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Congestive heart failure (CHF) is an incurable disease where a key objective of the treatment is to maintain the patient's quality of life (QoL) as much as possible. A model that predicts health-related QoL (HRQoL) based on physiological and ambient parameters can be used to monitor these parameters for the patient's benefit. Since it is difficult to predict how CHF progresses, in this study we tried to predict HRQoL for a particular patient as an individual, using two different datasets, collected while telemonitoring CHF patients. We used different types of imputation, classification models, number of classes and evaluation techniques for both datasets, but the main focus is on unifying the datasets, which allowed us to build cross-dataset models. The results showed that using general predictive models intended for previously unseen patients do not work well. Personalization significantly improves the prediction, both personalized models and personalized imputation, which is important due to many missing data in the datasets. However, this implies that applications using such predictive models would also need to collect some self-reported labels of HRQoL to be able to help patients effectively. [ABSTRACT FROM AUTHOR]

Background Brain cancer is a devastating and incurable disease that places a high burden of care on next of kin (NOK). NOK can play a core role in supporting end-of-life planning, including the decision to donate one's brain after death. Postmortem brain donation is crucial to research. As postmortem programs develop it is important to understand the experiences of NOK as they support a loved one in the donation decision. Methods Thirteen qualitative interviews were completed with NOK of people who had consented to donate their brains to the Mark Hughes Foundation (MHF) Biobank. A thematic analysis was carried out on the transcribed interviews. Results Four central themes were identified: (i) The carer role has additional responsibilities and psychological benefits when brain donation is being considered; (ii) Supporting a loved one to donate requires mutual trust, understanding, and a commitment to honor agency; (iii) Increasing awareness of brain donation is a priority for NOK, and (iv) Brain donation is seen as a natural continuation of the donor's altruistic values. Conclusions When a person with brain cancer decides to donate their brain to research, their NOK can experience additional burdens and benefits as the NOK–patient relationship evolves. Understanding this evolution and recognizing the importance of trust, advocacy, and altruism provides a guide for the integration of brain donation programs into clinical pathways and a basis for normalizing brain donation as an extension of organ donation frameworks. [ABSTRACT FROM AUTHOR]

Cyanin chloride, one of the active ingredients in figs, is a glycoside made of two sugars linked to a cyanidin aglycone. Although many studies have reported on the skin efficacy of cyanidin aglycone, there have been few reports on human psoriasis to date. Therefore, we focused on excessive inflammation and loss of skin barrier function, which are the main characteristics of psoriasis, and verified the function of cyanin chloride on the psoriasis. Cyanine chloride removed DPPH and ABTS radicals in a concentration-dependent manner and significantly inhibited NO production in LPS-induced RAW264.7 cells as well as suppressed inflammatory cytokines such as iNOS, COX-2, IL-6, and IL-1α/β. Moreover, we used TNF-α/IL-17A/IFN-γ-induced HaCaT cells, a human skin cell model of psoriasis. Cyanin chloride significantly inhibited the mRNA expression of inflammatory cytokines, such as IL-1α, IL-1β, and IL-6, and chemokines CXCL8 and CCL20 in TNF-α/IL-17A/IFN-γ-induced HaCaT cells. Cyanin chloride significantly inhibited the phosphorylation of STAT3 transcription factor in a concentration-dependent manner, confirming the regulatory function of CCL20 chemokine. Finally, cyanin chloride significantly restored the TEER value in TNF-α/IL-17A/IFN-γ-induced HaCaT cells, confirming the effect of strengthening the skin barrier function. In addition, cyanin chloride increased the mRNA levels of filaggrin which is cornified envelope proteins of the epidermal layer, in a concentration-dependent manner in normal epidermal cells. Taken together, the above results suggest that cyanin chloride can be considered a natural candidate for improving psoriasis, an incurable skin disease, not only by lowering excessive skin inflammatory reactions but also by restoring the skin barrier. [ABSTRACT FROM AUTHOR]

This study explores the theme of death in the collection Room Papers 8 by poet Amal Dunqul, presenting it as a meaningful aesthetic vision shaped by the poet's artistic and stylistic tools. The theme of death within the collection reveals clear semantic signs that reflect the poet's state during his battle with an incurable disease. The study aims to clarify these signs and what they reveal about the poet's psychological, social, emotional, and philosophical state by examining the language and structures that enrich this theme both aesthetically and semantically. It also considers the contrasts and antithetical dualities that enhance the poet's perspective on death, along with the repetitions that reinforce this theme, and the titles of the poems, which serve as gateways to understanding this poetic experience in light of what could be metaphorically termed the aesthetics of death. Methodologically, the study seeks to elucidate this field and describe and critique its representations using the principles of the stylistic approach, focusing on specific axes such as repetition, choice, displacement, and composition. The study concludes by affirming the centrality of the theme of death and its manifestations throughout the collection in various linguistic, structural, and metaphorical forms, showcasing Dunqul's unique style and artistic consciousness. [ABSTRACT FROM AUTHOR]

Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable disease characterized by the abnormal expansion of plasma cells in the bone marrow (BM). Numerous studies have shown that BM tumor cells can influence the tumor microenvironment (TME) through communication with extracellular vesicle circular RNAs (circRNAs), a type of noncoding RNA. Our study revealed that a circular RNA, circRFWD2 (hsa_circ_0015361), is expressed by MM cells and translated into a new protein, circRFWD2_369aa. We found that elevated levels of circRFWD2_369aa in MM peripheral blood samples were closely associated with poor outcomes in MM patients. Further investigation revealed that circRFWD2 promoted the degradation of p27 through the ubiquitination pathway, leading to increased proliferation of MM cells. We also confirmed the interaction between circRFWD2 and its downstream genes DDB1 and CUL4A, indicating that circRFWD2 could form an E3 ligase complex with other genes to mediate the ubiquitination of p27. Notably, the protein translated by a circular RNA of RFWD2 can also function as an E3 ligase. Our study highlights the potential of circRFWD2 as a biomarker for MM, which may improve the sensitivity and specificity of diagnosis and efficacy analyses. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a disease affecting the brain and the spinal cord, in which the immune system attacks the myelin that protects nerve fibres, thus causing permanent damage resulting in various types of disabilities. As a (to date) incurable disease, the experience of the patient becomes central in coping with the many symptoms, especially in the way it is communicated, not only to treating physicians, but also to society at large. Over the last years MS, which a century ago seemed to affect women and men alike, has shown an increasing prevalence in the female to male ratio, both in small cohorts (Kotzamani et al., 2012; Krökki et al. 2011), and worldwide (Sellner et al., 2011). In view of this tendency, the study of MS has begun to include a gender approach, focusing on the potential explanatory factors, but also on the specific circumstances affecting women (Jobin et al., 2010). In our paper, drawing from a sample extracted from online testimonials, an analysis will be carried out of the various metaphorical imagery used by women to explain their symptoms to doctors, relatives, and society at large. Following the traditional classification by Lakoff and Johnson (1980: 14), we shall explore the framings used, which may lead to positive or negative experiences of the disease and may have an empowering potential when patients «fight» MS in the general framework of managing the condition. [ABSTRACT FROM AUTHOR]

Although substantial quantities of potent therapies for multiple myeloma (MM) have been established, MM remains an incurable disease. In recent years, our understanding of the initiation, development, and metastasis of cancers has made a qualitative leap. Cancers attain the abilities to maintain proliferation signals, escape growth inhibitors, resist cell death, induce angiogenesis, and more importantly, escape anti-tumor immunity and reprogram metabolism, which are the hallmarks of cancers. Besides, different cancers have different tumor microenvironments (TME), thus, we pay more attention to the TME in the pathogenesis of MM. Many researchers have identified that myeloma cells interact with the components of TME, which is beneficial for their survival, ultimately causing the formation of immunosuppressive and high-metabolism TME. In the process, transforming growth factor-β (TGF-β), as a pivotal cytokine in the TME, controls various cells' fates and influences numerous metabolic pathways, including inhibiting immune cells to infiltrate the tumors, suppressing the activation of anti-tumor immune cells, facilitating more immunosuppressive cells, enhancing glucose and glutamine metabolism, dysregulating bone metabolism and so on. Thus, we consider TGF-β as the tumor promoter. However, in healthy cells and the early stage of tumors, it functions as a tumor suppressor. Due to the effect of context dependence, TGF-β has dual roles in TME, which attracts us to further explore whether targeting it can overcome obstacles in the treatment of MM by regulating the progression of myeloma, molecular mechanisms of drug resistance, and various signaling pathways in the immune and metabolic microenvironment. In this review, we predominantly discuss that TGF-β promotes the development of MM by influencing immunity and metabolism. [ABSTRACT FROM AUTHOR]

Metastatic breast cancer (MBC) is generally considered an incurable disease and even though new treatments are available, the median survival is approximately three years. The introduction of immune therapies for MBC highlights the importance of the immune system in cancer progression and treatment. CD163+ anti-inflammatory myeloid cells, including tumor associated macrophages (TAMs), are known to be of relevance in early breast cancer but their role in MBC is not yet established. Here we determine the levels of CD163+ immune cells in 139 patients with newly diagnosed MBC by using Immunohistochemistry (IHC) and gene expression analyses (GEX). We aim to determine changes and distribution of CD163+ immune cells during tumor progression from primary tumors (PT) to lymph node metastases (LNM) and distant metastases (DM). In addition, we evaluate associations between CD163+ immune cells, clinicopathological factors and disease outcome (progression-free and overall survival; PFS and OS, respectively). Despite similar distribution, high levels of CD163+ immune cells in the tumor nest of PT, but not in LNM or DM, associated with adverse prognostic features including higher grade and molecular subtype, as well as with shorter PFS and OS, however this observation was not significant after adjusted multivariate analyses. Finally, high levels of CD163+ immune cells in PT, as well as GEX in PT and synchronous LNM associated with shorter OS from the initial diagnosis. These results indicate that evaluating the levels of CD163+ immune cells may identify MBC patients with a worse prognosis. Unraveling the role of CD163+ immune cells in the complex immune responses in MBC is highly relevant for improving future immune therapies. [ABSTRACT FROM AUTHOR]

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]

