Search Results (156)

Background/Objectives: Revolutionary small molecule, targeted, tyrosine kinase inhibitors (TKIs) in the clinic have engendered the perception that optimal treatment has already been established for diseases like chronic myeloid leukemia (CML). Addressing BCR::ABL1 oncokinase domain mutations in CML is unlikely to redress disease recrudescence owing to persistent leukemia stem cells (LSCs). Therefore, it is necessary to consider an alternative strategic approach: disrupting LSC interactions with the protective microenvironment and/or immune system. The interaction of the TNF-α superfamily member, CD27, with its upregulated ligand, CD70, initiates survival signaling specifically in CML cells when BCR::ABL1 is inhibited by TKIs and thus represents an attractive target. Previous studies modulating the expression of CD27 on LSCs in a mouse model of advanced phase CML were encouraging. In our study, we explored the CD70/CD27 axis as a therapeutic target in early-phase disease. Methods: Primitive CD34+ cells from treatment-naïve chronic phase (CP) CML patients were drug-exposed in an in vitro co-culture system; combination drug treatments of the therapeutic anti-CD70 antibody and TKIs, nilotinib, were assessed in our CP CML murine model. Results: The blockade of the CD70/CD27 axis in combination with TKIs did not result in greater LSC elimination than with nilotinib as a single agent in our CP CML models. Nonetheless, there was an observed reduction in CD70+ cells with combination treatment. Conclusion: Further preclinical study of the antibody as an adjunct in CD70-expressing hematological malignancy is perhaps warranted. Full article

Angioleiomyoma is a benign soft tissue tumor originating from the smooth muscle of vascular structures. Though relatively uncommon, it frequently occurs in the lower extremities and is often misdiagnosed due to its nonspecific clinical presentation. We report the case of a 54-year-old female with chronic posterolateral heel pain initially attributed to insertional Achilles tendinopathy and Haglund’s deformity. After failure of conservative management, MRI revealed a well-circumscribed subcutaneous lesion with signal characteristics concerning for a soft tissue neoplasm. Surgical excision was performed, and histopathologic analysis confirmed a venous-type angioleiomyoma, characterized by thick-walled vascular channels and smooth muscle proliferation without atypia. Immunohistochemistry was positive for SMA, weakly positive for desmin, and ERG-positive in the vascular endothelium. The patient experienced complete symptom resolution postoperatively. Although not exceedingly rare, angioleiomyomas remain underrecognized in clinical practice, particularly in the foot and ankle, resulting in diagnostic delays averaging over five years. MRI demonstrated characteristic features described in recent literature, validating its utility in preoperative assessment. This case reinforces the importance of maintaining a broad differential when evaluating chronic, focal heel pain and supports the use of advanced imaging and histopathologic confirmation in atypical cases. Greater awareness of angioleiomyomas can help reduce diagnostic delays and improve outcomes in patients with chronic, unexplained soft tissue pain in the foot and ankle. Full article

Background/Objectives: The extent to which patient-reported outcome measures (PROMs) reflect objective functional recovery after surgical repair of acute Achilles tendon rupture remains unclear. This study aimed to evaluate the relationship between PROMs and objective functional performance, particularly the heel-rise test-based limb symmetry index (LSI). Methods: This retrospective cohort study included male patients who underwent primary open repair for acute Achilles tendon rupture between 2015 and 2023 and had a minimum follow-up of 12 months. Subjective outcomes were assessed using the Achilles Tendon Total Rupture Score (ATRS) and the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle–Hindfoot Score. Objective functional performance was evaluated using a single-leg heel-rise test, and LSI was calculated as the percentage performance of the injured limb relative to the uninjured limb. Patients were stratified into two groups according to LSI: ≥90% and <90%. Correlations between PROMs and LSI were analyzed using Spearman’s rank correlation coefficient. Results: A total of 76 male patients were included. The median age was 42 years (IQR, 35–46; range, 27–74), and the median follow-up duration was 41 months (IQR, 26–53; range, 12–80). The median ATRS was 97 points (IQR, 94–99), and the median AOFAS score was 98 points (IQR, 90–100). The median LSI was 87.5% (IQR, 81.4–93.3), and only 31 patients (40.8%) achieved an LSI ≥ 90%. Injured-side heel-rise performance was significantly higher in the LSI ≥ 90% group than in the LSI < 90% group (24.4 ± 5.4 vs. 21.6 ± 5.9 repetitions, p = 0.039). However, ATRS and AOFAS scores did not differ significantly between the groups. No significant correlation was found between LSI and either ATRS (Spearman’s rho = 0.190, p = 0.100) or AOFAS score (Spearman’s rho = 0.218, p = 0.058). Conclusions: Although PROM scores were high following surgical repair of acute Achilles tendon rupture, objective functional assessment revealed persistent limb-symmetry deficits in a substantial proportion of patients. ATRS and AOFAS scores showed no significant correlation with heel-rise LSI, suggesting that PROMs may not fully capture objective functional recovery. Therefore, PROMs should be interpreted alongside performance-based measures, particularly in patients with high functional demands. Full article

