Identification of NTRK fusions in pediatric mesenchymal tumors.

BACKGROUND: NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large series of pediatric and adolescent patients with advanced cancers. PROCEDURE: Genomic profiles from 2,031 advanced cancers from patients less than 21 years old who were assayed with comprehensive genomic profiling were reviewed to identify NTRK fusions. RESULTS: Total of nine cases (0.44%) harbored NTRK fusions, including novel partners. Four of these cases were in children less than 2 years old for which infantile fibrosarcoma was considered as a diagnosis, and two harbored the canonical ETV6-NTRK3. The remaining cases carried other diagnoses, at least one that carried the diagnosis of inflammatory myofibroblastic tumor. CONCLUSIONS: NTRK fusions occur in a subset of young patients with mesenchymal or sarcoma-like tumors at a low frequency, and are eminently druggable targets via either investigational agents or approved drugs.

Microneedle sensors for dermal interstitial fluid analysis.

The rapid advancement in personalized healthcare has driven the development of wearable biomedical devices for real-time biomarker monitoring and diagnosis. Traditional invasive blood-based diagnostics are painful and limited to sporadic health snapshots. To address these limitations, microneedle-based sensing platforms have emerged, utilizing interstitial fluid (ISF) as an alternative biofluid for continuous health monitoring in a minimally invasive and painless manner. This review aims to provide a comprehensive overview of microneedle sensor technology, covering microneedle design, fabrication methods, and sensing strategy. Additionally, it explores the integration of monitoring electronics for continuous on-body monitoring. Representative applications of microneedle sensing platforms for both monitoring and therapeutic purposes are introduced, highlighting their potential to revolutionize personalized healthcare. Finally, the review discusses the remaining challenges and future prospects of microneedle technology.

Toward Advanced Superomniphobicity: Hierarchical Insights from Serif-T Nanostructures to Microscale Wrinkles.

Developing a superomniphobic surface that exceeds the static and dynamic repellency observed in nature's springtails for various liquids presents a significant challenge in the realm of surface and interface science. However, progress in this field has been particularly limited when dealing with low-surface-tension liquids. This is because dynamic repellency values are typically at least 2 orders of magnitude lower than those observed with water droplets. Our study introduces an innovative hierarchical topography demonstrating exceptional dynamic repellency to low-surface-tension liquids. Inspired by the structural advantages found in springtails, we achieve a static contact angle of >160° and the complete rebound of droplet impact with a Weber number (We) of ∼104 using ethanol. These results surpass all existing benchmarks that have been reported thus far, including those of natural surfaces. The key insight from our research is the vital role of the microscale air pocket size, governed by wrinkle wavelength, in both static and dynamic repellency. Additionally, nanoscale air pockets within serif-T nanostructures prove to be essential for achieving omniphobicity. Our investigations into the wetting dynamics of ethanol droplets further reveal aspects such as the reduction in contact time and the occurrence of a fragmentation phenomenon beyond We ∼ 350, which has not been previously observed.

Hierarchical Topography with Tunable Micro- and Nanoarchitectonics for Highly Enhanced Cardiomyocyte Maturation via Multi-Scale Mechanotransduction.

Enhancing cardiomyocyte (CM) maturation by topographical cues is a critical issue in cardiac tissue engineering. Thus far, single-scale topographies with a broad range of feature shapes and dimensions have been utilized including grooves, pillars, and fibers. This study reports for the first time a hierarchical structure composed of nano-pillars (nPs) on micro-wrinkles (µWs) for effective maturation of CMs. Through capillary force lithography followed by a wrinkling process, vast size ranges of topographies are fabricated, and the responses of CMs are systematically investigated. Maturation of CMs on the hierarchical structures is highly enhanced compared to a single-scale topography: cardiac differentiation of H9C2s (rat cardiomyocytes) on the hierarchical topography is ≈ 2.8 and ≈ 1.9 times higher than those consisting of single-scale µWs and nPs. Both nPs and µWs have important roles in cardiac maturation, and the aspect ratio (height/diameter) of the nPs and the wavelength of the µWs are important in CM maturation. This enhancement is caused by strong focal adhesion and nucleus mediated mechanotransduction of CMs from the confinement effects of the different wavelengths of µWs and the cellular membrane protrusion on the nPs. This study demonstrates how a large family of hierarchical structures is used for cardiac maturation.

