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Фармакологическая модуляция CXCL12/CXCR4/ACKR3 для нейродисфункций — обзор.

Аксис CXCL12/CXCR4/ACKR3 является важным для развития и гомеостаза мозга. Нарушение регуляции CXCL12 или его рецепторов связано с различными расстройствами ЦНС, связанными с нарушениями нейропластичности, нейроинфляцией, нейродегенерацией и опухолями мозга. Эта сигнальная система представляет собой привлекательную целевую точку для терапии, и значительные усилия привели к разработке и применению специфических фармацевтических модуляторов для нейропатологий. Хотя фармацевтическая модуляция CXCR4 в последние десятилетия была активно изучена, целевой ACKR3 только недавно выделилась как критически

Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective.

A standard goal of medicinal chemists has been to discover efficient and potent drug candidates with specific enzyme-inhibitor abilities. In this regard, boron-based bioactive compounds have provided amphiphilic properties to facilitate interaction with protein targets. Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade. In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboran

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a

Therapeutic targeting in pediatric acute myeloid leukemia with aberrant HOX/MEIS1 expression.

Despite advances in the clinical management of childhood acute myeloid leukemia (AML) during the last decades, outcome remains fatal in approximately one third of patients. Primary chemoresistance, relapse and acute and long-term toxicities to conventional myelosuppressive therapies still constitute significant challenges and emphasize the unmet need for effective targeted therapies. Years of scientific efforts have translated into extensive insights on the heterogeneous spectrum of genetics and oncogenic signaling pathways of AML and identified a subset of patients characterized by upregulati

Timeline of Translational Formulation Technologies for Cancer Therapy: Successes, Failures, and Lessons Learned Therefrom.

Over the past few decades, the field of cancer therapy has seen a significant change in the way in which formulations are designed and developed, resulting in more efficient products that allow us to ultimately achieve improved drug bioavailability, efficacy, and safety. However, although many formulations have entered the market, many others have fallen by the wayside leaving the scientific community with several lessons to learn. The successes (and failures) achieved with formulations that have been approved in Europe and/or by the FDA for the three major types of cancer therapy (peptide-bas

No Effect of Vitamin C Administration on Neutrophil Recovery in Autologous Stem Cell Transplantation for Myeloma or Lymphoma: A Blinded, Randomized Placebo-Controlled Trial.

Vitamin C is an important micronutrient for various immune cells. It increases phagocytic cell function and is necessary for T and natural killer (NK) cell development. Patients in need of an autologous hematopoietic stem cell transplantation (HSCT) are often vitamin C-depleted. We therefore hypothesized that vitamin C supplementation could improve immune recovery in autologous HSCT patients. This blinded, placebo-controlled trial included 44 patients randomized to receive vitamin C or a placebo. The following outcome measures used were clinical and immunological parameters, among others: time

Regression of EGFR positive established solid tumors in mice with the conditionally active T cell engager TAK-186.

BackgroundDespite clinical success with T cell engagers (TCEs) targeting hematological malignancies, achieving a safe and efficacious dose in patients with solid tumors remains challenging. Due to potency, low levels of target antigen expression on normal tissues may not be tolerated. To overcome this, we engineered a novel conditionally active TCE design called COBRA (Conditional Bispecific Redirected Activation). Administered as prodrugs, COBRAs bind to cell surface antigens on both normal and tumor tissues but are preferentially activated within the tumor microenvironment.MethodsA COBRA was

SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols.

Transparent and accurate reporting in early phase dose-finding (EPDF) clinical trials is crucial for informing subsequent larger trials. The SPIRIT statement, designed for trial protocol content, does not adequately cover the distinctive features of EPDF trials. Recent findings indicate that the protocol contents in past EPDF trials frequently lacked completeness and clarity. To address this gap, the international consensus-driven SPIRIT-DEFINE checklist was developed through a robust methodological framework for guideline development, with the aim to improve completeness and clarity in EPDF t

Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: from pain relief towards disease modification.

PurposeChemotherapy-induced peripheral neuropathy (CIPN) with associated chronic pain is a common and disabling condition. Current treatments for neuropathic pain in CIPN are largely ineffective, with unfavorable side-effects. The capsaicin 8% patch (capsaicin 179 mg patch) is approved for the treatment of neuropathic pain: a single topical cutaneous application can produce effective pain relief for up to 12 weeks. We assessed the therapeutic potential of capsaicin 8% patch in patients with painful CIPN, and its mechanism of action.Patients and methods16 patients with chronic painful CIPN (mea

Bispecific T-cell engagers in childhood B-acute lymphoblastic leukemia.

Immunotherapy has revolutionized treatment for a wide variety of cancers yet its use has been relatively limited in childhood malignancies. With the introduction of bispecific T-cell engagers (BiTE®) and chimeric antigen T-cell receptor technologies, previously refractory patients have attained remission, including molecularly negative states of disease, thus providing the possibility of long-term cure. Blinatumomab is a widely available CD3-CD19 BiTE that has dramatically changed the landscape of therapy for some children with precursor-B acute lymphoblastic leukemias (B-ALL) and lymphoblasti

Macrophage Activation Markers, CD163 and CD206, in Acute-on-Chronic Liver Failure.

Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the ex

Abscopal Effect in Radiation Therapy: The Immune Mechanisms and Clinical Advances.

