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Leveraging the bacteria for enhanced cancer immunotherapy: from a perspective of synthetic biology.

In recent years, synthetic biology has been widely applied to engineer and program cellular behaviors. Using this approach, bacteria can be designed to express immunotherapeutic agents, improve tumor targeting, and deliver therapeutic payloads directly to tumor sites. To further improve efficacy, strategies such as hypoxia-responsive promoters, bacterial swarming, and extracellular vesicles (EVs) have been investigated, along with the synergistic effects of combining bacterial therapy with other treatments (e.g., photodynamic therapy, chemotherapy, immune checkpoint inhibitors). This review su

Протекционный субъект PSMD1 является ключевой терапевтической целью в множестве миеломы.

Мы пришли к выводу, что PSMD1 - ключевой субъект протеиновой регуляционной частицы 19S - был чрезмерно экспрессирован и коррелировал с плохим прогнозом в множестве миеломы (ММ). Генетическое истощение PSMD1 снизило жизнеспособность раковых клеток, вызвало поликутилизированное накопление белка и способствовало апоптозу. Протеомический анализ показал активацию иммунных путей, что свидетельствует о потенциале иммунной модуляции. Нацеливание PSMD1 на незначительную поражающую РНК (SIRNA), доставляемую через липидные наночастицы (LNPs), уменьшило рост опухоли в линиях клеток MM и первичных проб пац

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… In PSMD1-depleted cells, DNA damage was induced, leading to activation of the downstream innate immune sensing cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway ( Figure 3 D; supplemental Figure 4 C). …

Митохондриальная пригодность как функциональная контрольная точка в раке: метаболическая пластичность, эволюция опухолей и иммунотерапия.

Митохондрия все чаще признается в качестве динамичных регуляторов адаптации к раковым клеткам, иммунной функции и терапевтической реакции. Помимо их канонической роли в производстве энергии, митохондриальный метаболизм, динамика, контроль качества и сигнализация стресса влияют на выживание клеток опухоли и способность клеток иммунного эффекта поддерживать антитумберную активность в микроопухоли. В этом обзоре мы рассматриваем митохондриальную пригодность как многоаспектное функциональное достояние, включающее биоэнергетику, метаболическую гибкость, повторное гомеостаз, контроль качества митохо

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… Cytosolic mitochondrial DNA can activate cyclic GMP-AMP synthase and stimulator of interferon genes signaling, leading to interferon regulatory factor 3 activation and type I interferon responses [ 21 ]. In cancer, this signaling axis may have opposing consequences. … Tumor-directed mitochondrial injury may activate the cyclic GMP-AMP synthase-stimulator of interferon genes axis, promote immunogenic cell death, improve dendritic-cell activation, and increase the immunological visibility of cancer cells. …

Progress of Cancer Nanotechnology as Diagnostics, Therapeutics, and Theranostics Nanomedicine: Preclinical Promise and Translational Challenges.

Early detection, right therapeutic intervention, and simultaneous effectiveness mapping are considered the critical factors in successful cancer therapy. Nevertheless, these factors experience the limitations of conventional cancer diagnostics and therapeutics delivery approaches. Along with providing the targeted therapeutics delivery, advances in nanomedicines have allowed the combination of therapy and diagnostics in a single system (called cancer theranostics). This paper discusses the progress in the pre-clinical and clinical development of therapeutics, diagnostics, and theranostics canc

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates.

As a multifactorial and multiorgan syndrome, cancer cachexia is associated with decreased tolerance to antitumor treatments and increased morbidity and mortality rates. The current approaches for the treatment of this syndrome are not always effective and well established. Drug repurposing or repositioning consists of the investigation of pharmacological components that are already available or in clinical trials for certain diseases and explores if they can be used for new indications. Its advantages comparing to de novo drugs development are the reduced amount of time spent and costs. In thi

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… Trazodone is a potent agonist at 5-HT2C receptors mediating inhibition of the N-methyl-D-aspartate/nitric oxide/cyclic GMP pathway in rat cerebellum. J. Pharmacol. Exp. Ther. 1998;285:983–986. 154. Bossini L., Coluccia A., Casolaro I., Benbow J., Amodeo G., de Giorgi R., Fagiolini A. …

CAR-NK cell therapy for hematological malignancies.