Background: Esophagectomy remains the definitive curative treatment for esophageal cancer but is historically burdened by significant procedure-related morbidity. Anastomotic leakage (AL) is still the “Achilles’ heel” of esophageal surgery, serving as a primary benchmark for surgical quality due to its profound impact on patient recovery, healthcare costs, and long-term oncological outcomes. While surgical expertise and perioperative care have matured, reported AL rates remain persistently high. This necessitates a shift in focus from purely technical modifications toward integrated, data-driven preventive strategies. Purpose: Five years after our initial review, this update synthesizes the rapid evolution in AL prevention. We evaluate the transition from empirical surgical pragmatism to evidence-based protocols, integrating recent breakthroughs in real-time perfusion monitoring, prophylactic endoluminal technologies, and multidisciplinary patient optimization. This work provides a contemporary “roadmap” for navigating the complexities of esophageal reconstruction. Conclusions: The prevention of AL has evolved into a multimodal “bundle” that begins well before the index operation. This review highlights the critical shift toward quantitative perfusion assessment via indocyanine green fluorescence angiography, which is increasingly replacing subjective visual inspection as the standard for anastomotic site selection. We discuss the emerging role of gastric ischemic preconditioning as a biological strategy to enhance conduit vascularity, alongside the paradigm of proactive management using preemptive endoluminal vacuum therapy to mitigate septic sequelae in high-risk cases. Furthermore, we examine technical refinements in conduit construction and conditioning—focusing on the ‘tension-perfusion’ relationship—and the essential role of structured prehabilitation within enhanced recovery after surgery frameworks. While the quality of evidence remains heterogeneous, the move toward standardized reporting and objective monitoring marks a new era of precision in esophageal surgery. Full article

The polyamine metabolic pathway, an evolutionarily conserved nexus integrating nutrient sensing, translation control, and cellular proliferation, is fundamentally rewired in cancer. Melanoma, a malignancy of melanocytes notorious for its metastatic propensity and therapy resistance, exhibits a profound dependency on this pathway, extending beyond mere polyamine abundance to the specialized function of their derivative, hypusine. This review synthesizes cutting-edge insights into the deoxyhypusine synthase (DHPS)/eukaryotic initiation factor 5A (eIF5A) hypusination circuit as a critical amplifier of oncogenic signaling in melanoma. We dissect its role as a translational rheostat for pro-tumorigenic proteomes, a driver of phenotypic plasticity underpinning invasion and vasculogenic mimicry, and a modulator of the immunosuppressive tumor microenvironment. Moving beyond the classical inhibitor GC7, we explore the emergence of novel allosteric DHPS inhibitors with compelling preclinical efficacy. Finally, we propose a paradigm shift: targeting the DHPS/eIF5A axis represents a strategy to disrupt the “non-oncogene addiction” of melanoma—its reliance on hyperactive translation and adaptive survival mechanisms—offering a promising avenue alongside targeted therapies and immunotherapies. Full article

