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Acute kidney injury (AKI) constitutes a severe condition characterized by a sudden decrease in kidney function. Utilizing lineage-restricted stem/progenitor cells, directly reprogrammed from somatic cells, is a promising therapeutic option in personalized medicine for serious and incurable diseases such as AKI. The present study describes the therapeutic potential of induced nephron progenitor cell-sourced molecules (iNPC-SMs) as a cell-free strategy against cisplatin (CP)-induced nephrotoxicity, employing hyaluronic acid (HA) hydrogel-mediated local delivery to minimize systemic leakage and degradation. iNPC-SMs exhibited anti-apoptotic effects on HK-2 cells by inhibiting CP-induced ROS generation. Additionally, the localized biodistribution facilitated by hydrogel-mediated iNPC-SM delivery contributed to enhanced renal function, anti-inflammatory response, and renal regeneration in AKI mice. This study could serve as a 'proof of concept' for injectable hydrogel-mediated iNPC-SM delivery in AKI and as a model for further exploration of the development of cell-free regenerative medicine strategies. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases represent an increasing economic, social, and, above all, medical burden worldwide. The second most prevalent disease in this category is Parkinson's disease, surpassed only by Alzheimer's. It is a treatable but still incurable systemic disease with a pathogenesis that has not yet been elucidated. Several theories are currently being developed to explain the causes and progression of Parkinson's disease. Magnesium is one of the essential macronutrients and is absolutely necessary for life as we know it. The magnesium cation performs several important functions in the cell in the context of energetic metabolism, substrate metabolism, cell signalling, and the regulation of the homeostasis of other ions. Several of these cellular processes have been simultaneously described as being disrupted in the development and progression of Parkinson's disease. The relationship between magnesium homeostasis and the pathogenesis of Parkinson's disease has received little scientific attention to date. The aim of this review is to summarise and critically evaluate the current state of knowledge on the possible role of magnesium in the pathogenesis of Parkinson's disease and to outline possible future directions for research in this area. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia, in spite of recent advancements, is still an incurable disease; the majority of patients eventually acquire resistance to treatment through relapses. In all subtypes of chronic lymphocytic leukemia, the disruption of normal B-cell homeostasis is thought to be mostly caused by the absence of apoptosis. Consequently, apoptosis induction is crucial to the management of this illness. Damaged biological components can accumulate as a result of the oxidation of intracellular lipids, proteins, and DNA by reactive oxygen species. It is possible that cancer cells are more susceptible to apoptosis because of their increased production of reactive oxygen species. An excess of reactive oxygen species can lead to oxidative stress, which can harm biological elements like DNA and trigger apoptotic pathways that cause planned cell death. In order to upset the balance of oxidative stress in cells, recent therapeutic treatments in chronic lymphocytic leukemia have focused on either producing reactive oxygen species or inhibiting it. Examples include targets created in the field of nanomedicine, natural extracts and nutraceuticals, tailored therapy using biomarkers, and metabolic targets. Current developments in the complex connection between apoptosis, particularly ferroptosis and its involvement in epigenomics and alterations, have created a new paradigm. [ABSTRACT FROM AUTHOR]

Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular. [ABSTRACT FROM AUTHOR]

In the last decade, many small molecules, usually characterized by heterocyclic scaffolds, have been designed and synthesized as tyrosine kinase inhibitors (TKIs). Among them, several compounds have been tested at preclinical and clinical levels to treat glioblastoma multiforme (GBM). GBM is the most common and aggressive type of cancer originating in the brain and has an unfavorable prognosis, with a median survival of 15–16 months and a 5-year survival rate of 5%. Despite recent advances in treating GBM, it represents an incurable disease associated with treatment resistance and high recurrence rates. For these reasons, there is an urgent need for the development of new pharmacological agents to fight this malignancy. In this review, we reported the compounds published in the last five years, which showed promising activity in GBM preclinical models acting as TKIs. We grouped the compounds based on the targeted kinase: first, we reported receptor TKIs and then, cytoplasmic and peculiar kinase inhibitors. For each small molecule, we included the chemical structure, and we schematized the interaction with the target for some representative compounds with the aim of elucidating the mechanism of action. Finally, we cited the most relevant clinical trials. [ABSTRACT FROM AUTHOR]

Breast angiosarcoma is a rare malignancy, accounting for less than 1% of all soft tissue cancers. It comprises primitive and secondary subtypes, such as radiogenic breast angiosarcoma (RAS). Despite multimodal treatment, angiosarcomas represent an incurable disease for many patients and a significant cause of deterioration in their quality of life. Surgery is a cornerstone in management, but high recurrence rates are reported. Electrochemotherapy (ECT) is a practicable locoregional treatment for patients with advanced angiosarcoma as part of a multimodal therapeutic strategy. The palliative benefits of ECT include optimal patient compliance, good local hemostasis control, and positive local responses. Since only 22 cases are described in the literature, we reported a rare case of RAS treated with ECT after a multidisciplinary approach, including Next Generation Sequencing (NGS). A literature review on the feasibility of ECT in RAS management was also performed. [ABSTRACT FROM AUTHOR]

High-grade gliomas are considered an incurable disease. Despite all the various therapy options available, patient survival remains low, and the tumor usually returns. Tumor resistance to conventional therapy and stimulation of the migratory activity of surviving cells are the main factors that lead to recurrent tumors. When developing new treatment approaches, the effect is most often evaluated on standard and phenotypically depleted cancer cell lines. Moreover, there is much focus on the anti-proliferative effect of such therapies without considering the possible stimulation of migratory activity. In this paper, we studied how glioma cell migration changes after exposure to bi-(AID-1-T), an anti-proliferative aptamer. We investigated the effect of this aptamer on eight human glioma cell cultures (Grades III and IV) that were derived from patients' tumor tissue; the difference between primary and recurrent tumors was taken into account. Despite its strong anti-proliferative activity, bi-(AID-1-T) was shown to induce migration of recurrent tumor cells. This result shows the importance of studying the effect of therapeutic molecules on the invasive properties of glioma tumor cells in order to reduce the likelihood of inducing tumor recurrence. [ABSTRACT FROM AUTHOR]

