The relationships between the isoelectric point and: length of proteins, taxonomy and ecology of organisms

<p>Abstract</p> <p>Background</p> <p>The distribution of isoelectric point (pI) of proteins in a proteome is universal for all organisms. It is bimodal dividing the proteome into two sets of acidic and basic proteins. Different species however have different abundance of acidic and basic proteins that may be correlated with taxonomy, subcellular localization, ecological niche of organisms and proteome size.</p> <p>Results</p> <p>We have analysed 1784 proteomes encoded by chromosomes of Archaea, Bacteria, Eukaryota, and also mitochondria, plastids, prokaryotic plasmids, phages and viruses. We have found significant correlation in more than 95% of proteomes between the protein length and pI in proteomes – positive for acidic proteins and negative for the basic ones. Plastids, viruses and plasmids encode more basic proteomes while chromosomes of Archaea, Bacteria, Eukaryota, mitochondria and phages more acidic ones. Mitochondrial proteomes of Viridiplantae, Protista and Fungi are more basic than Metazoa. It results from the presence of basic proteins in the former proteomes and their absence from the latter ones and is related with reduction of metazoan genomes. Significant correlation was found between the pI bias of proteomes encoded by prokaryotic chromosomes and proteomes encoded by plasmids but there is no correlation between eukaryotic nuclear-coded proteomes and proteomes encoded by organelles. Detailed analyses of prokaryotic proteomes showed significant relationships between pI distribution and habitat, relation to the host cell and salinity of the environment, but no significant correlation with oxygen and temperature requirements. The salinity is positively correlated with acidicity of proteomes. Host-associated organisms and especially intracellular species have more basic proteomes than free-living ones. The higher rate of mutations accumulation in the intracellular parasites and endosymbionts is responsible for the basicity of their tiny proteomes that explains the observed positive correlation between the decrease of genome size and the increase of basicity of proteomes. The results indicate that even conserved proteins subjected to strong selectional constraints follow the global trend in the pI distribution.</p> <p>Conclusion</p> <p>The distribution of pI of proteins in proteomes shows clear relationships with length of proteins, subcellular localization, taxonomy and ecology of organisms. The distribution is also strongly affected by mutational pressure especially in intracellular organisms.</p

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

BACKGROUND: Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. METHODOLOGY/PRINCIPLE FINDINGS: EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). CONCLUSIONS/SIGNIFICANCE: Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma

Combined Tumor Cell-Based Vaccination and Interleukin-12 Gene Therapy Polarizes the Tumor Microenvironment in Mice

Tumor progression depends on tumor milieu, which influences neovasculature formation and immunosuppression. Combining immunotherapy with antiangiogenic/antivascular therapy might be an effective therapeutic approach. The aim of our study was to elaborate an anticancer therapeutic strategy based on the induction of immune response which leads to polarization of tumor milieu. To achieve this, we developed a tumor cell-based vaccine. CAMEL peptide was used as a B16-F10 cell death-inducing agent. The lysates were used as a vaccine to immunize mice bearing B16-F10 melanoma tumors. To further improve the therapeutic effect of the vaccine, we combined it with interleukin (IL)-12 gene therapy. IL-12, a cytokine with antiangiogenic properties, activates nonspecific and specific immune responses. We observed that combined therapy is significantly more effective (as compared with monotherapies) in inhibiting tumor growth. Furthermore, the tested combination polarizes the tumor microenvironment, which results in a switch from a proangiogenic/immunosuppressive to an antiangiogenic/immunostimulatory one. The switch manifests itself as a decreased number of tumor blood vessels, increased levels of tumor-infiltrating CD4+, CD8+ and NK cells, as well as lower level of suppressor lymphocytes (Treg). Our results suggest that polarizing tumor milieu by such combined therapy does inhibit tumor growth and seems to be a promising therapeutic strategy