AbstractChimeric antigen receptor (CAR)-natural killer (NK) cells represent a novel cell therapy platform distinguished from CAR T cells by their more favorable safety profile, easier off-the-shelf allogeneic manufacturing and consequent scalability, and their innate cytotoxicity without needing previous sensitization. CAR-NK cells derived from a variety of sources have been used against hematologic malignancies in several clinical trials, showing significant therapeutic responses and efficacy without severe adverse effects. Limitations that are being addressed in CAR-NK cell therapy include c

Targeted protein degradation: advances in drug discovery and clinical practice.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces chal

Sjögren Disease-B Cells at the Brink: From Autoimmunity to Lymphomagenesis and the Rise of Novel B Cell-Targeted Therapies.

Sjögren disease (SjD) is a common systemic autoimmune disorder characterized by inflammation of the exocrine glands, resulting in dryness. Patients frequently exhibit extraglandular manifestations affecting various organ systems. To date, there are no US Food and Drug Administration (FDA)-approved disease-modifying therapies for SjD. In this review, we explore the expanding field of SjD endotyping as a tool to enhance patient stratification, prognostication, and clinical decision-making. SjD endotypes driven by heightened B cell activity are linked to increased lymphoma risk. B cells play a ce

Advances of DNA Damage Repair-Related Drugs and Combination With Immunotherapy in Tumor Treatment.

Cancer therapy has been an important and popular area in cancer research. With medical technology developing, the appearance of various targeted drugs and immunotherapy offer more choices to cancer treatment. With the increase in drug use, people have found more and more cases in which tumors are resistant to DNA damage repair (DDR)-based drugs. Recently, the concept of combination therapy has been brought up in cancer research. It takes advantages of combining two or more therapies with different mechanisms, aiming to benefit from the synergistic effects and finally rescue patients irresponsi

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies.

Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs-oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive ef

The crosstalk network of non-coding RNAs: Emerging opportunities for the clinical application of osteoporosis.

Current methods for testing bone density lack the capability to detect patients with early bone loss, and existing osteoporosis therapies have limitations in their efficacy and safety. Therefore, the development of more precise and convenient diagnostic technologies and novel treatments is of paramount importance. Extracellular vesicle (EV)-mediated non-coding RNA (ncRNA) interaction networks enable both the detection of early bone loss and targeted therapy for enhanced treatment outcomes. In this review, we highlight the utility of EVs for carrying various ncRNAs (e.g., miRNAs, lncRNAs, and c

Advances in Peptidomimetics for Next-Generation Therapeutics: Strategies, Modifications, and Applications.

Over the past two decades, peptide drug discovery has experienced a remarkable renaissance, with organic chemistry and biotechnology emerging as pivotal tools for developing peptidomimetics that exhibit improved stability, specificity, and bioavailability compared to conventional peptides. This review systematically examines methodologies for modifying peptide backbones to achieve targeted properties, highlighting recent advances facilitated by modern biotechnological innovations for novel molecular transformations. Additionally, the review emphasizes the practical applications of peptides and

The use of RNA-based treatments in the field of cancer immunotherapy.

Over the past several decades, mRNA vaccines have evolved from a theoretical concept to a clinical reality. These vaccines offer several advantages over traditional vaccine techniques, including their high potency, rapid development, low-cost manufacturing, and safe administration. However, until recently, concerns over the instability and inefficient distribution of mRNA in vivo have limited their utility. Fortunately, recent technological advancements have mostly resolved these concerns, resulting in the development of numerous mRNA vaccination platforms for infectious diseases and various t

Circadian clock and cancer.