Heat shock proteins are named stress proteins or stress molecules due to their secretion being triggered by stress encountered by living beings. Although their primary documented role has been maintaining and regulating protein conformations to reduce effects of aberrant conditions faced by the host, heat shock proteins have been found to have therapeutic effects in the treatments of many diseases and conditions. Those derived from certain bacteria, in particular, have been found to have high immunomodulatory potential and are being considered as adjuvants and immune stimulators in immunocompromised individuals. Extensive research has been conducted establishing their role as potential vaccine antigens or epitopes targeted in cancer therapies. Certain neuropathies and assumedly incurable autoimmune diseases have also seen light in terms of therapeusis mediated by heat shock proteins. This review focuses on providing an extensive study about multiple moonlighting roles of heat shock proteins derived from microorganisms, at a molecular level, which are being used to immunise and treat diseases in many mammalian species, including humans. [ABSTRACT FROM AUTHOR]

Cancer is a widespread and incurable disease caused by genetic mutations, leading to uncontrolled cell proliferation and metastasis. Connexins (Cx) are transmembrane proteins that facilitate intercellular communication via hemichannels and gap junction channels. Among them, Cx46 is found mostly in the eye lens. However, in pathological conditions, Cx46 has been observed in various types of cancers, such as glioblastoma, melanoma, and breast cancer. It has been demonstrated that elevated Cx46 levels in breast cancer contribute to cellular resistance to hypoxia, and it is an enhancer of cancer aggressiveness supporting a pro-tumoral role. Accordingly, Cx46 is associated with an increase in cancer stem cell phenotype. These cells display radio- and chemoresistance, high proliferative abilities, self-renewal, and differentiation capacities. This review aims to consolidate the knowledge of the relationship between Cx46, its role in forming hemichannels and gap junctions, and its connection with cancer and cancer stem cells. [ABSTRACT FROM AUTHOR]

Psoriasis is an incurable skin disease that develops in about two-thirds of patients before the age of 40 and requires lifelong treatment; its pathological mechanisms have not been fully elucidated. The core pathological process of psoriasis is epidermal thickening caused by the excessive proliferation of epidermal keratinocytes, which is similar to the key feature of cancer; the malignant proliferation of cancer cells causes tumor enlargement, suggesting that there is a certain degree of commonality between psoriasis and cancer. This article reviews the pathological mechanisms that are common to psoriasis and cancer, including the interaction between cell proliferation and an abnormal immune microenvironment, metabolic reprogramming, and epigenetic reprogramming. In addition, there are common therapeutic agents and drug targets between psoriasis and cancer. Thus, psoriasis and cancer share a common pathological mechanisms–drug targets–therapeutic agents framework. On this basis, it is proposed that investigating psoriasis from a cancer perspective is beneficial to enriching the research strategies related to psoriasis. [ABSTRACT FROM AUTHOR]

Infectious diseases are constantly evolving to bypass antibiotics or create resistance against them. There is a piercing alarm for the need to improve the design of new effective antimicrobial agents such as antimicrobial peptides which are less prone to resistance and possess high sensitivity. This would guard public health in combating and overcoming stubborn pathogens and mitigate incurable diseases; however, the emergence of antimicrobial peptides' shortcomings ranging from untimely degradation by enzymes to difficulty in the design against specific targets is a major bottleneck in achieving these objectives. This review is aimed at highlighting the recent progress in antimicrobial peptide development in the area of nanotechnology-based delivery, selectivity indices, synthesis and characterization, their doping and coating, and the shortfall of these approaches. This review will raise awareness of antimicrobial peptides as prospective therapeutic agents in the medical and pharmaceutical industries, such as the sensitive treatment of diseases and their utilization. The knowledge from this development would guide the future design of these novel peptides and allow the development of highly specific, sensitive, and accurate antimicrobial peptides to initiate treatment regimens in patients to enable them to have accommodating lifestyles. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease characterized by the progressive death of motor neurons, leading to paralysis and death. It is a rare disease characterized by high patient-to-patient heterogeneity, which makes its study arduous and complex. Extracellular vesicles (EVs) have emerged as important players in the development of ALS. Thus, ALS phenotype-expressing cells can spread their abnormal bioactive cargo through the secretion of EVs, even in distant tissues. Importantly, owing to their nature and composition, EVs' formation and cargo can be exploited for better comprehension of this elusive disease and identification of novel biomarkers, as well as for potential therapeutic applications, such as those based on stem cell-derived exosomes. This review highlights recent advances in the identification of the role of EVs in ALS etiopathology and how EVs can be promising new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is an incurable neurodegenerative disease that is rarely diagnosed at an early stage. Although the understanding of PD-related mechanisms has greatly improved over the last decade, the diagnosis of PD is still based on neurological examination through the identification of motor symptoms, including bradykinesia, rigidity, postural instability, and resting tremor. The early phase of PD is characterized by subtle symptoms with a misdiagnosis rate of approximately 16–20%. The difficulty in recognizing early PD has implications for the potential use of novel therapeutic approaches. For this reason, it is important to discover PD brain biomarkers that can indicate early dopaminergic dysfunction through their changes in body fluids, such as saliva, urine, blood, or cerebrospinal fluid (CSF). For the CFS-based test, the invasiveness of sampling is a major limitation, whereas the other body fluids are easier to obtain and could also allow population screening. Following the identification of the crucial role of alpha-synuclein (α-syn) in the pathology of PD, a very large number of studies have summarized its changes in body fluids. However, methodological problems have led to the poor diagnostic/prognostic value of this protein and alternative biomarkers are currently being investigated. The aim of this paper is therefore to summarize studies on protein biomarkers that are alternatives to α-syn, particularly those that change in nigrostriatal areas and in biofluids, with a focus on blood, and, eventually, saliva and urine. [ABSTRACT FROM AUTHOR]