(1) Achilles tendon rupture is one of the most severe lower-limb injuries, frequently occurring during movements involving maximal dorsiflexion with the knee at near-full extension. Preventive strategies are crucial, particularly for athletes engaged in high-risk sports such as basketball. (2) In this work, we examined the effect of a novel Achilles brace on Achilles tendon loading during concentric and eccentric mechanisms associated with tendon rupture. (3) Twenty-eight young basketball players performed tests under two conditions: with the adaptive brace and without it (control). Participants were divided into two groups (n = 14 in both). The first group assessed concentric Achilles loading by performing three plantar-flexor strength tests in three different joint configurations: maximal dorsiflexion with the knee flexed (FKF); injury mechanism position—full plantar flexion with the knee extended (FKE); and neutral ankle position with the knee extended (NKE). The number of maximal heel-raise repetitions performed before onset of fatigue was recorded. The second group assessed eccentric tendon loading by performing single-leg forced maximal-velocity dorsiflexion with the knee extended. In all tests, the time between maximal plantar flexion and maximal dorsiflexion, as well as the ankle range of motion, was analyzed using 2D video. Paired t-tests were used to compare braced and control conditions. In all tests, the ankle range of motion (ROM) did not differ significantly between brace and control conditions. Wearing the brace significantly improved plantar-flexor muscle strength only in the FKE test (31 ± 1.3 repetitions with brace vs. 21 ± 1.3 in control, p < 0.05). No significant differences were found for the FKF (27 ± 1.3 vs. 25 ± 1.3) or NKE (25 ± 1.3 vs. 24 ± 1.3) positions. During drop eccentric loading, wearing the brace resulted in a significantly slower transition time from plantar flexion to dorsiflexion (460 ± 60 ms with brace vs. 320 ± 30 ms in control, p < 0.001). (4) In brief, the novel Achilles brace was found to significantly reduces Achilles tendon load during both concentric and eccentric activities, but only in high-risk joint positions. These findings suggest that the brace provides mechanical protection, and may reduce the risk of Achilles tendon rupture, in athletes exposed to high tendon stress. Full article

Heel pain is a very common foot condition. Mechanical factors are the most common cause of heel pain. The main causes of heel pain include plantar fasciitis, heel spurs, Achilles tendinopathy, heel neuritis, and heel bursitis. This case study aimed to manage pain in a patient with heel pain accompanied by pronounced pes planus. A 42-year-old woman presented with heel pain and pes planus. The pain was present in the normal standing position and at rest. After examination, a spur, plantar fasciitis, and Morton’s neuroma were diagnosed. The patient, who had not responded to medical and rehabilitative treatments, was evaluated using the visual analog scale and the 36-Item Short Form Survey quality of life questionnaire to assess pain during rest and walking using a newly developed combined exercise method. Significant improvements were observed in the final measurements. This study contributes significantly to our knowledge of the best physiotherapy treatments for patients with heel pain associated with spurs and plantar fasciitis. Full article

Fungi regularly occur on spacecrafts, posing a serious risk to humans and equipment. In this study, we characterized how the model organism Aspergillus nidulans responds to low-intensity, short-duration proton irradiation designed to simulate a solar particle event, a common stress factor in space. The oxidative stress-sensitive ∆atfA mutant exhibited a lower survival rate than the wild-type strain. Pretreatment of the wild-type strain with menadione sodium bisulfite (MSB), which activates oxidative stress defense mechanisms, increased tolerance to proton beam radiation. These data are consistent with the idea that oxidative defense contributes to cellular responses to ionizing radiation. Unexpectedly, the applied radiation decreased the tolerance to MSB. To understand this unusual behavior, we compared the transcriptomes of the irradiated and non-irradiated mycelia. As expected, proton beam irradiation upregulated many genes involved in DNA repair but downregulated a large number of antioxidant enzyme genes. The downregulation of three key antioxidant genes—prxA (thioredoxin peroxidase), trxB (thioredoxin reductase), and gsh1 (γ-glutamylcysteine synthase)—was further confirmed by RT-qPCR analysis. One possible explanation is that, due to the rapid elimination of reactive oxygen species generated by water radiolysis, the effects of radiolysis-derived electrons could transiently dominate redox signaling. This shift may interfere with redox sensing in the fungus, resulting in reduced antioxidant gene expression and increased sensitivity to oxidative stress. Oxidative stress sensitivity caused by proton radiation may be the Achilles heel of cells that can survive this stress. Full article

High degree conductive disorders (CD) requiring permanent pacemaker implantation (PPI) have modestly decreased over time and remain the main complications of TAVR. Furthermore, management strategies for CD occurring after TAVR remain controversial. We proposed a review evaluating mechanisms and risk of CD after TAVR, focusing on the role of ECG evaluation but also on the importance of anatomic parameters analyzed in multi-slice computed tomography (MSCT), as well as regarding procedural aspects. Considering the lack of clear recommendations for the evaluation of risk of CD and indications of PPI, this review tries to summarize strategies to anticipate and detect the risk of high degree CD, to decrease incidence of CD and to optimize PPI indications. Perspectives regarding ambulatory monitoring, use of machine learning and new pacing techniques are proposed. This review was narrative and included selection of literature using key words including: conductive disorders, TAVR and pacemaker implantation. Full article

