Insights into Free Drug Release from Efficacious -Acyl -Aminophenol Duocarmycin Prodrugs.

Acyclic and cyclic -acyl -aminophenol prodrugs of duocarmycin analogues were reported as members of a unique class of reductively cleaved prodrugs that map seamlessly onto the duocarmycin family of natural products. Although these prodrugs were explored with the expectations that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles, the remarkable stability of some such prodrugs suggests another mechanism of free drug release is operative. The prototype of such chemically unreactive -acyl -aminophenol prodrugs is , which proved remarkably efficacious in vertebrate tumor models; was found to lack the toxicity that is characteristic of traditional chemotherapeutic drugs as well as the free drugs in the class (e.

Clinical Evaluation of an Electronic Guidance System for Optimizing the Ultrasound Screening for Developmental Hip Dysplasia in Newborns.

Graf ultrasound screening is considered an established method for early detection of developmental dysplasia of the hip (DDH). Although characterized by a high degree of standardization to allow for good reproducibility of results, examination-related factors may still affect sonographic measurements. The relative tilt angle between the hip and the probe is a potential pitfall as it significantly influences sonographic measurements and consequently classification of DDH according to Graf.

A Novel Minimally Invasive Surgical Technique for Eight-Plate Hemiepiphysiodesis: Description and Evaluation.

Temporary hemiepiphysiodesis with tension band plates or eight-plates is a common surgical procedure to treat malalignment of the lower limb axis in skeletally immature patients. The objective of this study was to compare a new minimally invasive surgical procedure with the conventional procedure and evaluate its safety and effectiveness in order to reduce the risk of hypertrophic scarring, which may cause functional impairment as well as cosmetic issues. Sixty-five growth plates of either the femur or the tibia were evaluated in 33 patients treated for genu valgum or varum between 2010 and 2017.

Sulfotransferase 1C2 Increases Mitochondrial Respiration by Converting Mitochondrial Membrane Cholesterol to Cholesterol Sulfate.

Hypothesis: In this communication, we test the hypothesis that sulfotransferase 1C2 (SULT1C2, UniProt accession no. Q9WUW8) can modulate mitochondrial respiration by increasing state-III respiration.

Methods And Results: Using freshly isolated mitochondria, the addition of SULT1C2 and 3-phosphoadenosine 5 phosphosulfate (PAPS) results in an increased maximal respiratory capacity in response to the addition of succinate, ADP, and rotenone.

Maternal α-casein deficiency extends the lifespan of offspring and programmes their body composition.

Early nutrition has significant effects on physiological outcomes during adult life. We have analysed the effect of maternal α-casein (CSN1S1) deficiency on the physiological fate of dams and their offspring. α-casein deficiency reduces maternal milk protein concentration by more than 50% and attenuates the growth of pups to 27% (p < 0.

LL37/self-DNA complexes mediate monocyte reprogramming.

LL37 alone and in complex with self-DNA triggers inflammatory responses in myeloid cells and plays a crucial role in the development of systemic autoimmune diseases, like psoriasis and systemic lupus erythematosus. We demonstrated that LL37/self-DNA complexes induce long-term metabolic and epigenetic changes in monocytes, enhancing their responsiveness to subsequent stimuli. Monocytes trained with LL37/self-DNA complexes and those derived from psoriatic patients exhibited heightened glycolytic and oxidative phosphorylation rates, elevated release of proinflammatory cytokines, and affected naïve CD4 T cells.

The MOCART (magnetic resonance observation of cartilage repair tissue) 2.0 Ankle Score.

Objectives: The aim of this study was to introduce the MOCART 2.0 ankle score and evaluate its utility and reproducibility for the radiological assessment of cartilage repair tissue in the ankle joint.

Methods: The MOCART 2.

Acetaminophen influences musculoskeletal signaling but not adaptations to endurance exercise training.

Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6-week, low-dose ACE regimen on muscle and bone adaptations in exercising and non-exercising rats.

Evaluation of Spectral X-Ray Imaging for Panoramic Dental Images Based on a Simulation Framework.

