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Immunologic tumor microenvironment modulators for turning cold tumors hot.

Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein

Therapeutic Modulation of Autophagy in Leukaemia and Lymphoma.

Haematopoiesis is a tightly orchestrated process where a pool of hematopoietic stem and progenitor cells (HSPCs) with high self-renewal potential can give rise to both lymphoid and myeloid lineages. The HSPCs pool is reduced with ageing resulting in few HSPC clones maintaining haematopoiesis thereby reducing blood cell diversity, a phenomenon called clonal haematopoiesis. Clonal expansion of HSPCs carrying specific genetic mutations leads to increased risk for haematological malignancies. Therefore, it comes as no surprise that hematopoietic tumours develop in higher frequency in elderly peopl

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… More recently, other demonstrations for a cytoprotective role of autophagy in BL have been brought by the work of Hart et al., linking accumulation of unfolded proteins in the endoplasmic reticulum (ER) and subsequent higher level of unfolded protein response (UPR) to cytoprotective autophagy activation …

Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications.

Cellular signaling pathways involved in the maintenance of the equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited in the prevention and treatment of cancer. Epigallocatechin-3-gallate (EGCG) is the most abundant phenolic compound found in green tea. It has been shown to regulate multiple crucial cellular signaling pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, and others. Deregulation of the abovementioned pathways is involved in the pathophysiology of cancer. It has been demonstrated that EGCG may exe

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… Glucose-regulated protein 78 (GRP78) is a crucial component of the unfolded protein response. It works as a chaperone protein and is up-regulated in cancer cells, conferring the inhibition of apoptosis and the promotion of chemoresistance in treated cancer cells. …

Influence of the Mediterranean Diet on Healthy Aging.

The life expectancy of the global population has increased. Aging is a natural physiological process that poses major challenges in an increasingly long-lived and frail population. Several molecular mechanisms are involved in aging. Likewise, the gut microbiota, which is influenced by environmental factors such as diet, plays a crucial role in the modulation of these mechanisms. The Mediterranean diet, as well as the components present in it, offer some proof of this. Achieving healthy aging should be focused on the promotion of healthy lifestyle habits that reduce the development of pathologi

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… In response to this stress, the unfolded protein response (UPR) was generated [ 149 ]. Therefore, the UPR functioned as an adaptive mechanism during cancer progression [ 149 ]. Nevertheless, the activation of UPR at different stages of cancer evolution experienced a complex progression [ 149 ]. …

Viral warfare: unleashing engineered oncolytic viruses to outsmart cancer's defenses.

Oncolytic virotherapy (OVT) has emerged as a promising and innovative cancer treatment strategy that harnesses engineered viruses to selectively infect, replicate within, and destroys malignant cells while sparing healthy tissues. Beyond direct oncolysis, oncolytic viruses (OVs) exploit tumor-specific metabolic, antiviral, and immunological vulnerabilities to reshape the tumor microenvironment (TME) and initiate systemic antitumor immunity. Despite promising results from preclinical and clinical studies, several barriers, including inefficient intratumoral virus delivery, immune clearance, and

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… It enhances viral replication by inducing the unfolded protein response and upregulating HSP90, which supports viral polymerase activity. Bortezomib shifts virus-induced cell death from apoptosis to necroptosis, a more immunogenic form of cell death that can enhance antitumor immune responses. …

25th Annual Computational Neuroscience Meeting: CNS-2016.

A1 Functional advantages of cell-type heterogeneity in neural circuits Tatyana O. Sharpee A2 Mesoscopic modeling of propagating waves in visual cortex Alain Destexhe A3 Dynamics and biomarkers of mental disorders Mitsuo Kawato F1 Precise recruitment of spiking output at theta frequencies requires dendritic h-channels in multi-compartment models of oriens-lacunosum/moleculare hippocampal interneurons Vladislav Sekulić, Frances K. Skinner F2 Kernel methods in reconstruction of current sources from extracellular potentials for single cells and the whole brains Daniel K. Wójcik, Chaitanya Chintalu

Микроаэробный маленький белок от теплового шока способствует ризобию лимуминозараму/Писуму симбиозу и взаимодействует с широким диапазоном бактерироидных белков.