Multiple myeloma is the second-most common hematologic malignancy in adults worldwide. Despite ongoing advancement in therapeutic modalities, it remains an incurable disease with a 5-year survival rate of approximately 50%. The recent development and introduction of anti-BCMA immunotherapies into clinical practice, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, has radically shifted the treatment paradigm. However, despite the promising potential of these therapies for broader application, frequent and significant adverse effects have been reported, both in short- and in long-term settings, requiring increasing awareness and vigilance in the treating team, close monitoring, and prompt interventions with a multidisciplinary approach. In this review, we will discuss the toxicities associated with CAR-T cell and bispecific antibody therapies, focusing on results from major clinical studies and real-world observations. In addition, we will emphasize on effective strategies for prevention, monitoring and management, and provide expert recommendations. [ABSTRACT FROM AUTHOR]

Advanced mesothelioma is considered an incurable disease and new treatment strategies are needed. Previous studies have demonstrated that mitochondrial antioxidant defense proteins and the cell cycle may contribute to mesothelioma growth, and that the inhibition of these pathways may be effective against this cancer. We demonstrated that the antioxidant defense inhibitor auranofin and the cyclin-dependent kinase 4/6 inhibitor palbociclib could decrease mesothelioma cell proliferation alone or in combination. In addition, we determined the effects of these compounds on colony growth, cell cycle progression, and the expression of key antioxidant defense and cell cycle proteins. Auranofin and palbociclib were effective in decreasing cell growth and inhibiting the above-described activity across all assays. Further study of this drug combination will elucidate the contribution of these pathways to mesothelioma activity and may reveal a new treatment strategy. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials. Methods: A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected. Results: Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11–4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06–67.21%). Summary PFS was 4.56 months (95% CI: 3.57–5.55 months), and summary OS was 11.17 months (95% CI: 10.15–12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination. Conclusion: The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders, which are currently incurable diseases of the nervous system, are a constantly growing social concern. They are progressive and lead to gradual degeneration and/or death of nerve cells, resulting in cognitive deterioration or impaired motor functions. New therapies that would ensure better treatment results and contribute to a significant slowdown in the progression of neurodegenerative syndromes are constantly being sought. Vanadium (V), which is an element with a wide range of impacts on the mammalian organism, is at the forefront among the different metals studied for their potential therapeutic use. On the other hand, it is a well-known environmental and occupational pollutant and can exert adverse effects on human health. As a strong pro-oxidant, it can generate oxidative stress involved in neurodegeneration. Although the detrimental effects of vanadium on the CNS are relatively well recognized, the role of this metal in the pathophysiology of various neurological disorders, at realistic exposure levels in humans, is not yet well characterized. Hence, the main goal of this review is to summarize data on the neurological side effects/neurobehavioral alterations in humans, in relation to vanadium exposure, with the focus on the levels of this metal in biological fluids/brain tissues of subjects with some neurodegenerative syndromes. Data collected in the present review indicate that vanadium cannot be excluded as a factor playing a pivotal role in the etiopathogenesis of neurodegenerative illnesses, and point to the need for additional extensive epidemiological studies that will provide more evidence supporting the relationship between vanadium exposure and neurodegeneration in humans. Simultaneously, the reviewed data, clearly showing the environmental impact of vanadium on health, suggest that more attention should be paid to chronic diseases related to vanadium and to the assessment of the dose–response relationship. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, with 2.3 million new cases and 0.7 million deaths every year, represents a great medical challenge worldwide. These numbers confirm that approx. 30% of BC patients will develop an incurable disease requiring life-long, palliative systemic treatment. Endocrine treatment and chemotherapy administered in a sequential fashion are the basic treatment options in advanced ER+/HER2- BC, which is the most common BC type. The palliative, long-term treatment of advanced BC should not only be highly active but also minimally toxic to allow long-term survival with the optimal quality of life. A combination of metronomic chemotherapy (MC) with endocrine treatment (ET) in patients who failed earlier lines of ET represents an interesting and promising option. Methods: The methodology includes retrospective data analyses of pretreated, metastatic ER+/HER2- BC (mBC) patients who were treated with the FulVEC regimen combining fulvestrant and MC (cyclophosphamide, vinorelbine, and capecitabine). Results: Thirty-nine previously treated (median 2 lines 1–9) mBC patients received FulVEC. The median PFS and OS were 8.4 and 21.5 months, respectively. Biochemical responses (CA-15.3 serum marker decline ≥50%) were observed in 48.7%, and any increase in CA-15.3 was observed in 23.1% of patients. The activity of FulVEC was independent of previous treatments with fulvestrant of cytotoxic components of the FulVEC regimen. The treatment was safe and well tolerated. Conclusions: Metronomic chemo-endocrine therapy with FulVEC regimen represents an interesting option and compares favorably with other approaches in patients' refractory to endocrine treatments. A phase II randomized trial is warranted. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women. Despite advances in diagnosis and prognosis, distal metastases occur in these patients in up to 15% of cases within 3 years of diagnosis. The main organs in which BC metastasises are the bones, lungs, liver, and brain. Unfortunately, 90% of metastatic patients will die, making this an incurable disease. Researchers are therefore seeking biomarkers for diagnosis and metastasis in different organs. Optimally, such biomarkers should be easy to detect using, preferably, non-invasive methods, such as using miRNA molecules, which are small molecules of about 22 nt that have as their main function the post-transcriptional regulation of genes. Furthermore, due to their uncomplicated detection and reproducibility in the laboratory, they are a tool of complementary interest for diagnosis, prognosis, and treatment. With this in mind, in this review, we focus on describing the most current studies that propose using miRNA independently as a potential biomarker for the diagnosis and prediction of brain, lung, liver, and bone metastases, as well as to open a window of opportunity to deepen this area of study to eventually use miRNAs molecules in clinical practice for the benefit of BC patients. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an aggressive and incurable disease for most patients, characterized by periods of treatment, remission and relapse. The introduction of new classes of drugs, such as proteasome inhibitors (PIs), has improved survival outcomes in these patient populations. The proteasome is the core of the ubiquitin–proteasome system (UPS), a complex and conserved pathway involved in the control of multiple cellular processes, including cell cycle control, transcription, DNA damage repair, protein quality control and antigen presentation. To date, PIs represent the gold standard for the treatment of MM. Bortezomib was the first PI approved by the FDA, followed by next generation of PIs, namely carfilzomib and ixazomib. Natural agents play an important role in anti-tumor drug discovery, and many of them have recently been reported to inhibit the proteasome, thus representing a new potential source of anti-MM drugs. Based on the pivotal biological role of the proteasome and on PIs' significance in the management of MM, in this review we aim to briefly summarize recent evidence on natural compounds capable of inhibiting the proteasome, thus triggering anti-MM activity. [ABSTRACT FROM AUTHOR]