Modern photon counting detectors allow the calculation of virtual monoenergetic or material decomposed X-ray images but are not yet used for dental panoramic radiography systems. To assess the diagnostic potential and image quality of photon counting detectors in dental panoramic radiography, ethics approval from the local ethics committee was obtained for this retrospective study. Conventional CT scans of the head and neck region were segmented into bone and soft tissue.

Phylogenetic and Recombination Analysis of Clinical Vitreous Humor-Derived Adenovirus Isolates Reveals Discordance Between Serotype and Phylogeny.

Purpose: To sequence, identify, and perform phylogenetic and recombination analysis on three clinical adenovirus samples taken from the vitreous humor at the Bascom Palmer Eye Institute.

Methods: The PacBio Sequel II was used to sequence the genomes of the three clinical adenovirus isolates. To identify the isolates, a full genome-based multiple sequence alignment (MSA) of 722 mastadenoviruses was generated using multiple alignment using fast Fourier transform (MAFFT).

IL-17A-driven psoriasis is critically dependent on IL-36 signaling.

Plaque psoriasis is an autoinflammatory and autoimmune skin disease, affecting 1-3% of the population worldwide. Previously, high levels of IL-36 family cytokines were found in psoriatic skin lesions, thereby contributing to keratinocyte hyperproliferation and infiltration of immune cells such as neutrophils. While treatment with anti-IL36 receptor (IL36R) antibodies was recently approved for generalized pustular psoriasis (GPP), it remains unclear, if targeting the IL36R might also inhibit plaque psoriasis.

Warming nondormant tree roots advances aboveground spring phenology in temperate trees.

Climate warming advances the onset of tree growth in spring, but above- and belowground phenology are not always synchronized. These differences in growth responses may result from differences in root and bud dormancy dynamics, but root dormancy is largely unexplored. We measured dormancy in roots and leaf buds of Fagus sylvatica and Populus nigra by quantifying the warming sum required to initiate above- and belowground growth in October, January and February.

Immunomodulatory Effects of Histone Variant H2A.J in Ionizing Radiation Dermatitis.

Purpose: Histone variant H2A.J is associated with premature senescence after ionizing radiation (IR) and modulates senescence-associated secretory phenotype (SASP). Using constitutive H2A.

Generation and application of endogenously floxed alleles for cell-specific knockout in zebrafish.

The zebrafish is amenable to a variety of genetic approaches. However, lack of conditional deletion alleles limits stage- or cell-specific gene knockout. Here, we applied an existing protocol to establish a floxed allele for gata2a but failed to do so due to off-target integration and incomplete knockin.

Phylogenetic and Genomic Characterization of Whole Genome Sequences of Ocular Herpes Simplex Virus Type 1 Isolates Identifies Possible Virulence Determinants in Humans.

Purpose: There are limited data on the prevalence and genetic diversity of herpes simplex virus type 1 (HSV-1) virulence genes in ocular isolates. Here, we sequenced 36 HSV-1 ocular isolates, collected by the Bascom Palmer Eye Institute, a university-based eye hospital, from three different ocular anatomical sites (conjunctiva, cornea, and eyelid) and carried out a genomic and phylogenetic analyses.

Methods: The PacBio Sequel II long read platform was used for genome sequencing.

Thirty-Year Minimum Follow-Up Outcome of a Straight Cementless Rectangular Stem.

Background: Meta-diaphyseal fixation of straight, tapered, uncemented stems has been proven to be very reliable for total hip arthroplasty in 10 to 20 years of follow-up studies. The aim of the study was to evaluate whether the implant survival as well as radiological and functional outcome have changed in patients with a minimum follow-up of 30 years.

Methods: From a total of 210 patients, who received a straight, rectangular, tapered cementless stem and a threaded cup, there were 37 total hip arthroplasties (33 patients) still available for follow-up after a minimum of 30 years.

Disease parameters following ocular herpes simplex virus type 1 infection are similar in male and female BALB/C mice.