Lipid raft-associated gangliosides facilitate the early stages of SARS-CoV-2 entry by triggering the exposure of the receptor-binding domain (RBD) within the trimeric spike protein, which is initially sequestered. A broad range of in silico, cryoelectron microscopy and physicochemical approaches indicate that the RBD becomes accessible after a ganglioside-induced conformational rearrangement originating in the N-terminal domain (NTD) of one protomer and propagating to the neighboring RBD. We previously identified a triad of amino acids, Q134-F135-N137, as a strictly conserved element on the NTD. In the present review, we integrate a series of structural and experimental data revealing that this triad may act as a conformational transducer connected to a chain of residues that are capable of transmitting an internal conformational wave within the NTD. This wave is generated at the triad level after physical interactions with lipid raft gangliosides of the host cell membrane. It propagates inside the NTD and collides with the RBD of a neighboring protomer, triggering its unmasking. We also identify a chain of aromatic residues that are capable of controlling electron transfer through the NTD, leading us to hypothesize the existence of a dual conformational/quantum wave. In conclusion, the complete conservation of the Q134-F135-N137 triad despite six years of extensive NTD remodeling underscores its critical role in the viral life cycle. This triad represents a potential Achilles’ heel within the hyper-variable NTD, offering a stable target for therapeutic or vaccinal interventions to disrupt the conformational wave and prevent infection. These possibilities are discussed. Full article

Background: Video-based biomechanical running gait analysis is widely used to optimise technique, guide footwear selection, and identify orthopaedic risk factors. Despite the increasing availability of such assessments, it is often assumed—without strong empirical support—that key kinematic parameters of running gait remain stable over short periods of time. This study aimed to examine the short-term stability of key joint angles during running using a standard 2D video-based kinematic analysis. Specifically, it was investigated whether these angles change within the first 4 min of treadmill running under three defined conditions: barefoot at 12 km h⁻¹, shoed at 12 km h⁻¹, and shoed at 14 km h⁻¹, in a homogeneous sample of twelve young, trained, male recreational soccer players. Methods: Participants completed three four-minute runs. Joint angles were quantified manually from 2D video recordings. Temporal variation was analysed using repeated-measures statistics, intraclass correlation coefficients (ICCs), and minimal detectable changes (MDCs). Results: Six out of nine joint angles showed statistically significant temporal changes, mainly in hip extension, knee flexion, the Duchenne angle, the Trendelenburg angle, the leg axis angle, and heel-bottom angle. Lower leg angle and Achilles tendon angle remained stable. ICCs showed moderate to excellent agreement, indicating high within-session consistency across all angles. Discussion: Under the applied study protocol, significant short-term variations were observable in several joint angles during the first four minutes of running. These findings highlight the importance of analysing multiple strides and considering measurement uncertainty when interpreting short-duration running kinematics. Full article

Prostate cancer remains a leading cause of cancer-related mortality and castration-resistant prostate cancer (CRPC) is a critical therapeutic challenge. This review establishes a conceptual framework analyzing ferroptosis vulnerability through two principles: “robustness through redundancy” in defense systems and the “evolutionary arms race” between androgen receptor (AR) signaling and oxidative resistance. We traced the evolutionary trajectory of hormone-sensitive diseases, where the AR coordinates ferroptosis defenses via SLC7A11, MBOAT2, and PEX10 regulation through progressive adaptations: AR-V7 splice variants that maintain defense independently of androgens, AR amplification conferring hypersensitivity, and AR-independent JMJD6-ATF4 bypass in SPOP-mutated tumors. This transforms ferroptosis from a static vulnerability to a stage-specific strategy. Novel approaches include menadione-based VPS34 targeting, which induces triaptosis through an oxidative endosomal catastrophe. We categorized the rational combinations mechanistically as vertical inhibition (multi-step targeting of single pathways), horizontal inhibition (synthetic lethality across parallel defenses), and vulnerability induction (creating exploitable dependencies). Ferroptosis-induced immunogenic cell death enables synergy with checkpoint inhibitors, potentially transforming immunologically “cold” prostate tumors. This review establishes ferroptosis targeting as a precision medicine paradigm exploiting the tension between the oxidative requirements of cancer cells and their evolved, yet architecturally vulnerable, defense systems, providing a framework for stage-specific, biomarker-guided interventions. Full article

