Carpentersigmon8445

The thin line between efficacy and toxicity has challenged cancer therapy. As copper is an essential micronutrient and is important to tumor biology, CuII complexes emerged as an alternative to chemotherapy; however, its biological properties need to be better understood. Thus, we report in vitro the antitumor effects of two CuII complexes named [Cu(4-fh)(phen)(ClO4)2] (complex 1) and [Cu(4-nh)(phen)(ClO4)2]·H2O (complex 2), in which 4-fh = 4-fluorophenoxyacetic acid hydrazide; 4-nh = 4-nitrobenzoic hydrazide and phen = 1,10-phenanthroline. Both complexes presented cytotoxic activity against tumor cells, but only complex 1 showed significant selectivity. Complex 1 also induced DNA-damage, led to G0/G1 arrest and triggered apoptosis, which was initiated by an autophagy dysfunction. The significant in vitro selectivity and the action mechanism of complex 1 are noteworthy and reveal this prodrug as promising for anticancer therapy.Current prostate cancer risk classifications rely on clinicopathological parameters resulting in uncertainties for prognostication. To improve individual risk stratification, we examined the predictive value of selected proteins with respect to tumor heterogeneity and genomic instability. We assessed the degree of genomic instability in 50 radical prostatectomy specimens by DNA-Image-Cytometry and evaluated protein expression in related 199 tissue-microarray (TMA) cores. Immunohistochemical data of SATB1, SPIN1, TPM4, VIME and TBB5 were correlated with the degree of genomic instability, established clinical risk factors and overall survival. Genomic instability was associated with a GS ≥ 7 (p = 0.001) and worse overall survival (p = 0.008). A positive SATB1 expression was associated with a GS ≤ 6 (p = 0.040), genomic stability (p = 0.027), and was a predictor for increased overall survival (p = 0.023). High expression of SPIN1 was also associated with longer overall survival (p = 0.048) and lower preoperative PSA-values (p = 0.047). The combination of SATB1 expression, genomic instability, and GS lead to a novel Prostate Cancer Prediction Score (PCP-Score) which outperforms the current D'Amico et al. stratification for predicting overall survival. Low SATB1 expression, genomic instability and GS ≥ 7 were identified as markers for poor prognosis. Their combination overcomes current clinical risk stratification regimes.Using digitalized whole slide images (WSI) in routine histopathology practice is a revolutionary technology. This study aims to assess the clinical impacts of WSI quality and representation of the corresponding glass slides. 40,160 breast WSIs were examined and compared with their corresponding glass slides. The presence, frequency, location, tissue type, and the clinical impacts of missing tissue were assessed. Scanning time, type of the specimens, time to WSIs implementation, and quality control (QC) measures were also considered. The frequency of missing tissue ranged from 2% to 19%. The area size of the missed tissue ranged from 1-70%. In most cases (>75%), the missing tissue area size was less then 10% and peripherally located. In all cases the missed tissue was fat with or without small entrapped normal breast parenchyma. No missing tissue was identified in WSIs of the core biopsy specimens. QC measures improved images quality and reduced WSI failure rates by seven-fold. A negative linear correlation between the frequency of missing tissue and both the scanning time and the image file size was observed (p  less then  0.05). None of the WSI with missing tissues resulted in a change in the final diagnosis. Missing tissue on breast WSI is observed but with variable frequency and little diagnostic consequence. Balancing between WSI quality and scanning time/image file size should be considered and pathology laboratories should undertake their own assessments of risk and provide the relevant mitigations with the appropriate level of caution.High-grade endometrial stromal sarcomas (HGESSs) are more aggressive and have higher rates of resistance to endocrine therapy than low-grade endometrial stromal sarcomas (LGESSs). The pathogenesis of hormonal resistance in these lesions has yet to be defined. Here we sought to histologically and genetically characterize 3 LGESSs and their recurrences that underwent histologic high-grade transformation following endocrine therapy. For this, DNA from primary tumors and select subsequent recurrences were subject to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutation analyses were performed using validated bioinformatics methods. In addition, RNA from each case was evaluated for the presence of gene fusions using targeted RNA-sequencing. All patients initially presented with LGESS, developed HGESS recurrences, and received at least 2 lines of hormonal suppressive therapy. Gene fusions classically described as associated with LGESS were identified in all 3 cases, including JAZF1-PHF1, EPC1-PHF1 and JAZF1-SUZ12 fusions for Cases 1, 2 and 3, respectively. Targeted sequencing analysis revealed that none of the primary LGESS, however the HGESS recurrences of Cases 1 and 3, and the LGESS and HGESS recurrences of Case 2 post endocrine treatment harbored ESR1 p.Y537S hotspot mutations. These ESR1 ligand-binding domain mutations have been found as a mechanism of acquired endocrine resistance in breast cancer. Also, a reduction in estrogen receptor (ER) expression was observed in recurrences. Our findings suggest that the ESR1 p.Y537S hotspot mutation in LGESS with histologic high-grade transformation may be associated with endocrine resistance in these