Atrial fibrillation (AF) has been receiving a lot of attention from scientists and clinicians because it is an extremely common clinical condition. Due to its special hemodynamic changes, AF has a high rate of disability and mortality. So far, although AF has some therapeutic means, it is still an incurable disease because of its complex risk factors and pathophysiologic mechanisms, which is a difficult problem for global public health. Age is an important independent risk factor for AF, and the incidence of AF increases with age. To date, there is no comprehensive review on aging‐associated AF. In this review, we systematically discuss the pathophysiologic evidence for aging‐associated AF, and in particular explore the pathophysiologic mechanisms of mitochondrial dysfunction, telomere attrition, cellular senescence, disabled macroautophagy, and gut dysbiosis involved in recent studies with aging‐associated AF. We hope that by exploring the various dimensions of aging‐associated AF, we can better understand the specific relationship between age and AF, which may be crucial for innovative treatments of aging‐associated AF. [ABSTRACT FROM AUTHOR]

AbstractPurposeDesignMethodsFindingsImplicationsTo understand the scanxiety experience in pancreatic cancer (PC) survivors following curative surgical resection.A qualitative study with a hermeneutic phenomenological approach was used.Eighteen PC survivors participated. Data from in-depth, semi-structured interviews were analyzed and themes emerged from systematic line-by-line coding of the interview transcripts.Two key themes emerged: ‘the recurring cycle of scanxiety’ and ‘hope for lifelong remission’. Participants experienced similar patterns of scanxiety that impacted everyday life. Hope was an essential stabilizing component of the cancer-scan experience, and enabled participants to conceptualize a cure, despite the high likelihood of recurrent, incurable disease. A conceptual framework was developed to provide further insight.Everyday life is significantly affected during times of PC surveillance scans. This study enhances our understanding of the cancer-scan experience and provides a framework to guide care. [ABSTRACT FROM AUTHOR]

Traditional herbal medicine, rooted in a long history of use in East Asia, combines several herbs to create treatments showing high efficacy with minimal side effects, for specific diseases. Such combination therapies represent a potential reservoir of new drugs for treating multifactorial and incurable chronic diseases. However, the complexity of their mechanisms of action due to the combination of multiple compounds, has limited their research integration into modern pharmacological science. To address this challenge, we constructed drug-induced transcriptome data for herbal medicines through systematic experiments, analyzed with the aid of various omics databases. We introduce KORE-Map 1.0 (Korean medicine Omics Resource Extension Map), the first comprehensive resource of drug-derived transcriptome data for representative tonifying herbal medicines, effective in enhancing the immune system. This dataset aims to provide novel insights into the combinatorial mechanisms of these herbal medicines and to aid in the discovery of new therapeutic targets and indications for various incurable diseases. [ABSTRACT FROM AUTHOR]

Breast cancer, the most common malignant tumor among women worldwide, remains an incurable disease once it has spread to distant organs. The human epidermal growth factor receptor 2-positive and triple-negative molecular subtypes are associated with an increased risk of developing breast cancer. This study aimed to investigate the potential impact of crucial neutrophil extracellular traps-related genes on the survival of patients with human epidermal growth factor receptor 2-positive breast cancer and triple-negative breast cancer. 69 neutrophil extracellular traps-related genes were selected as the study subjects to their association with survival, immune infiltration impacts, interaction networks, and potential drugs for human epidermal growth factor receptor 2-positive breast cancer/triple-negative breast cancer. Using least absolute shrinkage and selection operator regression models based on 69 candidate neutrophil extracellular traps-related genes for predicting overall survival and progression-free survival, we identified 16 key human epidermal growth factor receptor 2 neutrophil extracellular trap genes and 4 key triple-negative breast cancer genes. We identified four core neutrophil extracellular traps-related genes: Alkaline phosphatase, biomineralization associated, autophagy related 7, colony stimulating factor 3 receptor, and cathelicidin antimicrobial peptide responsive element binding protein 5, which may influence breast cancer progression through mechanisms associated with neutrophil extracellular traps. The key neutrophil extracellular traps-related genes were closely correlated with neutrophils, myeloid dendritic cells macrophage, clusters of differentiation 4+ and clusters of differentiation 8+ T cells. Moreover, potential sensitizing drugs for human epidermal growth factor receptor 2-positive breast cancer and triple-negative breast cancer treatment identified using the genomics of therapeutics response portal and genomics of drug sensitivity in cancer databases may include; SB52334, 17-alkyladenine DNA glycosylase, bromodomain containing-K51490254, CAY10618, GMX-1778, daporinad, serdemetan, CIL70 and panobinostat. In summary, the key neutrophil extracellular traps-related genes may play important roles in the growth and development of human epidermal growth factor receptor 2-positive breast cancer and triple-negative breast cancer. They can impact different immune cells, tumor immune microenvironment and predict overall survival and progression-free survival of breast cancer. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Cultural Studies / Kültür Araştırmaları Dergisi is the property of Journal of Cultural Studies / Kultur Arastirmalari Dergisi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Follicular lymphoma (FL) is an indolent, germinal center B cell–derived lymphoid neoplasm, for which recent advances in treatment have substantially improved patient survival. However, FL remains an incurable and heterogeneous disease, with groups of patients experiencing early disease progression, histologic transformation, or a high risk of treatment-related toxicity. Additionally, FL is a continually relapsing disease, and response rates and disease-control intervals decrease with each subsequent line of therapy. In this review, we explore the current treatment landscape for relapsed or refractory FL and promising therapies in development, highlighting the efficacy and potential risks of each treatment. We provide a real-world perspective on the unmet needs of patients with FL. Novel therapeutic approaches in development offer a wide array of options for clinicians when treating relapsed or refractory FL. A nuanced approach is required to address the needs of individual patients, taking into consideration both the risks and benefits of each treatment option, as well as patient preferences. [ABSTRACT FROM AUTHOR]

