Int. J. Transl. Med., Volume 6, Issue 2 (June 2026) – 10 articles

Background/Objectives: Multiple myeloma (MM) is a genetically complex hematological neoplasm driven by accumulating genomic events. Despite therapeutic advances, MM remains an incurable disease with a complex molecular picture. Characterizing copy number alterations (CNAs) represents a promising strategy to identify dysregulated biological pathways and reveal novel therapeutic targets. This study aimed to characterize the CNA profile across pre-malignant gammopathies, MM, and plasma cell leukemia, identifying the key molecular pathways involved in disease progression. Methods: Genomic analysis via array comparative genomic hybridization (aCGH) was performed on bone marrow samples from 21 patients representing all disease stages. Data were analyzed in CytoGenomics software version 5.3.0.14 utilizing the GRCh38/hg38 human genome. CNAs were identified with the ADM-2 algorithm, followed by functional enrichment analysis to determine significantly overrepresented pathways. Results: Pre-malignant evaluation suggested a potential functional switch from innate immunity and olfactory signaling in Monoclonal Gammopathy of Undetermined Significance (MGUS) to DNA repair mechanisms in Smoldering Multiple Myeloma (SMM), marking early genomic instability. In active MM, 280 CNAs were detected. Low-risk (ISS-I) patients retained cell adhesion signatures, whereas high-risk (ISS-III) profiles exhibited extensive genomic instability affecting tissue remodeling and cytokine signaling. Conclusions: In summary, our descriptive findings suggest that early alterations in immune response and olfactory signaling pathways may emerge as potential triggers driving pre-malignant dyscrasias and active MM development. Full article

Background/Objectives: Posterior cortical atrophy, also referred to as Benson’s syndrome, is a presentation of Alzheimer’s disease that occurs in 5–15% of Alzheimer’s patients. Visual processing is the predominantly affected modality in posterior cortical atrophy, and symptoms such as prosopagnosia, simultanagnosia, alexia, optic ataxia, and visual hallucinations may occur, as well as blurred vision and visual distortions. Posterior cortical atrophy is considered to be a disease without a known cause or effective treatment. Methods: Here, we report a patient with posterior cortical atrophy who responded to a personalized, precision medicine protocol. Results: The patient had improved MRI volumetrics, symptoms, and cognitive testing. She regained the ability to read, use a computer, and undertake computer-based brain training, among other cognitive improvements. She has now sustained this improvement for over one year and continues to regain her independence and confidence. Conclusions: These results argue for additional laboratory testing in the evaluation of patients with posterior cortical atrophy, and they support the possibility of utilizing a similar approach in a proof-of-concept trial. Full article

Background/Objectives: Osteoarthritis (OA) is an age-related degenerative joint disease whose pathogenic mechanisms remain poorly understood. Experimental evidence implicates dysregulated mechanotransduction mediated by Piezo1 and TRPV4 channels, but how their interaction with inflammation may drive pathogenic state transitions remains unknown. Here, we aimed to study whether a Piezo1–TRPV4 network can intrinsically produce distinct stable physiological and pathological regimes. Methods: Based on literature data, we developed a nonlinear dynamical model describing closed-loop interactions involving Piezo1, TRPV4, and inflammation. The system was translated into a set of ordinary differential equations and studied using stability and bifurcation analysis. Results: Computational analysis revealed bistability, allowing the system to shift from a physiological to a pathogenic regime in response to specific stimuli. Critical bifurcation parameters were linked to Piezo1 and inflammation, suggesting that the bidirectional interaction between these two components represents a key node for interventions aimed at preventing or reversing transitions from non-pathogenic to pathogenic states. Conclusions: Our results suggest that OA pathogenesis may emerge from the intrinsic nonlinear dynamics of Piezo1/TRPV4/inflammation interactions. Bifurcation analysis indicates the sensitivity of TRPV4 to the inhibitory effect of Piezo1 as a key target for preventing or reversing pathogenic state transitions. Further investigations in preclinical and clinical settings are warranted to validate the model. Full article