The purpose of this research paper is to semantically analyze the concept of transhumanism in the publications of Russian scientists, as well as to study the influence of the idea of transhumanism as the leading philosophy of human improvement on the global differentiation of the world through a comparative analysis of the level of life expectancy in the Russian Federation, the USA, and China. Findings indicate that, in general, when setting the right goals based on the Russian cosmism and transhumanism concepts can and should bring certain positive benefits to humanity. First of all, this involves treatment of incurable and complex diseases and enhancement of human capabilities in space expansion. The scientific contribution and practical significance of the research lie in the development of three exponential models of life expectancy growth in accordance with the indicator of economic development that is based on the gross domestic product per capita level. [ABSTRACT FROM AUTHOR]

Amyloids are fibrillar proteins with a cross-β structure. Pathological amyloids are associated with the development of a number of incurable diseases, while functional amyloids regulate vital processes. The detection of unknown amyloids in living objects is a difficult task, and therefore the question of the prevalence and biological significance of amyloids remains open. We present a description of two methods, the combination of which makes it possible to find and identify amyloid proteins in the proteome of various organisms. The method of proteomic screening for amyloids allows the detection of the proteins that form SDS-resistant aggregates. SDS resistance is a general feature of amyloid fibrils. Protein aggregates resistant to SDS treatment can be collected by ultracentrifugation and further identified by mass spectrometry. However, in addition to amyloids, SDS-resistant aggregates contain some non-amyloid proteins. To test the amyloid properties of proteins identified by proteomic screening, we developed the method of fibril immunoprecipitation followed by Congo red staining and birefringence analysis. The methods of proteomic screening and immunoprecipitation of fibrillar proteins have been successfully tested and applied for the identification of amyloid proteins in yeast and vertebrates. [ABSTRACT FROM AUTHOR]

Fibrosis is a chronic progressive and incurable disease leading to organ dysfunction. It is characterized by the accumulation of extracellular matrix proteins produced by mesenchymal stem cells (MSCs) differentiating into myofibroblasts. Given the complexity of its pathophysiology, the search for effective treatments for fibrosis is of paramount importance. Metformin, a structural dimethyl analog of the galegine guanide extracted from the "French Lilac" (Fabaceae Galega officinalis), is the most widely used antidiabetic drug, recently recognized for its antifibrotic effects through ill-characterized mechanisms. The in vitro model of TGF-β1-induced fibrosis in human primary pulmonary mesenchymal stem cells (HPMSCs), identified as CD248+ and CD90+ cells, was used to study the effects of metformin extracts. These effects were tested on the expression of canonical MSC differentiation markers, immune/inflammatory factors and antioxidative stress molecules using qRT-PCR (mRNA, miRNA), immunofluorescence and ELISA experiments. Interestingly, metformin is able to reduce/modulate the expression of different actors involved in fibrosis. Indeed, TGF-β1 effects were markedly attenuated by metformin, as evidenced by reduced expression of three collagen types and Acta2 mRNAs. Furthermore, metformin attenuated the effects of TGF-β1 on the expression of PDGF, VEGF, erythropoietin, calcitonin and profibrotic miRs, possibly by controlling the expression of several key TGF/Smad factors. The expression of four major fibrogenic MMPs was also reduced by metformin treatment. In addition, metformin controlled MSC differentiation into lipofibroblasts and osteoblasts and had the ability to restore redox balance via the Nox4/Nrf2, AMP and Pi3K pathways. Overall, these results show that metformin is a candidate molecule for antifibrotic effect and/or aiming to combat the development of chronic inflammatory diseases worldwide. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic autoimmune disease, and until now, it remains an incurable disease. Therefore, the development of new drugs or agents that ameliorate the disease will have marketing potential. Taiwanofungus camphoratus (TC) is a specific fungus in Taiwan. It is demonstrated to have anticancer, anti-inflammation, and hepatoprotective effects. However, the effects of TC fermented extract on psoriasis are under investigation. In this research, we studied the ability of TC on antioxidative activity and the efficacy of TC on interleukin-17 (IL-17A)-induced intracellular oxidative stress, inflammation-relative, and proliferation-relative protein expression in human keratinocytes. The results of a DPPH radical scavenging assay, reducing power assay, and hydroxyl peroxide inhibition assay indicated that TC has a potent antioxidant ability. Furthermore, TC could reduce IL-17A-induced intracellular ROS generation and restore the NADPH level. In the investigation of pathogenesis, we discovered TC could regulate inflammatory and cell proliferation pathways via p-IKKα/p-p65 and p-mTOR/p-p70S6k signaling pathways in human keratinocytes. In conclusion, TC showed characteristics such as antioxidant, anti-inflammatory, and anti-psoriatic-associated responses. It is expected to be developed as a candidate for oxidative-stress-induced skin disorders or psoriasis treatment. [ABSTRACT FROM AUTHOR]

