Treatment of sepsis currently relies on eliminating the causal pathogen and supportive care, whereas almost no approaches to interfere with the defining event of a “dysregulated host response” are available. This review points to the striking correlation of two phenotypes of sepsis etiopathology with the concept of bipartite response patterns of higher organisms to microbial attacks. According to this concept, the phenotypes of sepsis can be interpreted as either resistance or tolerance responses to infection that got out of hand. This concept might allow focusing sepsis research and related patient studies on key conundrums of current sepsis research: how do resistance responses result in immunopathology and how can tolerance lead to systemic immunosuppression or even immunoparalysis? The heuristic vigor of these questions might inspire experimental efforts and clinical studies and ultimately advance the therapeutic armamentarium for sepsis care.

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The antiapoptotic B cell lymphoma-2 (Bcl-2) family members are apical regulators of the intrinsic pathway of apoptosis that orchestrate mitochondrial outer membrane permeabilization (MOMP) through interactions with their proapoptotic counterparts. Overexpression of antiapoptotic Bcl-2 family proteins has been linked to therapy resistance and poor prognosis in diverse cancers. Among the antiapoptotic Bcl-2 family members, predominant overexpression of the prosurvival myeloid cell leukemia-1 (Mcl-1) has been reported in a myriad of hematological malignancies and solid tumors, contributing to therapy resistance and poor outcomes, thus making it a potential druggable target. The unique structure of Mcl-1 and its complex regulatory mechanism makes it an adaptive prosurvival switch that ensures tumor cell survival despite therapeutic intervention. This review focusses on diverse mechanisms adopted by tumor cells to maintain sustained elevated levels of Mcl-1 and how high Mcl-1 levels contribute to resistance in conventional as well as targeted therapies. Moreover, recent developments in the Mcl-1-targeted therapeutics and the underlying challenges and considerations in designing novel Mcl-1 inhibitors are also discussed.

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Self-replicating RNA viruses have been commonly used for preventive and therapeutic interventions in the fields of infectious diseases and cancers. Both RNA viruses with single-stranded RNA genomes of positive and negative polarity have been utilized. Expression of viral surface proteins from self-replicating RNA virus vectors has elicited strong immune responses and provided protection against challenges with lethal doses of pathogens in various animal models using recombinant viral particles, RNA replicons, or plasmid-based replicon vectors. Similarly, immunization with self-replicating RNA virus vectors expressing tumor antigens has induced tumor-specific antibody (Ab) responses, inhibited tumor growth, eradicated tumors, and protected immunized animals against tumor challenges. Clinical trials have demonstrated good safety and tolerance of self-replicating RNA viruses. Although the number of clinical trials is low, robust immune responses and protection against challenges with pathogens and tumor cells have been achieved. The Ervebo vaccine against Ebola virus disease has been approved by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).

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The crown-like shaped viruses known as coronaviruses which were first reported in the 1960’s have caused three epidemics in the past two decades namely, coronavirus disease-19 (COVID-19), severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). SARS coronavirus 2 (SARS-CoV-2) was first reported in the latter half of December in Wuhan, a city of China, with people affected by deadly pneumonia with unknown etiology. Since then, the world has experienced two phases of virus spread with different symptoms and disease severity. This review embarks on the journey to investigate candidate molecules of this virus which can and are being investigated for various vaccine formulations and to discuss immunity developed against this virus.

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Alzheimer’s disease (AD) is a common neurological disease in the elderly, and the major manifestations are cognitive dysfunction, neuronal loss, and neuropathic lesions in the brain. In the process of AD pathogenesis, the inflammatory response plays an indispensable role. The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome containing NOD, leucine-rich repeat (LRR), and pyran domains is a multi-molecular complex that can detect dangerous signals related to neurological diseases. The assembly of NLRP3 inflammasome promotes the maturation of interleukin-1beta (IL-1β) and IL-18 mediated by caspase-1 in microglia, which leads to neuroinflammation and finally contributes to the occurrence and development of AD. This review aimed to clarify the structure and activating mechanism of NLRP3 inflammasome and its key role in the pathogenesis of AD, summarize the latest findings on the suppression of NLRP3 inflammasome activation for the treatment of AD, as well as indicate that targeting regulation of NLRP3 inflammasome assembly may be a potential strategy for the treatment of AD, providing a theoretical basis for the research of AD.

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The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in recent years have fuelled the ongoing development of this class of drugs. These novel agents combine the benefits of high specific targeting of oncogenic cell surface antigens with the additional cell kill from high potency cytotoxic payloads, thus achieving wider therapeutic windows. This review will summarise the clinical activity of ADCs in tumour types not covered elsewhere in this issue, such as gastrointestinal (GI) and genitourinary (GU) cancers and glioblastoma (GBM). In addition to the ongoing clinical testing of existing ADCs, there is substantial preclinical and early phase testing of newer ADCs or ADC incorporating strategies. This review will provide selected insights into such future development, focusing on the development of novel ADCs against new antigen targets in the tumour microenvironment (TME) and combination of ADCs with immuno-oncology (IO) agents.