Background/Objectives: Glypican-1 (GPC1) is a heparan sulfate proteoglycan that plays a critical role in regulating various signaling pathways and tumor development. Overexpression of GPC1 promotes tumor cell proliferation and invasiveness, and is associated with poor clinical outcomes. Therefore, anti-GPC1 monoclonal antibodies (mAbs) have been developed in various modalities for tumor therapy. Methods: We developed novel anti-GPC1 mAbs using a flow cytometry-based high-throughput screening approach, the Cell-Based Immunization and Screening (CBIS) method. Results: A clone G₁Mab-28 (IgG₁, κ) reacted with GPC1-overexpressed Chinese hamster ovary-K1 (CHO/GPC1), but not parental CHO-K1, in flow cytometry. Furthermore, G₁Mab-28 recognizes the endogenous GPC1-expressing human esophageal squamous cell carcinoma KYSE770 cell line. Furthermore, G₁Mab-28 specifically recognized only CHO/GPC1, but not the other GPC family-overexpressed CHO-K1. The dissociation constant values of G₁Mab-28 for CHO/GPC1 and KYSE770 were determined to be 3.3 × 10⁻⁸ M and 4.6 × 10⁻⁹ M, respectively. Moreover, G₁Mab-28 is suitable for Western blotting and immunohistochemistry. Conclusions: G₁Mab-28, established by the CBIS method, is versatile for basic research and is expected to contribute to antibody-based tumor therapy. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) improve outcomes in metastatic non-squamous non-small cell lung cancer (NSCLC), yet predictive biomarkers remain limited. This study investigated whether CD34-stained microvessel density (MVD) is associated with ICI efficacy. Methods: Patients with metastatic non-squamous NSCLC and tumor specimen suitable for anti-CD34 immunohistochemistry were included. In the derivation cohort, ROC analysis for objective response rate (ORR; CR + PR) identified a Youden-optimized threshold of 14.5 vessels/HPF (×400) (sensitivity 67%, specificity 93%; AUC 0.744, 95% CI 0.53–0.95; p = 0.021), which was applied without re-optimization to an internal validation cohort and a chemotherapy-only comparator. Results: In the derivation cohort, (n = 25), ORR was higher with MVD ≥ 14.5 than <14.5 (88.9% vs. 25.0%; p = 0.004) and OS/TFST were longer (OS: 53.0 vs. 17.1 months, p = 0.037; TFST: 50.0 vs. 6.0 months, p = 0.014). In the validation cohort (n = 13), MVD ≥ 14.5 was associated with longer TFST (9.0 vs. 4.0 months; p = 0.035) and numerically longer OS (12.0 vs. 7.0 months; p = 0.059). As a cut-off-independent sensitivity analysis, continuous MVD (per five vessels/HPF) was associated with longer TFST (HR 0.663, 95% CI 0.454–0.969; p = 0.034). No association was observed in the chemotherapy-only cohort. Conclusions: Higher CD34-MVD may be a feasible vascular metric associated with ICI outcomes that warrants prospective validation. Full article

Mild traumatic brain injury (mTBI) contributes substantially to years lived with disability (YLD), decreases health-related quality of life, and imposes significant costs on healthcare systems and society. Millions of people experience mTBI each year, and healthcare costs for mTBI in just the first year after injury exceed $44 billion USD. Despite the common occurrence of mTBI, estimates of incidence, prevalence, related disability, and costs vary widely. This variance is attributed to the underreporting of head impacts, inconsistent definitions of mTBI, and a lack of objective biomarkers. Currently available clinical blood biomarkers primarily assist in ruling out CT-detectable intracranial injury rather than definitively diagnosing mTBI itself, underscoring the continued need for objective, portable, and clinically specific biomarkers. Numerous imaging findings, blood proteins, and physiological measures are under investigation for these purposes, and some may have multiple uses. Specific biomarkers for acute diagnosis are needed urgently. Although many systematic reviews have been published, most focus on a single biomarker or class of biomarkers. Given the breadth of potential biomarker categories, conducting a comprehensive, systematic review across modalities is challenging. Here, we provide a narrative review summarizing the extant literature across major biomarker domains studied in adolescents and adults. We emphasize candidates supported by the most robust evidence to guide continued research and clinical translation. Full article

Background: The long-term cardiovascular safety of high-dose intravenous mesenchymal stem cell (MSC) therapy remains insufficiently characterized in real-world clinical settings. Methods: We conducted a single-center retrospective observational study of patients who received high-dose intravenous MSC therapy. Cardiovascular events were identified through follow-up records. Observed event incidence was compared descriptively with age-adjusted population reference data. Statistical analyses were performed using two-sided Poisson methods. Results: Among treated patients, a total of four cardiovascular events were recorded during follow-up. The observed incidence did not demonstrate an excess signal compared with reference population data. No clustering of events was observed in the early post-infusion period. Sensitivity analyses yielded consistent findings. Conclusions: In this real-world cohort, high-dose intravenous MSC therapy was not associated with an apparent increase in cardiovascular event incidence. Given the observational design and limited event number, larger prospective studies are warranted to further characterize long-term cardiovascular safety. Full article