Although multiple myeloma is an incurable disease, the past decade has witnessed significant improvement in patient outcomes. This was brought about by the development of T-cell redirection therapies such as chimeric antigen receptor (CAR) T-cells, which can leverage the natural ability of the immune system to fight myeloma cells. The approval of the B-cell maturation antigen (BCMA)-directed CAR T, idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) has resulted in a paradigm shift in the treatment of relapsed/refractory multiple myeloma. Overall response rates ranging from 73 to 97% are currently achievable. However, the limitations of KarMMa-1 and CARTITUDE-1 studies spurred the generation of real-world data to provide some insights into the effectiveness of ide-cel and cilta-cel among patients who were excluded from clinical trials, particularly those who received prior BCMA-targeted or other T-cell redirection therapies. Despite their unprecedented clinical efficacy in heavily pretreated patients, responses to CAR T remain non-durable. Although the underlying mechanisms of resistance to these agents haven't been fully elucidated, studies have suggested that resistance patterns could be multifaceted, implicating T-cell exhaustion and tumor intrinsic mechanisms such as BCMA target loss, upregulation of gammasecretase, and others. Herein, we provide a succinct overview of the development of CAR T-cells, manufacturing process, and associated toxicities/complications. In this review, we also recapitulate the existing literature pertaining MM CAR-T as well as emerging data from some of the ongoing clinical trials designed to mitigate the shortcomings of these agents, and improve the clinical efficacy of CAR T, especially in the relapsed/refractory setting. [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]

Copyright of Arab Journal for Scientific Publishing is the property of Research & Development of Human Recourses Center (REMAH) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Viral myocarditis (VMC) is the major reason for sudden cardiac death among both children and young adults. Of these, coxsackievirus B3 (CVB3) is the most common causative agent of myocarditis. Recently, the role of signaling pathways in the pathogenesis of VMC has been evaluated in several studies, which has provided a new perspective on identifying potential therapeutic targets for this hitherto incurable disease. In the present study, in vivo and in vitro experiments showed that CVB3 infection leads to increased Bim expression and triggers apoptosis. In addition, by knocking down Bim using RNAi, we further confirmed the biological function of Bim in apoptosis induced by CVB3 infection. We additionally found that Bim and forkhead box O1 class (FOXO1) inhibition significantly increased the viability of CVB3-infected cells while blocking viral replication and viral release. Moreover, CVB3-induced Bim expression was directly dependent on FOXO1 acetylation, which is catalyzed by the co-regulation of CBP and SirTs. Furthermore, the acetylation of FOXO1 was an important step in Bim activation and apoptosis induced by CVB3 infection. The findings of this study suggest that CVB3 infection induces apoptosis through the FOXO1 acetylation-Bim pathway, thus providing new insights for developing potential therapeutic targets for enteroviral myocarditis. [ABSTRACT FROM AUTHOR]

The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease. [ABSTRACT FROM AUTHOR]

The Orch-Or model cannot explain the reason for the observation of non-human intelligence contacts by dying or comatose patients, and furthermore, it ignores the immortality of human beings. Therefore, a new model is presented to answer all questions and find a solution for human immortality. In this model, intelligence is a quantum particle that by acceleration of a photon in every spark; comes from the black and white box regions of curved space time of Penrose's diagram and by connecting to particles; makes them intelligent. Like the Higgs boson, which binds to particles and gives them mass. The basic intelligence of every human enters our space-time region when the primary cell is born and remains free even after death. Free intelligences interact with the brain and penetrate into the brains of the patient and induce non-human intelligence contacts. On the other hand, the brains of healthy people do not have empty space to store information of free intelligence due to high activity, and therefore healthy people do not see non-human intelligence. This model not only explains the reason for the contact with non-human intelligence for dying patients, but also provides solutions for the treatment of incurable diseases by finding rogue intelligences in the human body. [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]

Pulmonary arterial hypertension (PAH) is a complex and incurable disease for which pulmonary vasodilators remain the core therapy. Of the three primary pathways that vasodilators target, the prostacyclin pathway was the earliest to be used and currently has the largest number of modalities for drug delivery. Inhaled treprostinil has been introduced as a treatment option in PAH and, more recently, pulmonary hypertension (PH) due to interstitial lung disease (PH-ILD), and the earlier nebulized form has been joined by a dry powder form allowing for more convenient use. In this review, we discuss inhaled treprostinil, focusing on the dry powder inhalation (DPI) formulation, and explore its dosing, applications, and evidence to support patient tolerance and acceptance. Recent trials underpinning the evidence for use of inhaled treprostinil and the most recent developments concerning the drug are discussed. Finally, the review looks briefly into premarket formulations of inhaled treprostinil and relevant early studies suggesting efficacy in PAH treatment. [ABSTRACT FROM AUTHOR]