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Recent anti-cancer strategies are based on the stimulation of anti-tumor immune reaction, exploiting distinct lymphocyte subsets. Among them, γδ T cells represent optimal anti-cancer candidates, especially in those tissues where they are highly localized, such as the respiratory or gastrointestinal tract. One important challenge has been the identification of stimulating drugs able to induce and maintain γδ T cell-mediated anti-cancer immune response. Amino-bisphosphonates (N-BPs) have been largely employed in anti-cancer clinical trials due to their ability to upregulate the accumulation of pyrophosphates that promote the activation of Vγ9Vδ2 T cells. This activation depends on the butyrophilin A family, which is crucial in contributing to Vγ9Vδ2 T cells stimulation but is not equally expressed in all cancer tissues. Thus, the clinical outcome of such treatments is still a challenge. In this viewpoint, a critical picture of γδ T cells as effective anti-cancer effectors is designed, with a specific focus on the best immune-stimulating therapeutic schemes involving this lymphocyte subset and the tools available to measure their efficacy and presence in tumor tissues. Some pre-clinical models, useful to measure γδ T cell anti-cancer potential and their response to stimulating drugs, therapeutic monoclonal antibodies, or bispecific antibodies are described. Computerized imaging and digital pathology are also proposed as a help in the identification of co-stimulatory molecules and localization of γδ T cell effectors. Finally, two types of novel drug preparation are proposed: nanoparticles loaded with N-BPs and pro-drug formulations that enhance the effectiveness of γδ T lymphocyte stimulation.

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Several studies investigated the side effect of adjuvant cancer treatments, and different types of preventive techniques or treatments have been assessed. Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurological side effect. Exercise training has been widely studied as an adjuvant therapy to prevent CIPN and improve post-chemotherapy functional outcome and quality of life (QoL). This narrative review aims to summarize the data obtained from the latest studies about physical activity (PA) for the prevention and treatment of CIPN and associated QoL measures. Literature research was conducted to obtain studies including PA interventions for patients with CIPN. Ten studies met inclusion criteria and were therefore summarized and discussed, focusing on exercise type and functional outcome. It seems clear that, regardless of the type of exercise, PA plays a positive role in the treatment of CIPN, providing a significant symptom improvement. There has been no standardization of type, quantity, and intensity of PA administered to the subjects in the various studies probably due to a physiological difference between samples, grade of neuropathy, and difference among therapies.

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Endocrine resistant breast cancer metastasis continues to serve as a significant clinical challenge with high morbidity and mortality for patients. As the number of breast cancer cases continues to rise, the rate of brain metastasis has also increased. For single lesions or a large symptomatic lesion with other smaller lesions, surgical resection is a viable option in non-eloquent regions. Stereotactic radiosurgery is a great option for post-operative therapy or for 10 or fewer small lesions (< 3 cm in size). Whole-brain radiation can be used sparingly for large tumor burdens but should encompass hippocampus sparing techniques. Chemotherapy options have remained relatively limited due to decreased permeability of the blood-brain barrier. Emerging monoclonal antibody treatments have offered initial promise, especially for endocrine resistant breast cancer metastasis.

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Cardiovascular diseases are among the leading causes of death worldwide, imposing major health threats. Reactive oxygen species (ROS) are one of the most important products from the process of redox reactions. In the onset and progression of cardiovascular diseases, ROS are believed to heavily influence homeostasis of lipids, proteins, DNA, mitochondria, and energy metabolism. As ROS production increases, the heart is damaged, leading to further production of ROS. The vicious cycle continues on as additional ROS are generated. For example, recent evidence indicated that connexin 43 (Cx43) deficiency and pyruvate kinase M2 (PKM2) activation led to a loss of protection in cardiomyocytes. In this context, a better understanding of the mechanisms behind ROS production is vital in determining effective treatment and management strategies for cardiovascular diseases.

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Improving the survival of patients with cholangiocarcinoma (CCA) has long proved challenging, although the treatment of this disease nowadays is on advancement. The historical invariability of survival outcomes and the limited number of agents known to be effective in the treatment of this disease has increased the number of studies designed to identify genetic targetable hits that can be efficacious for novel therapies. In this respect, the increasing feasibility of molecular profiling starting either from tumor tissue or circulating cell-free DNA (cfDNA) has led to an increased understanding of CCA biology. Intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) display different and typical patterns of actionable genomic alterations, which offer opportunity for therapeutic intervention. This review article will summarize the current knowledge on the genomic alterations of iCCA and eCCA, provide information on the main technologies for genomic profiling using either tumor tissue or cfDNA, and briefly discuss the main clinical trials with targeted agents in this disease.