The mitochondrial permeability transition pore (mPTP) plays a central role in myocardial injury. Upon reperfusion after myocardial infarction, oxidative stress, calcium overload, and ATP depletion promote mPTP opening, leading to mitochondrial dysfunction, cell death, and infarct expansion. This process affects various cardiac cell types differently, contributing to complex pathological remodelling. Key mitochondrial events, such as disruption of bioenergetics parameters, impaired mitophagy, and oxidative stress, drive regulated cell death. Emerging therapies targeting mitochondrial biology, dynamics, and transplantation offer promising strategies to mitigate damage and improve cardiac outcomes. Considering the potential to improve cardiac outcomes and redefine therapeutic approaches in the management of cardiovascular disease, mPTP modulation represents a compelling therapeutic target in myocardial infarction and ischemia–reperfusion injury management. Full article

Pyruvate:ferredoxin oxidoreductase (PFOR) is a key Achilles’ heel in anaerobic pathogens. We integrate electronic-structure calculations (DFT), cheminformatic QSAR metrics, and residue-resolved docking to distill a concise “recognition code” and translate it into practical design rules. Using nitazoxanide (Nita; ΔG_(bind) ≈ −10.0 kcal·mol⁻¹) as a well-established reference, productive binding requires a conserved triad: a hydrogen-bond donor addressing Thr-997 and Cys-840, a π–π stack with Phe-869, and a recurrent π–σ contact to Thr-997 that orients the scaffold. Deacetylation to tizoxanide unmasks the phenolic donor and raises local electrophilicity, yet it also slightly loosens pocket packing (−9.6 kcal·mol⁻¹). Strategic halogenation introduces a σ-hole interaction near Pro-29, tightening pose geometry without disrupting the donor network; the lead analogue yields −10.1 kcal·mol⁻¹, and two others match the reference by preserving the triad and hydrophobic belt. The result is a minimal, testable recipe—retain the phenolic donor, enforce Thr-997/Cys-840 and Phe-869, and add a calibrated halogen σ-hole—offering falsifiable predictions to surpass nitazoxanide and guiding synthesis and biophysical validation in targeted PFOR inhibition. Full article

Background and Clinical Significance: Psoriasis, a chronic immune-mediated inflammatory disease, can affect musculoskeletal structures, including the Achilles tendon. Achilles pain in psoriasis patients may arise from tendinitis or neuropathic pain due to peripheral nerve dysfunction, such as sural nerve (SN) involvement, a condition frequently misdiagnosed due to limitations in conventional diagnostics. Fascial tissues are critical in nerve compression syndromes. This case explores the application of a novel quantitative Sonoguide Digital Palpation (SDP) protocol and ultrasound (US)-guided hydrodissection (HD) for SN dysfunction mimicking Achilles tendinopathy in a psoriasis patient. Case Presentation: A 41-year-old male with psoriasis presented with acute onset of right heel stiffness and paresthesia. Physical examination, radiographs, and ultrasound were performed. SDP, employing a validated four-criterion diagnostic framework (including fascial mobility quantification and concordant pain provocation), identified crural fascia restriction affecting SN and reproduced patient’s concordant Achilles pain. High-resolution ultrasonography provided key morphological evidence, revealing a 2.6-fold enlargement of the sural nerve’s cross-sectional area (CSA) on the affected side (13 mm²) compared to the asymptomatic side (5 mm²). Notably, a positive Tinel’s sign was elicited over the psoriatic plaque. US-guided HD was performed using 50 cc of 5% dextrose in water (D5W) without local anesthetic below the psoriatic lesion. Post-HD, the patient reported immediate and significant pain relief (Numeric Pain Rating Scale (NPRS) score reduction from 8 to 2), confirming the prompt correction of a clinically important fascial restriction, associated with improved SN mobility, objectively verified by a post-procedure SDP assessment. At 24-month follow-up, sustained symptom relief and complete functional recovery were reported. Conclusions: This case highlights SDP’s ability to objectively visualize and confirm fascial restriction as a cause of nerve dysfunction by quantitatively reproducing concordant pain. The objective finding of nerve swelling provides sonographic substantiation for the functional diagnosis of nerve dysfunction. This integrated diagnostic approach, combining dynamic functional assessment with morphological confirmation, offers a novel paradigm for evaluating peripheral nerve disorders. US-guided HD of the SN with D5W without local anesthetic shows promise as both a diagnostic confirmatory tool and therapeutic intervention for neuropathic Achilles pain in psoriasis patients with SN involvement, aligning with its efficacy in other peripheral neuropathies. The significant nerve swelling (13 mm²) provides robust morphological corroboration of the functional impairment diagnosed by SDP, offering a more comprehensive diagnostic paradigm. Full article