Exposure to coal dust from mining-related activities has historically been linked to several preventable but incurable respiratory diseases. Although the findings of numerous biological studies have determined that the physicochemical and mineralogical aspects of dust particles greatly influence both cytotoxic and proinflammatory pathways, robust datasets which quantitatively define these characteristics of coal dust remain limited. This study aims to develop a robust characterisation routine applicable for real-world coal dust, using an auto-SEM-EDS system. In doing so, the study addresses both the validation of the particle mineralogical scans and the quantification of a range of coal particle characteristics relevant to respiratory harm. The findings presented demonstrate the application of auto-SEM-EDS-XRD systems to analyse and report on the physicochemical and mineralogical characteristics of thousands of dust-sized particles. Furthermore, by mineralogically mapping the particles, parameters such as liberation, mineral association and elemental distribution can be computed to understand the relationships between elements and minerals in the particles, which have yet to be quantified by other studies. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, the pathogenesis of which is based on alternations in the mitochondria of motor neurons, causing their progressive death. A growing body of evidence shows that more efficient mitophagy could prevent and/or treat this disorder by suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. Mitophagy has been considered one of the main mechanisms responsible for mitochondrial quality control. Since ALS is characterized by enormous oxidative stress, several edible phytochemicals that can activate mitophagy to remove damaged mitochondria could be considered a promising option to treat ALS by providing neuroprotection. Therefore, it is of great significance to explore the mechanisms of mitophagy in ALS and to understand the effects and/or molecular mechanisms of phytochemical action, which could translate into a treatment for neurodegenerative diseases, including ALS. [ABSTRACT FROM AUTHOR]

Despite significant developments in renal cell carcinoma (RCC) detection and molecular pathology, mortality has been steadily rising. Advanced RCC remains an incurable disease. Better clinical management tools, i.e., RCC biomarkers, have yet to emerge. Thymine-dimers (TDs) were traditionally considered photo-dependent pre-mutagenic lesions, occurring exclusively during ultra-violet light exposure. Non-oxidative, direct, and preferential byproducts of DNA photochemical reactions, TDs, have recently shown evidence regarding UVR-independent formation. In this study, we investigate, for the first time, TD expression within RCC tumor tissue and tumor-adjacent healthy renal parenchyma using a TD-targeted IHC monoclonal antibody, clone KTM53. Remarkably, out of the 54 RCCs evaluated, 77.8% showed nuclear TD-expression in RCC tumor tissue and 37% in the tumor-adjacent healthy renal parenchyma. A comprehensive report regarding quantitative/qualitative TD-targeted immunostaining was elaborated. Two main distribution models for TD expression within RCC tumor tissue were identified. Statistical analysis showed significant yet moderate correlations regarding TD-positivity in RCC tissue/tumor-adjacent healthy renal parenchyma and TNM stage at diagnosis/lymphatic dissemination, respectively, indicating possible prognostic relevance. We review possible explanations for UVR-independent TD formation and molecular implications regarding RCC carcinogenesis. Further rigorous molecular analysis is required in order to fully comprehend/validate the biological significance of this newly documented TD expression in RCC. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) is one of the most common malignancies and the leading causes of cancer-related death worldwide. Despite many therapeutic advances in the past decade, NSCLC remains an incurable disease for the majority of patients. Molecular targeted therapies and immunotherapies have significantly improved the prognosis of NSCLC. However, the vast majority of advanced NSCLC develop resistance to current therapies and eventually progress. In this review, we discuss current and potential therapies for NSCLC, focusing on targeted therapies and immunotherapies. We highlight the future role of metabolic therapies and combination therapies in NSCLC. [ABSTRACT FROM AUTHOR]

Transmissible spongiform encephalopathies are incurable neurodegenerative diseases, associated with the conversion of the physiological prion protein to its disease-associated counterpart. Even though immunization against transmissible spongiform encephalopathies has shown great potential, immune tolerance effects impede the use of active immunization protocols for successful prophylaxis. In this study, we evaluate the use of trypanosomes as biological platforms for the presentation of a prion antigenic peptide to the host immune system. Using the engineered trypanosomes in an immunization protocol without the use of adjuvants led to the development of a humoral immune response against the prion protein in wild type mice, without the appearance of adverse reactions. The immune reaction elicited with this protocol displayed in vitro therapeutic potential and was further evaluated in a bioassay where immunized mice were partially protected in a representative murine model of prion diseases. Further studies are underway to better characterize the immune reaction and optimize the immunization protocol. [ABSTRACT FROM AUTHOR]

