A Strong Neutrophil Elastase Proteolytic Fingerprint Marks the Carcinoma Tumor Proteome

Proteolytic cascades are deeply involved in critical stages of cancer progression. During the course of peptide-wise analysis of shotgun proteomic data sets representative of colon adenocarcinoma (AC) and ulcerative colitis (UC), we detected a cancer-specific proteolytic fingerprint com- posed of a set of numerous protein fragments cleaved C-terminally to V, I, A, T, or C residues, significantly over-represented in AC. A peptide set linked by a common VIATC cleavage consensus was the only prominent can- cer-specific proteolytic fingerprint detected. This se- quence consensus indicated neutrophil elastase as a source of the fingerprint. We also found that a large frac- tion of affected proteins are RNA processing proteins associated with the nuclear fraction and mostly cleaved within their functionally important RNA-binding domains. Thus, we detected a new class of cancer-specific pep- tides that are possible markers of tumor-infiltrating neu- trophil activity, which often correlates with the clinical outcome. Data are available via ProteomeXchange with identifiers: PXD005274 (Data set 1) and PXD004249 (Data set 2). Our results indicate the value of peptide-wise anal- ysis of large global proteomic analysis data sets as op- posed to protein-wise analysis, in which outlier differen- tial peptides are usually neglected

Bodily Sensory Inputs and Anomalous Bodily Experiences in Complex Regional Pain Syndrome: Evaluation of the Potential Effects of Sound Feedback

Neuroscientific studies have shown that human's mental body representations are not fixed but are constantly updated through sensory feedback, including sound feedback. This suggests potential new therapeutic sensory approaches for patients experiencing body-perception disturbances (BPD). BPD can occur in association with chronic pain, for example in Complex Regional Pain Syndrome (CRPS). BPD often impacts on emotional, social, and motor functioning. Here we present the results from a proof-of-principle pilot study investigating the potential value of using sound feedback for altering BPD and its related emotional state and motor behavior in those with CRPS. We build on previous findings that real-time alteration of the sounds produced by walking can alter healthy people's perception of their own body size, while also resulting in more active gait patterns and a more positive emotional state. In the present study we quantified the emotional state, BPD, pain levels and gait of twelve people with CRPS Type 1, who were exposed to real-time alteration of their walking sounds. Results confirm previous reports of the complexity of the BPD linked to CRPS, as participants could be classified into four BPD subgroups according to how they mentally visualize their body. Further, results suggest that sound feedback may affect the perceived size of the CRPS affected limb and the pain experienced, but that the effects may differ according to the type of BPD. Sound feedback affected CRPS descriptors and other bodily feelings and emotions including feelings of emotional dominance, limb detachment, position awareness, attention and negative feelings toward the limb. Gait also varied with sound feedback, affecting the foot contact time with the ground in a way consistent with experienced changes in body weight. Although, findings from this small pilot study should be interpreted with caution, they suggest potential applications for regenerating BDP and its related bodily feelings in a clinical setting for patients with chronic pain and BPD

Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer

Background Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy. Methods Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. Results In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r 2  = 0.23; p < 10 −16 ) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10 −16 ) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10 −43 ). Conclusions The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment

T1a renal cancer cryoablation : first experiences in Poland

Purpose: Cryoablation is one of the methods of treating patients with renal cancer with curative intent. This procedure is not widely available in Poland due to the lack of reimbursement until April 2023. The purpose of this study is to present the results of the first experiences in cryoablation of renal cell carcinoma in Poland. Material and methods: Patients with renal cell carcinoma in T1a stage (up to 4 cm in diameter) were treated with percutaneous cryoablation between December 2020 and December 2023. All patients were disqualified from surgical treatment due to age, comorbidities, or history of nephrectomy. Diagnosis was confirmed by computed tomography (CT)-guided core needle biopsy that was performed 2-4 weeks before cryoablation. Results: Twenty-five patients underwent CT-guided cryoablation of T1a renal cancer. The mean age of the patients as 77 years (43-91 years). The mean diameter of lesions was 27 mm (15-40 mm). None of the patients presented with local or distant recurrence within the mean 12-months of follow-up period (100% progression-free survival). Urine leak treated with a stent was detected in one patient. Four patients died within the follow-up period, but none of the deaths was directly related to the procedure. Conclusions: Cryoablation is an effective and safe procedure and should be available to more patients in Poland

Reconstructing the urban fabric of Nea Paphos by comparison with regularly planned Mediterranean cities, using 3D Procedural Modelling and Spatial Analysis

Nea Paphos, the Hellenistic-Roman capital of Cyprus, was established according to a regular Hippodamian street grid in the Hellenistic period. The city has been subjected to continuous archaeological research since the 1960s. Despite this, the possibilities for reconstructing its fabric were severely limited. This paper aims to gain a more in-depth understanding of the ways in which computational methods can be used in the analysis of ancient urban planning and the reconstruction of its elements, using the similarity of urban processes and social behavior in ancient Greek cities as its main premise. Therefore, a study based on Network and Space Syntax analysis was conducted for cities with a well-recognized urban layout of the Late Classical and Hellenistic periods, namely Olynthus and Priene, and other, less archaeologically explored harbor towns of the Hellenistic period, such as Piraeus and Ptolemais. The results of these studies were then extrapolated to hypothetical reconstructions of Nea Paphos in the Hellenistic period, mainly to propose the location of the main public buildings and to model the urban traffic. This methodology is experimental in its nature. The aim of this paper is to try to assess to what extent the adopted workflow can be useful in reconstructing the landscape of ancient cities

The influence of chlorine in indoor swimming pools on the composition of breathing phase of professional swimmers

Objectives: Swimming is one of the most popular forms of physical activity. Pool water is cleaned with chlorine, which - in combination with compounds contained in water - could form chloramines and trichloromethane in the swimmer’s lungs. The aim of the present study was to examine the effect of swimming training in an indoor pool on the composition of swimmers’ respiratory phase metabolomics, and develop a system to provide basic information about its impact on the swimmer’s airway mucosa metabolism, which could help to assess the risk of secondary respiratory tract diseases i.e. sport results, condition, and health including lung acute and chronic diseases). Design: A group of competitive swimmers participated in the study and samples of their respiratory phase before training, immediately after training, and 2 h after training were assessed. Methods: Sixteen male national and international-level competitive swimmers participated in this study. Respiratory phase analysis of the indoor swimming pool swimmers was performed. Gas chromatography combined with mass spectrometry (GCMS) was used in the measurements. All collected data were transferred to numerical analysis for trends of tracking and mapping. The breathing phase was collected on special porous material and analyzed using GCMS headspace. Results: The obtained samples of exhaled air were composed of significantly different metabolomics when compared before, during and after exercise training. This suggests that exposition to indoor chlorine causes changes in the airway mucosa Conclusion: This phenomenon may be explained by occurrence of a chlorine-initiated bio-reaction in the swimmers’ lungs. The obtained results indicate that chromatographic exhaled gas analysis is a sensitive method of pulmonary metabolomic changes assessment. Presented analysis of swimmers exhaled air indicates, that indoor swimming may be responsible for airway irritation caused by volatile chlorine compounds and their influence on lung metabolism