Bone mineral density deficits in pediatric patients treated for sarcoma.

BACKGROUND: Children treated for sarcoma are at risk of treatment-associated deficits in bone mineral density (BMD). We investigated the severity of risk factors for BMD deficits in this patient population. PROCEDURE: Using signed-rank test and logistic regression analysis, we retrospectively analyzed the relation of treatment variables and other potential risk factors to BMD (using quantitative computed tomography (QCT)) of 99 patients treated for pediatric sarcoma who had completed therapy at least 1 year previously. RESULTS: The study group (38% rhabdomyosarcoma (RMS), 25% osteosarcoma (OS), 24% Ewing-family tumors, and 12% non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS)) represented 22% of the sarcoma survivors treated between 1982 and 2003 who remained in follow-up at St. Jude. These patients underwent QCT between July 1, 1997 and February 5, 2003. Their median age was 8.7 years (range, 0.2-21.3 years) at diagnosis and 17.4 years (range, 3.3-30.2 years) at the time of BMD measurement; 58% were male and 82% Caucasian. Median BMD Z-score was -0.75 (range, -3.33-3.02), and median BMD was 168.0 mg/cc (range, 89.2-264.8 mg/cc). Risk of BMD deficit increased significantly with younger age at diagnosis (P = 0.044) and higher cumulative cyclophosphamide dose (P = 0.007). Patients with lower extremity primary disease had a significantly lower risk of BMD deficits than others. We found no association between BMD and body habitus, primary disease, lifestyle factors, or endocrinopathy. CONCLUSION: A significant subset of sarcoma survivors are at risk of BMD deficits warranting prospective study of BMD to verify our results and refine risk factors contributing to BMD deficits.

Ultrasmall Grained Pd Nanopattern H2 Sensor.

Precise control of the size and interfaces of Pd grains is very important for designing a high-performance H2 sensing channel because the transition of the Pd phase from α to ß occurs through units of single grains. However, unfortunately, the grain controllability of previous approaches has been limited to grains exceeding 10 nm in size and simple macroscopic channel structures have only shown monotonic response behavior for a wide concentration range of H2. In this work, for the first time, we found that Pd channels that are precisely grain-controlled show very different H2 sensing behavior. They display dual-switching response behavior with simultaneous variation of the positive and negative response direction within single sensor. The Pd nanopattern channel having smallest grain size/interface among previous works could be fabricated via unique lithographic approaches involving low-energy plasma (Ar+) bombardment. The ultrasmall grain size (5 nm) and narrow interface gap (<2 nm) controlled by Ar+ plasma bombardment enabled both the hydrogen-induced lattice expansion (HILE) (Δ RH2 < 0) and surface electron scattering (Δ RH2 > 0) mechanisms to be simultaneously applied to the single Pd channel, thereby inducing dual-switching response according to the H2 concentration range. In addition, the unique high-aspect-ratio high-resolution morphological characteristics made it possible to achieve highly sensitive H2 detecting performance (limit of detection: 2.5 ppm) without any hysteresis and irreversible performance degradation. These noteworthy new insights are attributed to high-resolution control of the grain size and the interfaces with the Pd nanostructure channel.

Distinct Mechanosensing of Human Neural Stem Cells on Extremely Limited Anisotropic Cellular Contact.