The abscopal effect is a systemic antitumor response to localized radiotherapy (RT) that has emerged as a central focus in the era of immunotherapy. Clinical evidence demonstrates that local RT can induce regression of distant, nonirradiated metastases, including cases of complete remission. However, the effect remains unpredictable, with marked variation in clinical outcomes ranging from complete regression to paradoxical progression. The mechanistic basis for this heterogeneity and optimal strategies to enhance abscopal effects remain incompletely understood. This review synthesizes current

Melatonin-micronutrients Osteopenia Treatment Study (MOTS): a translational study assessing melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7) on bone density, bone marker turnover and health related quality of life in postmenopausal osteopenic women following a one-year double-blind RCT and on osteoblast-osteoclast co-cultures.

This one-year double blind randomized control trial assessed the effects of nightly melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7; MSDK) on bone mineral density (BMD) and quality of life (QOL) in postmenopausal osteopenic women (ages 49-75). Compared to placebo, MSDK treatment increased BMD in lumbar spine (4.3%) and left femoral neck (2.2%), with an upward trend for total left hip (p=0.069). MSDK increased serum P1NP levels and reduced bone turnover (CTx:P1NP). Psychometric analyses indicated that mood and sleep quality improved for the MSDK group. MSDK-exposed human mesenchy

Hypophosphatemic Osteomalacia Induced by Low-Dose Adefovir-Related Fanconi Syndrome.

Adefovir dipivoxil (ADV), an antiviral agent for chronic hepatitis B virus infection, has been associated with nephrotoxicity, particularly Fanconi syndrome, even at low doses (10 mg/day). Fanconi syndrome is a generalized proximal tubular dysfunction leading to phosphate wasting and hypophosphatemic osteomalacia. Here, the author reports a case of a 58-year-old man with a 2-year history of bone pain involving the left foot, upper back, and left scapula, later extending to the right foot and chest wall, without antecedent trauma. Magnetic resonance imaging revealed insufficiency fractures in b

Targeting urological cancers with CAR-T cell therapy: current landscape and future directions.

BACKGROUND: Urological cancers, including renal, bladder, and prostate cancers, are among the most prevalent solid tumors. The success of chimeric antigen receptor (CAR)-T cell therapy in hematologic malignancies has spurred its exploration for treating urological cancers. MAIN BODY: In the past decade, preclinical studies have demonstrated promising antitumor activity of CAR-T cells against urological cancers. Meanwhile, multiple clinical trials are currently underway to evaluate their safety and efficacy. However, significant challenges impede the efficacy of CAR-T cell therapy in urological

Clinical characteristics and risk factors associated with COVID-19 disease severity in patients with cancer in Wuhan, China: a multicentre, retrospective, cohort study.

BackgroundCOVID-19 has spread globally. Epidemiological susceptibility to COVID-19 has been reported in patients with cancer. We aimed to systematically characterise clinical features and determine risk factors of COVID-19 disease severity for patients with cancer and COVID-19.MethodsIn this multicentre, retrospective, cohort study, we included all adult patients (aged ≥18 years) with any type of malignant solid tumours and haematological malignancy who were admitted to nine hospitals in Wuhan, China, with laboratory-confirmed COVID-19 between Jan 13 and March 18, 2020. Enrolled patients were

Economic burden of disease progression among multiple myeloma patients who have received transplant and at least one line of therapy in the US.

Effects of disease progression on healthcare resource utilization (HRU) and costs among multiple myeloma (MM) patients with ≥1 line of therapy (LOT) who received their first stem cell transplant (SCT) within 1 year of initial MM diagnosis were estimated using a large US claims database. Disease progression was defined as advancement to the next LOT, bone metastasis, hypercalcemia, soft tissue plasmacytoma, skeletal related events, acute kidney disease, or death within 12 months of LOT initiation. Annual HRU and costs in the first three LOTs (L1-L3) were compared for patients with versus withou

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… For patients with progression, the “index date” was defined as the date 30 days prior to documented progression (in order to capture care during “prodromal” period and terminal care for those who died). … For patients with progression, the “index date” (large red circle) was defined as the date 30 days prior to documented progression (in order to capture care during the “prodromal” period and terminal care for those who died). …

Critically ill patients with cancer: chances and limitations of intensive care medicine-a narrative review.

This narrative review deals with the challenge of defining adequate therapy goals and intensive care unit (ICU) admission criteria for critically ill patients with cancer. Several specific complications of critically ill patients with cancer require close collaborations of intensive care and cancer specialists. Intensivists require a basic understanding of the pathophysiology, diagnosis and therapy of common cancer-specific problems. Cancer specialists must be knowledgeable in preventing, detecting and treating imminent or manifest organ failures. In case of one or more organ dysfunctions, ICU

Сердечные биомаркеры для стратификации риска в недавно диагностированном миеломе высокого риска в пробе GMG-CONCEPT.

Сердечно-сосудистые неблагоприятные явления (CVAE) являются клиническими побочными эффектами во время лечения протеаозным ингибитором карфилзомиба. Мы изучили прогнозируемую ценность сердечных биомаркеров для начала CVAE у пациентов с недавно поставленным диагнозом множественной миэломы повышенного риска, обработанных изатуксимабом, карфиломибом, линалидомидом и дексаметазоном в исследовании GMG-CONCEPT (GMG-CONCEPT).NCT03104842). Пациенты, включенные в это перспективное, многоцентровое корреляционное исследование, имеют право на получение пробы сыворотки до начала лечения и на ≥ 1 позднее был

The use of smart technologies for enhancing palliative care: A systematic review.

IntroductionWith the rapid advancement of technology, smart technologies have permeated various sectors, including palliative care in healthcare. Based on the available literature, similar studies have elucidated the application of individual and isolated smart technologies in palliative care, with their benefits, and limitations. This research, therefore, focuses on the conceptualisation of various smart technologies and makes holistic recommendations on the effective and efficient use of smart technologies in healthcare to enhance palliative care.PurposeThe purpose of this study is to system