Chronic pain conditions impose a huge economic burden on affected individuals and society and is very significant. With this research paper we raise awareness of the effectiveness, safety and benefits of acupuncture for the treatment of chronic diseases. Acupuncture has been proven to be an exceptionally effective treatment option, especially for the following health issues: chronic pain, allergies, asthma, stress, anxiety, depression, migraines insomnia, hypertension, menopause and etc. Acupuncture has a great ability to create a feeling of relief from discomfort and pain. The treatment also targets the root of the illness and restores normal body functions. Acupuncture, as a treatment for chronic diseases incurable according to the WHO, works very effectively and positively, although the treatments are longer, the benefits for the patients are enormous on the one hand due to the improvement of the health condition and on the other hand due to the greater economic advantage and profitability. For these reasons, more and more people in the world decide to treat chronic diseases with acupuncture. A very important step is to share the knowledge and experience for TCM and enable the population to gain more knowledge about the treatment advantages and gradually accept it as a valuable health care treatment. [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]

Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease. [ABSTRACT FROM AUTHOR]

Introduction: Mantle cell lymphoma (MCL) is an incurable disease with an aggressive clinical course, and most patients eventually relapse after chemotherapy. Targeted therapies developed for relapsed/refractory MCL have been approved based on clinical trial data. However, real-world setting data are scarce and scattered. Areas Covered: This systematic review aimed to collect, synthesize, and describe the characteristics and treatment outcomes of patients with relapsed/refractory MCL after receiving a second or subsequent line of therapy in the real-world setting. Expert Opinion: R/R MCL is clinically and biologically heterogeneous and still represents a therapeutic challenge, with high-risk and early relapsed patients remaining an unmet medical need. This systematic review is limited by the quality of the available data and the difficulty of comparing outcomes in R/R MCL due to the heterogeneity of the disease, but the results suggest that covalent BTKis should be positioned as second-line therapy, followed by CAR T-cells in BTK-i-relapsed patients. Chemo-free and combination therapies with established chemoimmunotherapy backbones in the relapsed and front-line settings have been recently developed, and front-line options are being improved to move targeted and cellular therapies to earlier lines, including front-line therapy, in elderly and younger fit patients. In the upcoming years, many new targeted agents will play an important role and will be incorporated to the routine practice as their sequence, and outcomes in unselected patients are determined. [ABSTRACT FROM AUTHOR]

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies. [ABSTRACT FROM AUTHOR]

Introduction: Despite recent advances in diagnosis, prognostication, and treatment options, chronic lymphocytic leukemia (CLL) is still a largely incurable disease. New concepts on diagnosis, staging, treatment, and follow-up on CLL have been incorporated throughout recent years. The lack of regional consensus guidelines has led to varying practices in the management of patients with CLL in the region. This manuscript aims to reach a consensus among expert hematologists regarding the definitions, classifications, and related practices of CLL. The experts developed a set of statements utilizing their personal experience together with the current literature on CLL management. This consensus aims to provide guidance for healthcare professionals involved in the management of CLL and serves as a step in developing regional guidelines. Methods: Eight experts responded to 50 statements regarding the diagnosis, staging, treatment, and prognosis of CLL with three potential answering alternatives ranging between agree, disagree, and abstain. This consensus adopted a modified Delphi consensus methodology. A consensus was reached when at least 75% of the agreement to the answer was reached. This manuscript presents the scientific insights of the participating attendees, panel discussions, and the supporting literature review. Results: Of the 50 statements, a consensus was reached on almost all statements. Statements covered CLL-related topics, including diagnostic evaluation, staging, risk assessment, different patient profiles, prognostic evaluation, treatment decisions, therapy sequences, response evaluation, complications, and CLL during the COVID-19 pandemic. Conclusion: In recent years, CLL management has progressed significantly, with many diagnostic tests and several novel treatments becoming available. This consensus gathers decades of consolidated principles, novel research, and promising prospects for the management of this disease. [ABSTRACT FROM AUTHOR]

Cancer is an incurable fatal disease wreaking havoc on the population of countries either developed or developing. Hepatocellular carcinoma (HCC) is the fifth most frequent type of cancer having a poor prognosis. Globally, HCC management and treatment intervention using medicinal plants from generation to generation is rapidly increasing and remains an area of promising research. This review provided insight into medicinal plants' ethnomedicinal use, photochemistry and mechanisms of action on HCC exhibiting anti-cancer potentials subjected to scientific investigations. Furthermore, clinical, toxicity studies and detailed mechanisms of action would provide an understanding of the development of lead compounds in drug discovery and development for HCC. [ABSTRACT FROM AUTHOR]