Human neural stem cells (hNSCs) can alter their fate choice in response to the biophysical cues provided during development. In particular, it has been reported that the differentiation of neural stem cells (NSCs) is enhanced by anisotropic contact, which facilitates focal adhesion (FA) formation and cytoskeletal organization. However, a biomolecular mechanism governing how the cells process the biophysical cues from these anisotropic geometries to their fate commitment is still poorly understood due to the limited availability of geometrical diversities (contact width above 50 nm) applicable to cell studies. Here, we firstly demonstrate that the biomolecular mechanism for enhanced neurogenesis on an anisotropic nanostructure is critically dependent on the resolution of a contact feature. We observed a totally different cellular response to anisotropic geometries by first utilizing a high-resolution nanogroove (HRN) structure with an extremely narrow contact width (15 nm). The width scale is sufficiently low to suppress the integrin clustering and enable us to elucidate how the contact area influences the neurogenesis of hNSCs at an aligned state. Both the HRN and control nanogroove (CN) pattern with a contact width of 1 µm induced the spontaneous topographic alignment of hNSCs. However, intriguingly, the focal adhesion (FA) formation and cytoskeletal reorganization were substantially limited on the HRN, although the cells on the CN showed enhanced FA formation compared with flat surfaces. In particular, the hNSCs on the HRN surface exhibited a strikingly lower fraction of nuclear yes-associated protein (YAP) than on the CN surface, which was turned out to be regulated by Rho GTPase in the same way as the cells sense the mechanical properties of the environment. Considering the previously reported role of YAP on neurogenesis, our finding newly substantiates that YAP and Rho GTPase also can be transducers of hNSCs to process topographical alternation to fate decision. Furthermore, this study with the unprecedented high-resolution nanostructure suggests a novel geometry sensing model where the functional crosstalk between YAP signaling and Rho GTPase integrally regulate the fate commitment of the hNSCs.

A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation.

As survivors of pediatric allogeneic hematopoietic stem cell transplantations (HSCTs) increase in number, it is increasingly important to evaluate their well-being. We conducted this prospective cohort study to evaluate the cumulative incidence and risk factors for late sequelae of HSCT. Comprehensive surveillance tests were performed annually on every participant, regardless of signs and symptoms, to obtain accurate information on the time-of-onset of each late event to allow hazard function analyses. All participants included in this report had been followed for at least 3 years after HSCT. With a median follow-up of 9 years and a current age of 18.5 years, only 20 of the 155 participants (13%) had no late sequelae; 18 survivors (12%) had 1 chronic health condition, 71 (46%) had 2-4 conditions, and 46 (30%) had 5-9 conditions. Risk factors for increasing number of chronic conditions included young age at the time of HSCT, female sex, high radiation dose, and history of chronic graft-versus-host disease. The cumulative incidence at 10 years for common late events was as follows (ordered by the median time-of-onset): osteonecrosis 13.8%, chronic renal insufficiency 26.8%, hypothyroidism 45.1%, growth hormone deficiency 31.2%, female hypogonadism 57.4%, osteopenia 47.7%, cataracts 43.4%, pulmonary dysfunction 63.2%, and male hypogonadism 20.3%. Coexistence of multiple late sequelae was common in HSCT survivors. Our findings provide a basis for more effective patient counseling, optimal surveillance, and early intervention.

Sickle cell hepatopathy: clinical presentation, treatment, and outcome in pediatric and adult patients.

BACKGROUND: Standard diagnostic criteria and therapy are lacking for sickle cell hepatopathy, an uncommon complication of sickle cell disease. Here we propose diagnostic and therapeutic guidelines based on our experience and on reported cases. METHODS: We defined sickle hepatopathy by a total serum bilirubin concentration >13 mg/dl not explained by severe acute hemolysis, viral hepatitis, extrahepatic obstruction, or hepatic sequestration. We reviewed the records of all children with sickle hepatopathy seen at our institution during the past 20 years and the reported cases from the literature. Patients were categorized into two groups based on whether hepatic dysfunction at presentation was mild (Group I) or severe (Group II). RESULTS: Seven patients were identified from our institution and 37 patients from the literature. The 44 patients were evenly divided between the two groups. Group I patients had a significantly lower mean age (11.8 years vs. 24.5 years, P = 0.0001), maximum bilirubin level (36.2 mg/dl vs. 76.8 mg/dl, P = 0.0008), and frequency of treatment with exchange transfusions (P = 0.03). Overall, mortality was 4% in Group I and 64% in Group II (P = 0.0001). Gender and recurrence rate did not differ. Among Group II patients, only two of nine who received exchange transfusion died, whereas 12 of 13 who did not receive exchange transfusion died (P = 0.0015). CONCLUSIONS: Sickle cell hepatopathy is an uncommon complication characterized by extreme hyperbilirubinemia and either mild or severe hepatic dysfunction. Children and adults can present with either form; however, adults have a higher frequency of the severe form. Exchange transfusion may be the only effective management for initial episodes of severe sickle cell hepatopathy.