Inflammatory Markers in Women with Polycystic Ovary Syndrome

Several studies have reported the association between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation to be of uncertain cause: obesity, insulin resistance, or PCOS itself. The aim of the study was to investigate the WBC (white blood cell) count and CRP (C-reactive protein) concentration in women with PCOS and to determine the factors that affect their concentration. The study included 200 women aged 18-40 with PCOS and 105 healthy women as the control group, recruited in the Department of Gynaecological Endocrinology of Medical University in Warsaw from 2016 to 2018. Each patient underwent clinical, biochemical, and ultrasonographic assessments. WBC and CRP were significantly higher in the PCOS group (Z=−2,353, p=0,019 and Z=−2,453, p=0,014). WBC positively correlated with serum insulin at 0, 60, and 120 min during the oral glucose tolerance test (INS0: r=0,221, p=0,001; INS1: r=0,194, p=0,003; INS2: r=0,022, p=0,001), testosterone (r=0,130, p=0,046), androstenedione (r=0,212, p=0,001), and DHEAS (r=0,178, p=0,006) and negatively correlated with progesterone (r=−0,204, p=0,002), estradiol (r=−0,140, p=0,032), and SHBG (r=−0,308, p<0,001). CRP positively correlated with insulin concentration in 0, 60, and 120 min during the oral glucose tolerance test (INS0: r=0,343, p<0,001; INS1: r=0,276, p=0,001; INS2: r=0,320, p<001) and negatively correlated with progesterone (r=−0,194, p=0,030) and SHBG (-0,244, p=0,005). We also estimated positive correlation between BMI and serum CRP and WBC concentration. Multiple linear regression analysis showed that CRP values are positively associated with BMI (beta=0,374, p<0,001) and insulin level (INS1) (beta=0,282, p=0,004); and WBC results are negatively associated with SHGB (beta=−0,284, p<0,001) but positively associated with testosterone (beta=0,163, p=0,024) and BMI (beta=0,157, p=0,047). PCOS is associated with increased WBC and CRP concentrations. The main predicting factors of increased CRP are BMI and insulin resistance, but there is also a relationship between WBC count in PCOS and androgen concentration itself so that inflammation may be mediated not only through adiposity but also through increased androgen concentration

Takayasu’s arteritis: a rare disease in Poland

Introduction. Takayasu’s arteritis (TA) is a rare and potentially life-threatening granulomatous large-vessel vasculitis that involves mostly in the aorta and its proximal branches, and occurs most commonly in young females. This study measures the incidence and prevalence of TA, and assesses the gender distribution and territorial differences in the occurrences of this disease in Poland over a five-year period. To the best of our knowledge, this is the first evaluation of this rare disease in Poland based on a hospital morbidity database. Materials and method. Analyses were performed with population-based administrative data obtained from a national hospital morbidity study carried out between January 2011 – December 2015 by the Polish National Institute of Public Health. Yearly incidence rates and prevalence of TA were calculated using the number of TA patients and corresponding census data for the overall Polish population. Results. Data included 660 hospitalization records. The final study sample comprised 177 patients: 154 female (87%) and 23 male (13%) with first-time hospitalization for TA. The mean age was 45.4years (95% CI: 42.9–47.8; SD 16.8; range 4–81 years), median 47. The incidence rate of TA was estimated at 0.92 per million per year (95% CI: 0.68–1.16). Five-year TA prevalence was estimated to be 4,6 per million. Incidence rates of TA did not vary significantly between more urban and more rural regions. Conclusions. The incidence of TA in Poland was similar or lower to data reported by other European countries. The study provides epidemiological data on TA in Poland that may be useful while comparing it with other geographical regions

Psychiatric Rehabilitation Amidst COVID-19: Do Pandemic Restrictions Affect the Therapeutic Efficiency?