lesions. Furthermore, our data suggest that genetic analyses may be performed in recurrent LGESS following hormonal therapy, development of high-grade morphology, and/or altered/diminished ER expression.Convolutional neural networks (CNNs)-as a type of deep learning-have been specifically designed for highly heterogeneous data, such as natural images. learn more Neuroimaging data, however, is comparably homogeneous due to (1) the uniform structure of the brain and (2) additional efforts to spatially normalize the data to a standard template using linear and non-linear transformations. To harness spatial homogeneity of neuroimaging data, we suggest here a new CNN architecture that combines the idea of hierarchical abstraction in CNNs with a prior on the spatial homogeneity of neuroimaging data. Whereas early layers are trained globally using standard convolutional layers, we introduce patch individual filters (PIF) for higher, more abstract layers. By learning filters in individual latent space patches without sharing weights, PIF layers can learn abstract features faster and specific to regions. We thoroughly evaluated PIF layers for three different tasks and data sets, namely sex classification on UK Biobank data, Alz an inductive bias to harness spatial homogeneity of neuroimaging data.Histone lysine crotonylation is a posttranslational modification with demonstrated functions in transcriptional regulation. Here we report the discovery of a new type of histone posttranslational modification, lysine methacrylation (Kmea), corresponding to a structural isomer of crotonyllysine. We validate the identity of this modification using diverse chemical approaches and further confirm the occurrence of this type of histone mark by pan specific and site-specific anti-methacryllysine antibodies. In total, we identify 27 Kmea modified histone sites in HeLa cells using affinity enrichment with a pan Kmea antibody and mass spectrometry. Subsequent biochemical studies show that histone Kmea is a dynamic mark, which is controlled by HAT1 as a methacryltransferase and SIRT2 as a de-methacrylase. Altogether, these investigations uncover a new type of enzyme-catalyzed histone modification and suggest that methacrylyl-CoA generating metabolism is part of a growing number of epigenome-associated metabolic pathways.BACKGROUND Upper limb replantation has become an almost routine procedure, with digital and hand reattachments being the most commonly performed. These remain challenging procedures to reconstructive surgeons, especially when there is trauma to the detached limb. Injury to the overlying skin and soft tissue can lead to tissue necrosis, sepsis, and loss of the replanted limb. The use of skin grafts as well as a wide variety of muscular, musculo-cutaneous, fascio-cutaneous flaps, and free-transfer grafts has significantly diminished limb loss. We report on the use of a delayed fascio-cutaneous, pedicled groin flap to cover a defect on the dorsum of a hand replanted 6 weeks earlier. CASE REPORT A right-hand-dominant male laborer had his left hand completely severed by a sharpened machete. This was surgically replanted with limb salvage but there was an area of denuded tissue on the dorsum, devoid of epidermal coverage. A fascio-cutaneous, pedicled rotational flap arising from the left groin was used as definitive cover for the defect. This flap augmented the replantation process by producing a functional and visually acceptable replant, allowing the patient to undergo rehabilitation and eventually return to the workforce. CONCLUSIONS The fascio-cutaneous, pedicled, rotational groin flap is a thin, pliable, but robust flap which covered the defect created by the initial injury with a protective tissue layer. It allowed free movement of the extensor tendons by creating a smooth surface over which they could easily glide with retention of near-normal, functional hand movement.The pathogenesis of the aortic aneurysm (AA) includes several mechanisms, such as chronic sterile inflammation and homeostasis imbalance, with arteriosclerosis, hemodynamic forces, and genetic factors. In addition to the roles of these processes in the development of AA, neutrophilic activity may play a pivotal role (mostly in inflammation and thrombus formation). Neutrophils, which play a crucial role in innate immunity, can release neutrophil extracellular traps (NETs), one of the mechanisms against fighting pathogens, beside phagocytosis and degranulation. NETs are structures composed of nuclear elements (eg, chromatin and modified histones) and granular and cytoplasmic components, which can lead to inflammation and coagulation changes. In addition, the exacerbation of NETosis (the process of NET formation) can be noticed in vascular diseases, including in the development of AA and myocardial infarction and in diabetes, hypertension, and COPD, which are the risk factors of the presence of AA. The discharge of NETs, which are extracellular materials formed by citrullinated histones (Cit-H), cell-free DNA fibers (cf-DNA), and granular and cytoplasmic molecules, is a newly identified method of neutrophil activation that can be activated by endogenous inflammatory stimuli, which contribute to AA development. Cit-H and cf-DNA can be used as biomarkers of AA growth. By understanding the neutrophilic influence of NET release, a new pathway of screening AA growth (by measurement of biomarkers of NETosis) and pharmacological assessment (by repression of NET formation) can be developed. This review summarizes the current knowledge about the influence of NETs on AA growth in human and animal studies.