The chances and opportunities in modern biology inspired devising new therapeutics are mind blowing. The promises reach from successfully treating so-far incurable diseases like cancer and certain infections, to modulating and fine tuning the immune response to prolong the lifespan by inhibiting aging. However, as underlying therapies become more and more complex and sophisticated, it becomes increasingly difficult to find ways to ensure and predict the safety of these new therapeutics. The ICH guideline S6 (R1) from June 2011 EMA/CHMP/ICH/731268/ 1998 Committee for Medicinal Products for Human Use (CHMP) already stated "Conventional approaches to toxicity testing of pharmaceuticals may not be appropriate for biopharmaceuticals due to the unique and diverse structural and biological properties of the latter that may include species specificity, immunogenicity, and unpredicted pleiotropic activities" and is committed to a "flexible, case-by-case, science-based approach to preclinical safety evaluation". Initial approaches to this are described in the OECD Test Guidelines for new approach methods (NAM) with the newest update released in 2023 and alternative non-animal test guidelines (https://www.icapo.org/test-guidelines) provided from the International Council on Animal Protection in OECD Programmes (ICAPO; https://www.icapo.org). Beyond that, the European Union-funded innovative medicine initiative project Immune Safety Avatar (imSAVAR) decided to develop a systematic and holistic framework for non-clinical safety assessment of biopharmaceuticals and Advanced Therapy Medicinal Products (ATMP); thereby, the consortium focuses on immuno-regulatory therapeutics. Science-based approaches, such as the mechanistic description of adverse outcomes would be essential to demonstrate the safety of a particular new immuno-therapeutic agent. Here, we re-use the concept of adverse outcome pathways (AOP) to capture immune-related adverse outcomes (irAO), which are aimed to guide us to the use of relevant test systems and experiments. Thus, the focus within imSAVAR is on the use and (further) develop-ment of human and alternative models. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM), an incurable disease characterized by frequent relapses and a need for multiple treatments, often progresses to a relapse/refractory status resistant to all available drugs and drug classes. Bispecific antibodies, specifically BCMA T‐cell engagers, have emerged as effective treatments for MM, demonstrating impressive efficacy. However, these treatments can adversely affect the immune system, increasing vulnerability to infections. Methods/Results: This study evaluated the efficacy and safety of BCMA T‐cell engagers in 58 Swedish patients with poor MM prognosis. The patients exhibited a 69% overall response rate, with 69% survival and 60% progression‐free survival at 15 months. Conclusions: Despite the risk of infectious complications, the prognosis of MM patients can be significantly improved with vigilant monitoring and proactive management of infections. This real‐world data highlight the potential of BCMA T‐cell engagers in treating MM, emphasizing the need for careful patient monitoring to mitigate infection risks. [ABSTRACT FROM AUTHOR]

Metastatic colon cancer remains an incurable disease, and it is difficult for existing treatments to achieve the desired clinical outcome, especially for colon cancer patients who have received first-line treatment. Although immune checkpoint inhibitors (ICIs) have demonstrated durable clinical efficacy in a variety of solid tumors, their response requires an inflammatory tumor microenvironment. However, microsatellite-stable (MSS) colon cancer, which accounts for the majority of colorectal cancers, is a cold tumor that does not respond well to ICIs. Combination regimens open the door to the utility of ICIs in cold tumors. Although combination therapies have shown their advantage even for MSS colon cancer, it remains unclear whether combination therapies show their advantage in patients with pretreated metastatic colon cancer. We report a patient who has achieved complete remission and good tolerance with sintilimab plus bevacizumab and platinum-based chemotherapy after postoperative recurrence. The patient had KRAS mutation and MSS-type colon cancer, and his PD-1+CD8+ and CD3-CD19-CD14+CD16-HLA-DR were both positive. He has achieved a progression-free survival of 43 months and is still being followed up at our center. The above results suggest that this therapeutic regimen is a promising treatment modality for the management of pretreated, MSS-type and KRAS-mutated metastatic colorectal cancer although its application to the general public still needs to be validated in clinical trials. [ABSTRACT FROM AUTHOR]

Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA- mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA- mutated gynecological cancers prospectively treated with alpelisib within a controlled program. From April 2021 to December 2022, 36 patients with PIK3CA- mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2–3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers. • The PTEN-AKT-PI3K pathway is frequently altered in gynecological tumors. • Few available treatment options currently exist in gynecological cancers harboring PIK3CA mutations. • Alpelisib, an oral PI3K alpha-selective inhibitor, was associated with promising efficacy (ORR 28%; PFS 6.3 months). • Alpelisib was well tolerated. [ABSTRACT FROM AUTHOR]

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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]

Background: Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. Methods: The REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms. Discussion: Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery. Trial registration: ClinicalTrials.gov: NCT05848765; 08-May-2023. EudraCT: 2022-000677-75; 10-Feb-2022. [ABSTRACT FROM AUTHOR]

Cannabis, traditionally used for recreation due to psychoactive compounds in its leaves, flowers, and seeds, has not been thoroughly explored for potential therapeutic benefits. Δ9-trans-Tetrahydrocannabinol, a key cannabinoid in cannabis, causes hallucinogenic effects and delirium symptoms. In contrast, cannabidiol (CBD) does not induce hallucinations and has shown effectiveness in treating symptoms of various rare, incurable diseases. Cannabis exhibits neuroprotective, anti-inflammatory, anti-thrombotic, anti-bacterial, analgesic, and antiepileptic properties, recently attracting more attention. This review aims to summarize comprehensively the impact of cannabis on human health, focusing on endocannabinoids and their receptors. It also delves into recent CBD research advancements, highlighting the compound's potential medical applications. Overall, this paper provides valuable insights into the prospective development of medical cannabis, with a particular emphasis on CBD. [ABSTRACT FROM AUTHOR]