Community psychiatry is an effective and increasingly popular form of care for patients with mental disorders. Due to sanitary restrictions imposed by the COVID-19 pandemic, psychiatric rehabilitation programs had to adapt to the highly specific requirements and modify the offer of therapeutic activities for patients. Above all the activities focused on, social interactions were limited. The aim of the study was to assess the effectiveness of the modified rehabilitation program in light of the introduced sanitary restrictions due to COVID-19. This prospective observational single-centered study involved 41 patients diagnosed with organic mental disorders, psychotic disorders, affective disorders and anxiety disorders. The patients participated in a 6-week rehabilitation program which included varied forms of physical exercise, cognitive training, psychological training and Small Group Therapy. The quality-of-life assessment and the intensity of depression and anxiety symptoms were measured using standardized scales: Hospital Scale of Anxiety and Depression (HADS) and Short Form Health Survey (SF-36) at two time points before the initiation of the rehabilitation process and at the end of the program’s participation period. Median HADS D before admission to the rehabilitation center was 9 (IQR 6–12), and 5 (IQR 3–9) after 6-week participation (p p p > 0.05). The gender and age of the participants did not influence the results of the utilized standardized evaluation tools (p > 0.05 for both). We observed an improvement in the participants’ subjective assessment of the intensity of the depression symptoms and the quality of life after partaking in the available activities. There was no clear benefit regarding the subjective assessment of the intensity of anxiety symptoms among the study participants resulting from the introduction to the program

Peroxiredoxin-1 as a prognostic factor in patients with ovarian cancer

Introduction and objective. Peroxiredoxin-1 (PRDX-1) belongs to a family of antioxidant enzymes and has proved to be a versatile molecule regulating cell growth, differentiation and apoptosis. PRDX1-regulated signaling pathways play an important role in the progression and metastasis of human tumours, especially in breast, esophageal and lung cancers. The aim of the study was to evaluate the expression of PRDX-1 in ovarian cancer tissues, and to test the clinical value of PRDX-1 as a prognostic factor in this malignancy. Materials and method. PRDX-1 expression was assessed by automated immunohistochemistry in tumours taken from 55 patients with ovarian cancer during primary surgery. Specimen were formalin-fixed and preserved in paraffin-embedded blocks. The results were correlated with clinicopathological data. Results. A high expression of PRDX-1 was observed in 20% of cases, and was associated with worse compliance to chemotherapy protocol (P<0.002), worse response to chemotherapy (P<0.04), and higher levels of CA 125 after the 1st line treatment (P<0.004). PRDX-1 positive subjects had a significantly lower 5-year disease-free survival (9.1% vs. 42.6%, P<0.01) and a lower 5-year overall survival (9.1% vs. 56.7%; P<0.002). Multivariate analysis showed that a high expression of PRDX-1 is an independent prognostic factor of poor, overall survival (P<0.002) and a disease-free survival (P<0.01). Conclusion. Results of the study show that PRDX-1 expression in tumour tissues can be another biomarker of prognosis in patients with ovarian cancer

Novel Local “Off-the-Shelf” Immunotherapy for the Treatment of Myeloma Bone Disease

Myeloma bone disease (MBD) is one of the major complications in multiple myeloma (MM)—the second most frequent hematologic malignancy. It is characterized by the formation of bone lesions due to the local action of proliferating MM cells, and to date, no effective therapy has been developed. In this study, we propose a novel approach for the local treatment of MBD with a combination of natural killer cells (NKs) and mesenchymal stem cells (MSCs) within a fibrin scaffold, altogether known as FINM. The unique biological properties of the NKs and MSCs, joined to the injectable biocompatible fibrin, permitted to obtain an efficient “off-the-shelf” ready-to-use composite for the local treatment of MBD. Our in vitro analyses demonstrate that NKs within FINM exert a robust anti-tumor activity against MM cell lines and primary cells, with the capacity to suppress osteoclast activity (~60%) within in vitro 3D model of MBD. Furthermore, NKs’ post-thawing cytotoxic activity is significantly enhanced (~75%) in the presence of MSCs, which circumvents the decrease of NKs cytotoxicity after thawing, a well-known issue in the cryopreservation of NKs. To reduce the tumor escape, we combined FINM with other therapeutic agents (bortezomib (BZ), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)), observing a clear therapeutic synergistic effect in vitro. Finally, the therapeutic efficacy of FINM in combination with BZ and TRAIL was assessed in a mouse model of MM, achieving 16-fold smaller tumors compared to the control group without treatment. These results suggest the potential of FINM to serve as an allogeneic “off-the-shelf” approach to improve the outcomes of patients suffering from MBD