Sex related differences in the incidence or severity of infection have been described for multiple viruses. With herpes simplex viruses, the best example is HSV-2 genital infection where women have a higher incidence of infection and can have more severe infections than men. HSV-1 causes several types of infections including skin and mucosal ulcers, keratitis, and encephalitis in humans that do not appear to have a strong biological sex component.

Anatomically Integrated In-Place Visualization of Patient Data for Cooperative Tasks with a Case Study on a Neurosurgical Ward.

The workflow in modern hospitals entails that the medical treatment of a patient is distributed between several physicians and nurses. This leads to intensive cooperation, which takes place under particular time pressure and requires efficient conveyance of relevant patient-related medical data to colleagues. This requirement is difficult to achieve with traditional data representation approaches.

A robotic system for solo surgery in flexible ureteroscopy: development and evaluation with clinical users.

Purpose: The robotic system CoFlex for kidney stone removal via flexible ureteroscopy (fURS) by a single surgeon (solo surgery, abbreviated SSU) is introduced. It combines a versatile robotic arm and a commercially available ureteroscope to enable gravity compensation and safety functions like virtual walls. The haptic feedback from the operation site is comparable to manual fURS, as the surgeon actuates all ureteroscope DoF manually.

MyD88 and not TRIF knockout is sufficient to abolish LPS-induced inflammatory responses in bone-derived macrophages.

Macrophages play an important role in the response to infection and/or repair of injury in tissues. To examine the NF-κB pathway in response to an inflammatory stimulus, we used wild-type bone-marrow-derived macrophages (BMDMs) or BMDMs with knockout (KO) of myeloid differentiation primary response 88 (MyD88) and/or Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF) via CRISPR/Cas9. Following treatment of BMDMs with lipopolysaccharide (LPS) to induce an inflammatory response, translational signalling of NF-κB was quantified via immunoblot and cytokines were measured.

The dose-response effects of arachidonic acid on primary human skeletal myoblasts and myotubes.

Background: Cellular inflammatory response, mediated by arachidonic acid (AA) and cyclooxygenase, is a highly regulated process that leads to the repair of damaged tissue. Recent studies on murine C2C12 cells have demonstrated that AA supplementation leads to myotube hypertrophy. However, AA has not been tested on primary human muscle cells.

Perception and Quantization Model for Periodic Contour Modifications.

Periodic, wave-like modifications of 2D shape contours are often applied to convey quantitative data via images. However, to the best of our knowledge, there has been no in-depth investigation of the perceptual uniformity and legibility of these kind of approaches. In this paper, we design and perform a user study to evaluate the perception of periodic contour modifications related to their geometry and colour.

Preoperative blood markers for prediction of recurrence-free survival after surgical treatment of patients with stage III lung adenocarcinoma.

The possibility of the preoperative level of 42 indicators characterizing the cellular composition and metabolism in blood of patients with stage III lung adenocarcinoma (AC) to predict their relapse-free survival was studied. Blood samples of 451 patients with newly diagnosed AK stage III after their surgical treatment (resection volume - R0) have been investigated. The duration of the relapse-free period (period of observation - 1 year), cellular composition of the blood, concentration of C-RP, albumin, Cyfra 21-1 antigens, SCC, TPA, chemokines CXCL5, CXCL8, pyruvate kinase TuM2 PK isoenzyme, HIF-1α and hyaluronic acid in blood serum so as the proportion of blood cells with CXCR1 and CXCR2, CD44V6 receptors in blood serum were measured.

Celecoxib impairs primary human myoblast proliferation and differentiation independent of cyclooxygenase 2 inhibition.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of musculoskeletal injuries is commonplace in the general, athletic, and military populations. While NSAIDs have been studied in a variety of tissues, the effects of NSAIDs on skeletal muscle have not been fully defined. To address this, we investigated the degree to which the cyclooxygenase (COX)-2-selective NSAID celecoxib affects muscle cell proliferation, differentiation, anabolic signaling, and mitochondrial function in primary human skeletal myoblasts and myotubes.