Background: Conventional urothelial carcinoma (UC) requires accurate risk stratification, particularly differentiation between non-muscle-invasive (NMIBC) and muscle-invasive bladder cancer (MIBC) and between low- and high-grade tumors. This study evaluated immunohistochemical (IHC) expression of vitamin D receptor (VDR), β-catenin, and Ki-67 index in Egyptian patients with conventional UC. Methods: A cross-sectional study was conducted on 58 archived conventional UC cases diagnosed in 2023 at Al-Azhar University Hospitals. VDR positivity was defined as ≥10% cytoplasmic and/or nuclear tumor cell staining. Membranous β-catenin was considered preserved when >80% of tumor cell membranes were stained; otherwise, it was reduced. Nuclear β-catenin was considered positive when ≥5% of tumor nuclei were stained. Ki-67 was categorized as high using a ≥30% cutoff. Associations with grade, muscle invasion status, and lymphovascular invasion (LVI) were analyzed. Results: Mean age was 65.3 ± 9.3 years; 86.2% were males; 51.7% were MIBC. Compared with NMIBC, MIBC was significantly associated with high grade, non-papillary architecture, LVI, and high Ki-67. VDR positivity was detected in 82.7% of cases and showed no significant association with grade, muscle invasion, or LVI. Preserved membranous β-catenin was seen in 34.5% and was significantly associated with tumor grade but not with muscle invasion or LVI; nuclear β-catenin was absent. High Ki-67 (60.3%) was significantly associated with high grade and MIBC, with no association with age, sex, or LVI. Conclusions: In Egyptian conventional UC, Ki-67 was a significant marker for aggressive clinicopathologic features, while VDR lacked discriminatory associations and β-catenin findings were mainly grade-related. Full article

Background/Objectives: The increasing sensitivity of molecular diagnostic techniques has led to the frequent detection of low-level JAK2 V617F mutations in individuals without overt myeloproliferative neoplasms (MPNs), creating uncertainty regarding their biological and clinical significance. This study aimed to evaluate the clinical relevance, thrombotic risk, and hematologic evolution associated with low JAK2 V617F allele burden. Methods: We conducted a retrospective single-center study including adult patients tested for JAK2 V617F between January 2016 and December 2023. Patients with a variant allele frequency (VAF) <2% who did not meet WHO or 2022 International Consensus Classification diagnostic criteria for MPN at baseline were included. Clinical characteristics, laboratory parameters, molecular findings, thrombotic events, and longitudinal ou--comes were analyzed. Results: Among two-thousand-three-hundred-seventy-two tested subjects, 55 patients (9.2% of JAK2-positive cases) harbored a low-level JAK2 V617F mutation (median VAF 0.35%). Over a median follow-up of 31.7 months, 12 patients (21.8%) progressed to overt MPN. Baseline VAF was significantly higher in patients who evolved to MPN compared to non-progressors. Thrombotic events occurred in 30.9% of patients and were associated with higher VAF values irrespective of MPN diagnosis. Serial molecular analyses showed stable persistence of the mutant clone over time. Conclusions: Low-burden JAK2 V617F mutations represent clinically relevant clonal events associated with thrombotic risk and potential disease evolution. These findings support the need for structured clinical and molecular follow-up even in the absence of initial diagnostic criteria. Full article

Background: Despite well-established treatment and follow-up protocols for the management of colorectal cancer patients, recurrences are frequent. Post curative therapy, ctDNA-based molecular residual disease assessment has the ability to stratify patients into higher and lower risks of recurrence. Large-scale clinical trials are necessary to establish utility at a broad level, but physicians also need real-world evidence and case reports before utilizing MRD testing in routine practice. Methods: We analyzed real-world utilization patterns of Guardant Reveal in patients with CRC across stages by collating information from the test request form after the test was ordered as a part of routine practice in the AMEA region. Results: We report that 92% of the tests were utilized for stage II and stage III patients. The timing of the first MRD test order varies between stages, with a higher proportion of tests being ordered within the first 12 weeks of surgery for stage II (71.8%), while for stage III (50%) and stage IV oligometastatic (72%), the first test was ordered after 12 weeks of surgery. Conclusions: Case reports delineate physicians’ perspectives on actions taken on the basis of MRD test results and outcomes. Full article