Background: Recurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease. MYB is a putative oncogenic driver in ACC that is often overexpressed through an MYB‐NFIB rearrangement. The authors hypothesized that AKT inhibition with the allosteric inhibitor MK‐2206 could decrease MYB expression and induce tumor regression in patients with incurable ACC (ClinicalTrials.gov identifier NCT01604772). Methods: Patients with progressive, incurable ACC were enrolled and received MK‐2206 150 mg weekly; escalation to 200 mg was allowed. The primary end point was confirmed response. Secondary end points were progression‐free survival, overall survival, and safety. An exploratory analysis evaluating the effect of MK‐2206 on MYB expression was conducted in a subset of patients. Results: Sixteen patients were enrolled, and 14 were evaluable for efficacy. No confirmed responses were observed. Thirteen patients had stable disease, and one had disease progression as their best response. The median progression‐free survival was 9.7 months (95% CI, 3.8–11.8 months), and the median overall survival was 18.0 months (95% CI, 11.8–29.9 months). Nine of 16 patients (56%) had at least one grade 3 treatment‐related adverse event, and the most common were rash (38%), fatigue (19%), decreased lymphocyte count (13%), and hyperglycemia (13%). Twelve of 14 tumors (86%) had detectable MYB expression by immunohistochemistry, and seven of 14 tumors (50%) had an MYB‐NFIB gene rearrangement. Serial biopsies revealed decreased MYB levels with MK‐2206 in four of five patients. Conclusions: MK‐2206 failed to induce clinical responses in patients with incurable ACC. AKT inhibition may diminish MYB protein levels, although the effect was highly variable among patients. Novel approaches to target MYB in ACC are needed. This phase 2 clinical trial demonstrated that the AKT inhibitor MK‐2206 failed to induce clinical responses in patients with recurrent/metastatic adenoid cystic carcinoma. Tumor tissue analyses suggest that MK‐2206 treatment may have diminished intratumoral MYB protein levels. [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]

Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell lymphoproliferative disease with a high annual incidence in Western countries. As B-cell receptor (BCR) signaling and intrinsic apoptotic resistance play critical roles in the development and survival of CLL cells, therapeutic approaches targeting these pathways have been extensively investigated to tackle this incurable disease. Over the last decade, several Phase 3 trials have confirmed the superior efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax, a selective B-cell lymphoma 2 (BCL2) inhibitor, over chemoimmunotherapy. This has been demonstrated in both the treatment-naïve and relapsed/refractory (RR) settings and includes patients with high-risk molecular features. However, these drugs are not curative, with patients continuing to relapse after treatment with both cBTKis and BCL2is, and the optimal treatment strategy for these patients has not been defined. Several novel agents with distinct mechanisms have recently been developed for CLL which have demonstrated efficacy in patients who have previously received cBTKis and BCL2i. In particular, novel BCR-signaling targeting agents have shown promising efficacy in early-phase clinical trials for RR-CLL. Furthermore, cancer immunotherapies such as bispecific antibodies and chimeric antigen receptor T-cells have also shown anti-tumor activity in patients with heavily pretreated RR-CLL. Personalised approaches with these novel agents and combination strategies based on the understanding of resistance mechanisms have the potential to overcome the clinical challenge of what to do next for a patient who has already had a cBTKi and venetoclax. [ABSTRACT FROM AUTHOR]

Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome. Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function. [ABSTRACT FROM AUTHOR]

The article focuses attention on the fact that a structural element of everyone's subjective legal right to medical care is the right to access to a medicinal product. It is emphasized that the Covid-19 pandemic, the increase in the spectrum of incurable diseases and the number of patients suffering from them, Russia's aggression against Ukraine, the consequences of which are an increase in the number of military personnel and civilians who need the use of medicinal products created using the latest technologies, but which (medicines) are still not allowed in the state, the integration of Ukraine with the EU became the factors that actualized the discussion of scientists and practitioners on the issue of the conditions that must be observed by the EU member state in order to apply the provisions of Article 1. 5 of Directive 2001/83/EC of the European Parliament and of the Council on the Community Code regarding medicinal products intended for human use, the exception is to provide an EU member state with access to a patient to a medicinal product not authorized by the competent authorities of such a member state and thereby fulfill its obligation to provide everyone's constitutional right to medical care. The conditions that must be observed by the EU member state in order to apply the provisions of Article 1. 5 of the Exclusion Directives - for an EU member state to provide a patient with access to a medicinal product that is not authorized by the competent authorities of such a member state: 1) the presence of a norm of national law that allows the supply of a medicinal product for which a permit was not granted; 2) the goal is to meet the special needs of a specific seriously ill patient (private interest) and ensure the protection of public health (public interest); 3) be due to the absence on the national market of any authorized medicinal product - the equivalent of an unauthorized medicinal product; 4) delivery is made in response to a bona fide order on one's own initiative; 5) supply is carried out according to the prescription in accordance with the specifications of the authorized medical worker; 6) an unauthorized medicinal product is prescribed for use by a specific patient under his direct personal responsibility. The signs of the patient's special needs are highlighted: 1) the specific situation of the patient's state of health and the course of his illness; 2) medical reasoning, which is justified; 3) the patient's need for a certain medicinal product. The grounds for an unregistered medicinal product to be prescribed by a doctor are: the doctor's therapeutic considerations; results of research, analyzes of the patient. In a situation where there are authorized medicinal products on the market of an EU member state - analogues of prohibited medicinal products - the import of unauthorized medicinal products can be qualified as an act of non-fulfillment by the EU member state of its obligations, provided for in Article 1. 6 Directives. [ABSTRACT FROM AUTHOR]