Во время создания симбиоза с бобовыми растениями ризобия подвергается воздействию враждебной физической и химической микроокружающей среды, к которой требуется адаптация. Протеины реакции на стресс, включая небольшие белки от теплового удара (SHSP), ранее, как было установлено, дифференцировались в бактерироидах, индуцируемых ризобием лимуминозарум бv. viciae UPM791 в различных хост-узлах. В ходе этой работы мы провели функциональный анализ зависящих от принимающей стороны SHSP RLV_1399. Рlv_1399- Исключенный штамм мутантов был нарушен в симбиотических свойствах гороха, но не чечевиц. Выражени

Exploring the impact of m6A modification on immune diseases: mechanisms and therapeutic implication.

N6-methyladenosine (m6A) is a chemical modification of RNA and has become a widely discussed topic among scientific researchers in recent years. It is distributed in various organisms, including eukaryotes and bacteria. It has been found that m6A is composed of writers, erasers and readers and is involved in biological functions such as splicing, transport and translation of RNA. The balance of the human immune microenvironment is important for human health abnormalities. Increasing studies have found that m6A affects the development of immune diseases such as inflammatory enteritis and system

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… Stress responses in flavivirus-infected cells: activation of unfolded protein response and autophagy. Front Microbiol. (2014) 5:266. doi: 10.3389/fmicb.2014.00266 91. Shan Y, Chen W, Li Y. The role of M(6)a Rna methylation in autoimmune diseases: novel therapeutic opportunities. …

The CoV-2 outbreak: how hematologists could help to fight Covid-19.

COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in

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… TM7SF3, a novel p53-regulated homeostatic factor, attenuates cellular stress and the subsequent induction of the unfolded protein response. Cell Death Differ. 2017;24(1):132–143. doi: 10.1038/cdd.2016.108. 124. Niture S., Moore J., Kumar D. TNFAIP8: inflammation, immunity and human diseases. J. …

Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.

Nuclear receptors (NRs) are a large family of ligand-dependent transcription factors that regulate the expression of a wide range of target genes in response to endogenous and exogenous ligands, including steroid hormones, thyroid hormone, vitamin D, retinoic acid, fatty acids, and oxidative steroids. Upon ligand binding, nuclear receptors form dimer complexes with transcriptional cofactors, which interact with specific DNA sequences in the promoter or enhancer regions of target genes to modulate gene expression. This process plays a crucial role in many physiological processes such as reprodu

Aurora Kinase A: Integrating Insights into Cancer, Inflammation, and Infectious Diseases.

Aurora kinase A (AURKA) is crucial in regulating cell division and maintaining genomic stability, making it significant in cancer biology. This review explores AURKA's structural and functional roles, emphasizing its involvement in cell cycle progression. Beyond cancer, AURKA emerges as a multifaceted player in host cell modulation, exerting influence over inflammatory responses, cell death mechanisms, and autophagy pathways. Moreover, recent research highlights its involvement in viral and bacterial infections. Numerous viruses, for their replication and assembly, modulate host cell cycle pro

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… Aurora kinase a inhibitor TCS7010 demonstrates pro‑apoptotic effect through the unfolded protein response pathway in HCT116 colon cancer cells. Oncol Lett. 2017; doi: 10.3892/ol.2017.7023. 40. Xie Y, Zhu S, Zhong M, Yang M, Sun X, Liu J, Kroemer G, Lotze M, Zeh HJ, Kang R, et al. …

MYC inhibitors in multiple myeloma.

The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified. Since then, over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation, especially in hematologic diseases. Indeed, some of the earliest connections among the higher expression of proto-oncogenes (such as MYC), genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma, chronic myeloid leukemia and mouse plasmacytomas. Multiple myeloma (MM), in

Control of Breast Cancer Pathogenesis by Histone Methylation and the Hairless Histone Demethylase.