Multiple myeloma survival has increased in last 20 years because of new treatments, better clinical management due to novel diagnostic tools such as imaging, and better understanding of the disease, biologically and genetically. Novel drugs have been introduced that act with different therapeutic mechanisms, but so have novel therapeutic strategies such as consolidation and maintenance after autologous stem cell transplant. Imaging (such as PET-CT and MRI) has been applied at diagnosis and after therapy for minimal residual disease monitoring. Multiparametric flow and molecular NGS may detect, with high-sensitivity, residual monoclonal plasma cells in the bone marrow. With this novel therapeutic and biological approach, a considerable fraction of multiple myeloma patients can achieve durable remission or even MGUS-like regression, which can ultimately lead to disease disappearance. The big dogma, "Myeloma is an incurable disease", is hopefully fading. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most common hematological malignancy. Despite the huge therapeutic progress thanks to the introduction of novel therapies, MM remains an incurable disease. Extensive research is currently ongoing to find new options. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at a post-transcriptional level. Aberrant expression of miRNAs in MM is common. Depending on their role in MM development, miRNAs have been reported as oncogenes and tumor suppressors. It was demonstrated that specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways in the microenvironment and MM cells. These properties make miRNAs attractive targets in anti-myeloma therapy. However, only a few miRNA-based drugs have been entered into clinical trials. In this review, we discuss the role of the miRNAs in the pathogenesis of MM, their current status in preclinical/clinical trials, and the mechanisms by which miRNAs can theoretically achieve therapeutic benefit in MM treatment. [ABSTRACT FROM AUTHOR]

It is now well-established that microRNA dysregulation is a hallmark of human diseases, and that aberrant expression of miRNA is not randomly associated with human pathologies but plays a causal role in the pathological process. Investigations of the molecular mechanism that links miRNA dysregulation to pathophysiology can therefore further the understanding of human diseases. The biological effect of miRNA is thought to be mediated principally by miRNA target genes. Consequently, the target genes of dysregulated miRNA serve as a proxy for the biological interpretation of miRNA dysregulation, which is performed by target gene pathway enrichment analysis. However, this method unfortunately often fails to provide testable hypotheses concerning disease mechanisms. In this paper, we describe a method for the interpretation of miRNA dysregulation, which is based on miRNA host genes rather than target genes. Using this approach, we have recently identified the perturbations of lipid metabolism, and cholesterol in particular, in Duchenne muscular dystrophy (DMD). The host gene-based interpretation of miRNA dysregulation therefore represents an attractive alternative method for the biological interpretation of miRNA dysregulation. [ABSTRACT FROM AUTHOR]

Simple Summary: Dogs are the main host of Leishmania infantum, a parasite that causes an incurable disease called canine leishmaniasis. This parasite is transmitted through the bite of a sandfly (a small insect related to mosquitoes and flies) in tropical and subtropical countries, but direct transmission between dogs, and from pregnant dogs to their puppies, exists. We reviewed the advances in tools and techniques for the surveillance of the disease, its diagnosis, treatment, and prevention. Canine leishmaniasis is expanding to the Northern Hemisphere, where it is barely known, due to climate change and the importation of dogs. Surveillance is therefore necessary in order to determine the extent of the disease in these areas and to monitor the appearance of the sandflies. Molecular techniques and rapid serological tests are now widespread for diagnosis and epidemiological studies. Several vaccines have been developed in the last decade, and even though their efficacy is limited, these advances will pave the way for the development of better vaccines against Leishmania and other parasites. Although new pharmacological tools are available, we are still waiting for the ideal drug that can eliminate the parasite from target organs and limit transmission to sandflies, without the side effects of current antileishmanials. Dog are the main reservoir of Leishmania infantum, causing canine leishmaniasis, an incurable multisystemic disease that leads to death in symptomatic dogs, when not treated. This parasite causes visceral, cutaneous, and mucosal leishmaniasis in people in the Mediterranean Basin, North Africa, South America, and West Asia. This disease is mostly unknown by veterinarians outside the endemic areas, but the disease is expanding in the Northern Hemisphere due to travel and climate change. New methodologies to study the epidemiology of the disease have found new hosts of leishmaniasis and drawn a completely new picture of the parasite biological cycle. Canine leishmaniasis diagnosis has evolved over the years through the analysis of new samples using novel molecular techniques. Given the neglected nature of leishmaniasis, progress in drug discovery is slow, and the few drugs that reach clinical stages in humans are unlikely to be commercialised for dogs, but several approaches have been developed to support chemotherapy. New-generation vaccines developed during the last decade are now widely used, along with novel prevention strategies. The implications of the epidemiology, diagnosis, treatment, and prevention of canine leishmaniasis are fundamental to public health. [ABSTRACT FROM AUTHOR]

Leukemia is one of the most common primary malignancies of the hematologic system in both children and adults and remains a largely incurable or relapsing disease. The elucidation of disease subtypes based on mutational profiling has not improved clinical outcomes. IDH1/2 are critical enzymes of the TCA cycle that produces α-ketoglutarate (αKG). However, their mutated version is well reported in various cancer types, including leukemia, which produces D-2 hydroxyglutarate (D-2HG), an oncometabolite. Recently, some studies have shown that wild-type IDH1 is highly expressed in non-small cell lung carcinoma (NSCLC), primary glioblastomas (GBM), and several hematological malignancies and is correlated with disease progression. This work shows that the treatment of wild-type IDH1 leukemia cells with a specific IDH1 inhibitor shifted leukemic cells toward glycolysis from the oxidative phosphorylation (OXPHOS) phenotype. We also noticed a reduction in αKG in treated cells, possibly suggesting the inhibition of IDH1 enzymatic activity. Furthermore, we found that IDH1 inhibition reduced the metabolites related to one-carbon metabolism, which is essential for maintaining global methylation in leukemic cells. Finally, we observed that metabolic alteration in IDH1 inhibitor-treated leukemic cells promoted reactive oxygen species (ROS) formation and the loss of mitochondrial membrane potential, leading to apoptosis in leukemic cells. We showed that targeting wild-type IDH1 leukemic cells promotes metabolic alterations that can be exploited for combination therapies for a better outcome. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a disorder of the monoclonal plasma cells and is the second most common hematologic malignancy. Despite improvements in survival with newer treatment regimens, multiple myeloma remains an incurable disease and most patients experience multiple relapses. Multiple myeloma disease initiation and progression are highly dependent on complex genetic aberrations. This review will summarize the current knowledge of these genetic aberrations, how they affect prognosis and the response to treatment, and review sensitive molecular techniques for multiple myeloma workup, with the ultimate goal of detecting myeloma progression early, allowing for timely treatment initiation. [ABSTRACT FROM AUTHOR]

Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from Alu elements, and often result in autosomal dominant or recessive phenotypes with underlying cerebellar neuropathology. When transcribed (potentially bidirectionally), the expanded RNA forms complex secondary and tertiary structures that can give rise to RNA-mediated toxicity, including protein sequestration, pentapeptide synthesis, and mRNA dysregulation. Since several of these diseases have recently been discovered, our understanding of their pathological mechanisms is limited, and their therapeutic interventions underexplored. This review aims to highlight new in vitro and in vivo insights into these incurable diseases. [ABSTRACT FROM AUTHOR]

Natural products have historically played an important role as a source of therapeutic drugs for various diseases, and the development of medicinal natural products is still a field with high potential. Although diverse drugs have been developed for incurable diseases for several decades, discovering safe and efficient anticancer drugs remains a formidable challenge. Reptiles, as one source of Asian traditional medicines, are known to possess anticancer properties and have been used for a long time without a clarified scientific background. Recently, it has been reported that extracts, crude peptides, sera, and venom isolated from reptiles could effectively inhibit the survival and proliferation of various cancer cells. In this article, we summarize recent studies applying ingredients derived from reptiles in cancer therapy and discuss the difficulties and prospective development of natural product research. [ABSTRACT FROM AUTHOR]

The constant increase in drug resistance, occurrence of incurable diseases and high medical costs, have necessitated bio-prospecting of fungi as alternative sources of therapeutic compounds. This study aimed at assessing the antibacterial effect and mode of action of secondary metabolites from fungal endophyte associated with Aloe ferox Mill. Endophytic fungus was isolated from the gel of A. ferox and identified by internal transcribed spacer (ITS) rRNA gene sequence analysis. The targets of antibacterial activity were assessed based on minimum inhibitory concentration (MIC) and the effect of the extract on respiratory chain dehydrogenase (RCD) and membrane integrity. Fourier transform-infrared spectrophotometer (FTIR) was employed to ascertain functional groups. The fungus with the most promising antibiotic-production was identified as Aspergillus welwitschiae MK450668.1. Its extract exhibited antibacterial activity with the MIC values of 0.5 and 1 mg/mL against Staphylococcus aureus (ATCC 25925) and Escherichia coli (ATCC 25922). It demonstrated the inhibitory effect on the RCD activity and destruction of membrane integrity on the test bacteria. FTIR spectrum revealed hydroxyl, amine and alkene groups. A. welwitschiae MK450668.1 serves as a potential source of effective compounds to combat the challenge of drug resistance. [ABSTRACT FROM AUTHOR]

Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL, which in its primary splenic form is the focus of this review. Primary splenic follicular lymphoma (PSFL) is exceedingly infrequent. This type of lymphoproliferative disorder is understudied and, in most cases, clinically characterized by splenomegaly or cytopenias related to hypersplenism. The diagnosis requires correlation of histopathology of spleen, blood and/or bone marrow with the correct immunophenotype (determined by flow cytometry and/or immunohistochemistry) and if necessary, additional molecular profiling. Management of this incurable disease is evolving, and splenectomy remains the mainstream treatment for stage I PSFL. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. Given that MM is the second most common blood cancer with a characteristic and unavoidable relapse/refractory state during the course of the disease, the development of new therapeutic modalities is crucial. Belantamab mafodotin (belamaf, GSK2857916) is a first-in-class therapeutic, indicated for patients who have previously attempted four other treatments, including an anti-CD38 monoclonal antibody, a proteosome inhibitor, and an immunomodulatory agent. In November 2017, the FDA designated belamaf as a breakthrough therapy for heavily pretreated patients with relapsed/refractory multiple myeloma. In August 2020, the FDA granted accelerated approval as a monotherapy for relapsed or treatment-refractory multiple myeloma. The drug was also approved in the EU for this indication in late August 2020. Of note, belamaf is associated with the following adverse events: decreased platelets, corneal disease, decreased or blurred vision, anemia, infusion-related reactions, pyrexia, and fetal risk, among others. Further studies are necessary to evaluate efficacy in comparison to other standard treatment modalities and as future drugs in this class are developed. [ABSTRACT FROM AUTHOR]

Cancer survivors harboring inherited pathogenic variants in the breast cancer (BC) susceptibility genes BRCA1 or BRCA2 are at increased risk of ovarian cancer (OC) and also of contralateral BC. For these women, risk-reducing surgery (RRS) may contribute to risk management. However, women with locally advanced or metastatic breast cancer (ABC) were excluded from clinical trials evaluating the benefit of these procedures in the BRCA1/2 carriers, and thus, current guidelines do not recommend RRS in this specific setting. Although ABC remains an incurable disease, recent advances in treatment have led to increased survival, which, together with improvement in RRS techniques, raise questions about the potential role of RRS in the management of BRCA1/2 ABC patients. When should RRS be discussed as an option for BRCA1/2 patients diagnosed with ABC? To address this issue, we report two clinical cases that reflect new challenges in routine oncology practice. Team experience and patient motivations may shape multidisciplinary decisions in the absence of evidence-based data. A wise rationale may be the analysis of the competing risks of death by a previous ABC against risk of death by a secondary BC or OC, tailored to patient preferences. [ABSTRACT FROM AUTHOR]

