explored "CCL" signaling, which suggested a change in outgoing signaling coordinated by all microglia types targeting homeostatic microglia, surprisingly not targeting DAM1 or DAM2. We then analyzed enriched signaling pathways clustered by k-means river plots and identified pathways enriched and dampened with acute 3D6 treatment.
Discussion: Together these data supply evidence for significant involvement of microglia in the anti-Aβ response in the brain after just 3 days. Most interestingly, there are changes in cytokine/chemokine signaling across microglia subtypes, specifically with communication in CCL pathways targeting homeostatic microglia and T cells. These acute signaling changes provide novel insights and generate unique hypotheses on the brain's immediate immune reaction to anti-Aβ antibody.
Highlights: Intracranially injected anti-amyloid beta (anti-Aβ) antibody promotes an immediate microglial response.3D6 exposure resulted in fewer homeostatic and motile microglia subtypes. Acute 3D6 enriches for chemokine/cytokine signaling pathways
A novel two-sample Mendelian randomization framework integrating common and rare variants: application to assess the effect of HDL-C on preeclampsia risk
No full textMendelian randomization (MR) has become an important technique for establishing causal relationships between risk factors and health outcomes. By using genetic variants as instrumental variables, it can mitigate bias due to confounding and reverse causation in observational studies. Current MR analyses have predominantly used common genetic variants as instruments, which represent only part of the genetic architecture of complex traits. Rare variants, which can have larger effect sizes and provide unique biological insights, have been understudied due to statistical and methodological challenges. We introduce MR-common and annotation-informed rare variants (MR-CARV), a novel framework integrating common and rare genetic variants in two-sample MR. This method leverages comprehensive genetic data made available by high-throughput sequencing technologies and large-scale consortia. Rare variants are aggregated into functional categories, such as gene-coding, gene-noncoding, and nongene regions, by leveraging variant annotations and biological impact as weights. The effects of rare variant sets are then estimated with STAARpipeline and combined with the estimated effects of common variants by the existing MR methods. Simulation studies demonstrate that MR-CARV maintains robust type I error and achieves higher statistical power, with up to a 66.3% relative increase compared with existing methods only based on common variants. Consistent with these findings, application to real data on high-density lipoprotein cholesterol (HDL-C) and preeclampsia showed that MR-CARV [inverse variance weighted (IVW)] yielded a more precise and statistically significant effect estimate (-0.020, SE = 0.0102, =.0470) than IVW using only common variants (-0.023, SE = 0.0123, =.0659)
Unlocking Ethiopia's genomic landscape and its global significance: a call for inclusive genomics research
No full textEthiopia, located at the intersection of Africa and Eurasia, is a hub of human genetic diversity and cultural richness. Its proximity to the Middle East has historically positioned it as a vital trade corridor connecting Asia, Europe, and Africa. Located along both the “out of Africa” and “back to Africa” human migration routes, Ethiopia has become one of the most genetically, ethnically, culturally and linguistically, diverse countries in the world. This diversity is further shaped by adaptations to a wide range of environments, from the peaks of the Semien Mountains (4550 m or 14,928 feet above sea level) to the arid Danakil depression (100 m or 328 feet below sea level), both of which harbor rich fauna and flora. Despite its strategic location and rich genetic diversity, Ethiopian populations remain underrepresented in global genomics research. This review: (1) highlights key examples of genetic adaptations that shape the Ethiopian gene pool, including positive selection for high- and low-altitude adaptation, lactase persistence, UV exposure, disease resistance, sour taste perception, and metabolism, and (2) calls for genetics studies that incorporate the unique genetic evolutionary history of the Ethiopian population, which can generate important scientific insights. In the era of precision medicine, it is essential to include genetically diverse populations, such as Ethiopia’s, to ensure the advancement of clinical medicine for everyone