The introduction in 1998 of imatinib mesylate (IM), a first-generation BCR-ABL1 tyrosine kinase inhibitor (1G-TKI), to the treatment of chronic myelogenous leukemia patients in the chronic phase (CML-CP), significantly improved the prognosis of a previously incurable disease with a prognosed 5-year-long overall survival and progression-free survival of 91.7% and 94.7%, respectively. Long term follow-up studies of CML-CP patients verified the initial results, showing a 10-year overall response rate of 82-83.2%. In about one quarter of CML-CP patients, IM primary/secondary resistance or intolerance is diagnosed. After switching to a second generation BCR-ABL1 TKI (dasatinib, nilotinib, bosutinib), a complete cytogenetic response is obtained in only c. 50% of CML-CP patients. Also the frequency of deep molecular responses (DMR: MR4.0 and MR4.5) is relatively low. The results of 2G-TKI treatment are particularly unsatisfactory in patients carrying the TKI resistant BCR::ABL1 kinase domain mutants (BCR::ABL1 KD), especially BCR-ABL1 T315I. For this reason, other orally biocompatible compounds have been developed to target BCR-ABL T315I. One of these is ponatinib, which allows a major molecular response (MMR) and MR4.5 to be obtained in 40% and 24% of severely TKIs-pretreated CML-CP patients, respectively. The latter represent a new class of allosteric BCR-ABL1 tyrosine kinase inhibitor [asciminib (ABL001)], specifically targeting the ABL myristoyl pocket of BCR-ABL tyrosine kinase. Its application in CML-CP patients previously treated with at least two TKIs resulted in an MMR rate and a MR4.5 rate of 37.6% and 10.8%, respectively, at 96 weeks. The favorable asciminib response and tolerance profile was also confirmed in real--life conditions, even in subjects with previous ponatinib therapy failure (MR4.5 in 10.5%). Recent data suggests that asciminib may be used in the first line or in combination with a 1G- or 2G-TKI. This latter strategy may enhance the rate of DMR obtained and increase the number of patients eligible for an attempt at treatment-free remission. [ABSTRACT FROM AUTHOR]

Background: Advanced prostate cancer (PC) is characterized by insensitivity to androgen deprivation therapy and chemotherapy, resulting in poor outcome for most patients. Thus, advanced PC urgently needs novel therapeutic strategies. Mounting evidence points to splicing dysregulation as a hallmark of advanced PC. Moreover, pharmacologic inhibition of the splicing process is emerging as a promising option for this disease. Method: By using a representative androgen-insensitive PC cell line (22Rv1), we have investigated the genome-wide transcriptomic effects underlying the cytotoxic effects exerted by three splicing-targeting drugs: Pladienolide B, indisulam and THZ531. Bioinformatic analyses were performed to uncover the gene structural features underlying sensitivity to transcriptional and splicing regulation by these treatments. Biological pathways altered by these treatments were annotated by gene ontology analyses and validated by functional experiments in cell models. Results: Although eliciting similar cytotoxic effects on advanced PC cells, Pladienolide B, indisulam and THZ531 modulate specific transcriptional and splicing signatures. Drug sensitivity is associated with distinct gene structural features, expression levels and cis-acting sequence elements in the regulated exons and introns. Importantly, we identified PC-relevant genes (i.e. EZH2, MDM4) whose drug-induced splicing alteration exerts an impact on cell survival. Moreover, computational analyses uncovered a widespread impact of splicing-targeting drugs on intron retention, with enrichment in genes implicated in pre-mRNA 3'-end processing (i.e. CSTF3, PCF11). Coherently, advanced PC cells displayed high sensitivity to a specific inhibitor of the cleavage and polyadenylation complex, which enhances the effects of chemotherapeutic drugs that are already in use for this cancer. Conclusions: Our study uncovers intron retention as an actionable vulnerability for advanced PC, which may be exploited to improve therapeutic management of this currently incurable disease. [ABSTRACT FROM AUTHOR]

Summary: While bortezomib has significant benefits in multiple myeloma (MM) therapy, the disease remains incurable due to the invariable development of bortezomib resistance. This emphasises the need for advanced models for preclinical evaluation of new therapeutic approaches for bortezomib‐resistant MM. Here, we describe the development of an orthotopic syngeneic bortezomib‐resistant MM mouse model based on the most well‐characterised syngeneic MM mouse model derived from spontaneous MM‐forming C57BL/KaLwRij mice. Using bortezomib‐resistant 5TGM1 cells, we report and characterise a robust syngeneic mouse model of bortezomib‐resistant MM that is well suited to the evaluation of new therapeutic approaches for proteasome inhibitor‐resistant MM. [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]