Background We assessed whether the presence and severity of common cancer symptoms are associated with the health utility score (hus) generated from the EQ-5D (EuroQol Research Foundation, Rotterdam, Netherlands) in patients with cancer and evaluated whether it is possible pragmatically to integrate routine hus and symptom evaluation in our cancer population. Methods: Adult outpatients at Princess Margaret Cancer Centre with any cancer were surveyed cross-sectionally using the Edmonton Symptom Assessment System (esas) and the EQ-5D-3L, and results were compared using Spearman correlation coefficients and regression analyses. Results: Of 764 patients analyzed, 27% had incurable disease. We observed mild-to-moderate correlations between each esas symptom score and the hus (Spearman coefficients: -0.204 to -0.416; p < 0.0001 for each comparison), with the strongest associations being those for pain (R = -0.416), tiredness (R = -0.387), and depression (R =-0.354). Multivariable analyses identified pain and depression as highly associated (both p < 0.0001) and tiredness as associated (p = 0.03) with the hus. The ability of the esas to predict the hus was low, at 0.25. However, by mapping esas pain, anxiety, and depression scores to the corresponding EQ-5D questions, we could derive the hus using partial esas data, with Spearman correlations of 0.83-0.91 in comparisons with direct EQ-5D measurement of the hus. Conclusions: The hus derived from the EQ-5D-3L is associated with all major cancer symptoms as captured by the esas. The esas scores alone could not predict EQ-5D scores with high accuracy. However, esas-derived questions assessing the same domains as the EQ-5D-3L questions could be mapped to their corresponding EQ-5D questions to generate the hus, with high correlation to the directly measured hus. That finding suggests a potential approach to integrating routine symptom and hus evaluations after confirmatory studies. [ABSTRACT FROM AUTHOR]

Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas initial anti-angiogenic treatments focused mainly on blocking the formation of new blood vessels in cancer, emerging strategies are specifically influencing certain aspects of tumor endothelial cells. For instance, efforts are generated to normalize tumor blood vessels in order to improve tumor perfusion and ameliorate the outcome of chemo-, radio-, and immunotherapy. In addition, treatment options that enhance the properties of tumor blood vessels that support a host's anti-tumor immune response are being explored. Hence, upcoming anti-angiogenic strategies will shape some specific aspects of the tumor blood vessels that are no longer limited to abrogating angiogenesis. In this review, we enumerate approaches that target tumor endothelial cells to provide anti-cancer benefits and discuss their therapeutic potential. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a malignant tumor for which there are no effective treatment strategies. In this study, we developed a targeted strategy for prostate-specific membrane-antigen (PSMA)-positive PCa in vitro based on 2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid (ACUPA) modified polyethylene glycol (PEG)-Cholesterol micelles containing wogonin (WOG), which was named ACUPA-M-WOG. ACUPA-M-WOG was conventionally prepared using a self-assembling method, which produced stable pArticle size and ζ potential. Moreover, ACUPA-M-WOG showed good drug encapsulating capacity and drug release profiles. Fluorescence activated cell sorting (FACS) results suggested that ACUPA modified PEG-Cholesterol micelles could effectively enhance the drug uptake on PSMA(+) PCa cells, and the cytotoxicity of ACUPA-M-WOG was stronger than other controls according to in vitro cellular proliferation and apoptosis assays, separately through methyl thiazolyl tetrazolium (MTT) and Annexin V/Propidium Iodide (PI) staining. Finally, the molecular mechanisms of ACUPA-M-WOG's effects on human PSMA(+) PCa were investigated, and were mainly the intrinsic or extrinsic apoptosis signaling pathways. The Western blot results suggested that ACUPA-M-WOG could enhance the WOG-induced apoptosis, which was mainly via the intrinsic signaling pathway rather than the extrinsic signaling pathway. In conclusion, ACUPA-M-WOG was successfully developed for WOG-selective delivery to PSMA(+) PCa cells and had stronger inhibition than free drugs, which might make it an effective strategy for PSMA(+) PCa. [ABSTRACT FROM AUTHOR]

Carbon ion radiation is a promising treatment for brain cancer; however, the immune system involved long-term systemic effects evoke a concern of complementary and alternative therapies in clinical treatment. To clarify radiotherapy caused fundamental changes in peripheral immune system, examinations were performed based on established models in vitro and in vivo. We found that brain-localized carbon ion radiation of neural cells induced complex changes in the peripheral blood, thymus, and spleen at one, two, and three months after its application. Atrophy, apoptosis, and abnormal T-cell distributions were observed in rats receiving a single high dose of radiation. Radiation downregulated the expression of proteins involved in T-cell development at the transcriptional level and increased the proportion of CD3+CD4-CD8+ T-cells in the thymus and the proportion of CD3+CD4+CD8- T-cells in the spleen. These data show that brain irradiation severely affects the peripheral immune system, even at relatively long times after irradiation. In addition, they provide valuable information that will implement the design of biological-based strategies that will aid brain cancer patients suffering from the long-term side effects of radiation. [ABSTRACT FROM AUTHOR]

One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects' positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals' FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = -0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment. [ABSTRACT FROM AUTHOR]

Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility. [ABSTRACT FROM AUTHOR]