Breast cancer is a highly heterogeneous disease, encompassing many subtypes that have distinct origins, behaviors, and prognoses. Although traditionally seen as a genetic disease, breast cancer is now also known to involve epigenetic abnormalities. Epigenetic regulators, such as DNA methyltransferases and histone-modifying enzymes, play essential roles in gene regulation and cancer development. Dysregulation of epigenetic regulator activity has been causally linked with breast cancer pathogenesis. Hairless (HR) encodes a 130-kDa transcription factor that is essential for development and tissue

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… KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer . J Exp Med. 2018 ; 215 ( 11 ): 2833 - 2849 . 30266800 10.1084/jem.20180439 PMC6219741 72. Luo W , Chang R , Zhong J , Pandey A , Semenza GL . …

Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an "innocent bystander".

Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific "immune-related adverse events" (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique "innocent bystander" effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include

Targeting Amyloid Fibrils by Passive Immunotherapy in Systemic Amyloidosis.

Systemic amyloidoses are characterized by the unrelenting deposition of autologous proteins as highly ordered fibrils in target organs. The ensuing, potentially fatal organ dysfunction is the result of the combined damage caused by the proteotoxic effect of prefibrillar species and by the cytotoxicity and the structural alterations produced by the amyloid fibrils. Current therapy is focused on eliminating the amyloid protein, thus extinguishing the amyloid cascade at its origin. While this approach may end the cell damage caused by prefibrillar aggregates and prevent further amyloid accumulati

Beyond DNA Damage: Exploring the Immunomodulatory Effects of Cyclophosphamide in Multiple Myeloma.

The alkylating agent cyclophosphamide has been used in the treatment of multiple myeloma for over 60 years. At low doses, cyclophosphamide also has significant immunomodulatory activity, which can be used to modify the immunosuppressive tumor microenvironment in order to augment responses to existing therapies. Immune-mediated therapies are becoming more widespread in modern approaches to myeloma treatment. In this review, we discuss the effects cyclophosphamide has on the immune system, and how it can be used synergistically with other treatment modalities including the immunomodulatory agent

Diabetes and Cancer: Cancer Should Be Screened in Routine Diabetes Assessment.

Cancer incidence appears to be increased in both type 1 and type 2 diabetes mellitus (DM). DM represents a risk factor for cancer, particularly hepatocellular, hepatobiliary, pancreas, breast, ovarian, endometrial, and gastrointestinal cancers. In addition, there is evidence showing that DM is associated with increased cancer mortality. Common risk factors such as age, obesity, physical inactivity and smoking may contribute to increased cancer risk in patients with DM. Although the mechanistic process that may link diabetes to cancer is not completely understood yet, biological mechanisms link

Management of refractory autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: current perspectives.

Autoimmune hemolytic anemia (AIHA) is increasingly observed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reported incidence between 4% and 6%. The disease is generally severe and refractory to standard therapy, with high mortality, and there are neither defined therapies, nor prospective clinical trials addressing the best treatment. Most of the knowledge on the therapy of AIHAs derives from primary forms, which are highly heterogeneous as well, further complicating the management of post-allo-HSCT forms. The review addresses the risk factors associated with pos

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… The drug leads to the accumulation of polyubiquitinated proteins, inducing the death of both short- and long-lived plasma cells by activation of the terminal-unfolded protein response. …

Natural and semisynthetic candidate molecules for COVID-19 prophylaxis and treatment.

Coronaviruses (CoVs) represent a family of viruses that have numerous animal hosts, and they cause severe respiratory, as well as systemic and enteric infections, in humans. Currently, there are limited antiviral strategies for treating patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The lack of specific antiviral medicines and SARS-CoV-2 vaccines continues to aggravate the situation. Natural product-based antiviral drugs have been used in the two previous CoV outbreaks: Middle East respiratory syndrome coronavirus (MERS-CoV) and the first SARS-CoV. This re

Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies.

Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients' quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the main