Circadian rhythms play a critical role in regulating physiological and behavioral processes, such as the sleep-wake cycle, hormone secretion, and metabolism. These rhythms are controlled by endogenous biological clocks, which are synchronized with environmental cues, primarily the light-dark cycle. Notably, disruption or reprogramming of circadian rhythms is closely associated with cancer initiation, progression, and treatment response. At the molecular level, the dysregulation of core clock genes can disturb normal cellular rhythms, leading to aberrant cell proliferation, impaired DNA repair,

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… At the level of innate immunity, the clock rhythmically regulates pattern recognition and inflammatory amplification [e.g., via the TLR-IRF/NF-κB axis and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-type I interferon pathway], as well as chemotactic and adhesion signals … Cyclic GMP-AMP synthase; CLOCK. Circadian locomotor output cycles kaput; CXCL. C-X-C motif chemokine ligand; CXCR. C-X-C chemokine receptor; FOXP3. Forkhead box P3; HDAC3. Histone deacetylase 3; HIF. Hypoxia inducible factor; ICAM-1. Intercellular adhesion molecule 1; IFN. Interferon; IL. …

The Black Hole: CAR T Cell Therapy in AML.

Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed/refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen-targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything. One must consider the fact that only around 30% of

Unraveling the mechanisms of bone diseases: targeting dendritic cells in osteoimmunology for internal homeostasis balance.

Bone repair and regeneration is a complex spatiotemporal process recruiting a variety of cell types, which need to precisely mediated for effective healing post-damage. The concept of osteoimmunology emphasizes the extensive and intricate crosstalk between the bone and the immune system. Despite the significant advancements in understanding osteoimmunology, the precise role of dendritic cells (DCs) in this field remains under investigation. As key antigen-presenting cells, DCs are critical in orchestrating adaptive immune responses and maintaining tissue homeostasis. Recent researches have fur

The Power of Movement: How Exercise Influences Chemotherapy-Induced Peripheral Neuropathy.

As the number of cancer patients and survivors increases, we face a rising challenge: the long-term impact of the adverse effects of cancer treatment. One of the known adverse effects is chemotherapy-induced peripheral neuropathy (CIPN), which courses with pain complaints. The treatments of CIPN have reduced efficacy. The neurobiological causes of CIPN have been mainly ascribed to peripheral nerve damage, but recent studies show effects in the brain, namely in the descending pain modulatory systems. Physical exercise seems to be associated with better outcomes in CIPN patients, but the mechani

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… Alpha(2)-Adrenoceptor agonist xylazine induces peripheral antinociceptive effect by activation of the L-arginine/nitric oxide/cyclic GMP pathway in rat. Eur. J. Pharmacol. 2009;613:64–67. doi: 10.1016/j.ejphar.2009.04.031. 116. Hoyer D., Hannon J.P., Martin G.R. …

Unlocking Novel Therapeutic Potential of Angiotensin II Receptor Blockers.

Pharmaceutical companies keep producing novel drugs and drug treatments for improving the life of every sick individual, most often following a pattern; a specific drug for a specific condition. Evidence suggests that different medications can have a positive effect on different pathological conditions. The full potential of existing therapies can be revealed through drug repurposing-also referred to as drug repositioning, reprofiling, or re-tasking-which involves identifying new therapeutic uses for approved or investigational drugs beyond their original indications. One significant target in

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… Nitric Oxide and Cyclic GMP For-mation upon Electrical Field Stimulation Cause Relaxation of Corpus Cavernosum Smooth Muscle. Biochem. Biophys. Res. Commun. 1990;170:843–850. doi: 10.1016/0006-291X(90)92168-Y. 28. Baldaçara L. Duloxetine: An Update. Res. Soc. …

Аккумулирование опустошающих липидов в Arf1-Ablanted Neurorons способствует нейродегенерации с помощью mtDNA и активации воспаляющих путей в Микроглии.

В нейронах и глиальных клетках были обнаружены липидные метаболические расстройства у пациентов с нейродегенеративной (ND) и животных. Однако патологическая связь между липидными капельками и НУ остается слабой. Недавняя работа высветила полезность модели мыши Arf1-knockout с учетом особенностей нейронов и соответствующих клеток для разъяснения связи между расстройствами липидного метаболизма и амиотропическим боковым склерозом (ALS) и множественным склерозом (MS). В этом исследовании было установлено, что недостача арф1 вызвала первичный синтез избытка жирной кислоты через ось АКТ-mTORC1-SREB

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations.

PurposeTo determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects.Patients and methodsIn total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on

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… Preclinical data suggest that DNA damage detected by the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway triggers a proinflammatory cascade of cytokines [ 17 ]. …