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Altered immunity may have destructive consequences for the integrated central nervous system. This immune response often affects progressive neurodegenerative diseases such as Parkinson’s disease and/or psychiatric disorders such as schizophrenia. In particular, schizophrenia pathogenesis may be mediated by multiple neuro-immune interaction pathways. Gut microbiota might affect the brain and/or immune function. Significant machineries of immunity are commonly affected by the commensal gut microbiota. Therefore, schizophrenia may be connected with the gut-immune system. In addition, the brain and immune systems cooperate on multiple levels. The brain could save several pieces of information about specific inflammation in a body. This immunological memory named “engrams”, also called memory traces, could restore the initial disease state, which may help to explain key features of schizophrenia. Based on this concept, therapeutic strategies for schizophrenia could be the modification of the gut microbiota. Probiotics and/or fecal microbiota transplantation are now emerging as the most promising treatments for the modification. More consideration of the roles of gut microbiota will conduct the further development of immune-based therapeutics for the prevention and/or treatments of psychiatric disorders.

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The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions.

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A case of combined acute and chronic liver injury related to consumption of multi-ingredient nutritional oral supplements containing Aloe Vera gel and vitamin A among other vitamins, minerals and dietary elements such as fish and calamari oil in a 59-year-old female with unexplained hypertransaminasemia is reported. A unique complex liver injury was diagnosed on liver biopsy combining histological features of protracted acute hepatitis, mild manifestation of hypervitaminosis A and lipogranulomatous reaction attributed to Aloe Vera, vitamin A and lipids, respectively. Normalization of liver tests was achieved after discontinuation of all nutritional supplements. Updated Roussel Uclaf Causality Assessment Method (RUCAM) score (+8, probable) further supported herb-induced liver injury. The present case highlights the increasing incidence of complex histological liver injury linked to the constantly growing consumption of multi-ingredient dietary supplements and alternative medications.

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Until now, despite 30 years of intensive work, the RV144 human immunodeficiency virus (HIV) vaccine trial initiated in 2003 remains so far the most protective vaccine prototype of all those tested (32% reduction in the infection rate three years after the vaccination) and the HIV epidemic is still spreading worldwide. In addition, antiretroviral therapy (ART) for people living with HIV is given for life as no other pharmacological intervention has allowed to maintain an undetectable viral load after ART withdrawal. Pr Andrieu and colleagues discovered tolerogenic CD8+T-cells that suppress simian immunodeficiency virus (SIV) specific activation, ensuing SIV reverse transcription suppression and viral replication-defective in Chinese macaques vaccinated by intragastric route with inactivated SIV particles + Lactobacillus rhamnosus. Moreover, in HIV-infected elite controllers with specific genetic features (HLA-1-Bw4-80i and KIR3DL1 genes), Pr Andrieu found out that similar tolerogenic CD8+T-cells suppress in the same manner HIV-specific activation, HIV reverse transcription, and HIV replication. These data justify the development of a tolerogenic vaccine composed of inactivated HIV particles + Lactobacillus rhamnosus that could be used as a preventive or therapeutic vaccine.

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Antibody-drug conjugates (ADCs) represent a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies to the cytotoxicity of classic chemotherapy agents. These drugs have been extensively studied both in solid and hematologic malignancies, leading to substantial improvement in the therapeutic landscape for several tumors. Despite no ADC have been yet approved for the treatment of gynecological malignancies, some agents have shown promising results and might have the potential to become part of the standard of care. Among them, mirvetuximab soravtansine has shown activity in platinum-resistant ovarian cancer with high folate-α receptor expression, as a single agent and in combination. Tisotumab vedotin is active in patients with pre-treated cervical cancer, and further investigation is ongoing. The purpose of this review is to summarize the structural and functional characteristics of ADCs and analyze the most recent and promising data regarding the clinical development of ADCs in gynecological malignancies. The available data on the efficacy of the more studied ADCs in ovarian, endometrial, and cervical cancers will be discussed along with toxicities of special interest, the mechanisms of resistance, and future possible drugs combination.

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Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) molecule approved for the treatment of both type 2 diabetes (T2D) and obesity. Semaglutide has a greater impact on glycated haemoglobin (HbA1c) reduction, compared to other GLP-1 RAs, and is the first molecule of this class available in oral formulation for T2D therapy, representing a useful option for subjects and physicians less prone to start an injective drug. Interestingly, due to its remarkable effects on weight reduction, higher than other GLP-1 RAs and very close to bariatric surgery, semaglutide is designated to change the approach to obesity therapy also in the subject not affected by diabetes. In addition to these favorable features, semaglutide, similarly to other GLP-1 RAs, offers beneficial effects on cardio-vascular (CV), renal, and liver protection, making this molecule an advantageous choice in the therapeutic management of “diabesity” (coexistence of both diabetes and obesity) and its co-morbidity.

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